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WO2023034336A2 - Improved treatments for advanced/metastatic cancers with checkpoint inhibitor resistance or resistance susceptibility - Google Patents

Improved treatments for advanced/metastatic cancers with checkpoint inhibitor resistance or resistance susceptibility Download PDF

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WO2023034336A2
WO2023034336A2 PCT/US2022/042088 US2022042088W WO2023034336A2 WO 2023034336 A2 WO2023034336 A2 WO 2023034336A2 US 2022042088 W US2022042088 W US 2022042088W WO 2023034336 A2 WO2023034336 A2 WO 2023034336A2
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inhibitor
cancer
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WO2023034336A3 (en
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Andrew BEELEN
Rajesh Kumar MALIK
John Seung-Hoon YI
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G1 Therapeutics Inc
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G1 Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies

Definitions

  • Ipilimumab a human IgGl k anti-CTLA-4 monoclonal antibody (sold under the brand name YERVOY®), was approved by the by the United States (US) Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma.
  • Ipilimumab is the first and only United State Food and Drug Administration-approved CTLA-4 inhibitor.
  • Pembrolizumab (KEYTRUDA®) monotherapy has also demonstrated improved objective response rates (ORR) in patients with PD-L1 positive TNBC tumors ranging from 18.5% to 21.4%, compared with response rates ranging from 5.3% to 9.6% in patients with PD-L1 negative tumors.
  • ORR objective response rates
  • ICI resistance Additional mechanisms of ICI resistance include genetic, epigenetic, and cellular signaling alterations that dysregulate neoantigen presentation/processing and disrupt cytotoxic T cells activity as well as mechanisms in which non-cancerous stromal or immune cells promote growth and resistance to ICIs (Liu et al., Mechanisms of resistance to immune checkpoint blockade. Am J Clin Dermatol. 2019; 20(1): 41-54; Barrueto et al., Resistance to checkpoint inhibition in cancer immunotherapy. Transl One. 2020; 13 : 100738; Jenkins et al., Mechanisms of resistance to immune checkpoint inhibitors. Brit J Cancer.
  • the present invention provides improved methods for treating select patients with locally advanced, recurrent, or metastatic cancer whose cancers have progressed on, have developed resistance to, or are susceptible to developing resistance to a PD-1 or PD-L1 checkpoint inhibitor, the methods including administering an effective amount of the short acting, selective, and reversible cyclin dependent kinase (CDK) 4/6 inhibitor trilaciclib, or a pharmaceutically acceptable salt thereof, in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor, or a Cluster of Differentiation 73 (CD73; Ecto-5 'nucleotidase (NT5E)) checkpoint inhibitor.
  • the treatment protocols described herein reduce tumor microenvironment immune changes or tumor cell immune effector signal downregulation allowing for tumor immune escape, and the synergistic combination of the administered agents can reverse and/or significantly delay the development of ICI resistance, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations.
  • the treatment protocols described herein provide therapeutic efficacy through immune modulation of T cells, including the enhancement of cytotoxic CD8+ T-cell function and maturation into memory CD8+ T-cells and the inhibition of T reg function and differentiation.
  • the result of this extended efficacy is an improvement in host immune response to the tumor, providing improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS), for these difficult to treat patients.
  • OS overall survival
  • PFS progression free survival
  • the methods provided herein can be used to activate an immune response in a subject.
  • administration of trilaciclib in combination with one or more additional agents leads to alterations in intratumor immune T cell subsets favoring effector T-cell function, including stimulation of IFN-y production in exhausted T-cells (Example 1, FIG. 1), reductions in the proportion of Tregs among CD4+ T cells in the tumor (see, e.g., Example 3, FIG. 6), an increase in CD8+ T cells to Tregs ratio in the tumor (see, e.g., Example 3, FIG. 7), and/or an increase in activated CD8+ T cells (see, e.g., Example 3, FIG. 8).
  • the synergistic combination of CDK4/6 inhibitor trilaciclib with one or more additional agents including but not limited to checkpoint inhibitors may reverse and/or significantly delay the resistance to checkpoint inhibition and provide better efficacies of therapeutic regimens in difficult to treat patient populations.
  • the administration of the CDK4/6 inhibitor trilaciclib synergizes when combined with a PD-1 or PD-L1 inhibitor and an additional checkpoint inhibitor, for example a checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, or a CD73 inhibitor, to provide substantially reduced tumor progression (see, e.g., Examples 5, 6, 7, 8, 9, 10, and 11; FIGs.
  • Adenosine accumulation favors tumor growth and metastasis through epidermal growth factor receptor (EGFR) signaling and inhibition of tumor apoptosis, whereas inactivation of CD73 can attenuate this adenosine-mediated process.
  • CD73 also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs.
  • MMPs matrix metalloproteinases
  • the immunosuppressive tumor microenvironment in the patient’s tumor which renders the previously administered ICI ineffective or less effective and allows the tumor to progress — can be significantly overcome, improving the ability of the patient’s immune system to reduce or control tumor burden, improving quality of life, and improving overall survival in these difficult to treat subsets of patients.
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycles), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42 -day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle.
  • trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week, the PD-Ll or PD-1 inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor.
  • the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor.
  • trilaciclib is administered one or more times per week. In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer, triple negative breast cancer, colorectal cancer or urothelial cancer.
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second- line locally advanced or metastatic urothelial carcinoma.
  • the colorectal cancer has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and an oncolytic virus, for example, but not limited to an oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxviruses, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • an oncolytic virus for example, but not limited to an oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxviruses, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (
  • the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles.
  • the patient is administered a treatment cycle until disease progression.
  • anti-tumor activity is enhanced by cell cycle independent and dependent mechanisms, including the selective reduction of intra-tumoral T reg populations, preservation of pro-inflammatory immune effector cells such as tumor infiltrating lymphocytes, and an increased durability in treatment response.
  • the controlled inhibition of CDK4/6 with trilaciclib in combination with a chemotherapeutic agent and the multi- immune checkpoint inhibitors as described herein provides a significant increase in anti-tumor effects compared to the administration of a chemotherapeutic agent and immune checkpoint inhibitor alone, or the continuous inhibition of CDK4/6 with a CDK4/6 inhibitor dosed daily, including longer acting CDK4/6 inhibitors, in combination with an immune checkpoint inhibitor.
  • the chemotherapeutic agent to be administered can be a chemotherapeutic agent generally administered as part of the standard of care for the stage of the cancer being treated.
  • chemotherapeutic agents for example, but not limited to, protein synthesis inhibiting or DNA- damaging chemotherapeutic agents, tend to be non-specific and toxic to normal, rapidly dividing cells, including immune effector cells, and hematological toxicities such as myelosuppression are a common side effect of chemotherapeutic treatment.
  • Immune effector cells generally require the activity of CDK4/6 for proliferation, i.e., they are CDK4/6-replication dependent (see Roberts et al. Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy. JNCI 2012;104(6):476-487).
  • an additional immune checkpoint inhibitor into the therapeutic protocol, the development of resistance to the effects of immune checkpoint inhibitors due to long-term use and tumor microenvironment immune changes or tumor cell immune effector signal downregulation can be reversed or significantly delayed, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations.
  • ICD immunogenic cell death
  • CTR calreticulin
  • HMGB1 high mobility group box 1
  • extracellular ATP extracellular ATP
  • type I interferon type I interferon
  • cancer cell- derived nucleic acids e.g., cancer cell- derived nucleic acids
  • Chemotherapy can also enhance tumor antigen presentation by upregulating the expression of tumor antigens themselves, or of the MHC class I molecules to which the antigens bind.
  • chemotherapy may upregulate costimulatory molecules (B7-1) or downregulate coinhibitory molecules (PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, enhancing the strength of effector T-cell activity.
  • Chemotherapy may also render tumor cells more sensitive to T cell-mediated lysis through fas-, perforin-, and Granzyme B-dependent mechanisms.
  • PD1 inhibitors for use in the methods described herein include, for example, but are not limited to, nivolumab (OPDIVO®; Bristol Myers Squibb), pembrolizumab (KEYTRUDA®; Merck), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®; GlaxoSmithKline), pidilizumab (Medivation), AMP-224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IBI308; InnoventZEli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012; Incyte Corporation and MacroGenics), tislelizumab (BGB-A317; BeiGene), toripalimab
  • camrelizumab SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation
  • CS1003 Cstone Pharmaceuticals
  • zimberelimab AB122; Arcus Biosciences
  • JTX-4014 Jounce Therapeutics
  • PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol- Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curis) and BGB-A333 (BeiGene).
  • LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), MGD013 (Macrogenics), RO7247669 (Hoffman - LaRoche), EMB-02
  • TIM-3 inhibitors for use in the methods described herein include, for example, but are not limited to, cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca), TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.), and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
  • TSR-022 cobolimab
  • Tesaro Tesaro
  • RG7769 Genetech
  • MAS825 Novartis
  • TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB
  • CD 73 Ecto-5 'nucleotidase; (NT5E) checkpoint inhibitors for use in the methods described herein include, for example, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers).
  • Chemotherapeutic agents for use in the present methods include those associated with a standard of care treatment for the specific stage and prior treatment status of the cancer being treated.
  • suitable chemotherapeutic agents for use in the present methods include, but are not limited to: platinum containing drugs, for example carboplatin, cisplatin, and oxaliplatin; a taxane, for example paclitaxel, docetaxel, or paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel); a topoisomerase inhibitor, for example topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, and teniposide; cyclophosphamide; vinblastine; gemcitabine; 5-fluoruracil (5-FU); eribulin; pemetrexed; mitomycin; sacituzumab govite
  • the chemotherapeutic agent for use in the present methods is a chemotherapeutic agent capable of inducing an immune-mediated response.
  • Chemotherapies capable of inducing an immune-mediated responses are generally known in the art and include, but are not limited to, alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitoxantrone, gemcitabine, and 5 -fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan, and etopo
  • the chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, or the pharmaceutically acceptable salts or any thereof, and combinations of any thereof.
  • trilaciclib is administered each day during a cycle that a chemotherapeutic agent is administered, the PD-1 or PD-L1 inhibitor is administered at least on day 1 of each cycle, and the additional immune checkpoint inhibitor selected from a TIGIT inhibitor, TIM-3 inhibitor, LAG-3 inhibitor, or CD73 inhibitor is administered concomitantly with the PD-1 or PD-L1 inhibitor.
  • the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle.
  • trilaciclib is further administered alone once a week during the cycle.
  • trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional checkpoint inhibitor are administered on day 1 of a 14-day cycle.
  • trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib and the chemotherapeutic agent are administered on day 1 of a 21 -day cycle, and the PD-1 or PD- L1 inhibitor and additional immune checkpoint inhibitor are administered on day 1 of the 21 -day cycle.
  • trilaciclib is further administered alone on day 7 and day 14 of the 21 -day cycle.
  • trilaciclib and the chemotherapeutic agent are administered on day 1-3 of a 21 -day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 21-day cycle. In some embodiments, trilaciclib is further administered alone on day 7 and day 14 of the 21-day cycle. In some embodiments, trilaciclib and the chemotherapeutic agent are administered on days 1, 8, and 15 of a 28-day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 28- day cycle.
  • trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28- day cycle. In some embodiments, trilaciclib is again administered on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, the patient is administered 2 or more treatment cycles, for example, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, or more.
  • the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein the trilaciclib, PD-1 or PD- L1 inhibitor, and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
  • the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks. In some embodiments, the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor.
  • the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle.
  • the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks.
  • the patient is administered trilaciclib, a PD- 1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week, wherein the PD-1 or PD-L1 inhibitor is administered once over a duration of a first cycle, wherein the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is different than the duration of the second cycle.
  • NSCLC Non-Small Cell Luns Cancer
  • the treatment protocols described herein are administered to a patient having metastatic or locally advanced non-small cell lung cancer (NSCLC).
  • NSCLC metastatic or locally advanced non-small cell lung cancer
  • the patient has metastatic or locally advanced squamous cell NSCLC.
  • the patient has metastatic or locally advanced non-squamous cell NSCLC.
  • the patient is not eligible for therapy targeted to a driver NSCLC mutation.
  • the patient has NSCLC with a driver mutation but the patient is not eligible to receive therapy targeted to the driver NSCLC mutation.
  • the patient has NSCLC whose driver mutation status is unknown.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by a USFDA-approved, or CE mark test.
  • the patient has a tumor expressing PD-L1 as determined by a tumor proportion score (TPS), which is the number of PD-L1 -positive tumor cells divided by the total number of PD-L1 -positive plus PD-L1 -negative tumor cells, multiplied by 100, as determined by an FDA-approved, or CE Mark test.
  • TPS tumor proportion score
  • the patient > 1%.
  • the patient has a tumor expressing PD-L1 as determined by stained immune cells (%IC).
  • the IC is > 10%.
  • the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%.
  • the chemotherapeutic agent is nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof.
  • the chemotherapeutic agent is docetaxel.
  • the chemotherapeutic agent is gemcitabine.
  • the chemotherapeutic agent is vinorelbine.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first line or second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus.
  • the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • the oncolytic virus is paleorep.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%.
  • the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is a combination of chemotherapeutic agents selected from pemetrexed, gemcitabine, paclitaxel, nab-paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin.
  • the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin.
  • the chemotherapeutic agent is paclitaxel and carboplatin.
  • the chemotherapeutic agent is nab-paclitaxel and carboplatin.
  • the chemotherapeutic agent is docetaxel.
  • the chemotherapeutic agent is pemetrexed and carboplatin, cisplatin, or oxaliplatin.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof.
  • the chemotherapeutic agent is docetaxel.
  • the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression.
  • the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with a TPS > 1%.
  • the patient has a tumor expressing PD-L1 with a TC > 1%.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first line or second- line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus.
  • the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus.
  • the oncolytic virus is paleorep.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%.
  • the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
  • the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, and whose tumor expresses PD-L1, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD- L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test.
  • the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent.
  • the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%.
  • the administration of a treatment protocol described herein to the patient subgroups described herein may provide enhanced anti-tumor efficacy in patients.
  • the administration of a treatment protocol described herein in the particular patient subgroups described above provides improved progression free survival (PFS) and/or overall survival (OS).
  • PFS progression free survival
  • OS overall survival
  • an improvement in PFS is based on per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1).
  • the administration of a treatment protocol described herein to the patient subgroups described above provides improved myelopreservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells such as lymphocytes including T- lymphocytes.
  • HSPCs hematopoietic stem and progenitor cells
  • immune effector cells such as lymphocytes including T- lymphocytes.
  • the administration of a treatment protocol described herein provides a reduction in all-cause dose reductions or cycle delays and relative dose intensity for chemotherapy.
  • the administration of a treatment protocol described herein provides a reduction in i) hospitalizations, including but not limited to those due to all causes, febrile neutropenia/neutropenia, anemia/RBC transfusion, thrombocytopenia/bleeding and infections) or ii) antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.
  • the administration of a treatment protocol described herein provides an improvement to one or more of: Functional Assessment of Cancer Therapy-General (FACT- G) domain scores (physical, social/family, emotional, and functional well-being); Functional Assessment of Cancer Therapy -Anemia (FACT-An); 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.
  • FACT- G Functional Assessment of Cancer Therapy-General
  • FACT-An Functional Assessment of Cancer Therapy-Anemia
  • EQ-5D-5L 5-level EQ-5D
  • PGIC Patient Global Impression of Change
  • PGIS Patient Global Impression of Severity
  • FIG. 6 shows the proportion of Tregs in total tumor treated with vehicle, oxaliplatin/PD-Ll, or trilaciclib/oxaliplatin/PD-Ll on days 5 and 9.
  • the x-axis is the results on Day 5 and Day 9 and the y-axis is the % Tregs of CD4+ T cells in the tumor measured as a percentage.
  • FIG. 10A is a bar graph illustrating the quantification of IL-2 cytokine production produced by MC38 tumor infiltrating T lymphocytes.
  • mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IL-2 from CD4+ T cells (*p ⁇ 0.001).
  • the x-axis is the treatment groups and the y-axis is the percentage of IL-2 from CD4 + cells.
  • FIG. 10B is a bar graph illustrating the quantification of IFNy cytokine production produced by MC38 tumor infiltrating T lymphocytes.
  • mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IFNy from CD8 + T cells (*p ⁇ 0.001).
  • the x-axis is the treatment groups and the y-axis is the percentage of IFNy from CD8 + T cells.
  • FIG. 11B shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 11D shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with citrate buffer (negative control).
  • the mice were treated with citrate buffer (negative control) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. HE shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 11H shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 11 J shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 1 IK shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib, an anti-PDl inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 12C shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. Drug dosing was terminated on day 63.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 12D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only.
  • the mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 121 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (lOOmg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 12K shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13 A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration.
  • the x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 13B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration. Drug dosing was terminated on day 63.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 13C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only.
  • the mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 13H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor.
  • the x- axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 14C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination.
  • the x-axis is days post treatment measured in days and the y- axis is tumor volume measured in mm 3 .
  • FIG. 15A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor and/or anti-TIM3 inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
  • FIG. 15B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-LAG3 inhibitor (10 mg/kg, 2 times a week).
  • the x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
  • FIG. 15C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIM3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week).
  • the x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
  • FIG. 15D shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 15E shows Overall Survival of Balb/C mice implanted with mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIM3 inhibitor alone or in combination.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week) from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 15F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control).
  • the mice were treated with citrate buffer as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only.
  • the mice were treated with CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only.
  • the mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 151 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-LAG3 inhibitor only.
  • the mice were treated with anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIM3 inhibitor only.
  • the mice were treated with anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15L shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination.
  • the mice were treated with anti-PD-1 inhibitor (5mg/kg, two times per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15M shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15N shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-LAG3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 150 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIM3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15P shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-LAG3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-LAG3 inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 15Q shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIM3 inhibitor (5 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 16A shows tumor growth curves of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • CT-26 murine colorectal cancer cells were injected subcutaneously into Balb/c mice. The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 16B shows Overall Survival of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • CT-26 murine colorectal carcinoma cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 17A shows tumor growth curves of C57BL/6 mice implanted with AT3-OVA murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • AT3-OVA murine breast carcinoma cells were injected subcutaneously into C57BL/6 mice.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 17B shows Overall Survival of Balb/C mice implanted with AT3-OVA breast cancer (BC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination.
  • AT3-OVA murine breast carcinoma cells were injected subcutaneously into Balb/C mice.
  • the mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • FIG. 18 shows tumor growth curves of Balb/C mice implanted with S2WTP3 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • S2WTP3 murine breast carcinoma cells were injected subcutaneously into Balb/c mice.
  • the mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti- TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma.
  • FIG 20A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-CD73 inhibitor alone or in combination.
  • CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice.
  • the mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-CD73 inhibitor (5 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell implantation. Treatment continued for six weeks.
  • the x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm 3 .
  • FIG. 20B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination.
  • the x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
  • the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric
  • the term "prodrug” means a compound which when administered to a host in vivo is converted into the parent drug.
  • parent drug means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, and neither biologically nor otherwise inappropriate for administration to a host, typically a human.
  • trilaciclib can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes that can be incorporated into trilaciclib for use in the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 3 IP, 32P, 35S, 36CI, and 1251 respectively.
  • isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H) may be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C
  • isotopes of carbon e.g., 13 C and 14 C
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 90, 95 or 99% enriched at a desired location.
  • the CDK4/6 inhibitors, chemotherapy, or checkpoint inhibitors can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Trilaciclib or another CDK4/6 inhibitor described herein for use in the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes the use of a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, de-acetone, de-DMSO.
  • a solvate can be in a liquid or solid form.
  • hematopoietic stem and progenitor cell includes, but are not limited to, long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), hematopoietic progenitor cells (HPCs), multipotent progenitors (MPPs), oligodendrocyte pre-progenitors (OPPs), monocyte progenitors, granulocyte progenitors, common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-monocyte progenitors (GMPs), granulocyte progenitors, monocyte progenitors, and megakaryocyte-erythroid progenitors (MEPs), megakaryocyte progenitors, erythroid progenitors, HSC/MPPs (CD45dim/CD34+/CD38-), OPPs (LT-HSCs), short term hematopoi
  • Immune effector cell generally refers to an immune cell that performs one or more specific functions.
  • Immune effector cells are known in the art and include for example, but are not limited to, T-cells, including Naive T-cells, Memory T-cells, Activated T-cells (T helper (CD4+) and Cytotoxic T cells (CD8+)), TH1 activated T-cells, TH2 activated T-cells, TH17 activated T-cells, Naive B cells, Memory B cells, plasmablasts, dendritic cells, monocytes, and natural killer (NK) cells.
  • T-cells including Naive T-cells, Memory T-cells, Activated T-cells (T helper (CD4+) and Cytotoxic T cells (CD8+)
  • T helper CD4+
  • CD8+ Cytotoxic T cells
  • TH1 activated T-cells TH2 activated T-cells
  • TH17 activated T-cells
  • Naive B cells
  • patient typically a human patient, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
  • animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
  • CDK4/6-replication independent cancer refers to a cancer that does not significantly require the activity of CDK4/6 for replication. Cancers of such type are often, but not always, characterized by (e.g., that has cells that exhibit) an increased level of CDK2 activity or by reduced expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s), such as, but not limited to pl07 and pl30.
  • the increased level of CDK2 activity or reduced or deficient expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s) can be increased or reduced, for example, compared to normal cells.
  • CDK4/6-replication dependent cancer refers to a cancer that requires the activity of CDK4/6 for replication or proliferation, or which may be growth inhibited through the activity of a selective CDK4/6 inhibitor.
  • Cancers and disorders of such type may be characterized by (e.g., that has cells that exhibit) the presence of a functional Retinoblastoma (Rb) protein.
  • Rb Retinoblastoma
  • Such cancers and disorders are classified as being Rb-positive.
  • Rb- positive abnormal cellular proliferation disorders, and variations of this term as used herein, refer to disorders or diseases caused by uncontrolled or abnormal cellular division which are characterized by the presence of a functional Retinoblastoma protein, which can include cancers.
  • the non-small cell lung cancer NSCLC
  • triple negative breast cancer TNBC
  • colorectal cancer CRC
  • metastatic urothelial cancer mUC
  • another solid tumor to be treated is generally PD-L1 positive.
  • the NSCLC, TNBC, colorectal, mUC, or another solid tumor to be treated is PD-L1 negative.
  • PD-L1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1.
  • PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745). Binding of PD-L1 with PD-1 inhibits T cell proliferation, cytokine production and cytolytic activity, leading to the functional inactivation or exhaustion of T cells.
  • B7.1 is a molecule expressed on antigen presenting cells and activated T cells.
  • PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down-regulation of immune responses, including inhibition of T-cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007; 27(1): 111-122).
  • PD-L1 expression has been observed in immune cells and tumor cells. See Dong H, Zhu G, Tamada K, Chen L.
  • PD-L1 expression can be determined by methods known in the art.
  • PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol -Meyers Squibb as a companion test for treatment with pembrolizumab (KEYTRUDA®).
  • IHC in vitro diagnostic immunohistochemistry
  • KYTRUDA® pembrolizumab
  • This scoring method evaluates the number of PD-Ll-staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells.
  • CPS is used to assess PD-L1 expression in: metastatic or unresectable, recurrent HNSCC, advanced esophageal or GEJ carcinoma, metastatic urothelial cancer (mUC), colorectal cancer, advanced cervical cancer and advanced triple-negative breast cancer.
  • Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining. Staining can show PD-L1 expression from 1% to 100%.
  • TPS is used to assess PD-L1 expression in advanced NSCLC, metastatic urothelial cancer (mUC), colorectal cancer and other solid tumors.
  • PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab (OPDIVO®).
  • IHC in vitro diagnostic immunohistochemistry
  • OPDIVO® nivolumab
  • This qualitative assay uses the Monoclonal rabbit anti-PD-Ll, Clone 28-8 and the EnVision FLEX visualization system on the Autostainer Link 48 platform to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue.
  • FFPE paraffin-embedded
  • Determination of PD-L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity.
  • the cutoff for mUC is >5% IC
  • the cutoff for TNBC is >1% IC
  • the cutoff for NSCLC is >50% TC or 10% IC.
  • the NSCLC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive NSCLC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive NSCLC of >10% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the TNBC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive TNBC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive TNBC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) or >1% of PD-L1 staining tumor-infiltrating immune cells (IC). as confirmed by an in vitro diagnostic (IVD) assay, for example, the Dako PD-L1-22C3 pharmDx kit or the Ventana SP-142 assay or another suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status TNBC with >10% PD-L1 staining of tumor cells as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status TNBC with >1% PD-L1 staining of immune cells as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative TNBC.
  • the colorectal cancer (CRC) patient being treated in the first-line or second-line therapeutic protocol described herein has a documented tumor shown by an FDA- approved or CE Mark test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • the CRC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive CRC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive CRC of >1% PD-L1 staining tumor-infiltrating immune cells (IC) or >1% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status CRC with >1% PD-L1 staining of tumor cells (TC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status negative CRC.
  • the mUC patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC of >5% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP- 142 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >25% PD-L1 staining of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or other suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >5% PD-L1 staining of immune cells (IC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of tumor cells (%TC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of immune cells (%IC) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status positive mUC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or another suitable assay.
  • IVD in vitro diagnostic
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative mUC.
  • the solid tumor patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive squamous cell carcinoma of the head and neck (SCCHN) of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS).
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive cervical cancer of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA- approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive esophageal cancer of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA-approved or CE Mark test.
  • the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status gastroesophageal junction cancer with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test.
  • the NSCLC, TNBC, CRC, mUC, or another solid tumor to be treated is CDK4/6 -negative.
  • the NSCLC, TNBC, CRC, mUC or another solid tumor to be treated is CDK4/6-positive.
  • the NSCLC, TNBC, CRC, mUC or another solid tumor is CDK4/6 indeterminate.
  • CDK4/6 replication independent cancers generally have a retinoblastoma gene (Rbl) aberration.
  • the gene product of Rbl — Rb-protein — is a downstream target of CDK4/6.
  • RBI is commonly dysregulated in cancer cells through deletion, mutation or epigenetic modification resulting in loss of RB expression, as well as by aberrant CDK kinase activity leading to excessive phosphorylation and inactivation of RB function (Chen et al. Novel RBI -Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types. Clin Cancer Res. 2019; 25(14); Sherr, C.J., and McCormick, F. The RB and p53 pathways in cancer. Cancer Cell, 2002; 2: 103 12.).
  • CCNE1/2 cyclin E
  • CCNE1/2 is part of a parallel pathway that provides functional redundancy with CDK4/6 and helps to transition cells from the G1 to S phase.
  • CDK 4/6 replication dependent TNBCs generally have an intact and functional Rb pathway and/ increased expression of CDK4/6 activators (cyclin D), and/or a d-type cyclin activating features (DCAF) — including CCND1 translocation, CCND1-3 3’UTR loss, and amplification of CCND2 or CCND3 (see Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6): 761-76). Tumors that are wildtype for RB and CCNE1/2 as well as have one of the DCAF described above are generally classified as “CDK4/6 dependent”.
  • CDK4/6-replication dependent or CDK4/6- replication independent are generally classified as “CDK4/6 indeterminate” since they cannot be confirmed as CDK4/6 dependent or independent.
  • the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication dependent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication independent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6 indeterminate.
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Retinoblastoma protein 1 (Rbl) loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TTIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Rb 1 loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
  • 3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
  • an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM- 3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Retinoblastoma protein 1 (Rbl) loss which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
  • the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 independent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 dependent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
  • TMB-H tumor mutational burden-high
  • NSCLC advanced/metastatic non-small cell lung cancer
  • TNBC advanced/metastatic triple negative breast cancer
  • CRC advanced/metastatic and unresectable colorectal cancer
  • mUC advanced/metastatic urothelial carcinoma
  • an advanced/metastatic other solid tumor for example, squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer (GEJ), an esoph
  • Example of immune checkpoint inhibitors and immune modulating agents include, but are not limited to, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, CD73 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, TIGIT inhibitor, Siglec-15 inhibitor, B7-H3 (CD272) inhibitor, BTLA inhibitor (CD272), small molecule, peptide, nucleotide, or another inhibitor.
  • the immune modulator is an antibody, such as a monoclonal antibody.
  • PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK- 301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curi
  • the patient has previously been administered a dual PD-L1/PD-1 inhibitor. In some embodiments, the patient has previously been administered a PD-L1/VISTA inhibitor.
  • PD-L1-VISTA inhibitors include, but are not limited to, CA-170 (Curis Inc.).
  • the immune checkpoint inhibitor is a VISTA immune checkpoint inhibitor.
  • VISTA inhibitors include, but are not limited to, JNJ-61610588 (Johnson & Johnson).
  • LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab /OMP- 313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/P
  • the patient has previously been administered an immune checkpoint inhibitor including, for example, but not limited to, a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 13 lI-8H9/omburtamab (Y-mabs), and I-8H9/omburtamab (Y-mabs), an indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitor such as Indoximod and INCB024360, a killer immunoglobulin-like receptors (KIRs) immune checkpoint inhibitor such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and/or -5).
  • a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) M
  • anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552.
  • the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/joumal. pone.0021146), or crossreacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
  • the patient has previously been administered an immune checkpoint inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • an immune checkpoint inhibitor directed to CD39 including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • the patient has previously been administered an immune checkpoint inhibitor directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87, and TAB004/JS004 (Junshi Biosciences).
  • BTLA B and T lymphocyte attenuator molecule
  • the patient has previously been administered a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
  • Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
  • a chemotherapeutic agent is also administered as part of the therapeutic protocol.
  • the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD-L1 inhibitor and an additional ICI as described herein increases the efficacy of immune checkpoint inhibition, including overcoming the development of resistance to previously administered PD-1 or PD-L1 inhibitors and/or reducing or delaying the onset of resistance, resulting in the extended efficacy of the anti -cancer protocol.
  • the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD- L1 inhibitor and an additional ICI as described herein provides for improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS) and reduced or delayed resistance to ICI therapy for these difficult to treat patients.
  • OS overall survival
  • PFS progression free survival
  • Trilaciclib (2'-((5-(4-methylpiperazin-l-yl) pyridin-2-yl) amino)-7',8'-dihydro-6'H-spiro (cyclohexane- l,9'-pyrazino (l',2':l,5) pyrrolo(2,3-d) pyrimidin)-6'-one) is a highly selective
  • CDK4/6 inhibitor having the structure:
  • Trilaciclib or its pharmaceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier.
  • Trilaciclib is available commercially as COSELA® (G1 Therapeutics, Inc.). Trilaciclib is described in US 2013-0237544, incorporated herein by reference in its entirety. Trilaciclib can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety. Trilaciclib can be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally.
  • Trilaciclib can be administered intravenously as described herein.
  • trilaciclib is in the form of a dihydrochloride optionally as a hydrate.
  • trilaciclib can be used in the present invention as a dihydrochloride, dihydrate or as a pharmaceutical composition formed from trilaciclib dihydrochloride, dihydrate.
  • trilaciclib is administered at between about 180 mg/m 2 and 300 mg/m 2 .
  • trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or about 280 mg/m 2 .
  • trilaciclib is administered at least 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, or 240 mg/m 2 .
  • trilaciclib is administered at about 240 mg/m 2 , prior to administration of the chemotherapeutic agent prior to about 4 hours or less, for example about 4 hours or less, 3 hours or less, 2 hours or less, about 1 hour or less, or about 30 minutes prior to administration of the chemotherapeutic, or first chemotherapeutic to be administered in a combination protocol, respectively.
  • trilaciclib is administered intravenously over a period of about 30 minutes. In some embodiments, trilaciclib is completely administered prior to administration.
  • a different CDK4/6 inhibitor is administered.
  • the CDK4/6 inhibitor used instead of trilaciclib in the protocols described herein is ribociclib (Novartis), palbociclib (Pfizer), or abemaciclib (Eli Lilly), or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is lerociclib, which has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
  • lerociclib is administered as a pharmaceutically acceptable salt, for example, the dihydrocloride salt.
  • the CDK4/6 inhibitor has the structure: or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
  • a CDK4/6 inhibitor selected from Palbociclib, ribociclib, or abemaciclib is used instead of trilaciclib.
  • the first immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression.
  • the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®), pidilizumab (Medivation), AMP -224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IB 1308; Innovent/Eli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012); Incyte Corporation and MacroGenics
  • the PD-1 inhibitor is nivolumab (OPDIVO®) administered in an effective amount for the treatment of unresectable or metastatic melanoma, early-stage and metastatic non-small cell lung cancer (NSCLC), intermediate or poor risk advanced renal cell carcinoma (RCC), relapsed or progressed classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), locally advanced or metastatic urothelial carcinoma (mUC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), hepatocellular carcinoma, unresectable malignant pleural mesothelioma, adjuvant or metastatic esophageal carcinoma, gastroesophageal junction (GEJ) cancer and gastric cancer.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks for NSCLC,
  • the PD-1 inhibitor is cemiplimab (LIBTAYO®) administered in an effective amount for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), locally advanced or metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic basal cell carcinoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC).
  • cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression.
  • cemiplimab is administered prior to chemotherapy.
  • the first immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression.
  • PD-L1 inhibitors include, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS- 1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (A
  • the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (TECENTRIQ®) administered in an effective amount for the treatment of locally advanced or metastatic urothelial carcinoma (mUC), unresectable or metastatic melanoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC), metastatic non-small cell lung cancer (NSCLC), unresectable or metastatic hepatocellular carcinoma or metastatic small cell lung cancer (SCLC).
  • atezolizumab is administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
  • atezolizumab is administered prior to chemotherapy.
  • the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab (BAVENCIO®) administered in an effective amount for the treatment of Merkel cell carcinoma, metastatic urothelial carcinoma (mUC), renal cell carcinoma (RCC), metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC).
  • avelumab is administered at 800 mg every 2 weeks. In one embodiment, avelumab is administered prior to chemotherapy.
  • T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors
  • TIGIT also called WUCAM, Vstm3, VSIG9
  • WUCAM WUCAM
  • Vstm3 a receptor of the Ig superfamily, which plays a critical role in limiting adaptive and innate immunity
  • TIGIT participates in a complex regulatory network involving multiple inhibitory receptors (e.g., CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • multiple inhibitory receptors e.g., CD96/TACTILE, CD112R/PVRIG
  • DNAM-1/CD226 competing costimulatory receptor
  • multiple ligands e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function.
  • TIGIT is co-expressed with PD-1 on tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) in mice and humans
  • TILs tumor-infiltrating lymphocytes
  • TIGIT and PD-1 impair tumor antigen-specific CD8 + T cells in melanoma patients. J Clin Invest 2015; 125: 2046-58; Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26 :923-37).
  • TIGIT is highly expressed by T re gs in peripheral blood mononuclear cells of healthy donors and patients with cancer and further upregulated in the TME (Joller et al., Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Thl and Thl7 cell responses. Immunity 2014; 40: 569-81; Zhang et al., Genome-Wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 2013; 122: 2823-36).
  • the additional immune checkpoint inhibitor is a TIGIT inhibitor that blocks the interaction of TIGIT and CD 155 by binding to the TIGIT receptor, and in turn inhibits immune suppression.
  • TIGIT inhibitors include, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB-154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (M
  • the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression. In one embodiment, the TIGIT inhibitor blocks the interaction between TIGIT and CD155 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor.
  • the CDK4/6 inhibitor, the PD-1 or PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
  • the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the TIGIT inhibitor blocks the interaction between TIGIT and CD 155 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
  • T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors
  • T-cell immunoglobulin and mucin domain 3 (encoded by Haver ) is an immunoglobulin (Ig) and mucin domain-containing cell surface molecule that was originally discovered as a cell surface marker specific to interferon (IFN-y) producing CD4 + T helper 1 (Thl) and CD8 + T cytotoxic 1 (Tel) cell (Monney et al., Thl-specific cell surface protein TIM-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536- 41).
  • IFN-y interferon
  • Thl T helper 1
  • Tel T cytotoxic 1
  • Tim-3 is coregulated and co-expressed along with other immune checkpoint receptors (PD- 1, Lag-3, and TIGIT) on CD4 + and CD8 + T cells (Chihara et al., Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 2018; 558: 454-9; DeLong et al., 11-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors. Immuno Horizons 2019; 3: 13-25).
  • TIM-3 expression specifically marks the most dysfunctional or terminally exhausted subset of CD8 + T cells (Fourcade et al., Upregulation of TIM-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.
  • the additional immune checkpoint inhibitor is a TIM-3 inhibitor that blocks the interaction of TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 by binding to the TIM-3 receptor, and in turn inhibits immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • TIM-3 inhibitors include, but are not limited to, Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the TIM-3 and PD-1 bispecific RO7121661 (Roche).
  • the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression.
  • the TIM- 3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1 to inhibit immune suppression.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the TIM-3 inhibitor is used without chemotherapy.
  • the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the TIM-3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression.
  • PtdSer phosphatidylserine
  • HMGB1 high-mobility group protein Bl
  • CEACAM-1 CEACAM-1
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIM-3 inhibitor is used without chemotherapy.
  • LAG-3 (CD223) is encoded by the LAG-3 gene.
  • LAG-3 is a member of the immunoglobulin superfamily (IgSF) and exerts a wide variety of biologic impacts on T cell function (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 : 1393-405).
  • LAG-3 is expressed on cell membranes of natural killer cells (NK), B cells, tumor-infiltrating lymphocytes (TIL), a subset of T cells, and dendritic cells (DC) (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4.
  • NK natural killer cells
  • TIL tumor-infiltrating lymphocytes
  • DC dendritic cells
  • lymphocyte activation gene 3 (LAG-3)
  • LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems.
  • LAG-3 protein binds a nonholomorphic region of major histocompatibility complex 2 (MHC class II) with greater affinity than CD 4 (Baixeras et al., Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992; 176: 327- 37).
  • MHC class II major histocompatibility complex 2
  • LAG-3 is one of the various immune-checkpoint receptors that are coordinately upregulated on both regulatory T cells (Tregs) and anergic T cells, and the simultaneous blockade of these receptors can result in an enhanced reversal of this anergic state relative to the blockade of one receptor alone (Grosso et al., Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009; 182: 6659-69).
  • the LAG-3/MHC class II molecule interaction leads to the downregulation of CD4+ Ag-specific T cell clone proliferation and cytokine secretion (Huard et al., T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol 1996; 26: 1180-6).
  • the additional immune checkpoint inhibitor is a LAG-3 inhibitor that blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • LAG-3 inhibitors include, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen, LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologie
  • the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the LAG-3 inhibitor is relatlimab.
  • the PD-1 inhibitor blocks the interaction between PD-1 and PD- L1 to inhibit immune suppression.
  • the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • MHC class II major histocompatibility complex 2
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
  • the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the LAG-3 inhibitor is relatlimab.
  • the PD- L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression.
  • the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression.
  • MHC class II major histocompatibility complex 2
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
  • CD73 commonly serves to convert AMP to adenosine (Allard et al., "Chapter Fifteen - Measurement of CD73 enzymatic activity using luminescence-based and colorimetric assays", Methods in Enzymology, Tumor Immunology and Immunotherapy - Molecular Methods, Academic Press, 629: 269-289).
  • CD73 is a membrane-bound extracellular enzyme overexpressed in several types of cancer. Its expression has been linked to poor prognosis in melanoma, colorectal, gastric, triple negative breast cancer, and to a pro-metastatic phenotype in prostate cancer (Stagg J et al., CD73- deficient mice are resistant to carcinogenesis. Cancer Res.
  • CD39 adenosine triphosphate (ATP) into adenosine.
  • ATP adenosine triphosphate
  • CD73 is active on the last step of the degradation pathway, where it is the enzyme that degrades AMP into adenosine. The CD73 blockade promotes anti-tumor immunity by reducing adenosine accumulation.
  • anti-CD73 mAbs stimulate antitumor immunity and reduce tumor metastasis in mouse tumor models and could enhance the efficacy of treatment with anti-PDl or anti-CTLA4 antibodies (Allard et al., Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 Oct 15; 19(20):5626-35).
  • Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma (Vijay an D et al., Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709-724).
  • Adenosine is a well-described immunosuppressive agent which attenuates the effector functions of various immune cell populations, including T cells, and enhances the suppressive functions of T regs.
  • Adenosine accumulation favors tumor growth and metastasis through effects on tumor cells and stroma.
  • activation of CD73 on tumor cells favors cell adhesion potentially through epidermal growth factor receptor (EGFR) signaling (indicated by dashed arrow) and inhibits tumor apoptosis.
  • EGFR epidermal growth factor receptor
  • CD73 activation also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs.
  • MMPs matrix metalloproteinases
  • A2BR activation on tumor cells promotes proliferation and angiogenesis through secretion of vascular endothelial growth factor (VEGF).
  • VEGF vascular endothelial growth factor
  • CAFs cancer-associated fibroblasts
  • FGF2 fibroblast growth factor 2
  • FAP fibroblast activation protein
  • A2BR activation leads to elevated release of CXCL12 by these FAP+ fibroblasts, thus increasing the number of CD31+ endothelial cells within the tumor.
  • A2BR can engage the G protein-coupled receptor Gq-protein kinase C (PKC) signaling pathway to activate interleukin-6 (IL-6), which in turn mediates epithelial-to-mesenchymal transition (EMT).
  • GPC G protein-coupled receptor Gq-protein kinase C
  • tumor exosomes co-express CD39 and CD73, which might be associated with tumor dissemination to distant organs (Vijayan, D., Young, A., Teng, M. W. L., & Smyth, M. J. (2017). Targeting immunosuppressive adenosine in cancer. Nature Reviews Cancer, 17(12), 709-724).
  • the additional immune checkpoint inhibitor is a CD73 inhibitor that specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity.
  • the CD73 inhibitor can relieve the inhibitory effect of adenosine on the proliferation and tumor-killing activity of CD8+ T cells, and weaken the stimulation of adenosine on immunosuppressive cells, so as to modulate the tumor microenvironment and enhance the antitumor immune response.
  • CD73 inhibitors include, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti-CD73-TGFP- Trap Bifunctional Antibody dalutrafusp alf
  • the CD73 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression.
  • the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity.
  • the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor.
  • the CDK4/6 inhibitor, the PD-1 inhibitor and the CD73 inhibitor is used without chemotherapy.
  • the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5 '-nucleotidase activity.
  • the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor.
  • the CDK4/6 inhibitor, the PD-L1 inhibitor and the CD73 inhibitor is used without chemotherapy. Additional Immune Checkpoint Inhibitors
  • the alternative immune checkpoint inhibitor is an inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
  • the alternative immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
  • Siglec-15 sialic acid-binding immunoglobulin-like lectin 15
  • the chemotherapeutic agent is toxic to immune effector cells. In one embodiment the chemotherapeutic agent inhibits cell growth. In one embodiment, the cytotoxic chemotherapeutic agent administered is a DNA damaging chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, DNA polymerase inhibitor, an anticancer enzyme, RAC1 inhibitor, thymidylate synthase inhibitor, oxazophosphorine compound, integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, antifolate or a folate antimetabolite. Cytotoxic Chemotherapeutic Agents
  • Cytotoxic, DNA-damaging chemotherapeutic agents tend to be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells such as HSPC and immune effector cells.
  • DNA-damaging chemotherapy or chemotherapeutic agent refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of undesirable cells, for example cancer cells, wherein the cytotoxic effect of the agent can be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, the inhibition of another nucleic acid-related activity (e.g., protein synthesis), or any other cytotoxic effect.
  • a cytostatic or cytotoxic agent i.e., a compound
  • alkylating agents include alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as a benzodizepa, carboquone, meturedepa, and uredepa; ethylenimines and methylmelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitroso ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine.
  • aziridines such as
  • DNA-damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozocin.
  • Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine P-l-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphi dicolin, 8- azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleosides, 5-bromodeoxycytidine, cytosine P-l-D-arabinoside, diazooxynorleucine, dideoxynucle
  • Chemotherapeutic protein synthesis inhibitors include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5 -fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl imidodiphosphate, kanamycin, kasugamycin, kirromycin, and O-methyl threonine.
  • Additional protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycine, puromycin, ricin, shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.
  • Inhibitors of DNA synthesis include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents, such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining; and other agents, such as distamycin and netropsin.
  • alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards
  • intercalating agents such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining
  • other agents such as distamycin and netropsin.
  • Topoisomerase inhibitors such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; inhibitors of cell division, including colcemide, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, a-amanitine and other fungal amatoxins, cordycepin (3 '-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydigin also can be used as the DNA damaging compound.
  • RNA synthesis inhibitors including actinomycin D, a-amanitine and other fungal amatoxins, cordycepin (3 '-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydig
  • the chemotherapeutic agent is a DNA complex binder such as camptothecin, or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU, or fotesmustine; a guanine alkylating agent such as temozolomide, a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52, halichondrins, such as halichondrin B, dolastatins, such as dolastatin 10 and dolastatin 15, hemiasterlins, such as hemiasterlin A and hemiasterlin B, colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; a DNA polymerase inhibitor such as cytarabine; an anticancer enzyme such as asparaginas, 5-
  • the topoisomerase inhibitor is a type I inhibitor. In another embodiment the topoisomerase inhibitor is a type II inhibitor.
  • DNA-damaging chemotherapeutic agents whose toxic effects can be mitigated by the presently disclosed selective CDK4/6 inhibitors include, but are not limited to, cisplatin, hydrogen peroxide, carboplatin, procarbazine, ifosfamide, bleomycin, plicamycin, taxol, transplatinum, thiotepa, oxaliplatin, and the like, and similar acting-type agents.
  • the DNA damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, camptothecin, and etoposide.
  • chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • General anticancer pharmaceutical agents include: Vincristine (ONCOVIN®), liposomal vincristine (MARQIBO®), doxorubicin (ADRIAMYCIN®), Cytarabine (cytosine arabinoside, ara-C, or CYTOSAR®), L-asparaginase (ELSPAR®) or PEG-L- asparaginase (pegaspargase or ONCASPAR®), Etoposide (VP- 16), Teniposide (VUMON®), 6- mercaptopurine (6-MP or PURINETHOL®), Prednisone, and Dexamethasone (DECADRON®).
  • chemotherapeutic agents include but are not limited to 5- fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC)), anti-mitotic agents, cisdichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (formerly actinomycin), daunorubicin HC1, daunorubicin citrate, denileukin diftitox, dihydroxy anthracin dione, Docetaxel, doxorubicin HC1, E.
  • coli L-asparaginase Erwinia L-asparaginase, etoposide citrovorum factor, etoposide phosphate, gemcitabine HC1, idarubicin HC1, interferon a-2b, irinotecan HC1, maytansinoid, mechlorethamine HC1, melphalan HC1, mithramycin, mitomycin C, mitotane, paclitaxel, polifeprosan 20 with carmustine implant, procarbazine HC1, streptozotocin, teniposide, thiotepa, topotecan HC1, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.
  • cytotoxic chemotherapeutic agents for use with the present invention include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vismodegib, azacytidine, doxifluridine, vindesine, and vinorelbine.
  • the chemotherapeutic agent is a DNA complex binder. In one embodiment the chemotherapeutic agent is a tubulin binder. In one embodiment the chemotherapeutic agent is an alkylating agent. In one embodiment the chemotherapeutic agent is a thiolate alkylating agent. Additional Chemotherapeutic Agents
  • Chemotherapeutic agents useful in the present invention include, but are not limited to, Trastuzumab (HERCEPTIN®), Pertuzumab (PERJETA®), Lapatinib (TYKERB®), Gefitinib (IRES SA®), Erlotinib (TARCEVA®), Cetuximab (ERBITUX®), Panitumumab (VECTIBIX®), Vandetanib (CAPRELSA®), Vemurafenib (ZELBORAF®), Vorinostat (ZOLINZA®), Romidepsin (ISTODAX®), Bexarotene (TARGRETIN®), Alitretinoin (PANRETIN®), Tretinoin (VESANOID®), Carfilzomib (KYPROLIS®), Pralatrexate (FOLOTYN®), Bevacizumab (AVASTIN®), Ziv-aflibercept (ZALTRAP®), Sorafenib (NEXAVAR
  • Additional chemotherapeutic agents may include an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.
  • Partial anti -estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • the chemotherapeutic agent may include a kinase inhibitor, including but not limited to a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’ s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • PI3K phosphoinositide 3-kinase
  • BTK Bruton’ s tyrosine kinase
  • Syk spleen tyrosine kinase
  • BTK inhibitors are well known.
  • BTK inhibitors include ibrutinib (also known as PCI-32765)(ImbruvicaTM) (l-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin- 4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6- (4-(2-hydroxyethyl)piperaz
  • Syk inhibitors are well known, and include, for example, Cerdulatinib (4- (cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)amino)pyrimidine-5- carboxamide), entospletinib (6-(lH-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[l,2- a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4- pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib di sodium salt (sodium (6-((5-
  • the chemotherapeutic agent can also be a B-cell lymphoma 2 (Bcl-2) protein inhibitor.
  • BCL-2 inhibitors are known in the art, and include, for example, ABT-199 (4-[4-[[2-(4- Chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4- [[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5- yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l-phenylsulfanylbutan-2-yl
  • Additional chemotherapeutic agents for use in the methods contemplated herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof), RAF inhibitors, apoptotic compounds, topoisomerase inhibitors, AKT inhibitors, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, or FLT-3 inhibitors, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.
  • Examples of MEK inhibitors include but are not limited to trametinib /GSK1120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5- carboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-(
  • RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
  • ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378.
  • HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
  • ERK inhibitors include SCH772984 (Merck/Schering-Plough), VTX-1 le (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.
  • Raf inhibitors are well known, and include, for example, Vemurafinib (N-[3-[[5-(4- Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-l- propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-
  • topoisomerase I inhibitors useful in the present invention include (S)-10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline- 3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), (1S,9S)-1- Amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo(de)pyrano(3 ' ,4' : 6,7)indolizino(l ,2-b)quinoline- 10,13 -d
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • the co-formulation of immune checkpoint inhibitors comprises a PD-L1 or PD-1 immune checkpoint inhibitor and an additional immune checkpoint inhibitor selected from the group consisting of a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the PD-L1 or PD- 1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at different amounts.
  • the PD-L1 or PD-1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at the same amounts.
  • the additional immune checkpoint inhibitor is a TIGIT inhibitor.
  • the additional immune checkpoint inhibitor is a TIM-3 inhibitor.
  • the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
  • the trilaciclib is administered once a week.
  • nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
  • nivolumab and relatlimab are administered once every two weeks.
  • nivolumab and relatlimab are administered once every three weeks.
  • nivolumab and relatlimab are administered once every four weeks.
  • nivolumab and relatlimab are administered once every six weeks.
  • the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • the melanoma is unresectable or metastatic melanoma.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a TIGIT immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CD73 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC).
  • NSCLC non-small cell lung cancer
  • TNBC triple negative breast cancer
  • CRC metastatic colorectal cancer
  • mUC metastatic urothelial cancer
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second-line metastatic triple negative breast cancer.
  • the patient has second-line metastatic colorectal cancer (CRC).
  • the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
  • the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), and B and T lymphocyte attenuator (BTLA) protein.
  • PD-L2 program death-ligand 2
  • CTLA-4 CTLA-4
  • IDO indoleamine 2,3 -dioxygenase
  • KIRs killer immunoglobulin-like receptors
  • an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
  • the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC).
  • NSCLC non-small cell lung cancer
  • TNBC triple negative breast cancer
  • CRC metastatic colorectal cancer
  • mUC metastatic urothelial cancer
  • the patient has second-line metastatic non-squamous or squamous NSCLC.
  • the patient has second-line metastatic triple negative breast cancer.
  • the patient has second-line metastatic colorectal cancer (CRC).
  • the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a PD-L2 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CTLA-4 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • the CTLA-4 immune checkpoint inhibitor is ipilimumab.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a KIR immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a CEACAM immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • trilaciclib is administered once a week
  • the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use
  • the additional immune checkpoint is a BTLA immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
  • the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle.
  • trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD- L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21 -day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28-day cycle, and trilaciclib is administered again on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week.
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42-day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle.
  • trilaciclib is administered one or more times per week.
  • trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor.
  • the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib.
  • the patient has a tumor expressing PD-L1.
  • the patient has a tumor expressing PD-L1 as determined by an FDA-approved, or CE Mark test.
  • Non-limiting examples of combination chemotherapy regimens for the first-line treatment of locally advanced or metastatic squamous cell NSCLC include cisplatin 75 mg/m 2 IV on day 1 plus paclitaxel 175 mg/m 2 IV on day 1 every 21 days, cisplatin 100 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1, 8, and 15 every 28 days, cisplatin 60 mg/m 2 IV on day 1 plus gemcitabine 1000 mg/m 2 IV on days 1 and 8 every 21 days, cisplatin 75 mg/m 2 IV on day 1 plus docetaxel 75 mg/m 2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m 2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m 2 IV on days 1, 8, and 15 every 28 days, protein-bound paclitaxel 100 mg/m 2 IV on days 1, 8, and 15 of every 21 days plus
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 . In some embodiments, the trilaciclib is administered at about 240 mg/m 2 .
  • the immune checkpoint inhibitor is a PD-1 inhibitor.
  • the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®).
  • the PD-1 inhibitor is nivolumab.
  • nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks.
  • the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes. In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor.
  • the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®).
  • the PD-LI inhibitor is atezolizumab.
  • atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year.
  • the PD-LI inhibitor is avelumab.
  • avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes.
  • the PD-LI inhibitor is durvalumab.
  • durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
  • the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154;
  • the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor.
  • the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
  • trilaciclib, the PD-1 or PD-L1 inhibitor, and the TIM-3 inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle.
  • the PD-1 or PD-L1 inhibitor comprises PD-1 inhibitor dostarlimab.
  • the TIM-3 inhibitor comprises cobolimab.
  • trilaciclib, dostarlimab, and cobolimab are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle.
  • the 21-day cycle is repeated in the absence of disease progression or unacceptable toxicity.
  • dostarlimab and cobolimab are administered intravenously over 30 minutes. In some embodiments, dostarlimab is administered at a dose of about 500 mg. In some embodiments, cobolimab is administered at a dose of about 300 mg.
  • the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor.
  • the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen.
  • trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen.
  • trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 .
  • the trilaciclib is administered at about 240 mg/m 2 .
  • the immune checkpoint inhibitor is a PD-1 inhibitor.
  • the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®).
  • the PD-1 inhibitor is nivolumab.
  • nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles.
  • nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks.
  • the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448;
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • TNBC triple negative breast cancer
  • the patient has a tumor expressing PD-L1.
  • a CDK4/6 inhibitor in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • TTIGIT T cell immunoreceptor with Ig and ITIM domains
  • TIM-3 T-cell immunoglobulin mucin-3
  • LAG-3 Lymphocyte-activation gene 3
  • CD73 Cluster of Differentiation 73
  • Non-limiting examples of first-line adjuvant therapy for metastatic TNBC include: Capecitabine 1,000-1,250 mg/m 2 orally twice daily on days 1-14, repeat cycle every 3 weeks; Carboplatin AUC 6 IV over 30 minutes on day 1, repeat cycle every 3 or 4 weeks; Cisplatin 75 mg/m 2 IV over 60 minutes on day 1, repeat cycle every 3 weeks; Doxorubicin 60-75 mg/m 2 IV push on day 1, repeat cycle every 3 weeks or Doxorubicin 20 mg/m 2 IV push on day 1, repeat cycle weekly; Eribulin 1.4 mg/m 2 IV push on days 1 and 8, repeat cycle every 3 weeks; Gemcitabine 800-1,200 mg/m 2 IV over 30 minutes on days 1, 8, and 15, repeat cycle every 4 weeks; Liposomal Doxorubicin 40-50 mg/m 2 IV on day 1, repeat cycle every 4 weeks; Paclitaxel 175 mg/m 2 IV over 3 hours on day 1, repeat cycle every 3 weeks or Paclitaxel 80 mg/m 2 IV over 60 minutes on day 1, repeat cycle weekly; Vinor
  • the CDK4/6 inhibitor is trilaciclib.
  • trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m 2 . In some embodiments, the trilaciclib is administered at about 240 mg/m 2 .
  • the PD-LI inhibitor is durvalumab.
  • durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
  • the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor.
  • the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154;
  • the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor.
  • the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), bootszelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenic
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
  • the patient has a tumor expressing PD-L1.
  • the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
  • a CDK4/6 inhibitor in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • T cell immunoreceptor with Ig and ITIM domains T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor
  • a metastatic urothelial carcinoma treatment protocol such as, but not limited to: postoperative adjuvant intravesical chemotherapy for metastatic urothelial carcinoma, first-line chemotherapy for metastatic urothelial carcinoma, and second-line chemotherapy for metastatic
  • the additional checkpoint inhibitor is a CD73 checkpoint inhibitor.
  • the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
  • Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein.
  • the technology for forming liposomal suspensions is well known in the art.
  • the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles.
  • the active compound due to the water solubility of the active compound, the active compound can be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free.
  • the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome.
  • pharmaceutically acceptable salts refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the presently disclosed host matter.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the presently disclosed compounds. These salts can be prepared during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents.
  • Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-m ethylglucamine, and procaine.
  • the base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
  • the free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.
  • Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like.
  • Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TIGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • embodiment 1 or 2 wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma. 4. The use of any of embodiments 1-3, wherein the solid cancer is small cell lung cancer.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
  • TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
  • TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • any of embodiments 1-30 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitax
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • embodiment 41 or 42 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • embodiment 58 wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG- 3) inhibitor.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • embodiment 72 or 73 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • embodiment 86 wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
  • embodiment 88 wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelima
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • any of embodiments 72-95 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
  • CDK4/6 cyclin dependent kinase 4/6
  • embodiment 106 wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
  • embodiment 109 wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
  • nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
  • nivolumab and relatlimab are administered once every four weeks.
  • 114. The use of any of embodiments 106-111, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, herein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
  • embodiment 221, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent. 223.
  • the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • embodiment 226, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent. 228.
  • the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, or head and neck squamous cell carcinoma.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • any of embodiments 226-237 wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a composition for use for the treatment of a human patient with cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the composition for use comprises a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; and, wherein the treatment comprises: a. administering to the patient an effective amount of trilaciclib, b. administering to the patient an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c.
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TAGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • composition of embodiment 248, wherein the treatment further comprises administering to the patient an effective amount of a chemotherapeutic agent.
  • composition of embodiment 248 or 249, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • composition of embodiment 252 wherein the patient has previously received a PD- 1 or PD-L1 inhibitor and has experienced disease progression. 254. The composition of any of embodiments 248-253, wherein the patient is administered an effective amount of a PD-1 inhibitor.
  • composition of embodiment 254, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP-224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
  • the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP-224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab
  • composition of embodiment 255, wherein the PD-1 inhibitor is nivolumab.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
  • composition of embodiment 259, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, bootszelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
  • composition of embodiment 260, wherein the LAG-3 inhibitor is relatlimab.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
  • composition of embodiment 262, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
  • composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
  • composition of embodiment 275 or 276, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • a method of treating a human having cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c.
  • CDK4/6 cyclin dependent kinase 4/6
  • PD- 1 programmed cell death protein-1
  • PD-L1 programmed death-ligand- 1
  • an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
  • TIGIT T cell immunoreceptor with immunoglobulin and ITIM domain
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • LAG-3 lymphocyte activation gene-3
  • CD73 Cluster of Differentiation 73
  • invention 280 or 282 wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
  • PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
  • PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
  • TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
  • CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
  • chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
  • chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, caba
  • a method of treating a human having cancer wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure: (trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
  • TIM-3 T-cell immunoglobulin and mucin domain 3
  • embodiment 320 or 322 wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.

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Abstract

This invention is in the area of improved therapeutic methods for difficult to treat locally advanced and/or metastatic cancers in patients whose cancer has advanced while being treated with an immune checkpoint inhibitor due to the development of resistance to the inhibitory effects of the immune checkpoint inhibitor or whose cancer is susceptible to the development of resistance to the effects of an immune checkpoint inhibitor. The methods of the present invention are particularly suitable for a select group of hard-to-treat patients with advanced/metastatic triple negative breast cancer (TNBC), recurrent or metastatic non-small cell lung cancer (NSCLC), advanced or metastatic and unresectable colorectal cancer and locally advanced or metastatic urothelial carcinoma, and provides extended progression free survival (PFS) and/or increased overall survival (OS) in these patient populations.

Description

IMPROVED TREATMENTS FOR ADVANCED/METASTATIC CANCERS WITH CHECKPOINT INHIBITOR RESISTANCE OR RESISTANCE SUSCEPTIBILITY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application 63/238,739, filed on August 30, 2021; and U.S. Provisional Application 63/399,977, filed on August 22, 2022; the entirety of each of these application is hereby incorporated by reference for all purposes.
FIELD OF THE INVENTION
This invention is in the area of improved therapeutic methods for difficult to treat locally advanced and/or metastatic cancers in patients whose cancer has advanced while being treated with an immune checkpoint inhibitor due to the development of resistance to the inhibitory effects of the immune checkpoint inhibitor or whose cancer is susceptible to the development of resistance to the effects of an immune checkpoint inhibitor. The methods of the present invention may be particularly suitable for a select group of hard-to-treat patients with advanced/metastatic breast cancer, including triple negative breast cancer (TNBC), recurrent or metastatic colorectal cancer, recurrent or metastatic non-small cell lung cancer (NSCLC), and locally advanced or metastatic urothelial carcinoma, among others, and may provide extended progression free survival (PFS) and/or increased overall survival (OS) in these patient populations.
BACKGROUND OF THE INVENTION
The paramount achievement in cancer treatment in the last decade has undoubtedly been the introduction of T cell targeted immunomodulators blocking the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein- 1 (PD-1), and programmed death -ligand- 1 (PD-L1). Both CTLA-4 and PD-1 play a role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family and mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). PD-L1 is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti -turn or T cell reactivity and promotes immune control over the cancerous cells.
In 2011, ipilimumab, a human IgGl k anti-CTLA-4 monoclonal antibody (sold under the brand name YERVOY®), was approved by the by the United States (US) Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma. Ipilimumab is the first and only United State Food and Drug Administration-approved CTLA-4 inhibitor.
Since the USFDA approval of ipilimumab in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy: PD-1 inhibitors nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and PD-L1 inhibitors atezolizumab (TECENTRIQ®), avelumab (BEVENCIO®), and durvalumab (IMFINZI®). Immune checkpoint inhibitors (ICI) have become some of the most widely prescribed anticancer therapies. The importance of these remarkable breakthroughs in cancer treatment was recognized in 2018, when two researchers, James Allison and Tasuku Honjo, who are credited with pioneering the use of immune checkpoint inhibitors to treat cancers, were awarded the Nobel Prize in Medicine (see Ledford, Heidi, et al. Cancer immunologists scoop medicine Nobel prize. Nature, vol. 562, no. 7725, Oct. 2018, pp. 20+).
The effectiveness of these agents in cancer treatment has established immunotherapy as an alternative modality in cancer treatment. In some solid tumors (e.g., metastatic melanoma and non-small-cell lung cancer), immunotherapy is the first line of treatment. These targeted immunotherapies have provided improved outcomes for a number of difficult to treat cancers. For example, in 2019, accelerated approval was granted by the USFDA and European Medicines Agency (EMA) for atezolizumab (TECENTRIQ®), a PD-L1 blocking antibody (immune checkpoint inhibitor [ICI]), in combination with nab -paclitaxel for patients with PD-L1 positive locally advanced/metastatic TNBC (see TECENTRIQ® Package Insert). The USFDA accelerated approval was based on the clinical trial results indicating improved progression-free survival (PFS) for patients with PD-L1 positive TNBC (Hazard ratio [HR]: 0.60 [0.48, 0.77]; p<0.0001; median 7.4 months vs. 4.8 months). In addition, the PD-L1 positive subset lived for an average of 25 months when treated with atezolizumab plus nab-paclitaxel, compared with 18 months when given placebo plus nab-paclitaxel. The efficacy improvement observed with the addition of atezolizumab to nab-paclitaxel was associated with immune related adverse events that occurred at relatively low frequencies, which could cause significant morbidity and mortality.
Pembrolizumab (KEYTRUDA®) monotherapy has also demonstrated improved objective response rates (ORR) in patients with PD-L1 positive TNBC tumors ranging from 18.5% to 21.4%, compared with response rates ranging from 5.3% to 9.6% in patients with PD-L1 negative tumors. Similarly, when pembrolizumab was used in combination with chemotherapy to treat TNBC, statistically significant and clinically meaningful improvements in PFS were observed for patients with PD-L1 positive tumors (overall PFS: 7.5 vs 5.6 months; combined positive score [CPS] >1 PFS: 7.6 vs 5.6; CPS>10 PFS: 9.7 vs 5.6) (Cortes J et al., KEYNOTE-355: Randomized, doubleblind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol. 2020;38(15)). These data led to a recent accelerated approval in the US of pembrolizumab in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS >10) as determined by an FDA approved test (KEYTRUDA® Package Insert).
Pembrolizumab (KEYTRUDA®) monotherapy has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability -high or mismatch repair-deficient metastatic colorectal cancer. At final analysis (median follow-up of 44.5 months [IQR 39.7-49.8]), median overall survival was not reached (NR; 95% CI 49.2-NR) with pembrolizumab vs 36.7 months (27.6-NR) with chemotherapy (hazard ratio [HR] 0.74; 95% CI 0.53-1.03; p=0.036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified a of 0.025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16.5 months (95% CI 5.4-38.1) with pembrolizumab versus 8 2 months (6.1-10.2) with chemotherapy (HR 0.59, 95% CI 0.45-0.79) (Diaz Jr. et al., “Pembrolizumab versus chemotherapy for microsatellite instability- high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study”, The Lancet Oncology, VOLUME 23, ISSUE 5, P659- 670, MAY 01, 2022. These data led to a recent accelerated approval in the US of pembrolizumab for the treatment of patients with locally recurrent unresectable or metastatic colon cancer and has been shown by a laboratory test to be microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR). (KEYTRUD A® Package Insert). In non-small cell lung cancer, for example, multiple randomized trials, in both squamous and non-squamous histology, have established that overall survival (OS) is improved with the addition of programmed cell death protein 1 (PD- l)/programmed death-ligand 1 (PD-L1) inhibitors (Spigel, 2019; Reck, 2016; Gandhi, 2018; Paz- Ares, 2018). Those with high levels of PD-L1 expression typically receive pembrolizumab or atezolizumab monotherapy in the first line followed by platinum-based chemotherapy in order to maximize treatment response and minimize toxicity. Those with a higher burden of disease requiring more aggressive initial treatment or with lower levels of PD-L1 expression typically receive immunotherapy in combination with a platinum-based chemotherapy doublet.
Likewise, durvalumab and avelumab have both shown promising results in the treatment of urothelial carcinoma, which currently has limited first-line chemotherapeutic treatment options (see Teets et al., Avelumab: A novel anti-PD-Ll agent in the treatment of Merkel cell carcinoma and urothelial cell carcinoma. Crit Rev Immunol. 2018; 38(3): 159-206; Wills et al., Durvalumab: a newly approved checkpoint inhibitor for the treatment of urothelial carcinoma. Curr Probl Cancer. 2018; 43(3): 181-194).
Despite the compelling clinical efficacy of ICIs, up to 50% of patients with PD-L1 positive tumors show resistance or relapse after, for example, administration of ICIs (Herbst et al., Predictive correlates of response to the anti-PD-Ll antibody MPDL3280A in cancer patients. Nature. 2014; 515(7528): 563-567). After an initial response to immune checkpoint inhibitors, acquired resistance occurs in most patients (Bai et al., Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017; 8(66): 110693-110707). Major factors contributing to resistance include constitutive PD-L1 expression in cancer cells, lack of tumor antigens, ineffective antigen presentation, activation of oncogenic pathways, mutations in IFN-y signaling, and factors within the tumor microenvironment including exhausted T cells, Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) (Bai et al., Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade. Oncotarget. 2017; 8(66): 110693-110707). Additional mechanisms of ICI resistance include genetic, epigenetic, and cellular signaling alterations that dysregulate neoantigen presentation/processing and disrupt cytotoxic T cells activity as well as mechanisms in which non-cancerous stromal or immune cells promote growth and resistance to ICIs (Liu et al., Mechanisms of resistance to immune checkpoint blockade. Am J Clin Dermatol. 2019; 20(1): 41-54; Barrueto et al., Resistance to checkpoint inhibition in cancer immunotherapy. Transl One. 2020; 13 : 100738; Jenkins et al., Mechanisms of resistance to immune checkpoint inhibitors. Brit J Cancer. 2018; 118: 9-16; Borcherding et al., Keeping tumors in check: A mechanistic review of clinical response and resistance to immune checkpoint blockade in cancer. J Mol Biol. 2018; 430: 2014-29; Gide et al., Primary and acquired resistance to immune checkpoint inhibitors in metastatic melanoma. Clin Cancer Res. 2018; 24(6)).
Because of the limited treatment available to patients with locally advanced or metastatic cancer who have advanced on immune-checkpoint inhibitors or are susceptible to the development of resistance, novel therapies whose mechanisms broadly target these ICI mechanisms of resistance and are capable of reversing or preventing such resistance are needed.
SUMMARY OF THE INVENTION
The present invention provides improved methods for treating select patients with locally advanced, recurrent, or metastatic cancer whose cancers have progressed on, have developed resistance to, or are susceptible to developing resistance to a PD-1 or PD-L1 checkpoint inhibitor, the methods including administering an effective amount of the short acting, selective, and reversible cyclin dependent kinase (CDK) 4/6 inhibitor trilaciclib, or a pharmaceutically acceptable salt thereof, in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor, or a Cluster of Differentiation 73 (CD73; Ecto-5 'nucleotidase (NT5E)) checkpoint inhibitor.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol. In certain embodiments, the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD-L1 inhibitor and, importantly, an additional ICI as described herein increases the efficacy of immune checkpoint inhibition, including overcoming the development of resistance to previously administered PD-1 or PD-L1 inhibitors and/or reducing or delaying the onset of resistance, resulting in the extended efficacy of the anti-cancer protocol. The treatment protocols described herein reduce tumor microenvironment immune changes or tumor cell immune effector signal downregulation allowing for tumor immune escape, and the synergistic combination of the administered agents can reverse and/or significantly delay the development of ICI resistance, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations. Furthermore, the treatment protocols described herein provide therapeutic efficacy through immune modulation of T cells, including the enhancement of cytotoxic CD8+ T-cell function and maturation into memory CD8+ T-cells and the inhibition of Treg function and differentiation. The result of this extended efficacy is an improvement in host immune response to the tumor, providing improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS), for these difficult to treat patients. Particular cancers susceptible to treatment with the methods of the present invention include, but are not limited to, non-small cell lung cancer (NSCLC), advanced/metastatic triple negative breast cancer (TNBC), colorectal cancer, and advanced/metastatic urothelial carcinoma, amongst others.
The methods provided herein can be used to activate an immune response in a subject. For example, administration of trilaciclib in combination with one or more additional agents leads to alterations in intratumor immune T cell subsets favoring effector T-cell function, including stimulation of IFN-y production in exhausted T-cells (Example 1, FIG. 1), reductions in the proportion of Tregs among CD4+ T cells in the tumor (see, e.g., Example 3, FIG. 6), an increase in CD8+ T cells to Tregs ratio in the tumor (see, e.g., Example 3, FIG. 7), and/or an increase in activated CD8+ T cells (see, e.g., Example 3, FIG. 8). The administration of trilaciclib in combination with an anti-PD-1 antibody leads to synergistic increases in the IL-2 from CD4+ T cells and IFN-y in CD8+ T cells (see, e.g., Example 4, FIG. 10A-10B). Furthermore, the methods provided herein can be used to reduce tumor growth and extend overall survival to a subject, for example a human, having a tumor. For example, the combined administration of the CDK4/6 inhibitor trilaciclib with a checkpoint inhibitor provides reduced tumor progression and extended overall survival (see, e.g., Examples 2 and 4; FIGs. 2A-5B and 9) compared to regimens not comprising trilaciclib. In some embodiments, the methods described provide weekly administration of the CDK4/6 inhibitor trilaciclib. Weekly administration of trilaciclib in combination with one or more additional agents provided durable tumor remission and extended overall survival (see, e.g., Examples 2, 5, 6, 7, 8, 9, 10, and 11; FIGs. 2A-5B, 11 A-l IK, 12A-12K, 13A-13H, 15A-15Q, 16A-16B, 17A-B, 18, and 20A-20B). Comparatively, delayed administration of trilaciclib led to reduced efficacy (see, e.g., Example 6, FIGs. 14A-14C).
The synergistic combination of CDK4/6 inhibitor trilaciclib with one or more additional agents including but not limited to checkpoint inhibitors may reverse and/or significantly delay the resistance to checkpoint inhibition and provide better efficacies of therapeutic regimens in difficult to treat patient populations. Additionally, the administration of the CDK4/6 inhibitor trilaciclib synergizes when combined with a PD-1 or PD-L1 inhibitor and an additional checkpoint inhibitor, for example a checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, or a CD73 inhibitor, to provide substantially reduced tumor progression (see, e.g., Examples 5, 6, 7, 8, 9, 10, and 11; FIGs. 11 A-l IB, UK, 12A-12B, 12K, 13A, 15A-15C, 15P- 15Q, 16A, 17A, 18, 20A) and extended overall survival (see, e.g., Examples 5, 6, 7, 8, 9, and 11; FIGs. 11C, 12C, 13B, 15D-15E, 16B, 17B, 20B) compared to regimens not comprising trilaciclib.
The methods described herein provide enhanced anti-tumor efficacy and survival benefits in a variety of different animal cancer models including, for example, MC38 colon carcinoma mice (Examples 2, 3, and 4; FIGs. 2A-4B, 6-8, and 9-10B), CT26 colorectal carcinoma mice (Examples 6, 7, 8, and 11; FIGs. 5A-B, 12A-12K, 13A-13H, 14A-14C, 15A-15Q, 16A-16B, and 20A-20B), mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) breast cancer model mice (Example 5; FIGs. 11 A-l IK), AT3-OVA breast cancer model mice (Example 9; FIGs. 17A-17B), S2WTP3 breast cancer model mice (Example 10; FIG. 18). Certain cancer models, for example colorectal cancers, are often associated with the development of immune checkpoint inhibitor drug resistance. As shown in Figures 20A-B, in a CT-26 colorectal cancer model, the use of trilaciclib in combination with a PD-1 or PD-L1 inhibitor and an additional ICI (e.g., CD73 inhibitor) leads to increased survival and tumor growth reduction.
In some embodiments, the methods provided herein comprise the administration of trilaciclib, a PD-1 or PD-Li inhibitor, and in further combination with a CD73 inhibitor. CD73 is a membrane-bound extracellular enzyme which degrades adenosine triphosphate (ATP) into adenosine and is overexpressed in several types of cancer. Adenosine is an immunosuppressive agent which attenuates the effector functions of immune cells, for example T cells, and enhances the suppressive functions of T regs (FIG. 19). Adenosine accumulation favors tumor growth and metastasis through epidermal growth factor receptor (EGFR) signaling and inhibition of tumor apoptosis, whereas inactivation of CD73 can attenuate this adenosine-mediated process. CD73 also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs.
Mechanisms of ICI resistance include genetic, epigenetic, and cellular signaling alterations that dysregulate neoantigen presentation/processing and disrupt cytotoxic T cell activity as well as mechanisms in which non-cancerous stromal or immune cells promote growth and resistance to ICIs. An additional mechanism is co-expression of additional co-inhibitory checkpoints such as T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin domain 3 (TIM-3), Lymphocyte activation gene-3 (LAG-3) and Cluster of Differentiation 73 (CD73; Ecto-5 'nucleotidase (NT5E)) checkpoint inhibitor. By administering trilaciclib in combination with a PD-1 or PD-L1 inhibitor and an additional co-inhibitory immune checkpoint inhibitor selected from a TIGIT inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, or CD73 inhibitor, and optionally a chemotherapeutic agent as described herein, one or more mechanisms leading to ICI resistance and disease progression can be overcome, resulting in increased antigen presentation (major histocompatibility complex (MHC) class I), enhanced T cell clonality and tumor infiltration, inhibition of regulatory T cell proliferation, decreased expression of T cell exhaustion markers (programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), T-cell immunoglobulin and mucin domain 3 (TIM3)), stabilized expression of PD-L1 on tumor cells, promotion of dendritic cell migration, adenosine, or increased T-effector cell function through high interferon-gamma (IFN-y) production. By administering the therapeutic combinations described herein to these difficult to treat patient subgroups, the immunosuppressive tumor microenvironment in the patient’s tumor — which renders the previously administered ICI ineffective or less effective and allows the tumor to progress — can be significantly overcome, improving the ability of the patient’s immune system to reduce or control tumor burden, improving quality of life, and improving overall survival in these difficult to treat subsets of patients.
In some aspects, the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycles), and trilaciclib is administered again on day 7 of each 14-day cycle. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21- day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28-day cycle, and trilaciclib is administered again on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42 -day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle.
In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week, the PD-Ll or PD-1 inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above.
In some embodiments, the cancer is a non-small cell lung cancer, triple negative breast cancer, colorectal cancer or urothelial cancer. In some embodiments, the patient has second-line metastatic non-squamous or squamous NSCLC. In some embodiments, the patient has second- line locally advanced or metastatic urothelial carcinoma. In some embodiments, the colorectal cancer has been shown by a laboratory test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
In some alternative embodiments, the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), a CD47 inhibitor, a CD39 inhibitor, or a B and T lymphocyte attenuator (BTLA) protein inhibitor.
In an alternative embodiment to the embodiments above, the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and a multiple tyrosine kinase (MTK) inhibitor instead of an additional immune checkpoint inhibitor, for example, but not limited to, lenvatinib, sitravatinib, and cabozantinib.
In yet another alternative embodiment to the embodiments above, the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and an oncolytic virus, for example, but not limited to an oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxviruses, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. Oncolytic viruses include, but are not limited to, paleorep (Reolysin®, Oncolytics Biotech), hemagglutinating virus of Japan-envelope (GEN0101), seprehvir, talimogene laherparepvec (T-VEC), adenovirus VCN-01, adenovirus ICORVIR-5, HF10, GL-ONC1, DNX- 2401, and enadenotucirev,
In some embodiments, the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles. In some embodiments, the patient is administered a treatment cycle until disease progression. In some aspects, patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, or a CD73 inhibitor, and an additional cytotoxic chemotherapeutic agent, wherein trilaciclib is administered prior to the administration of the cytotoxic chemotherapeutic agent, for example, less than 24 hours, less than 16 hours, less than 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 2 hours, less than 1 hour, or about 30 minutes prior to each administration of the chemotherapeutic agent, and the PD-1 or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered on day 1 of each therapeutic treatment cycle (or cycles).
It has been found that by using trilaciclib during a chemotherapeutic agent/immune checkpoint inhibitor combination therapy regimen, immune effector cells such as T lymphocytes are protected from chemotherapeutic agent toxicity and released from a transient cell-cycle arrest in the presence of chemotherapy-induced immunogenic cell death, in a manner that provides for significantly improved priming and activation of an anti-cancer immune response and anti-cancer effect than without the use of trilaciclib. It has also been found that by using trilaciclib during a chemotherapeutic agent/immune checkpoint inhibitor therapy regimen, anti-tumor activity is enhanced by cell cycle independent and dependent mechanisms, including the selective reduction of intra-tumoral Treg populations, preservation of pro-inflammatory immune effector cells such as tumor infiltrating lymphocytes, and an increased durability in treatment response. The controlled inhibition of CDK4/6 with trilaciclib in combination with a chemotherapeutic agent and the multi- immune checkpoint inhibitors as described herein, provides a significant increase in anti-tumor effects compared to the administration of a chemotherapeutic agent and immune checkpoint inhibitor alone, or the continuous inhibition of CDK4/6 with a CDK4/6 inhibitor dosed daily, including longer acting CDK4/6 inhibitors, in combination with an immune checkpoint inhibitor. The chemotherapeutic agent to be administered can be a chemotherapeutic agent generally administered as part of the standard of care for the stage of the cancer being treated. Many chemotherapeutic agents, for example, but not limited to, protein synthesis inhibiting or DNA- damaging chemotherapeutic agents, tend to be non-specific and toxic to normal, rapidly dividing cells, including immune effector cells, and hematological toxicities such as myelosuppression are a common side effect of chemotherapeutic treatment. Immune effector cells generally require the activity of CDK4/6 for proliferation, i.e., they are CDK4/6-replication dependent (see Roberts et al. Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy. JNCI 2012;104(6):476-487). All major intra-tumor immune cell types, for example CD4+ T-cells, CD8+ T-cells, and natural killer (NK) cells are sensitive to CDK4/6 inhibition. By using trilaciclib during chemotherapy treatment, immune effector cells, which are sensitive to the damaging effects of chemotherapeutic agents during proliferation, are transiently arrested in the G0/G1 phase of the cell cycle. By protecting these cells from the damaging effects of chemotherapeutic agents, the use of specifically-timed administration of trilaciclib preserves immune function, enhances T-cell activation, and increases the efficacy of immune checkpoint inhibitors, significantly improving the anti-cancer immune response. Importantly, by incorporating an additional immune checkpoint inhibitor into the therapeutic protocol, the development of resistance to the effects of immune checkpoint inhibitors due to long-term use and tumor microenvironment immune changes or tumor cell immune effector signal downregulation can be reversed or significantly delayed, providing for long-term efficacy of the therapeutic protocol in difficult to treat patient populations.
It has also been discovered that certain chemotherapies, but not all, are able to trigger a pathway in the tumor cell referred to as “immunogenic cell death” (“ICD”) (see generally, Locy, H., et al., Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend, Frontiers in Immunology, 2018; 9: 2090). ICD is a form of regulated cell death that induces the release of tumor associated antigens and triggers an anti-tumor immune response. Id. ICD involves the release of Damage- Associated Molecular Pathways (“DAMPS”) that alert the host’s immune system that the cell is damaged. There are six DAMPs that facilitate cell death: calreticulin (“CRT”), high mobility group box 1 (HMGB1), extracellular ATP, type I interferon, cancer cell- derived nucleic acids and ANXA1. These DAMPs determine the strength and durability of the ICD anti-tumor response. See also, Wang, et al, Immunogenic effects of chemotherapy induced tumour cell death, Genes & Diseases (2018) 5, 194-203.
Chemotherapeutic agents may also induce an immunogenic effect by disrupting strategies that tumors use to evade the immune response. See, e.g., Emens et al., The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies. Cancer Immunol Res; 3(5) May 2015. For example, chemotherapy can modulate distinct features of tumor immunobiology in a drug-, dose-, and schedule-dependent manner, and distinct chemotherapy drugs may modulate the intrinsic immunogenicity of tumor cells through a variety of mechanisms (see, e.g., Chen G, Emens LA. Chemoimmunotherapy: reengineering tumor immunity. Cancer Immunol Immunother 2013; 62: 203-16.). Chemotherapy can also enhance tumor antigen presentation by upregulating the expression of tumor antigens themselves, or of the MHC class I molecules to which the antigens bind. Alternatively, chemotherapy may upregulate costimulatory molecules (B7-1) or downregulate coinhibitory molecules (PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, enhancing the strength of effector T-cell activity. Chemotherapy may also render tumor cells more sensitive to T cell-mediated lysis through fas-, perforin-, and Granzyme B-dependent mechanisms.
PD1 inhibitors for use in the methods described herein include, for example, but are not limited to, nivolumab (OPDIVO®; Bristol Myers Squibb), pembrolizumab (KEYTRUDA®; Merck), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®; GlaxoSmithKline), pidilizumab (Medivation), AMP-224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IBI308; InnoventZEli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012; Incyte Corporation and MacroGenics), tislelizumab (BGB-A317; BeiGene), toripalimab (JS001; Coherus BioSciences, Inc. and Shanghai Junshi Biosciences Co., Ltd.), camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone Pharmaceuticals), zimberelimab (AB122; Arcus Biosciences) and JTX-4014 (Jounce Therapeutics).
PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol- Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curis) and BGB-A333 (BeiGene). In some embodiments, a dual PD-L1/PD-1 inhibitor is administered as provided herein.
LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), MGD013 (Macrogenics), RO7247669 (Hoffman - LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA- 03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
TIM-3 inhibitors for use in the methods described herein include, for example, but are not limited to, cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca), TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.), and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb- 7 (Stanwei Biotech), SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI- 804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
Cluster of Differentiation (CD) 73 (Ecto-5 'nucleotidase; (NT5E) checkpoint inhibitors for use in the methods described herein include, for example, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti-CD73-TGFP- Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Chemotherapeutic agents for use in the present methods include those associated with a standard of care treatment for the specific stage and prior treatment status of the cancer being treated. Examples of suitable chemotherapeutic agents for use in the present methods include, but are not limited to: platinum containing drugs, for example carboplatin, cisplatin, and oxaliplatin; a taxane, for example paclitaxel, docetaxel, or paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel); a topoisomerase inhibitor, for example topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, and teniposide; cyclophosphamide; vinblastine; gemcitabine; 5-fluoruracil (5-FU); eribulin; pemetrexed; mitomycin; sacituzumab govitecan; valrubicin; vinorelbine tartrate; and their pharmaceutically acceptable salts; or combinations thereof. In some embodiments, the chemotherapeutic agent for use in the present methods is a chemotherapeutic agent capable of inducing an immune-mediated response. Chemotherapies capable of inducing an immune-mediated responses are generally known in the art and include, but are not limited to, alkylating agents such as cyclophosphamide, trabectedin, temozolomide, melphalan, dacarbazine, and oxaliplatin; antimetabolites such as methotrexate, mitoxantrone, gemcitabine, and 5 -fluorouracil (5-FU); cytotoxic antibiotics such as bleomycin and anthracyclines, including doxorubicin, daunorubicin, epirubicin, idarubicin, and valrubicin; taxanes, such as paclitaxel, cabazitaxel, and docetaxel; topoisomerase inhibitors such as topotecan, irinotecan, and etoposide; platinum compounds such as carboplatin, oxaliplatin and cisplatin; bortezomib, an inhibitor of the 26S proteasome subunit; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside; or the pharmaceutically acceptable salts thereof, and combinations of any thereof. In some embodiments, the chemotherapy is selected from idarubicin, epirubicin, doxorubicin, mitoxantrone, oxaliplatin, bortezomib, gemcitabine, and cyclophosphamide, or the pharmaceutically acceptable salts or any thereof, and combinations of any thereof.
In some embodiments, trilaciclib is administered each day during a cycle that a chemotherapeutic agent is administered, the PD-1 or PD-L1 inhibitor is administered at least on day 1 of each cycle, and the additional immune checkpoint inhibitor selected from a TIGIT inhibitor, TIM-3 inhibitor, LAG-3 inhibitor, or CD73 inhibitor is administered concomitantly with the PD-1 or PD-L1 inhibitor. In some embodiments, the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle. In some embodiments, after day 1 of the cycle, trilaciclib is further administered alone once a week during the cycle. For example, in some embodiments, trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional checkpoint inhibitor are administered on day 1 of a 14-day cycle. In some embodiments, trilaciclib is administered again on day 7 of each 14-day cycle. In some embodiments, trilaciclib and the chemotherapeutic agent are administered on day 1 of a 21 -day cycle, and the PD-1 or PD- L1 inhibitor and additional immune checkpoint inhibitor are administered on day 1 of the 21 -day cycle. In some embodiments, trilaciclib is further administered alone on day 7 and day 14 of the 21 -day cycle. In some embodiments, trilaciclib and the chemotherapeutic agent are administered on day 1-3 of a 21 -day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 21-day cycle. In some embodiments, trilaciclib is further administered alone on day 7 and day 14 of the 21-day cycle. In some embodiments, trilaciclib and the chemotherapeutic agent are administered on days 1, 8, and 15 of a 28-day cycle, and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor is administered on day 1 of the 28- day cycle. In some embodiments, trilaciclib, the chemotherapeutic agent, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28- day cycle. In some embodiments, trilaciclib is again administered on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, the patient is administered 2 or more treatment cycles, for example, at least 2 cycles, at least 3 cycles, at least 4 cycles, at least 5 cycles, at least 6 cycles, or more. In some embodiments, following cessation of the treatment cycle comprising a chemotherapeutic agent, the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein the trilaciclib, PD-1 or PD- L1 inhibitor, and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks. In some embodiments, the PD-1 or PD-L1 inhibitor is not administered concomitantly with the additional checkpoint inhibitor. In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and wherein the duration of the first cycle is different than the duration of the second cycle. In some embodiments, following cessation of the treatment cycle comprising a chemotherapeutic agent, the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week and the PD-1 or PD-L1 inhibitor and additional immune checkpoint inhibitor are administered concomitantly once a week, once every two weeks, once every three weeks, once every 4 weeks, or once every six weeks. In some embodiments, following cessation of the treatment cycle comprising a chemotherapeutic agent, the patient is administered trilaciclib, a PD- 1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor in one or more maintenance phase cycles, wherein trilaciclib is administered once a week, wherein the PD-1 or PD-L1 inhibitor is administered once over a duration of a first cycle, wherein the additional immune checkpoint inhibitor is administered once over a duration of a second cycle, wherein the duration of the first cycle is different than the duration of the second cycle.
Non-Small Cell Luns Cancer (NSCLC)
In one aspect, the treatment protocols described herein are administered to a patient having metastatic or locally advanced non-small cell lung cancer (NSCLC). In some embodiments, the patient has metastatic or locally advanced squamous cell NSCLC. In some embodiments, the patient has metastatic or locally advanced non-squamous cell NSCLC. In some embodiments, the patient is not eligible for therapy targeted to a driver NSCLC mutation. In some embodiments, the patient has NSCLC with a driver mutation but the patient is not eligible to receive therapy targeted to the driver NSCLC mutation. In some embodiments, the patient has NSCLC whose driver mutation status is unknown.
Squamous NSCLC
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by a USFDA-approved, or CE mark test. In some embodiments, the patient has a tumor expressing PD-L1 as determined by a tumor proportion score (TPS), which is the number of PD-L1 -positive tumor cells divided by the total number of PD-L1 -positive plus PD-L1 -negative tumor cells, multiplied by 100, as determined by an FDA-approved, or CE Mark test. In some embodiments, the TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained immune cells (%IC). In some embodiments, the IC is > 10%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In some embodiments, the TC is > 25%. In some embodiments, the TC is > 50%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a combination of chemotherapeutic agents selected from gemcitabine, vinorelbine, paclitaxel, nab-paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the chemotherapeutic agent is gemcitabine. In some embodiments, the chemotherapeutic agent is vinorelbine. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive. In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor. In some embodiments, the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first line or second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%. In some embodiments, the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
Non-squamous NSCLC
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a combination of chemotherapeutic agents selected from pemetrexed, gemcitabine, paclitaxel, nab-paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the chemotherapeutic agent is pemetrexed and carboplatin, cisplatin, or oxaliplatin. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive. In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from docetaxel, gemcitabine, vinorelbine, or a combination thereof. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor. In some embodiments, the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first line or second- line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD- L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 10%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC > 50%. In some embodiments, the patient is also administered a chemotherapeutic agent selected from pemetrexed, gemcitabine, paclitaxel, nab -paclitaxel, and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, docetaxel, or vinorelbine, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
Triple Negative Breast Cancer
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, and whose tumor expresses PD-L1, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD- L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-Llwith an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) of >10. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a chemotherapeutic agent selected from gemcitabine, vinorelbine, capecitabine, ixabepilone, eribulin, paclitaxel, nab-paclitaxel, cyclophosphamide, 5 -fluorouracil, doxorubicin, sacituzumab govitecan, etoposide, or a platinum- drug, for example cisplatin, carboplatin, or oxaliplatin, or pharmaceutically acceptable salts of any thereof, or combinations thereof. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel or nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is doxorubicin and cyclophosphamide. In some embodiments, the chemotherapeutic agent is capecitabine, docetaxel, and cyclophosphamide. In some embodiments, the chemotherapeutic agent is docetaxel, cyclophosphamide, and paclitaxel or nab-paclitaxel. In some embodiments, the chemotherapeutic agent is capecitabine and cisplatin. In some embodiments, the chemotherapeutic agent is docetaxel and capecitabine. In some embodiments, the chemotherapeutic agent is ixabepilone and capecitabine. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic triple negative breast cancer (TNBC) in a second-line advanced/metastatic setting, and whose tumor expresses PD-L1, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD- L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-Llwith an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) of >10. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a chemotherapeutic agent selected from gemcitabine, vinorelbine, capecitabine, ixabepilone, eribulin, paclitaxel, nab-paclitaxel, cyclophosphamide, 5-fluorouraclil, doxorubicin, sacituzumab govitecan, etoposide, or a platinum- drug, for example cisplatin, carboplatin, or oxaliplatin, or pharmaceutically acceptable salts of any thereof, or combinations thereof. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel or nab-paclitaxel and carboplatin. In some embodiments, the chemotherapeutic agent is doxorubicin and cyclophosphamide. In some embodiments, the chemotherapeutic agent is capecitabine, docetaxel, and cyclophosphamide. In some embodiments, the chemotherapeutic agent is docetaxel, cyclophosphamide, and paclitaxel or nab-paclitaxel. In some embodiments, the chemotherapeutic agent is capecitabine and cisplatin. In some embodiments, the chemotherapeutic agent is docetaxel and capecitabine. In some embodiments, the chemotherapeutic agent is ixabepilone and capecitabine. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic TNBC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC> 1%. In some embodiments, the patient has a tumor expressing PD-L1 with a CPS > 10. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-Ll treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic TNBC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV- 1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) of >10. In some embodiments, the patient is also administered a chemotherapeutic agent selected from gemcitabine, vinorelbine, capecitabine, ixabepilone, eribulin, paclitaxel, nab-paclitaxel, cyclophosphamide, 5 -fluorouracil, doxorubicin, sacituzumab govitecan, etoposide, or a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
Colorectal Cancer
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, aPD-1 orPD-Ll inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 as determined by a combined positive score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100, as determined by an FDA- approved test. In some embodiments, the tumor has a CPS > 10. In some embodiments, the patient has a tumor expressing PD-L1 as determined by a tumor proportion score (TPS), which measures the proportion of tumor cells with PD-L1 membrane staining only (% of TC), as determined by an FDA-approved or CE Mark test. In some embodiments, the TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained immune cells (%IC). In some embodiments, the IC is > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a combination of chemotherapeutic agents selected from 5 -Fluorouracil (5-FU), Capecitabine (XELODA®), Irinotecan (CAMPTOSAR®), Trifluridine and tipiracil (LONSURF®) and a platinum-drug, for example cisplatin, carboplatin, oxaliplatin., or a combination thereof. In some embodiments, leucovorin is administered in combination with chemotherapeutic combinations. In some embodiments, the combination of chemotherapeutic agents is a combination of folinic acid (leucovorin), 5- fluorouracil and irinotecan (FOLFIRI). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5 -fluorouracil and oxaliplatin (FOLFOX). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5- fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor, or a CD73 inhibitor. In some embodiments, the patient has a tumor shown by an FDA-approved, or CE Mark test to be microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a combination of chemotherapeutic agents selected from 5 -Fluorouracil (5-FU), Capecitabine (XELODA®), Irinotecan (CAMPTOSAR®), Trifluridine and tipiracil (LONSURF®) and a platinum-drug, for example cisplatin, carboplatin, oxaliplatin, or a combination thereof. In some embodiments, leucovorin is administered in combination with chemotherapeutic combinations. In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5- fluorouracil and irinotecan (FOLFIRI). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5 -fluorouracil and oxaliplatin (FOLFOX). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5- fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor shown by an FDA-approved, or CE Mark test to be microsatellite instability-high (MSLH) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, a chemotherapeutic agent and a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the VEGF inhibitor is selected from bevacizumab (Avastin), Ramucirumab (Cyramza), or ziv-aflibercept (Zaltrap). In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a combination of chemotherapeutic agents selected from 5 -Fluorouracil (5-FU), Capecitabine (XELODA®), Irinotecan (CAMPTOSAR®), Trifluridine and tipiracil (LONSURF®) and a platinum-drug, for example cisplatin, carboplatin, or oxaliplatin or combinations thereof. In some embodiments, leucovorin is administered in combination with chemotherapeutic combinations. In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5- fluorouracil and irinotecan (FOLFIRI). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5 -fluorouracil and oxaliplatin (FOLFOX). In some embodiments, the combination of chemotherapeutic agents is folinic acid (leucovorin), 5- fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI). In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive. In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the VEGF inhibitor is selected from bevacizumab (Avastin®), Ramucirumab (Cyramza®), or ziv-aflibercept (Zaltrap®). In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an epidermal growth factor (EGFR) inhibitor. In some embodiments, the EGFR inhibitor is selected from cetuximab (Erbitux®) or panitumumab (Vectibix®). In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic or unresectable colorectal cancer in a first line or second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC > 1%. In some embodiments, the patient has a tumor expressing PD-L1 as determined by stained tumor cells (%TC). In some embodiments, the TC is > 1%. Urothelial Cancer
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic urothelial cancer (mUC) of the bladder in a first-line advanced/metastatic setting, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a chemotherapeutic agent selected from enfortumab vedotin, gemcitabine, cisplatin, carboplatin, eribulin, methotrexate, vinblastine, vinflunine, doxorubicin, epirubicin, ifosfamide, paclitaxel, nab-paclitaxel, docetaxel, or pharmaceutically acceptable salts of any thereof, or combinations thereof. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is methotrexate, vinblastine, doxorubicin, and cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel, gemcitabine, and cisplatin. In some embodiments, the chemotherapeutic agent is methotrexate, carboplatin, and vinblastine. In some embodiments, the chemotherapeutic agent is gemcitabine and paclitaxel or docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic urothelial cancer (mUC) of the bladder in a second-line advanced/metastatic setting, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor which expresses PD- L1 as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is a chemotherapeutic agent selected from paclitaxel, docetaxel, vinflunine, sacituzumab govitecan, pemetrexed, paclitaxel, nab-paclitaxel, docetaxel, gemcitabine, isofamide, and oxaliplatin, or pharmaceutically acceptable salts of any thereof, or combinations thereof. In some embodiments, the chemotherapeutic agent is gemcitabine and carboplatin or cisplatin. In some embodiments, the chemotherapeutic agent is methotrexate, vinblastine, doxorubicin, and cisplatin. In some embodiments, the chemotherapeutic agent is paclitaxel, gemcitabine, and cisplatin. In some embodiments, the chemotherapeutic agent is methotrexate, carboplatin, and vinblastine. In some embodiments, the chemotherapeutic agent is gemcitabine and paclitaxel or docetaxel. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic urothelial cancer (mUC) of the bladder in a second-line advanced/metastatic setting, and wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or metastatic urothelial cancer (MUC) of the bladder in a first-line or second-line advanced/metastatic setting wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor expressing PD-L1, as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10 as determined by an FDA-approved test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of >5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the patient is also administered a chemotherapeutic agent selected from paclitaxel, docetaxel, vinflunine, sacituzumab govitecan, pemetrexed, paclitaxel, nab -paclitaxel, docetaxel, gemcitabine, isofamide, enfortumab vedotin, eribulin, methotrexate, vinblastine, and oxaliplatin, doxorubicin, epirubicin, ifosfamide, or pharmaceutically acceptable salts of any thereof, or combinations thereof.
Solid Tumors
In some aspects, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or a metastatic solid tumor in a first or second-line advanced/metastatic setting, and wherein the patient is administered trilaciclib, a chemotherapeutic agent or agents, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10. In some embodiments, the chemotherapeutic agent administered is a standard of care chemotherapeutic agent. In some embodiments, the patient has previously received a PD-1 or PD- L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In some aspects, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or a metastatic solid tumor in a first or second-line advanced/metastatic setting, and wherein the patient is administered trilaciclib, a PD- 1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 1%. In some embodiments, the patient has a tumor expressing PD-L1 with an IC of > 5%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 25%. In some embodiments, the patient has a tumor expressing PD-L1 with a TC of > 50%. In some embodiments, the patient has a tumor expressing PD-L1 with a TPS of >1%. In some embodiments, the patient has a tumor expressing PD-L1 with a combined positive score (CPS) > 10. In some embodiments, the patient has previously received a PD-1 or PD-L1 inhibitor and experienced disease progression. In some embodiments, the patient is PD-1 or PD-L1 treatment naive.
In some aspects, the improved methods of treatment described herein are administered to a patient having locally advanced, recurrent unresectable, or a metastatic solid tumor in a first or second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an oncolytic virus. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the oncolytic virus is selected from oncolytic adenovirus, oncolytic HSV-1, an oncolytic reovirus, an oncolytic poxvirus, an oncolytic Newcastle Disease virus, an oncolytic measles virus, an oncolytic Seneca Valley virus, a hemagglutinating virus of Japan Envelope (HVJ-E) virus, an oncolytic gamma-herpes virus, an oncolytic parvovirus, or an oncolytic retrovirus. In some embodiments, the oncolytic virus is paleorep. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient is also administered a chemotherapeutic agent.
Improved Patient Outcomes
The administration of a treatment protocol described herein to the patient subgroups described herein may provide enhanced anti-tumor efficacy in patients. In some embodiments, the administration of a treatment protocol described herein in the particular patient subgroups described above provides improved progression free survival (PFS) and/or overall survival (OS). In some embodiments, an improvement in PFS is based on per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). In some embodiments, the administration of a treatment protocol described herein to the patient subgroups described above provides improved myelopreservation of hematopoietic stem and progenitor cells (HSPCs) and immune effector cells such as lymphocytes including T- lymphocytes. In some embodiments, the administration of a treatment protocol described herein to the patient subgroups described above provides reduced chemotherapy-induced myelosuppression (CIM). In some embodiments, the administration of a treatment protocol described herein provides myelopreservation of the neutrophil lineage in patients compared to those receiving the chemotherapy without trilaciclib. In some embodiments, the administration of a treatment protocol described herein provides a reduction in the duration of severe (Grade 4) neutropenia.
In some embodiments, the administration of a treatment protocol described herein provides a reduction in severe neutropenia events, a reduction in granulocyte-colony stimulating factor (G- CSF) treatment, or a reduction in febrile neutropenia (FN) adverse events (AEs). In some embodiments, the administration of a treatment protocol described herein provides a reduction in Grade 3 or 4 decreased hemoglobin laboratory values, red blood cell (RBC) transfusions, or erythropoiesis-stimulating agent (ESA) administration. In some embodiments, the administration of a treatment protocol described herein provides a reduction in Grade 3 or 4 decreased platelet count laboratory values and/or the number of platelet transfusions. In some embodiments, the administration of a treatment protocol described herein provides a reduction in Grade 3 or 4 hematologic laboratory values.
In some embodiments, the administration of a treatment protocol described herein provides a reduction in all-cause dose reductions or cycle delays and relative dose intensity for chemotherapy. In some embodiments, the administration of a treatment protocol described herein provides a reduction in i) hospitalizations, including but not limited to those due to all causes, febrile neutropenia/neutropenia, anemia/RBC transfusion, thrombocytopenia/bleeding and infections) or ii) antibiotic use, including but not limited to intravenous (IV), oral, and oral and IV administered antibiotics.
In some embodiments, the administration of a treatment protocol described herein provides a reduction of chemotherapy-induced fatigue (CIF) in patients. In some embodiments, the reduction of CIF is a reduction in the time to first confirmed deterioration of fatigue (TTCD- fatigue), as measured by the Functional Assessment of Cancer Therapy -Fatigue (FACIT-F).
In some embodiments, the administration of a treatment protocol described herein provides an improvement to one or more of: Functional Assessment of Cancer Therapy-General (FACT- G) domain scores (physical, social/family, emotional, and functional well-being); Functional Assessment of Cancer Therapy -Anemia (FACT-An); 5-level EQ-5D (EQ-5D-5L); Patient Global Impression of Change (PGIC) fatigue item; or Patient Global Impression of Severity (PGIS) fatigue item.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows a line graph that shows the concentration of test compound (trilaciclib alone or trilaciclib plus anti-LAG-3) measured in nanomoles on the x-axis. The y-axis shows the concentration of IFN-y measured in picograms/milliliter.
FIG. 2 A shows a line graph illustrating tumor growth. Tumor growth of MC38 mice treated with chemotherapy/ICI ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 2B shows a survival curve line graph. Overall Survival of MC38 mice treated with oxaliplatin/PD-1 ± trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is percent survival.
FIG. 3A shows a line graph illustrating tumor growth. Tumor growth of MC38 mice treated with oxaliplatin/PD-1 ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 3B shows a survival curve line graph. Overall Survival of MC38 mice treated with oxaliplatin/PD-1 ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is percent survival.
FIG. 4 A shows a line graph illustrating tumor growth. Tumor growth of MC38 mice treated with 5-FU/PD-L1 ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3. The right panel shows
FIG. 4B shows a survival curve line graph. Overall Survival of MC38 mice treated with 5-FU/PD-L1 ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is percent survival.
FIG. 5 A shows a line graph illustrating tumor growth. Tumor growth of CT26 mice treated with oxaliplatin/PD-Ll ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 5B shows a survival curve line graph. Overall Survival of CT26 mice treated with oxaliplatin/PD-Ll ±trilaciclib combination therapy (n=10-15 per treatment group) was measured. The x-axis is days of treatment measured in days and the y-axis is percent survival.
FIG. 6 shows the proportion of Tregs in total tumor treated with vehicle, oxaliplatin/PD-Ll, or trilaciclib/oxaliplatin/PD-Ll on days 5 and 9. The x-axis is the results on Day 5 and Day 9 and the y-axis is the % Tregs of CD4+ T cells in the tumor measured as a percentage.
FIG. 7 shows the ratio of CD8+ T cells to Tregs (% CD8+ T cells/% Tregs) in the tumor (n=5-
8 tumors analyzed per treatment group and time point). The x-axis is the results on Day 5 and Day
9 and the y-axis is the ratio of CD8+ T cells to Tregs in the tumor measured as a percentage.
FIG. 8 shows the proportion of activated (% CD69+) cells in CD8+ T cells. *P<0.05. The x-axis shows the treatment group (vehicle, oxaliplatin/PD-Ll, and trilaciclib/oxaliplatin/PD-Ll). The y-axis is the percentage of activated (% CD69+) cells in CD8+ T cells.
FIG. 9 shows tumor growth curves of MC38 treated with CDK4/6 inhibitor or PD-1 antibody alone or in combination. MC38 murine cancer cells were injected subcutaneously into C57BL/6 mice. The mice were treated with either trilaciclib (100 mg/kg) intermittently (3 days on, 4 days off) with or without PD-1 antibody (200 pg/mouse, 3 times a week) as indicated starting from day 3 (MC38). Tumor volumes were monitored every 2-3 days. Each graph shows representative results from two independent experiments. (n=8) (*p<0.001). The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 10A is a bar graph illustrating the quantification of IL-2 cytokine production produced by MC38 tumor infiltrating T lymphocytes. At the end of the treatment (day 17), mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IL-2 from CD4+ T cells (*p<0.001). The x-axis is the treatment groups and the y-axis is the percentage of IL-2 from CD4+ cells.
FIG. 10B is a bar graph illustrating the quantification of IFNy cytokine production produced by MC38 tumor infiltrating T lymphocytes. At the end of the treatment (day 17), mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IFNy from CD8+ T cells (*p<0.001). The x-axis is the treatment groups and the y-axis is the percentage of IFNy from CD8+ T cells.
FIG. 11A shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 11B shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
FIG. 11C shows Overall Survival of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice. The mice were treated with CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 11D shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with citrate buffer (negative control). MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with citrate buffer (negative control) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. HE shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib only. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 11F shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with an anti-TIGIT inhibitor only. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 11G shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with an anti-PD-1 inhibitor only. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 11H shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. I ll shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination. MMTV- PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 11 J shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 1 IK shows tumor growth curves of Balb/C mice implanted with MMTV-PyMT murine tumor cells and then treated with trilaciclib, an anti-PDl inhibitor and an anti-TIGIT inhibitor in combination. MMTV-PyMT murine mammary tumor cells were injected subcutaneously into Balb/C mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. The x- axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. The x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
FIG. 12C shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PDl inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. Drug dosing was terminated on day 63. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 12D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control). CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with citrate buffer as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination. CT- 26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-PD-1 inhibitor (5 mg/kg, two times per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 121 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (lOOmg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 12K shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13 A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration. The x- axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
FIG. 13B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with or without trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell administration. Drug dosing was terminated on day 63. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 13C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control). CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with citrate buffer as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13D shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13E shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 13H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 14A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIGIT inhibitor. The mice (n=8) were treated with an anti- TIGIT inhibitor (10 mg/kg, 2 times per week) starting from day 7 or Day 10 as indicated. The x- axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 14B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIGIT inhibitor in combination. The mice (n=8) were treated with trilaciclib (100 mg/kg, once per week) and anti-TIGIT inhibitor (10 mg/kg, 2 times per week) starting from day 7 or Day 10 as indicated. The x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 14C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIGIT inhibitor in combination. The mice (n=8) were treated with trilaciclib (100 mg/kg, once per week), anti-TIGIT inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) starting from Day 7 or Day 10 as indicated. The x-axis is days post treatment measured in days and the y- axis is tumor volume measured in mm3.
FIG. 15A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor and/or anti-TIM3 inhibitor alone or in combination. CT26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-LAG3 inhibitor (10 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (5 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor growth (fold change).
FIG. 15B shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination. CT26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice then randomized into treatment groups once the average tumor volume reached 40-80 mm3 (n=5-8). The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-LAG3 inhibitor (10 mg/kg, 2 times a week). The x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
FIG. 15C shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-TIM3 inhibitor alone or in combination. CT26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice then randomized into treatment groups once the average tumor volume reached 40-80 mm3 (n=5-8). The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week). The x-axis is days of treatment measured in days and the y- axis is tumor growth (fold change).
FIG. 15D shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-LAG3 inhibitor alone or in combination. CT26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-LAG3 inhibitor (10 mg/kg, 2 times a week) from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 15E shows Overall Survival of Balb/C mice implanted with mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIM3 inhibitor alone or in combination. CT26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIM3 inhibitor (10 mg/kg, 2 times a week) from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 15F shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with citrate buffer (negative control). CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=4). The mice were treated with citrate buffer as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15G shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15H shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 151 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-LAG3 inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15J shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-TIM3 inhibitor only. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15K shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PDl inhibitor and an anti-LAG3 inhibitor in combination. CT- 26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-PDl inhibitor (5 mg/kg, two times per week) and anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15L shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination. CT- 26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with anti-PD-1 inhibitor (5mg/kg, two times per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15M shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-PD-1 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15N shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-LAG3 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-LAG3 inhibitor (10 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 150 shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and an anti-TIM3 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week) and anti-TIM3 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15P shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-LAG3 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week), anti-LAG3 inhibitor (10 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 15Q shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib, an anti-PD-1 inhibitor and an anti-TIM3 inhibitor in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8). The mice were treated with trilaciclib (100 mg/kg, once per week), anti-TIM3 inhibitor (5 mg/kg, 2 times per week) and anti-PD-1 inhibitor (5 mg/kg, 2 times per week) as indicated starting from day 7 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 16A shows tumor growth curves of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colorectal cancer cells were injected subcutaneously into Balb/c mice. The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation. The x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3. FIG. 16B shows Overall Survival of Balb/C mice implanted with CT26 colorectal cancer (CRC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination. CT-26 murine colorectal carcinoma cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 17A shows tumor growth curves of C57BL/6 mice implanted with AT3-OVA murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. AT3-OVA murine breast carcinoma cells were injected subcutaneously into C57BL/6 mice. The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti-TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 10 after tumor cell implantation. The x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3.
FIG. 17B shows Overall Survival of Balb/C mice implanted with AT3-OVA breast cancer (BC) murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti- TIGIT inhibitor alone or in combination. AT3-OVA murine breast carcinoma cells were injected subcutaneously into Balb/C mice. The mice were treated with trilaciclib (100 mg/kg, once per week), anti-PD-1 inhibitor (5 mg/kg, 2 times a week), and/or anti-TIGIT inhibitor (10 mg/kg, 2 times a week) alone or in combinations as indicated starting from day 10 after tumor cell administration. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
FIG. 18 shows tumor growth curves of Balb/C mice implanted with S2WTP3 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. S2WTP3 murine breast carcinoma cells were injected subcutaneously into Balb/c mice. The mice were treated with either CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) with or without anti- TIGIT inhibitor (10 mg/kg, 2 times a week) as indicated starting from day 7. The x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3.
Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma.
Figure 20A shows tumor growth curves of Balb/C mice implanted with CT26 murine tumor cells and then treated with trilaciclib and/or anti-PD-1 inhibitor and/or anti-CD73 inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice. The mice were treated with either trilaciclib (100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5mg/kg, 2 times a week) with or without anti-CD73 inhibitor (5 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell implantation. Treatment continued for six weeks. The x-axis is days post treatment measured in days and the y-axis is tumor volume measured in mm3.
Figure 20B shows Overall Survival of Balb/C mice implanted with CT26 murine tumor cells and then treated with CDK4/6 inhibitor and/or anti-PD-1 inhibitor and/or anti-TIGIT inhibitor alone or in combination. CT-26 murine colon carcinoma cells were injected subcutaneously into Balb/c mice (n=8/group). The mice were treated with or without CDK4/6 inhibitor (trilaciclib 100 mg/kg, once per week) with or without anti-PD-1 inhibitor (5 mg/kg, 2 times a week) and with or without anti-CD73 inhibitor (5 mg/kg, 2 times a week) as indicated starting from day 7 after tumor cell implantation. Treatment continued for six weeks. The x-axis is days of treatment measured in days and the y-axis is probability of survival measured in percentage.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed application. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.
Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
In some embodiments of each compound described herein, the compound may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or isomer, such as a rotamer, as if each is specifically described unless specifically excluded by context.
The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term “or” means “and/or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.
An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit.
To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease, disorder, or side-effect experienced by a patient (i.e., palliative treatment) or to decrease a cause or effect of the disease, disorder (i.e., disease-modifying treatment), or side effect experienced by a patient as a result of the administration of a therapeutic agent.
Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
As used herein, “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier. “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic or organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). Wherein the methods described herein identify the administration of a particular compound, it is understood that administration of the compound’s pharmaceutically acceptable salt, if applicable, is encompassed as an embodiment.
As used herein, the term "prodrug" means a compound which when administered to a host in vivo is converted into the parent drug. As used herein, the term "parent drug" means any of the presently described chemical compounds that are useful to treat any of the disorders described herein, or to control or improve the underlying cause or symptoms associated with any physiological or pathological disorder described herein in a host, typically a human. Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent. Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein. Nonlimiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.
The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
A “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, and neither biologically nor otherwise inappropriate for administration to a host, typically a human.
In non-limiting embodiments, trilaciclib can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
Examples of isotopes that can be incorporated into trilaciclib for use in the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 3 IP, 32P, 35S, 36CI, and 1251 respectively. In one non-limiting embodiment, isotopically labelled compounds can be used in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired result. Alternatively, or in addition, isotopes of carbon, e.g., 13C and 14C, may be used. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
In non-limiting embodiments, the CDK4/6 inhibitors, chemotherapy, or checkpoint inhibitors can be used in a form that has at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
Trilaciclib or another CDK4/6 inhibitor described herein for use in the present invention may form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes the use of a solvated form of the compound. The term "solvate" refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, de-acetone, de-DMSO. A solvate can be in a liquid or solid form.
As generally contemplated herein, the term “hematopoietic stem and progenitor cell” (HSPC) includes, but are not limited to, long term hematopoietic stem cells (LT-HSCs), short term hematopoietic stem cells (ST-HSCs), hematopoietic progenitor cells (HPCs), multipotent progenitors (MPPs), oligodendrocyte pre-progenitors (OPPs), monocyte progenitors, granulocyte progenitors, common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-monocyte progenitors (GMPs), granulocyte progenitors, monocyte progenitors, and megakaryocyte-erythroid progenitors (MEPs), megakaryocyte progenitors, erythroid progenitors, HSC/MPPs (CD45dim/CD34+/CD38-), OPPs (CD45dim/CD34+/CD38+), monocyte progenitors (CD45+/CD14+/CDl lb+), granulocyte progenitors (CD45+/CD14-/CD1 lb+), erythroid progenitors (CD45-/CD71+), and megakaryocyte progenitors (CD45+/CD61+).
The term “immune effector cell” generally refers to an immune cell that performs one or more specific functions. Immune effector cells are known in the art and include for example, but are not limited to, T-cells, including Naive T-cells, Memory T-cells, Activated T-cells (T helper (CD4+) and Cytotoxic T cells (CD8+)), TH1 activated T-cells, TH2 activated T-cells, TH17 activated T-cells, Naive B cells, Memory B cells, plasmablasts, dendritic cells, monocytes, and natural killer (NK) cells.
The “patient,” “host,” or “subject” treated is typically a human patient, although it is to be understood the methods described herein are effective with respect to other animals, such as mammals. More particularly, the term patient can include animals used in assays such as those used in preclinical testing including but not limited to mice, rats, monkeys, dogs, pigs and rabbits; as well as domesticated swine (pigs and hogs), ruminants, equine, poultry, felines, bovines, murines, canines, and the like.
In some embodiments, the term “CDK4/6-replication independent cancer” refers to a cancer that does not significantly require the activity of CDK4/6 for replication. Cancers of such type are often, but not always, characterized by (e.g., that has cells that exhibit) an increased level of CDK2 activity or by reduced expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s), such as, but not limited to pl07 and pl30. The increased level of CDK2 activity or reduced or deficient expression of retinoblastoma tumor suppressor protein or retinoblastoma family member protein(s) can be increased or reduced, for example, compared to normal cells. In some embodiments, the increased level of CDK2 activity can be associated with (e.g., can result from or be observed along with) MYC proto-oncogene amplification or overexpression. In some embodiments, the increased level of CDK2 activity can be associated with overexpression of Cyclin El, Cyclin E2, or Cyclin A.
In some embodiments, the term “CDK4/6-replication dependent cancer” refers to a cancer that requires the activity of CDK4/6 for replication or proliferation, or which may be growth inhibited through the activity of a selective CDK4/6 inhibitor. Cancers and disorders of such type may be characterized by (e.g., that has cells that exhibit) the presence of a functional Retinoblastoma (Rb) protein. Such cancers and disorders are classified as being Rb-positive. Rb- positive abnormal cellular proliferation disorders, and variations of this term as used herein, refer to disorders or diseases caused by uncontrolled or abnormal cellular division which are characterized by the presence of a functional Retinoblastoma protein, which can include cancers.
As used herein, the term “immune checkpoint inhibitor (ICI)” refers to therapy targeting immune checkpoint proteins, key regulators of the immune system that when expressed can dampen the immune response to an immunologic stimulus. Some cancers express ligands for the checkpoint inhibitors and can protect themselves from attack by binding to immune checkpoint targets. ICIs block inhibitory checkpoints, restoring immune system function. ICIs include those targeting immune checkpoint proteins such as PD-1, PD-1 Ligand- 1 (PD-L1), PD-1 Ligand-2 (PD- L2), CTLA-4, LAG-3, TIM-3, cluster of differentiation 73 (CD73), and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and B and T lymphocyte attenuator (BTLA) protein. Immune checkpoint inhibitors are known in the art.
PD-L1 Status
As provided herein, the non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC), metastatic urothelial cancer (mUC), or another solid tumor to be treated is generally PD-L1 positive. In alternative embodiments, the NSCLC, TNBC, colorectal, mUC, or another solid tumor to be treated is PD-L1 negative.
PD-L1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1. PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer (Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745). Binding of PD-L1 with PD-1 inhibits T cell proliferation, cytokine production and cytolytic activity, leading to the functional inactivation or exhaustion of T cells. B7.1 is a molecule expressed on antigen presenting cells and activated T cells. PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down-regulation of immune responses, including inhibition of T-cell activation and cytokine production (see Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007; 27(1): 111-122). PD-L1 expression has been observed in immune cells and tumor cells. See Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin- 10 secretion. Nat Med. 1999; 5(12): 1365-1369; Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-Ll antibody MPDL3280A in cancer patients. Nature. 2014; 515(7528): 563-567. Aberrant expression of PD- L1 on tumor cells has been reported to impede anti -tumor immunity, resulting in immune evasion.
PD-L1 expression can be determined by methods known in the art. For example, PD-L1 expression can be detected using PD-L1 IHC 22C3 pharmDx, the FDA-approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Bristol -Meyers Squibb as a companion test for treatment with pembrolizumab (KEYTRUDA®). This is a qualitative assay using Monoclonal Mouse Anti-PD-Ll, Clone 22C3 PD-L1 and the EnVision FLEX visualization system on the Autostainer Link 48 platform to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue. Expression levels can be measured using the Combined Positive Score (CPS). This scoring method evaluates the number of PD-Ll-staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells. CPS is used to assess PD-L1 expression in: metastatic or unresectable, recurrent HNSCC, advanced esophageal or GEJ carcinoma, metastatic urothelial cancer (mUC), colorectal cancer, advanced cervical cancer and advanced triple-negative breast cancer. Expression levels can be measured using the tumor proportion score (TPS), which measures the percentage of viable tumor cells showing partial or complete membrane staining. Staining can show PD-L1 expression from 1% to 100%. TPS is used to assess PD-L1 expression in advanced NSCLC, metastatic urothelial cancer (mUC), colorectal cancer and other solid tumors.
PD-L1 expression can also be detected using PD-L1 IHC 28-8 pharmDx, the FDA- approved in vitro diagnostic immunohistochemistry (IHC) test developed by Dako and Merck as a companion test for treatment with nivolumab (OPDIVO®). This qualitative assay uses the Monoclonal rabbit anti-PD-Ll, Clone 28-8 and the EnVision FLEX visualization system on the Autostainer Link 48 platform to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human cancer tissue. PD-L1 protein expression results are reported as a percentage of viable tumor cells showing any level of membrane staining (%TC). %TC is used to assess PD-L1 expression in advanced non-squamous NSCLC, colorectal cancer (CRC), metastatic urothelial carcinoma (mUC), and other solid tumors such as cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma and esophageal cancer. .
Other commercially available tests for PD-L1 detection include the Ventana SP263 assay (developed by Ventana in collaboration with AstraZeneca) that utilizes monoclonal rabbit anti- PD-Ll, Clone SP263 and the Ventana SP142 Assay (developed by Ventana in collaboration with Genentech/Roche) that uses rabbit monoclonal anti-PD-Ll clone SP142. VENTANA PD-L1 (SP263) Assay is a qualitative immunohistochemical assay using rabbit monoclonal anti-PD-Ll clone SP263 intended for use in the assessment of the PD-L1 protein in formalin-fixed, paraffin- embedded (FFPE) urothelial carcinoma tissue stained with the OptiView DAB IHC Detection Kit on a VENTANA BenchMark ULTRA instrument. PD-L1 status is determined by the percentage of tumor cells with any membrane staining above background (%TC) or by the percentage of tumor-associated immune cells with staining (IC%) at any intensity above background. The percent of tumor area occupied by any tumor-associated immune cells (Immune Cells Present, ICP) is used to determine IC%, which is the percent area of ICP exhibiting PD-L1 positive immune cell staining. PD-L1 status is considered High if any of the following are met: > 25% of tumor cells exhibit membrane staining; or, ICP > 1% and IC% > 25%; or, ICP = 1% and IC+ = 100%. The VENTANA PD-L1 (SP142) Assay is a qualitative immunohistochemical assay using rabbit monoclonal anti-PD-Ll clone SP142 intended for use in the assessment of the programmed deathligand 1 (PD-L1) protein in tumor cells and tumor-infiltrating immune cells in the formalin-fixed, paraffin-embedded (FFPE) tissues including metastatic urothelial carcinoma (mUC), triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) stained with the OptiView DAB IHC Detection Kit and the OptiView Amplification Kit on a BenchMark ULTRA instrument. Results are used to determine the viability of treating with TECENTRIQ® (Roche/Genentech). Determination of PD-L1 status is indication-specific, and evaluation is based on either the proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (% IC) of any intensity or the percentage of PD-L1 expressing tumor cells (% TC) of any intensity. The cutoff for mUC is >5% IC, the cutoff for TNBC is >1% IC and the cutoff for NSCLC is >50% TC or 10% IC.
In some embodiments, the NSCLC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive NSCLC. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive NSCLC of >10% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status NSCLC with >25% PD-L1 staining of tumor cells as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status NSCLC with >1% PD-L1 staining of tumor cells (TC) as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status negative NSCLC. In some embodiments, the TNBC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive TNBC. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive TNBC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) or >1% of PD-L1 staining tumor-infiltrating immune cells (IC). as confirmed by an in vitro diagnostic (IVD) assay, for example, the Dako PD-L1-22C3 pharmDx kit or the Ventana SP-142 assay or another suitable assay. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status TNBC with >10% PD-L1 staining of tumor cells as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In an alternative embodiment, the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status TNBC with >1% PD-L1 staining of immune cells as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative TNBC.
In some embodiments, the colorectal cancer (CRC) patient being treated in the first-line or second-line therapeutic protocol described herein has a documented tumor shown by an FDA- approved or CE Mark test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In some embodiments, the CRC patient being treated in the first-line or second-line therapeutic protocol described herein has a documented PD-L1 status positive CRC. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive CRC of >1% PD-L1 staining tumor-infiltrating immune cells (IC) or >1% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status CRC with >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS)as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status CRC with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status CRC with >1% PD-L1 staining of tumor cells (TC) as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status negative CRC.
In some embodiments, the mUC patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive mUC of >5% PD-L1 staining tumor-infiltrating immune cells (IC) or >50% of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP- 142 assay or other suitable assay. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >25% PD-L1 staining of tumor cells (TC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or other suitable assay. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >5% PD-L1 staining of immune cells (IC) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-142 assay or other suitable assay. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of tumor cells (%TC) as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second- line therapeutic protocol has a documented PD-L1 status mUC with >1% PD-L1 staining of immune cells (%IC) as determined by an FDA-approved or CE Mark test. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status positive mUC of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as confirmed by an in vitro diagnostic (IVD) assay, for example, the Ventana SP-263 assay or another suitable assay. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status mUC with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test. In an alternative embodiment, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD- L1 status negative mUC.
In some embodiments, the solid tumor patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive squamous cell carcinoma of the head and neck (SCCHN) of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS). In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive cervical cancer of >1% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA- approved or CE Mark test. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status positive esophageal cancer of >10% PD-L1 staining cells (tumor cells, lymphocytes, macrophages) relative to all viable tumor cells (CPS) as determined by an FDA-approved or CE Mark test. In some embodiments, the patient being treated in the first-line or second-line therapeutic protocol has a documented PD-L1 status gastroesophageal junction cancer with >1% viable tumor cells showing partial or complete membrane staining (TPS) at any intensity as determined by an FDA-approved or CE Mark test.
CDK4/6 Status
As provided herein, the NSCLC, TNBC, CRC, mUC, or another solid tumor to be treated is CDK4/6 -negative. In alternative embodiments, the NSCLC, TNBC, CRC, mUC or another solid tumor to be treated is CDK4/6-positive. In still other alternative embodiments, the NSCLC, TNBC, CRC, mUC or another solid tumor is CDK4/6 indeterminate. CDK4/6 replication independent cancers generally have a retinoblastoma gene (Rbl) aberration. The gene product of Rbl — Rb-protein — is a downstream target of CDK4/6. RBI is commonly dysregulated in cancer cells through deletion, mutation or epigenetic modification resulting in loss of RB expression, as well as by aberrant CDK kinase activity leading to excessive phosphorylation and inactivation of RB function (Chen et al. Novel RBI -Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types. Clin Cancer Res. 2019; 25(14); Sherr, C.J., and McCormick, F. The RB and p53 pathways in cancer. Cancer Cell, 2002; 2: 103 12.). CCNE1/2 (cyclin E) is part of a parallel pathway that provides functional redundancy with CDK4/6 and helps to transition cells from the G1 to S phase. Overexpression will decrease the reliance on the CDK4/6 pathway leading to CDK4/6 independence (Turner et al., Cyclin El Expression and Palbociclib Efficacy in Previously Treated Hormone Receptor-Positive Metastatic Breast Cancer. J Clin Oncol. 2019; 37(14): 1169-78.). Therefore, a tumor with either CCNE1/2 amplification or RB loss will generally be considered “CDK4/6 independent”.
Cancers that are CDK4/6 replication dependent require the activity of CDK4/6 for replication or proliferation. CDK 4/6 replication dependent TNBCs generally have an intact and functional Rb pathway and/ increased expression of CDK4/6 activators (cyclin D), and/or a d-type cyclin activating features (DCAF) — including CCND1 translocation, CCND1-3 3’UTR loss, and amplification of CCND2 or CCND3 (see Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6): 761-76). Tumors that are wildtype for RB and CCNE1/2 as well as have one of the DCAF described above are generally classified as “CDK4/6 dependent”.
Tumors that cannot be classified as either CDK4/6-replication dependent or CDK4/6- replication independent are generally classified as “CDK4/6 indeterminate” since they cannot be confirmed as CDK4/6 dependent or independent.
In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication dependent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6-replication independent. In some embodiments, the NSCLC, TNBC, CRC, mUC or other solid tumor is classified as CDK4/6 indeterminate.
Methods of determining CDK4/6 genetic signature analysis are known in the art and involve the utilization of tumor tissue collected from a patients’ biopsy (NSCLC, TNBC, CRC, mUC or another solid tumor primary or metastatic site) and are described in Shapiro GI. Genomic biomarkers predicting response to selective CDK4/6 inhibition: Progress in an elusive search. Cancer Cell. 2017; 32(6): 721-3 and Gong et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK5 inhibitor abemaciclib. Cancer Cell. 2017; 32(6): 761-76.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation (CD) 73 inhibitor has a CDK4/6 independent NSCLC having at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 dependent NSCLC which does not have 1) at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
2) does have a) wild type: i) CCNE1; ii) CCNE2; and iii) RBI; and
3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 independent TNBC having at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rbl) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 dependent TNBC which does not have 1) at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
2) does have a) wild type: i) CCNE1; ii) CCNE2; and iii) RBI; and
3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 independent CRC having at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rbl) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 dependent CRC which does not have
1) at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
2) does have a wild type: i) CCNE1; ii) CCNE2; and iii) RBI; and
3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 independent mUC having at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rbl) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)).
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 dependent mUC which does not have
1) at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
2) does have a wild type: i) CCNE1; ii) CCNE2; and iii) RBI; and
3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 independent solid tumor having at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rbl) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained)). In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the patient receiving trilaciclib in a specifically timed therapeutic protocol with an effective amount of a PD-1 or PD-L1 checkpoint inhibitor, and an effective amount of an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITEM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM- 3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor, has a CDK4/6 dependent solid tumor which does not have
1) at least one of the following: a. a CCNE1 amplification; b. a CCNE2 amplification; or c. a Retinoblastoma protein 1 (Rb 1) loss, which is defined as i) homozygous deletion, ii) a frameshift mutation, or iii) a stop-gained mutation (i.e., a mutation that results in a premature termination codon (a stop codon was gained));
2) does have a wild type: i) CCNE1; ii) CCNE2; and iii) RBI; and
3) has at least one of the following D-cyclin activating features: i) CCND2 amplification; ii) CCND3 amplification; and iii) CCD 1-3 3’ UTR loss defined as a homozygous or heterozygous deletion of any of these UTRs.
In some aspects, an effective amount of a chemotherapeutic agent is also administered as part of the therapeutic protocol.
In some embodiments, the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 independent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer. In some embodiments, the solid tumor patient being treated in a specifically timed protocol has a documented CDK4/6 dependent solid tumor selected from the group consisting of cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal cancer.
Prior Exposure to Immune Checkpoint Inhibitor Treatment
In certain aspects of the present invention, provided herein are methods of treating patients with advanced/metastatic non-small cell lung cancer (NSCLC), advanced/metastatic triple negative breast cancer (TNBC), advanced/metastatic and unresectable colorectal cancer (CRC), advanced/metastatic urothelial carcinoma (mUC), or an advanced/metastatic other solid tumor, for example, squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer (GEJ), an esophageal adenocarcinoma, or an esophageal cancer who have prior exposure to an immune checkpoint inhibitor, for example a programmed cell death protein- 1 (PD- 1) and/or programmed death-ligand- 1 (PD-L1) inhibitor, either as monotherapy in the first-line treatment setting or in combination with a first line chemotherapeutic regimen in the case of NSCLC and TNBC or alternatively in a first-line chemotherapeutic setting in the case of CRC, mUC and other solid tumors, and who have developed therapeutic resistance to the immune checkpoint inhibitor leading to disease progression after an initial response. By administering the short acting, selective, and reversible cyclin dependent kinase (CDK) 4/6 inhibitor trilaciclib in a therapeutic protocol that includes the administration of a PD-1 or PD-L1 inhibitor and further includes the administration of an additional ICI selected from a TIGIT inhibitor, TIM-3 inhibitor, LAG-3 inhibitor or CD73 inhibitor either with or without chemotherapy, mechanisms of immune checkpoint inhibitor resistance resulting in the dysregulation of cytotoxic T-cell activity within the tumor microenvironment (TME) can be overcome, increasing the limited treatment options these patients have in the second-line and third-line setting, and increasing overall survival in a subset of difficult to treat patients.
Example of immune checkpoint inhibitors and immune modulating agents include, but are not limited to, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, CD73 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, TIGIT inhibitor, Siglec-15 inhibitor, B7-H3 (CD272) inhibitor, BTLA inhibitor (CD272), small molecule, peptide, nucleotide, or another inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody.
In some embodiments, the patient has previously been administered a PD-1 inhibitor. PD- 1 inhibitors for use in the methods described herein include, for example, but are not limited to, nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®), pidilizumab (Medivation), AMP -224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IBI308; Innovent/Eli Lilly), sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012; Incyte Corporation and MacroGenics), tislelizumab (BGB-A317; BeiGene), toripalimab (JS001), camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone Pharmaceuticals), zimberelimab (AB122; Arcus Biosciences) and JTX-4014 (Jounce Therapeutics).
In some embodiments, the patient has previously been administered a PD-L1 inhibitor. PD-L1 inhibitors for use in the methods described herein include, for example, but are not limited to, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK- 301; Checkpoint Therapeutics), sugemalimab (CS-1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curis) and BGB-A333 (BeiGene).
In some embodiments, the patient has previously been administered a dual PD-L1/PD-1 inhibitor. In some embodiments, the patient has previously been administered a PD-L1/VISTA inhibitor. PD-L1-VISTA inhibitors include, but are not limited to, CA-170 (Curis Inc.). In some embodiments, the immune checkpoint inhibitor is a VISTA immune checkpoint inhibitor. VISTA inhibitors include, but are not limited to, JNJ-61610588 (Johnson & Johnson).
In some embodiments, the patient has previously been administered a CTLA-4 immune checkpoint inhibitor. CTLA-4 inhibitors include, but are not limited to, ipilimumab (YERVOY®, Bristol Myers Squibb); tremelimumab (AstraZeneca/Medlmmune), zalifrelimab (AGEN1884; Agenus) and AGEN2041 (Agenus).
In some embodiments, the patient has previously been administered a LAG-3 immune checkpoint inhibitor. LAG-3 inhibitors for use in the methods described herein include, for example, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In some embodiments, the patient has previously been administered a TIM-3 immune checkpoint inhibitor. TIM-3 inhibitors for use in the methods described herein include, for example, but are not limited to, Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In some embodiments, the patient has previously been administered a TIGIT (T cell immunoreceptor with Ig and ITIM domains) immune checkpoint inhibitor. TIGIT (T cell immunoreceptor with Ig and ITIM domains) inhibitors for use in the methods described herein include, for example, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab /OMP- 313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR- 1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals); NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech), the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In some embodiments, the patient has previously been administered a CD73 (Ecto- 5 'nucleotidase; (NT5E) checkpoint inhibitor. CD73 checkpoint inhibitor for use in the methods described herein include, for example, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT 199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti-CD73-TGFP- Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
In some embodiments, the patient has previously been administered an immune checkpoint inhibitor including, for example, but not limited to, a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 13 lI-8H9/omburtamab (Y-mabs), and I-8H9/omburtamab (Y-mabs), an indoleamine 2,3-dioxygenase (IDO) immune checkpoint inhibitor such as Indoximod and INCB024360, a killer immunoglobulin-like receptors (KIRs) immune checkpoint inhibitor such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and/or -5). Exemplary anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/joumal. pone.0021146), or crossreacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
In some embodiments, the patient has previously been administered an immune checkpoint inhibitor directed to CD47, including, but not limited to, Hu5F9-G4 (Stanford University/Forty Seven), TI-061 (Arch Oncology), TTI-622 (Trillum Therapeutics), TTI-621 (Trillum Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), OSE-172 (Boehringer Ingelheim/OSE Immunotherapeutics), NI-1701 (Novimmune TG Therapeutics), IBI188 (Innovent Biologies); CC-95251 (Celgene), CC-90002 (Celgene/Inibrx), AO- 176 (Arch Oncology), ALX148 (ALX Oncology), IMM01 (ImmuneOnco Biopharma), IMM2504 (ImmuneOnco Biopharma), IMM2502 (ImmuneOnco Biopharma), IMM03 (ImmuneOnco Biopharma), IMC-002 (ImmuneOncia Therapeutics), IBI322 (Innovent Biologies), HMBD-004B (Hummingbird Bioscience), HMBD-004A (Hummingbird Bioscience), HLX24 (Henlius), FSI-189 (Forty Seven), DSP107 (KAHR Medical), CTX-5861 (Compass Therapeutics), BAT6004 (Bio-Thera), AUR-105 (Aurigene), AUR-104 (Aurigene), ANTI-CD47 (Biocad), ABP-500 (Abpro), ABP-160 (Abpro), TJC4 (I-MAB Biopharma), TJC4-CK (I-MAB Biopharma), SY102 (Saiyuan), SL- 172154 (Shattuck Labs), PSTx-23 (Paradigm Shift Therapeutics), PDL1/ CD47BsAb (Hanmi Pharmaceuticals), NI-1801 (Novimmune), MBT-001 (Morphiex), LYN00301 (LynkCell), and BH-29xx (Beijing Hanmi).
In some embodiments, the patient has previously been administered an immune checkpoint inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
In some embodiments, the patient has previously been administered an immune checkpoint inhibitor directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87, and TAB004/JS004 (Junshi Biosciences).
In some embodiments, the patient has previously been administered a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
Improved Treatment Regimens
As contemplated herein, the administration of the short acting, selective, and reversible cyclin dependent kinase (CDK) 4/6 inhibitor trilaciclib, or a pharmaceutically acceptable salt thereof, in a specifically timed therapeutic protocol with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitor or a CD73 inhibitor. In some aspects, a chemotherapeutic agent is also administered as part of the therapeutic protocol. In certain embodiments, the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD-L1 inhibitor and an additional ICI as described herein increases the efficacy of immune checkpoint inhibition, including overcoming the development of resistance to previously administered PD-1 or PD-L1 inhibitors and/or reducing or delaying the onset of resistance, resulting in the extended efficacy of the anti -cancer protocol. In certain embodiments, the administration of the selective CDK4/6 inhibitor trilaciclib in conjunction with a PD-1 or PD- L1 inhibitor and an additional ICI as described herein provides for improved survival outcomes, including overall survival (OS) and/or progression free survival (PFS) and reduced or delayed resistance to ICI therapy for these difficult to treat patients. Particular cancers susceptible to treatment with the methods of the present invention include, but are not limited to, non-small cell lung cancer (NSCLC), advanced/metastatic triple negative breast cancer (TNBC), advanced/metastatic and unresectable colorectal cancer (CRC), advanced/metastatic urothelial carcinoma (mUC) as well as other solid tumors that include, but are not limited to, cervical cancer, squamous cell carcinoma of the head and neck (SCCHN), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma, basal cell carcinoma, small cell lung cancer (SCLC), melanoma, malignant pleural mesothelioma, renal cell carcinoma, hepatocellular carcinoma, microsatellite instability-high or mismatch repair deficient cancer, endometrial carcinoma, tumor mutational burden-high (TMB-H) cancer, gastric cancer, gastroesophageal junction cancer, esophageal adenocarcinoma and esophageal cancer. .
Trilaciclib
Trilaciclib (2'-((5-(4-methylpiperazin-l-yl) pyridin-2-yl) amino)-7',8'-dihydro-6'H-spiro (cyclohexane- l,9'-pyrazino (l',2':l,5) pyrrolo(2,3-d) pyrimidin)-6'-one) is a highly selective
CDK4/6 inhibitor having the structure:
Figure imgf000079_0001
As provided herein, trilaciclib or its pharmaceutically acceptable salt, composition, isotopic analog, or prodrug thereof is administered in a suitable carrier. Trilaciclib is available commercially as COSELA® (G1 Therapeutics, Inc.). Trilaciclib is described in US 2013-0237544, incorporated herein by reference in its entirety. Trilaciclib can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety. Trilaciclib can be administered in any manner that achieves the desired outcome, including systemically, parenterally, intravenously, intramuscularly, subcutaneously, or intradermally. For injection, trilaciclib may be provided, in some embodiments, for example, as a 300 mg/vial as a sterile, lyophilized, yellow cake providing 300 mg of trilaciclib (equivalent to 349 mg of trilaciclib dihydrochloride, dihydrate). The product, for example, may be supplied in single-use 20-mL clear glass vials which does not contain a preservative. For example, prior to administration, trilaciclib for injection, 300 mg/vial may be reconstituted with 19.5 ml of 0.9% sodium chloride injection or 5% dextrose injection. This reconstituted solution has a trilaciclib concentration of 15 mg/mL and would typically be subsequently diluted prior to intravenous administration. Trilaciclib can be administered intravenously as described herein. In certain embodiments, trilaciclib is in the form of a dihydrochloride optionally as a hydrate. For example, trilaciclib can be used in the present invention as a dihydrochloride, dihydrate or as a pharmaceutical composition formed from trilaciclib dihydrochloride, dihydrate. In some embodiments, trilaciclib is administered at between about 180 mg/m2 and 300 mg/m2. In some embodiments, trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or about 280 mg/m2. In some embodiments, trilaciclib is administered at least 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, or 240 mg/m2. In some embodiments, trilaciclib is administered at about 240 mg/m2, prior to administration of the chemotherapeutic agent prior to about 4 hours or less, for example about 4 hours or less, 3 hours or less, 2 hours or less, about 1 hour or less, or about 30 minutes prior to administration of the chemotherapeutic, or first chemotherapeutic to be administered in a combination protocol, respectively. In some embodiments, trilaciclib is administered intravenously over a period of about 30 minutes. In some embodiments, trilaciclib is completely administered prior to administration.
In an alternative embodiment, a different CDK4/6 inhibitor is administered. For example, in alternative embodiments, the CDK4/6 inhibitor used instead of trilaciclib in the protocols described herein is ribociclib (Novartis), palbociclib (Pfizer), or abemaciclib (Eli Lilly), or a pharmaceutically acceptable salt thereof. In an additional alternative embodiment, the CDK4/6 inhibitor is lerociclib, which has the structure:
Figure imgf000080_0001
or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety. In some embodiments, lerociclib is administered as a pharmaceutically acceptable salt, for example, the dihydrocloride salt.
In an additional alternative embodiment, the CDK4/6 inhibitor has the structure:
Figure imgf000081_0001
or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, which is described in US 2013-0237544, incorporated herein by reference in its entirety, and can be synthesized as described in US 2019-0135820, incorporated herein by reference in its entirety.
In an alternative embodiment, a CDK4/6 inhibitor selected from Palbociclib, ribociclib, or abemaciclib is used instead of trilaciclib.
PD-1 inhibitors
In one embodiment, the first immune checkpoint inhibitor is a PD-1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibits immune suppression. In one embodiment, the immune checkpoint inhibitor is a PD-1 immune checkpoint inhibitor selected from nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®; Regeneron), dostarlimab (JEMPERLI®), pidilizumab (Medivation), AMP -224 (AstraZeneca/Medimmune), AMP-514 (AstraZeneca), sintilimab (IB 1308; Innovent/Eli Lilly) sasanlimab (PF-06801591; Pfizer), spartalizumab (PDR001; Novartis), retifanlimab (MGA012/INCMGA00012); Incyte Corporation and MacroGenics), tislelizumab (BGB-A317; BeiGene), toripalimab (JS001), camrelizumab (SHR-1210; Jiangsu Hengrui Medicine Company and Incyte Corporation), CS1003 (Cstone Pharmaceuticals), zimberelimab (AB122; Arcus Biosciences) and JTX-4014 (Jounce Therapeutics).
In one embodiment, the PD-1 inhibitor is nivolumab (OPDIVO®) administered in an effective amount for the treatment of unresectable or metastatic melanoma, early-stage and metastatic non-small cell lung cancer (NSCLC), intermediate or poor risk advanced renal cell carcinoma (RCC), relapsed or progressed classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), locally advanced or metastatic urothelial carcinoma (mUC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), hepatocellular carcinoma, unresectable malignant pleural mesothelioma, adjuvant or metastatic esophageal carcinoma, gastroesophageal junction (GEJ) cancer and gastric cancer. In one embodiment, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks for NSCLC, CRC and mUC. In one embodiment, nivolumab is administered prior to chemotherapy.
In some embodiments, the PD-1 inhibitor is pembrolizumab (KEYTRUDA®) administered in an effective amount for the treatment of unresectable or metastatic melanoma, metastatic nonsmall cell lung cancer (NSCLC), , intermediate or high-risk advanced renal cell carcinoma (RCC), relapsed or refractory classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), locally advanced or metastatic urothelial carcinoma (mUC), tumor mutational burden-High (TMB-H) cancer, locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC), recurrent or metastatic cutaneous squamous cell carcinoma (cSCC), microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC), hepatocellular carcinoma, adjuvant or metastatic esophageal carcinoma, gastroesophageal junction (GEJ) cancer, advanced endometrial carcinoma, recurrent locally advanced or metastatic Merkel cell carcinoma, locally advanced unresectable or metastatic gastric cancer, recurrent or metastatic cervical cancer, or Primary Mediastinal Large B-Cell Lymphoma (PMBCL). In one embodiment, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks for NSCLC, TNBC, CRC and mUC. In one embodiment, pembrolizumab is administered prior to chemotherapy.
In one embodiment, the PD-1 inhibitor is cemiplimab (LIBTAYO®) administered in an effective amount for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC), locally advanced or metastatic non-small cell lung cancer (NSCLC), locally advanced or metastatic basal cell carcinoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC). In one embodiment, cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression. In one embodiment, cemiplimab is administered prior to chemotherapy.
In one embodiment, the PD-1 inhibitor is dostarlimab (JEMPERLI®) administered in an effective amount for the treatment of mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, solid tumors that have progressed with no alternative treatment options, metastatic non-small cell lung cancer (NSCLC), metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC). In one embodiment, dostarlimab is administered at 500 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression. In one embodiment, dostarlimab is administered prior to chemotherapy.
PD-L1 inhibitors
In one embodiment, the first immune checkpoint inhibitor is a PD-L1 inhibitor that blocks the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression. PD-L1 inhibitors include, atezolizumab (TECENTRIQ®, Genentech), durvalumab (IMFINZI®, AstraZeneca); avelumab (BAVENCIO®; Merck), envafolimab (KN035; Alphamab), BMS-936559 (Bristol-Myers Squibb), BMS-986189 (Bristol-Myers Squibb), lodapolimab (LY3300054; Eli Lilly), cosibelimab (CK-301; Checkpoint Therapeutics), sugemalimab (CS- 1001; Cstone Pharmaceuticals), adebrelimab (SHR-1316; Jiangsu HengRui Medicine), CBT-502 (CBT Pharma), AUNP12 (Aurigene), CA-170 (Aurigene/Curis) and BGB-A333 (BeiGene).
In one embodiment, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor atezolizumab (TECENTRIQ®) administered in an effective amount for the treatment of locally advanced or metastatic urothelial carcinoma (mUC), unresectable or metastatic melanoma, metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC), metastatic non-small cell lung cancer (NSCLC), unresectable or metastatic hepatocellular carcinoma or metastatic small cell lung cancer (SCLC). In one embodiment, atezolizumab is administered at 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. In one embodiment, atezolizumab is administered prior to chemotherapy.
In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor durvalumab (IMFINZI®) administered in an effective amount for the treatment of non-small cell lung cancer (NSCLC), extensive-stage small cell lung cancer (SCLC), metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC). In one embodiment, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients who weigh less than 30 kg. In one embodiment, durvalumab is administered prior to chemotherapy.
In another aspect of this embodiment, the immune checkpoint inhibitor is the PD-L1 immune checkpoint inhibitor avelumab (BAVENCIO®) administered in an effective amount for the treatment of Merkel cell carcinoma, metastatic urothelial carcinoma (mUC), renal cell carcinoma (RCC), metastatic triple-negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial carcinoma (mUC). In one embodiment, avelumab is administered at 800 mg every 2 weeks. In one embodiment, avelumab is administered prior to chemotherapy.
T cell immunoreceptor with immunoglobulin and HIM domain (TIGIT) Inhibitors
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a promising new target for cancer immunotherapy. TIGIT is upregulated by immune cells, including activated T cells, natural killer cells, and regulatory T cells. TIGIT binds to two ligands, CD155 (PVR) and CD112 (PVRL2, nectin-2), that are expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (Stanietsky et al., The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A 2009; 106: 17858-63).
TIGIT (also called WUCAM, Vstm3, VSIG9) is a receptor of the Ig superfamily, which plays a critical role in limiting adaptive and innate immunity (Boles et al., A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol 2009; 39:695-703). TIGIT participates in a complex regulatory network involving multiple inhibitory receptors (e.g., CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (e.g., CD155 (PVR/NECL-5), CD112 (Nectin- 2/PVRL2) (Levin et al., Vstm3 is a member of the CD28 family and an important modulator of T- cell function. Eur J Immunol 2011; 41 : 902-15; Bottino et al., Identification of PVR (CD155) and nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003; 198: 557-67; Seth et al., The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1. Biochem Biophys Res Commun 2007; 364: 959-65; Zhu et al., Identification of CD112R as a novel checkpoint for human T cells. J Exp Med 2016; 213: 167- 76).
TIGIT is expressed by activated CD8+ T and CD4+ T cells, natural killer (NK) cells, regulatory T cells (Tregs), and follicular T helper cells in humans (Joller et al., Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 2011; 186: 1338-42; Wu et al., Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. Eur J Immunol 2016; 46: 1152-61). In sharp contrast with DNAM-1/CD226, TIGIT is weakly expressed by naive T cells. In cancer, TIGIT is co-expressed with PD-1 on tumor antigen-specific CD8+ T cells and CD8+ tumor-infiltrating lymphocytes (TILs) in mice and humans (Chauvin et al., TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015; 125: 2046-58; Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26 :923-37). It is also co-expressed with other inhibitory receptors, such as T cell immunoglobulin and mucin domaincontaining molecule-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3), on exhausted CD8+ T cell subsets in tumors (Chauvin et al., TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest 2015; 125: 2046-58; Johnston et al., The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 2014; 26 :923-37). Further, TIGIT is highly expressed by Tregs in peripheral blood mononuclear cells of healthy donors and patients with cancer and further upregulated in the TME (Joller et al., Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Thl and Thl7 cell responses. Immunity 2014; 40: 569-81; Zhang et al., Genome-Wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 2013; 122: 2823-36).
In one embodiment, the additional immune checkpoint inhibitor is a TIGIT inhibitor that blocks the interaction of TIGIT and CD 155 by binding to the TIGIT receptor, and in turn inhibits immune suppression. TIGIT inhibitors include, but are not limited to, Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB-154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech), the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression. In one embodiment, the TIGIT inhibitor blocks the interaction between TIGIT and CD155 to inhibit immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-1 or PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIGIT inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression. In one embodiment, the TIGIT inhibitor blocks the interaction between TIGIT and CD 155 to inhibit immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIGIT inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIGIT inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIGIT inhibitor is used without chemotherapy.
T-cell immunoglobulin and mucin domain 3 (TIMS) inhibitors
T-cell immunoglobulin and mucin domain 3 (TIM-3) (encoded by Haver ) is an immunoglobulin (Ig) and mucin domain-containing cell surface molecule that was originally discovered as a cell surface marker specific to interferon (IFN-y) producing CD4+ T helper 1 (Thl) and CD8+ T cytotoxic 1 (Tel) cell (Monney et al., Thl-specific cell surface protein TIM-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002; 415: 536- 41). Tim-3 is coregulated and co-expressed along with other immune checkpoint receptors (PD- 1, Lag-3, and TIGIT) on CD4+ and CD8+ T cells (Chihara et al., Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 2018; 558: 454-9; DeLong et al., 11-27 and TCR stimulation promote T cell expression of multiple inhibitory receptors. Immuno Horizons 2019; 3: 13-25). In cancer, TIM-3 expression specifically marks the most dysfunctional or terminally exhausted subset of CD8+ T cells (Fourcade et al., Upregulation of TIM-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 2010; 207: 2175-86; Sakuishi et al., Targeting TIM-3 and PD-1 pathways to reverse T cell exhaustion and restore anti -tumor immunity. J Exp Med 2010; 207: 2187-94). Four ligands for TIM-3 have been identified: galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and CEACAM-1.
In one embodiment, the additional immune checkpoint inhibitor is a TIM-3 inhibitor that blocks the interaction of TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 by binding to the TIM-3 receptor, and in turn inhibits immune suppression. TIM-3 inhibitors include, but are not limited to, Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS-986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the TIM-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression. In one embodiment, the TIM- 3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-1 inhibitor and the TIM-3 inhibitor is used without chemotherapy.
In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the TIM-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression. In one embodiment, the TIM-3 inhibitor blocks the interaction between TIM-3 and galectin-9, phosphatidylserine (PtdSer), high-mobility group protein Bl (HMGB1), and/or CEACAM-1 to inhibit immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, TIM-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and TIM-3 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-L1 inhibitor and the TIM-3 inhibitor is used without chemotherapy. Lymphocyte activation gene-3 (LAG-3) inhibitors
LAG-3 (CD223) is encoded by the LAG-3 gene. LAG-3 is a member of the immunoglobulin superfamily (IgSF) and exerts a wide variety of biologic impacts on T cell function (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 : 1393-405). LAG-3 is expressed on cell membranes of natural killer cells (NK), B cells, tumor-infiltrating lymphocytes (TIL), a subset of T cells, and dendritic cells (DC) (Triebel et al., LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990; 171 : 1393-405); Kisielow et al., Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005; 35: 2081-8; Grosso et al., LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 2007; 117: 3383-92; Workman et al., LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol 2009; 182: 1885-91; Andreae et al., Maturation and activation of dendritic cells induced by lymphocyte activation gene-3 (CD223). J Immunol 2002; 168: 3874-80). The LAG-3 protein binds a nonholomorphic region of major histocompatibility complex 2 (MHC class II) with greater affinity than CD 4 (Baixeras et al., Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J Exp Med 1992; 176: 327- 37). LAG-3 is one of the various immune-checkpoint receptors that are coordinately upregulated on both regulatory T cells (Tregs) and anergic T cells, and the simultaneous blockade of these receptors can result in an enhanced reversal of this anergic state relative to the blockade of one receptor alone (Grosso et al., Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 2009; 182: 6659-69). The LAG-3/MHC class II molecule interaction leads to the downregulation of CD4+ Ag-specific T cell clone proliferation and cytokine secretion (Huard et al., T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding. Eur J Immunol 1996; 26: 1180-6).
In one embodiment, the additional immune checkpoint inhibitor is a LAG-3 inhibitor that blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression. LAG-3 inhibitors include, but are not limited to, relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK-4280; Merck), fianlimab (REGN3767; Regeneron), TSR- 033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen, LBL-007 (Nanjing Leads Biolabs Co., Ltd), IBI110 (Innovent Biologies), IBI323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the LAG-3 inhibitor is relatlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD- L1 to inhibit immune suppression. In one embodiment, the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the LAG-3 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD-L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the LAG-3 inhibitor is relatlimab. In one embodiment, the PD- L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression. In one embodiment, the LAG-3 inhibitor blocks the interaction of LAG-3 with major histocompatibility complex 2 (MHC class II) by binding to the LAG-3 receptor, and in turn inhibits immune suppression. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, LAG-3 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and LAG-3 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-L1 inhibitor and the LAG-3 inhibitor is used without chemotherapy.
Ecto-5'nucleotidase; Cluster of differentiation 73 (NT5E; CD73) inhibitors
5 '-nucleotidase (5 '-NT), also known as ecto-5 '-nucleotidase or CD73 (cluster of differentiation 73), is an enzyme that in humans is encoded by the NT5E gene (Misumi Yet al., (August 1990). "Primary structure of human placental 5'-nucleotidase and identification of the glycolipid anchor in the mature form". European Journal of Biochemistry. 191 (3): 563-9). CD73 commonly serves to convert AMP to adenosine (Allard et al., "Chapter Fifteen - Measurement of CD73 enzymatic activity using luminescence-based and colorimetric assays", Methods in Enzymology, Tumor Immunology and Immunotherapy - Molecular Methods, Academic Press, 629: 269-289). CD73 is a membrane-bound extracellular enzyme overexpressed in several types of cancer. Its expression has been linked to poor prognosis in melanoma, colorectal, gastric, triple negative breast cancer, and to a pro-metastatic phenotype in prostate cancer (Stagg J et al., CD73- deficient mice are resistant to carcinogenesis. Cancer Res. 2012 May 1 ;72(9):2190-6). Together with CD39, it plays a major role in promoting immunosuppression through the pathway degrading adenosine triphosphate (ATP) into adenosine. Within the tumor microenvironment, ATP promotes the immune cell-mediated killing of cancer cells. In contrast, adenosine accumulation causes immune suppression, dysregulation of immune cell infiltrates and stimulates angiogenesis, resulting in tumor spreading. CD73 is active on the last step of the degradation pathway, where it is the enzyme that degrades AMP into adenosine. The CD73 blockade promotes anti-tumor immunity by reducing adenosine accumulation. Accordingly, anti-CD73 mAbs stimulate antitumor immunity and reduce tumor metastasis in mouse tumor models and could enhance the efficacy of treatment with anti-PDl or anti-CTLA4 antibodies (Allard et al., Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res. 2013 Oct 15; 19(20):5626-35). Figure 19 shows a visual depiction of the effect of adenosinergic molecules on the tumor and surrounding stroma (Vijay an D et al., Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017 Dec;17(12):709-724). Adenosine is a well-described immunosuppressive agent which attenuates the effector functions of various immune cell populations, including T cells, and enhances the suppressive functions of T regs. Adenosine accumulation favors tumor growth and metastasis through effects on tumor cells and stroma. For example, activation of CD73 on tumor cells favors cell adhesion potentially through epidermal growth factor receptor (EGFR) signaling (indicated by dashed arrow) and inhibits tumor apoptosis. CD73 activation also releases matrix metalloproteinases (MMPs) that facilitate breakdown of extracellular matrix (ECM), thus enabling tumor cells to invade and migrate to distant organs. In addition, A2BR activation on tumor cells promotes proliferation and angiogenesis through secretion of vascular endothelial growth factor (VEGF). In cancer-associated fibroblasts (CAFs), A2BR induces fibroblast growth factor 2 (FGF2) expression and increases the number of fibroblast activation protein (FAP)-positive fibroblasts. A2BR activation leads to elevated release of CXCL12 by these FAP+ fibroblasts, thus increasing the number of CD31+ endothelial cells within the tumor. A2BR can engage the G protein-coupled receptor Gq-protein kinase C (PKC) signaling pathway to activate interleukin-6 (IL-6), which in turn mediates epithelial-to-mesenchymal transition (EMT). Additionally, some tumor exosomes co-express CD39 and CD73, which might be associated with tumor dissemination to distant organs (Vijayan, D., Young, A., Teng, M. W. L., & Smyth, M. J. (2017). Targeting immunosuppressive adenosine in cancer. Nature Reviews Cancer, 17(12), 709-724).
In one embodiment, the additional immune checkpoint inhibitor is a CD73 inhibitor that specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity. By reducing the production of adenosine, the CD73 inhibitor can relieve the inhibitory effect of adenosine on the proliferation and tumor-killing activity of CD8+ T cells, and weaken the stimulation of adenosine on immunosuppressive cells, so as to modulate the tumor microenvironment and enhance the antitumor immune response. CD73 inhibitors include, but are not limited to, HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, Astra Zeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS- 986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti-CD73-TGFP- Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-1 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-1 inhibitor is nivolumab. In one embodiment, the PD-1 inhibitor is pembrolizumab. In one embodiment, the PD-1 inhibitor is cemiplimab. In one embodiment, the PD-1 inhibitor is dostarlimab. In one embodiment, the PD-1 inhibitor blocks the interaction between PD-1 and PD-L1 to inhibit immune suppression. In one embodiment, the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5'-nucleotidase activity. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-1 inhibitor and the CD73 inhibitor is used without chemotherapy.
In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor and the PD-L1 inhibitor. In one embodiment, the CD73 inhibitor is used in combination with the CDK4/6 inhibitor, the PD-L1 inhibitor and chemotherapy. In one embodiment, the CDK4/6 inhibitor is trilaciclib. In one embodiment, the PD-L1 inhibitor is atezolizumab. In one embodiment, the PD- L1 inhibitor is durvalumab. In one embodiment, the PD-L1 inhibitor is avelumab. In one embodiment, the PD-L1 inhibitor blocks the interaction between PD-L1 and CD80 to inhibit immune suppression. In one embodiment, the CD73 inhibitor specifically binds to CD73 and blocks its extracellular 5 '-nucleotidase activity. In one embodiment, the combination of the CDK4/6 inhibitor, the PD-L1 inhibitor, CD73 inhibitor and chemotherapy results in greater tumor suppression than the combination without the CDK4/6 inhibitor and CD73 inhibitor. In one embodiment, the CDK4/6 inhibitor, the PD-L1 inhibitor and the CD73 inhibitor is used without chemotherapy. Additional Immune Checkpoint Inhibitors
In some embodiments, instead of the patient being administered a TIGIT, LAG-3, TIM-3 or CD73 checkpoint inhibitor, the patient is administered an alternative immune checkpoint inhibitor. In some embodiments, the alternative immune checkpoint inhibitor is a B7-H3/CD276 immune checkpoint inhibitor such as enoblituzumab (MGA217, Macrogenics) MGD009 (Macrogenics), 131I-8H9/omburtamab (Y-mabs), and I-8H9/omburtamab (Y-mabs), an indoleamine 2,3 -dioxygenase (IDO) immune checkpoint inhibitor such as Indoximod and INCB024360, a killer immunoglobulin-like receptors (KIRs) immune checkpoint inhibitor such as Lirilumab (BMS-986015), a carcinoembryonic antigen cell adhesion molecule (CEACAM) inhibitor (e.g., CEACAM-1, -3 and/or -5). Exemplary anti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366 and WO 2014/022332, e.g., a monoclonal antibody 34B 1, 26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US 2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552. In other embodiments, the anti-CEACAM antibody binds to CEACAM-5 as described in, e.g., Zheng et al. PLoS One. 2010 September 2; 5(9). pii: el2529 (DOI: 10: 1371/journal. pone.0021146), or cross-reacts with CEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US 2014/0271618.
In some embodiments, the alternative immune checkpoint inhibitor is an inhibitor directed to CD47, including, but not limited to, Hu5F9-G4 (Stanford University /Forty Seven), TL061 (Arch Oncology), TTI-622 (Trillum Therapeutics), TTI-621 (Trillum Therapeutics), SRF231 (Surface Oncology), SHR-1603 (Hengrui), OSE-172 (Boehringer Ingelheim/OSE Immunotherapeutics), NL1701 (Novimmune TG Therapeutics), IBI188 (Innovent Biologies); CC- 95251 (Celgene), CC-90002 (Celgene/Inibrx), AO-176 (Arch Oncology), ALX148 (ALX Oncology), IMMOl (ImmuneOnco Biopharma), IMM2504 (ImmuneOnco Biopharma), IMM2502 (ImmuneOnco Biopharma), IMM03 (ImmuneOnco Biopharma), IMC-002 (ImmuneOncia Therapeutics), IB 1322 (Innovent Biologies), HMBD-004B (Hummingbird Bioscience), HMBD- 004A (Hummingbird Bioscience), HLX24 (Henlius), FSI-189 (Forty Seven), DSP 107 (KAHR Medical), CTX-5861 (Compass Therapeutics), BAT6004 (Bio-Thera), AUR-105 (Aurigene), AUR-104 (Aurigene), ANTLCD47 (Biocad), ABP-500 (Abpro), ABP-160 (Abpro), TJC4 (I- MAB Biopharma), TJC4-CK (I-MAB Biopharma), SY102 (Saiyuan), SL- 172154 (Shattuck Labs), PSTx-23 (Paradigm Shift Therapeutics), PDL1/ CD47BsAb (Hanmi Pharmaceuticals), NI-1801 (Novimmune), MBT-001 (Morphiex), LYN00301 (LynkCell), and BH-29xx (Beijing Hanmi).
In some embodiments, the alternative immune checkpoint inhibitor is an inhibitor directed to CD39, including, but not limited to TTX-030 (Tizona Therapeutics), IPH5201 (Innate Pharma/AstraZeneca), SRF-617 (Surface Oncology), ES002 (Elpisciences), 9-8B (Igenica), and an antisense oligonucleotide (Secama)
In some embodiments, the alternative immune checkpoint inhibitor is an inhibitor directed to B and T lymphocyte attenuator molecule (BTLA), for example as described in Zhang et al., Monoclonal antibodies to B and T lymphocyte attenuator (BTLA) have no effect on in vitro B cell proliferation and act to inhibit in vitro T cell proliferation when presented in a cis, but not trans, format relative to the activating stimulus, Clin Exp Immunol. 2011 Jan; 163(1): 77-87, and TAB004/JS004 (Junshi Biosciences).
In some embodiments, the alternative immune checkpoint inhibitor is a sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) inhibitor, including, but not limited to, NC318 (an anti- Siglec-15 mAb).
Chemotherapeutic Agents
The administration of trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from TIGIT inhibitor, TIM-3 inhibitor, LAG-3 inhibitor and CD73 inhibitor can be in combination with any standard chemotherapeutic agent treatment modality.
In one embodiment, the chemotherapeutic agent is toxic to immune effector cells. In one embodiment the chemotherapeutic agent inhibits cell growth. In one embodiment, the cytotoxic chemotherapeutic agent administered is a DNA damaging chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a protein synthesis inhibitor, a DNA-damaging chemotherapeutic, an alkylating agent, a topoisomerase inhibitor, an RNA synthesis inhibitor, a DNA complex binder, a thiolate alkylating agent, a guanine alkylating agent, a tubulin binder, DNA polymerase inhibitor, an anticancer enzyme, RAC1 inhibitor, thymidylate synthase inhibitor, oxazophosphorine compound, integrin inhibitor such as cilengitide, camptothecin or homocamptothecin, antifolate or a folate antimetabolite. Cytotoxic Chemotherapeutic Agents
Cytotoxic, DNA-damaging chemotherapeutic agents tend to be non-specific and, particularly at high doses, toxic to normal, rapidly dividing cells such as HSPC and immune effector cells. As used herein the term “DNA-damaging” chemotherapy or chemotherapeutic agent refers to treatment with a cytostatic or cytotoxic agent (i.e., a compound) to reduce or eliminate the growth or proliferation of undesirable cells, for example cancer cells, wherein the cytotoxic effect of the agent can be the result of one or more of nucleic acid intercalation or binding, DNA or RNA alkylation, inhibition of RNA or DNA synthesis, the inhibition of another nucleic acid-related activity (e.g., protein synthesis), or any other cytotoxic effect. Such compounds include, but are not limited to, DNA damaging compounds that can kill cells. “DNA damaging” chemotherapeutic agents include, but are not limited to, alkylating agents, DNA intercalators, protein synthesis inhibitors, inhibitors of DNA or RNA synthesis, DNA base analogs, topoisomerase inhibitors, telomerase inhibitors, and telomeric DNA binding compounds. For example, alkylating agents include alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as a benzodizepa, carboquone, meturedepa, and uredepa; ethylenimines and methylmelamines, such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylol melamine; nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichine, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitroso ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine. Other DNA-damaging chemotherapeutic agents include daunorubicin, doxorubicin, idarubicin, epirubicin, mitomycin, and streptozocin. Chemotherapeutic antimetabolites include gemcitabine, mercaptopurine, thioguanine, cladribine, fludarabine phosphate, fluorouracil (5-FU), floxuridine, cytarabine, pentostatin, methotrexate, azathioprine, acyclovir, adenine P-l-D-arabinoside, amethopterin, aminopterin, 2-aminopurine, aphi dicolin, 8- azaguanine, azaserine, 6-azauracil, 2'-azido-2'-deoxynucleosides, 5-bromodeoxycytidine, cytosine P-l-D-arabinoside, diazooxynorleucine, dideoxynucleosides, 5 -fluorodeoxy cytidine, 5- fluorodeoxyuridine, and hydroxyurea.
Chemotherapeutic protein synthesis inhibitors include abrin, aurintricarboxylic acid, chloramphenicol, colicin E3, cycloheximide, diphtheria toxin, edeine A, emetine, erythromycin, ethionine, fluoride, 5 -fluorotryptophan, fusidic acid, guanylyl methylene diphosphonate and guanylyl imidodiphosphate, kanamycin, kasugamycin, kirromycin, and O-methyl threonine. Additional protein synthesis inhibitors include modeccin, neomycin, norvaline, pactamycin, paromomycine, puromycin, ricin, shiga toxin, showdomycin, sparsomycin, spectinomycin, streptomycin, tetracycline, thiostrepton, and trimethoprim.
Inhibitors of DNA synthesis, include alkylating agents such as dimethyl sulfate, nitrogen and sulfur mustards; intercalating agents, such as acridine dyes, actinomycins, anthracenes, benzopyrene, ethidium bromide, propidium diiodide-intertwining; and other agents, such as distamycin and netropsin. Topoisomerase inhibitors, such as irinotecan, teniposide, coumermycin, nalidixic acid, novobiocin, and oxolinic acid; inhibitors of cell division, including colcemide, mitoxantrone, colchicine, vinblastine, and vincristine; and RNA synthesis inhibitors including actinomycin D, a-amanitine and other fungal amatoxins, cordycepin (3 '-deoxyadenosine), dichlororibofuranosyl benzimidazole, rifampicine, streptovaricin, and streptolydigin also can be used as the DNA damaging compound.
In one embodiment the chemotherapeutic agent is a DNA complex binder such as camptothecin, or etoposide; a thiolate alkylating agent such as nitrosourea, BCNU, CCNU, ACNU, or fotesmustine; a guanine alkylating agent such as temozolomide, a tubulin binder such as vinblastine, vincristine, vinorelbine, vinflunine, cryptophycin 52, halichondrins, such as halichondrin B, dolastatins, such as dolastatin 10 and dolastatin 15, hemiasterlins, such as hemiasterlin A and hemiasterlin B, colchicine, combrestatins, 2-methoxyestradiol, E7010, paclitaxel, docetaxel, epothilone, discodermolide; a DNA polymerase inhibitor such as cytarabine; an anticancer enzyme such as asparaginase; a Rael inhibitor such as 6-thioguanine; a thymidylate synthase inhibitor such as capecitabine or 5-FU; a oxazophosphorine compound such as Cytoxan; a integrin inhibitor such as cilengitide; an antifolate such as pralatrexate; a folate antimetabolite such as pemetrexed; or a camptothecin or homocamptothecin such as diflomotecan.
In one embodiment the topoisomerase inhibitor is a type I inhibitor. In another embodiment the topoisomerase inhibitor is a type II inhibitor.
Other DNA-damaging chemotherapeutic agents whose toxic effects can be mitigated by the presently disclosed selective CDK4/6 inhibitors include, but are not limited to, cisplatin, hydrogen peroxide, carboplatin, procarbazine, ifosfamide, bleomycin, plicamycin, taxol, transplatinum, thiotepa, oxaliplatin, and the like, and similar acting-type agents. In one embodiment, the DNA damaging chemotherapeutic agent is selected from the group consisting of cisplatin, carboplatin, camptothecin, and etoposide.
Other suitable chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (ONCOVIN®), liposomal vincristine (MARQIBO®), doxorubicin (ADRIAMYCIN®), Cytarabine (cytosine arabinoside, ara-C, or CYTOSAR®), L-asparaginase (ELSPAR®) or PEG-L- asparaginase (pegaspargase or ONCASPAR®), Etoposide (VP- 16), Teniposide (VUMON®), 6- mercaptopurine (6-MP or PURINETHOL®), Prednisone, and Dexamethasone (DECADRON®). Examples of additional suitable chemotherapeutic agents include but are not limited to 5- fluorouracil, dacarbazine, alkylating agents, anthramycin (AMC)), anti-mitotic agents, cisdichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antimetabolites, asparaginase, BCG live (intravesical), bleomycin sulfate, calicheamicin, cytochalasin B, dactinomycin (formerly actinomycin), daunorubicin HC1, daunorubicin citrate, denileukin diftitox, dihydroxy anthracin dione, Docetaxel, doxorubicin HC1, E. coli L-asparaginase, Erwinia L-asparaginase, etoposide citrovorum factor, etoposide phosphate, gemcitabine HC1, idarubicin HC1, interferon a-2b, irinotecan HC1, maytansinoid, mechlorethamine HC1, melphalan HC1, mithramycin, mitomycin C, mitotane, paclitaxel, polifeprosan 20 with carmustine implant, procarbazine HC1, streptozotocin, teniposide, thiotepa, topotecan HC1, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.
Additional cytotoxic chemotherapeutic agents for use with the present invention include: epirubicin, abraxane, taxotere, epothilone, tafluposide, vismodegib, azacytidine, doxifluridine, vindesine, and vinorelbine.
In one embodiment the chemotherapeutic agent is a DNA complex binder. In one embodiment the chemotherapeutic agent is a tubulin binder. In one embodiment the chemotherapeutic agent is an alkylating agent. In one embodiment the chemotherapeutic agent is a thiolate alkylating agent. Additional Chemotherapeutic Agents
Additional chemotherapeutic agents that may be used as described herein may include 2- methoxyestradiol or 2ME2, finasunate, etaracizumab (MEDI-522), HLL1, huN901-DMl, atiprimod, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, plitidepsin, P276- 00, tipifarnib, lenalidomide, thalidomide, pomalidomide, simvastatin, and celecoxib. Chemotherapeutic agents useful in the present invention include, but are not limited to, Trastuzumab (HERCEPTIN®), Pertuzumab (PERJETA®), Lapatinib (TYKERB®), Gefitinib (IRES SA®), Erlotinib (TARCEVA®), Cetuximab (ERBITUX®), Panitumumab (VECTIBIX®), Vandetanib (CAPRELSA®), Vemurafenib (ZELBORAF®), Vorinostat (ZOLINZA®), Romidepsin (ISTODAX®), Bexarotene (TARGRETIN®), Alitretinoin (PANRETIN®), Tretinoin (VESANOID®), Carfilzomib (KYPROLIS®), Pralatrexate (FOLOTYN®), Bevacizumab (AVASTIN®), Ziv-aflibercept (ZALTRAP®), Sorafenib (NEXAVAR®), Sunitinib (SUTENT®), Pazopanib (VOTRIENT®), Regorafenib (STIVARGA®), and Cabozantinib (COMETRIQ®).
Additional chemotherapeutic agents contemplated include, but are not limited to, a calcineurin inhibitor, e.g., a cyclosporin or an ascomycin, e.g., Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g., rapamycin or a derivative thereof, e.g., Sirolimus (RAPAMUNE®), Everolimus (CERTICAN®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g., ridaforolimus, campath 1H, a SIP receptor modulator, a dual mTORCl and mTORC2 inhibitor, e.g., Vistusertib (AZD2014), e.g., fmgolimod or an analogue thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, e.g., sodium salt, or a prodrug thereof, e.g., Mycophenolate Mofetil (CELLCEPT®), OKT3 (Orthoclone OKT3®), Prednisone (ATGAM®), Thymoglobulin®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizoribine, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ELIDEL®), Abatacept, belatacept, LFA31g, etanercept (sold as ENBREL® by ImmuneXcite), adalimumab (HUMIRA®), infliximab (REMICADE®), an anti-LFA-1 antibody, natalizumab (ANTEGREN®), Enlimomab, gavilimomab, Golimumab, antithymocyte immunoglobulin, siplizumab, Alefacept, efalizumab, Pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac, indomethacin, dasatinib (SPRYCEL®) nilotinib (TASIGNA®), bosutinib (BOSULIF®), Imatinib mesylate (GLEEVEC®) and ponatinib (ICLUSIG®) amifostine, dolasetron mesylate, dronabinol, epoetin-a, etidronate, filgrastim, fluconazole, goserelin acetate, gramicidin D, granisetron, leucovorin calcium, lidocaine, Mesna, ondansetron HC1, pilocarpine HC1, porfimer sodium, vatalanib, 1- dehydrotestosterone, allopurinol sodium, Betamethasone, sodium phosphate and betamethasone acetate, calcium leucovorin, conjugated estrogens, dexrazoxane, dibromomannitol, esterified estrogens, estradiol, estramustine phosphate sodium, ethinyl estradiol, flutamide, folinic acid, glucocorticoids, leuprolide acetate, levamisole HC1, medroxyprogesterone acetate, megestrol acetate, methyltestosterone, nilutamide, octreotide acetate, pamidronate disodium, procaine, propranolol, testolactone, tetracaine, toremifene citrate, and sargramostim.
In one embodiment the chemotherapeutic agent is an estrogen receptor ligand such as tamoxifen, raloxifene, fulvestrant, anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, or toremifene; an androgen receptor ligand such as bicalutamide, enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, or cimetidine; an aromatase inhibitor such as letrozole, anastrozole, or exemestane; an antiinflammatory such as prednisone; an oxidase inhibitor such as allopurinol; an anticancer antibody; an anticancer monoclonal antibody; an antibody against CD40 such as lucatumumab or dacetuzumab; an antibody against CD20 such as rituximab; an antibody that binds CD52 such as alemtuzumab; an antibody that binds integrin such as volociximab or natalizumab; an antibody against interleukin-6 receptor such as tocilizumab; an interleukin-2 memetic such as aldesleukin; an antibody that targets IGF1 like figitumumab; an antibody that targets DR4 such as mapatumumab; an antibody that targets TRAIL-R2 such as lexatumumab or dulanermin; a fusion protein such as atacicept; a B cell inhibitor such as atacicept; a proteasome inhibitor such as carfilzomib, bortezomib, or marizomib; a HSP90 inhibitor such as tanespimycin; a HDAC inhibitor such as vorinostat, belinostat or panobinostat; a MAPK ligand such as talmapimod; a PKC inhibitor such as enzastaurin; a HER2 receptor ligand such as trastuzumab, lapatinib, or pertuzumab; an EGFR inhibitor such as gefitinib, erlotinib, cetuximab, panitumumab, or vandetanib; a natural product such as romidepsin; a retinoid such as bexarotene, tretinoin, or alitretinoin; a receptor tyrosine kinase (RTK) inhibitor such as lenvatinib, sitravatinib, cabozantinib, sunitinib, regorafenib, or pazopanib; or a VEGF inhibitor such as ziv-aflibercept, bevacizumab or dovitinib.
In one embodiment, the combinations of a CDK4/6 inhibitor, chemotherapeutic agent, and multiple immune checkpoint inhibitors are further combined with the use of hematopoietic growth factors including, but not limited to, granulocyte colony stimulating factor (G-CSF, for example, sold as NEUPOGEN® (filgrastim), NEULASTA® (peg-filgrastim), or lenograstim), granulocytemacrophage colony stimulating factor (GM-CSF, for example sold as molgramostim and sargramostim (LEUKINE®)), M-CSF (macrophage colony stimulating factor), Thrombopoietin (megakaryocyte growth development factor (MGDF), for example sold as ROMIPLOSTIM® and ELTROMBOPAG®) interleukin (IL)-12, interleukin-3, interleukin- 11 (adipogenesis inhibiting factor or oprelvekin), SCF (stem cell factor, steel factor, kit-ligand, or KL) and erythropoietin (EPO), and their derivatives (sold as for example epoetin-a as DARBEPOEITIN®, EPOCEPT®, NANOKINE®, EPOFIT®, EPOGEN®, EPREX®, and PROCRIT®; epoetin-p sold as for example NEORECORMON®, RECORMON® and MICERA®), epoetin-delta (sold as for example DYNEPO®), epoetin- omega (sold as for example EPOMAX®), epoetin zeta (sold as for example SILAPO® and RETACRIT®) as well as for example EPOCEPT®, EPOTRUST®, ERYPRO® Safe, REPOITIN®, VINTOR®, EPOFIT®, ERYKINE®, WEPOX®, ESPOGEN®, RELIPOEITIN®, SHANPOEITIN®, ZYROP® and EPIAO®). In one embodiment, the hematopoietic growth factor administration is timed so that the CDK4/6 inhibitor’s effect on HSPCs has dissipated. In one embodiment, the growth factor is administered at least 20 hours after the administration of the CDK4/6 inhibitor.
Additional chemotherapeutic agents may include an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist. Partial anti -estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allyl estrenol, chloromadinone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, nor ethisterone acetate, progesterone, and spironolactone.
Additional chemotherapeutic agents may include an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In one embodiment, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include: chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
The chemotherapeutic agent may include a kinase inhibitor, including but not limited to a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’ s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
PI3k inhibitors are well known. Examples of PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, GDC-0032 (2-[4-[2-(2- Isopropyl-5-methyl- 1 ,2,4-triazol-3 -yl)-5,6-dihydroimidazo[ 1 ,2-d] [ 1 ,4]benzoxazepin-9- yl]pyrazol-l-yl]-2-methylpropanamide), MLN-1117 ((2R)-l-Phenoxy-2-butanyl hydrogen (S)- methylphosphonate; or Methyl(oxo) {[(2R)-l-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-Nl-[4-Methyl-5-[2-(2,2,2-trifhioro-l,l-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-l,2- pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)- 6-quinolinyl]-3-pyridinyl}benzenesulfonamide), TGX-221 ((±)-7-Methyl-2-(morpholin-4-yl)-9- (l-phenylaminoethyl)-pyrido[l,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-l-(2-methyl-3- (trifluoromethyl)benzyl)-6-morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN- 193 ((R)-2-((l-(7-methyl-2-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidin-
9-yl)ethyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820 ((S)- l-(4-((2-(2-aminopyrimidin-
5-yl)-7-methyl-4-mohydroxypropan- 1 -one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-l-[9H-purin-6- ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3- ((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3- dihydroimidazo[l,2-c]quinaz), AS 252424 (5-[l-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]- meth-(Z)-ylidene]-thiazolidine-2, 4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-Di(4-morpholinyl)-4- pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-Indazol-4-yl)-6-[[4-
(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin-l-yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126
((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15- pentaoxo- 1 -(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7, 10,13,16- tetraazaoctadecan- 18-oate), PF-05212384 (N-[4-[[4-(Dimethylamino)- 1 - piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-l, 3, 5-tri azin-2 -yl)phenyl]urea), LY3023414, BEZ235 (2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH- imidazo[4,5-c]quinolin-l-yl]phenyl}propanenitrile), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,l laS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,l la-dimethyl-l,4,7-trioxo-2,3,3a,9,10,ll-hexahydroindeno[4,5h]isochromen-
10-yl] acetate (also known as sonolisib)), and the structure described in W02014/071109 having the formula:
BTK inhibitors are well known. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765)(Imbruvica™) (l-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidin-l-yl]prop-2-en-l-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin- 4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6- (4-(2-hydroxyethyl)piperazin-l-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC- 0834 ([R-N-(3-(6-(4-(l,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5- dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[l,2-a]pyrazin-6-yl)phenyl)benzamide, CGI- 1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4- carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4-((4- ((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-l-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-lH-imidazo[4,5- g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(l,4-dimethyl-3-oxopiperazin-2- yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4, 5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(l,4-dimethyl-3- oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)- 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-l,2,3-triazol-2-yl)phenyl)amino)-2-(((lR,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (l-(l-acryloylindolin- 6-yl)-9-(l-methyl-lH-pyrazol-4-yl)benzo[h][l,6]naphthyridin-2(lH)-one), and RN486 (6- cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{l-methyl-5-[5-(4-methyl-piperazin-l-yl)-pyridin- 2-ylamino]-6-oxo-l,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-l-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference.
Syk inhibitors are well known, and include, for example, Cerdulatinib (4- (cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-l-yl)phenyl)amino)pyrimidine-5- carboxamide), entospletinib (6-(lH-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[l,2- a]pyrazin-8-amine), fostamatinib ([6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4- pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib di sodium salt (sodium (6-((5-fluoro-2-((3,4,5- trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2- b][l,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-Dimethoxyphenyl)- imidazo[l,2-c]pyrimidin-5-ylamino)-nicotinamide HC1), RO9021 (6-[(lR,2S)-2-Amino- cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevec; 4-[(4-methylpiperazin-l-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3- yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3- aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1- (tert-butyl)-3-(4-chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-
(((lR,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-l,2,3-triazol-2-yl)phenyl)amino)-2-(((lR,2S)-2-aminocyclohexyl)amino)pyrimidine- 5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4- diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5- trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][l,4]oxazin- 3(4H)-one), YM193306(see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein).
The chemotherapeutic agent can also be a B-cell lymphoma 2 (Bcl-2) protein inhibitor. BCL-2 inhibitors are known in the art, and include, for example, ABT-199 (4-[4-[[2-(4- Chlorophenyl)-4,4-dimethylcyclohex-l-en-l-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4- [[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5- yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-l-yl]-N-[4- [[(2R)-4-(dimethylamino)-l-phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl] sulfonylbenzamide), ABT-263 ((R)-4-(4-((4'-chl oro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1, l'-biphenyl]-2-yl)methyl)piperazin-l-yl)-N-((4-((4-morpholino-l-(phenylthio)butan-2- yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3 ,5- dimethyl-lH-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2- ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4-(l- cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2-(l , 1 - Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(l- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), or G3139 (Oblimersen).
Additional chemotherapeutic agents for use in the methods contemplated herein include, but are not limited to, midazolam, MEK inhibitors, RAS inhibitors, ERK inhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP 90 inhibitors, or a combination thereof), RAF inhibitors, apoptotic compounds, topoisomerase inhibitors, AKT inhibitors, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, or FLT-3 inhibitors, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof. Examples of MEK inhibitors include but are not limited to trametinib /GSK1120212 (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5- carboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib/BAY869766/RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6- methoxyphenyl)-l-(2,3-dihydroxypropyl)cyclopropane-l-sulfonamide), PD-0325901 (N-[(2R)- 2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8- methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162/ARRY438162 (5-[(4-Bromo-2- fluorophenyl)amino]-4-fluoro-N-(2-hy droxy ethoxy)- 1 -methyl- lH-benzimidazole-6 carboxamide), R05126766 (3-[[3-Fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4- methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655/CH4987655 (3,4-difluoro-2- ((2-fluoro-4-iodophenyl)amino)-N-(2 -hy droxy ethoxy)-5-((3-oxo-l,2-oxazinan-2 yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2 -hydroxy ethoxy)- l,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide). Examples of RAS inhibitors include but are not limited to Reolysin and siG12D LODER. Examples of ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
Known ERK inhibitors include SCH772984 (Merck/Schering-Plough), VTX-1 le (Vertex), DEL-22379, Ulixertinib (BVD-523, VRT752271), GDC-0994, FR 180204, XMD8-92, and ERK5-IN-1.
Raf inhibitors are well known, and include, for example, Vemurafinib (N-[3-[[5-(4- Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-l- propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-
(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- m ethylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(l-methyl-6- (pyridin-3-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-
(trifluoromethyl)phenyl)benzamide), RAF -265 (l-methyl-5-[2-[5-(trifluoromethyl)-lH-imidazol- 2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2 -Bromoal disine (2-Bromo-6,7-dihydro-lH,5H-pyrrolo[2,3-c]azepine-4, 8-dione), Raf Kinase Inhibitor IV (2- chloro-5-(2-phenyl-5-(pyridin-4-yl)-lH-imidazol-4-yl)phenol), and Sorafenib N-Oxide (4-[4- [[[[4-Chloro-3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl- 2pyridinecarboxaMide 1 -Oxide).
Known topoisomerase I inhibitors useful in the present invention include (S)-10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline- 3,14(4H,12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14-(4H,12H)-dione (camptothecin), (1S,9S)-1- Amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H- benzo(de)pyrano(3 ' ,4' : 6,7)indolizino(l ,2-b)quinoline- 10,13 -di one (exatecan), (7 -(4- m ethylpiperazinom ethylene)- 10,11 -ethylenedi oxy-20(S)-camptothecin (lurtotecan), or (S)-4,l l- diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxolH-pyrano[3’,4’:6,7]-indolizino[l,2- b]quinolin-9-yl-[l,4’bipiperi dine]- 1’ -carboxylate (irinotecan), (R)-5-ethyl-9,10-difluoro-5- hydroxy-4,5-dihydrooxepino[3',4':6,7]indolizino[l,2-b]quinoline-3,15(lH,13H)-dione (diflomotecan), (4S)-11-((E)-((1, l-Dimethylethoxy)imino)methyl)-4-ethyl-4-hydroxy-l, 12- dihydro- 14H-pyrano(3 ',4' : 6,7)indolizino(l ,2-b)quinoline-3 , 14(4H)-dione (gimatecan), (S)-8- ethyl-8-hydroxy-15-((4-methylpiperazin-l-yl)methyl)-l l,14-dihydro-2H-[l,4]dioxino[2,3- g]pyrano[3',4':6,7]indolizino[l,2-b]quinoline-9,12(3H,8H)-dione (lurtotecan), (4S)-4-Ethyl-4- hydroxy-1 l-[2-[(l-methylethyl)amino]ethyl]-lEI-pyrano[3?,4?:6,7]indolizino[l,2-b]quinoline- 3, 14(4H, 12H)-dione (belotecan), 6-((l,3-dihydroxypropan-2-yl)amino)-2,10-dihydroxy-12- ((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-12,13- dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (edotecarin), 8,9-dimethoxy-5- (2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5H-dibenzo(c,h)(l,6)naphthyridin-6-one (topovale), benzo[6,7]indolizino[l,2-b]quinolin-l l(13H)-one (rosettacin), (S)-4-ethyl-4-hydroxy- 1 l-(2-(trimethylsilyl)ethyl)-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14(4H,12H)-dione (cositecan), tetrakis{(4S)-9-[([l,4'-bipiperidinyl]-l'-carbonyl)oxy]-4,l l-diethyl-3,14-dioxo- 3,4,12,14- tetrahydro-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-4-yl} N,N',N",N"'- {methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(l-oxoethylene)]}tetraglycinate tetrahydrochloride (etirinotecan pegol), 10-hydroxy-camptothecin (HOCPT), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin), and 10-hydroxy-9-nitrocamptothecin (CPT109), (R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-((4-methylpiperidin-l-yl)methyl)-4,5- dihydrooxepino[3',4':6,7]indolizino[l,2-b]quinoline-3,15(lH,13H)-dione (elmotecan). Therapeutic Protocols
In some aspects, the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD- L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21 -day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28-day cycle, and trilaciclib is administered again on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42-day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, trilaciclib is administered once a week in combination with the administration of an effective amount of a co-formulation of immune checkpoint inhibitors once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, the co-formulation of immune checkpoint inhibitors comprises a PD-L1 or PD-1 immune checkpoint inhibitor and an additional immune checkpoint inhibitor selected from the group consisting of a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the PD-L1 or PD- 1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at different amounts. In some embodiments, the PD-L1 or PD-1 immune checkpoint inhibitor and the additional immune checkpoint inhibitor are dosed at the same amounts. In some embodiments, the additional immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the additional immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the additional immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, a PD-1 inhibitor is administered and a LAG-3 inhibitor is administered, and wherein the PD-1 inhibitor is nivolumab and the LAG-3 inhibitor is relatlimab. In some embodiments, nivolumab and relatlimab are administered as a single 30-minute infusion. In some embodiments, nivolumab and relatlimab are administered once every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks. In some embodiments, nivolumab and relatlimab are administered once every four weeks. In some embodiments, the additional immune checkpoint inhibitor is a CD73 inhibitor. In some embodiments, the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a LAG-3 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, the LAG-3 immune checkpoint inhibitor is relatlimab. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and relatlimab is administered in accordance with its standard administration label according to its approved use.
In one aspect, described herein is a method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises administering to the human an effective amount of a cyclin dependent kinase 4/6 CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is trilaciclib, or a pharmaceutically acceptable salt thereof, administering to the human an effective amount of nivolumab, and, administering to the human an effective amount of relatlimab. In some embodiments, the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent. In some embodiments, the treatment is administered to the human in a first-line setting. In some embodiments, the treatment is administered to the human in a second-line setting. In some embodiments, the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression. In some embodiments, the trilaciclib is administered once a week. In some embodiments, nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks. In some embodiments, nivolumab and relatlimab are administered once every two weeks. In some embodiments, nivolumab and relatlimab are administered once every three weeks. In some embodiments, nivolumab and relatlimab are administered once every four weeks. In some embodiments, nivolumab and relatlimab are administered once every six weeks. In some embodiments, nivolumab and relatlimab are administered once every twelve weeks. In some embodiments, nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle, wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks, wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks, and, wherein the duration of the first cycle is different than the duration of the second cycle. In some embodiments, trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent. In some embodiments, trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid. In some embodiments, the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof. In some embodiments, the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma. In some embodiments, the melanoma is unresectable or metastatic melanoma.
In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a TIGIT immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a TIM-3 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a CD73 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks.
In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above. In some embodiments, the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC). In some embodiments, the patient has second-line metastatic non-squamous or squamous NSCLC. In some embodiments, the patient has second-line metastatic triple negative breast cancer. In some embodiments, the patient has second-line metastatic colorectal cancer (CRC). In some embodiments, the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
In some alternative embodiments, the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), and B and T lymphocyte attenuator (BTLA) protein. In an alternative embodiment to the embodiments above, the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and a multiple tyrosine kinase (MTK) inhibitor instead of an additional immune checkpoint inhibitor, for example, but not limited to, lenvatinib, sitravatinib, and cabozantinib. In some embodiments, the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles. In some embodiments, the patient is administered a treatment cycle until disease progression. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks and additional immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is administered in accordance with its standard administration label according to its approved use. In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above. In some embodiments, the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), metastatic colorectal cancer (CRC) or metastatic urothelial cancer (mUC). In some embodiments, the patient has second-line metastatic non-squamous or squamous NSCLC. In some embodiments, the patient has second-line metastatic triple negative breast cancer. In some embodiments, the patient has second-line metastatic colorectal cancer (CRC). In some embodiments, the patient has second-line locally advanced or metastatic urothelial carcinoma (mUC).
In some alternative embodiments, the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), and B and T lymphocyte attenuator (BTLA) protein. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a PD-L2 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a CTLA-4 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, the CTLA-4 immune checkpoint inhibitor is ipilimumab. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and ipilimumab is administered in accordance with its standard administration label according to its approved use. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and ipilimumab is administered once every three weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a VISTA immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD- L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a B7- H3/CD276 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD- L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a IDO immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a KIR immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a CEACAM immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a Siglec-15 immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 immune checkpoint inhibitor is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint is a BTLA immune checkpoint inhibitor and is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or once every twelve weeks. In an alternative embodiment to the embodiments above, the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 immune checkpoint inhibitor as described herein, and a multiple tyrosine kinase (MTK) inhibitor instead of an additional immune checkpoint inhibitor, for example, but not limited to, lenvatinib, sitravatinib, and cabozantinib. In some embodiments, the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles. In some embodiments, the patient is administered a treatment cycle until disease progression.
As contemplated herein, the administration of trilaciclib, in combination with a chemotherapeutic agent, or agents, a PD-1 or PD-L1 immune checkpoint inhibitor and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor is timed specifically at a dose described herein so that the G0/G1 arrest induced by trilaciclib is short term and transient in nature. Cells that are quiescent within the G1 phase of the cell cycle are more resistant to the damaging effect of the chemotherapeutic agents than proliferating cells. The therapeutic protocols are specific for the solid tumor being treated. In some embodiments, trilaciclib is administered prior to the administration of the chemotherapeutic agent, or agents, for example, less than 24 hours, less than 16 hours, less that 12 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 2 hours, less than 1 hour, or about 30 minutes prior to each administration of the chemotherapeutic agent, and the PD-1 or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered on day 1 of each therapeutic treatment cycle, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor.
In some aspects, the therapeutic protocol is administered to patients with advanced or metastatic cancer whose disease has advanced following previous treatment with a PD-1 or PD- L1 inhibitor, an indication of the development of immune checkpoint inhibitor resistance. Accordingly, such patients are administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor, wherein the additional checkpoint inhibitor is selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 14-day therapeutic treatment cycle (or cycle), and trilaciclib is administered again on day 7 of each 14-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD- L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21 -day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 28-day cycle, and trilaciclib is administered again on day 7, day 14, and day 21 of each 28-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the additional immune checkpoint inhibitor are administered on day 1 of each 42-day cycle, and trilaciclib is administered again on day 7, day 14, day 21, day 28, and day 35 of each 42-day cycle. In some embodiments, trilaciclib is administered one or more times per week. In some embodiments, trilaciclib is administered once a week during treatment, and the PD-1 or PD-L1 and additional immune checkpoint inhibitor are administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, trilaciclib is administered once a week, the PD-L1 or PD-1 is administered in accordance with its standard administration label according to its approved use, and the additional immune checkpoint inhibitor is administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, the additional immune checkpoint inhibitor is not administered concurrently with the PD-L1 or PD-1 inhibitor. In some embodiments, an initial loading dose of trilaciclib is administered alone about 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days prior to the initiation of a first treatment cycle as described above. In some embodiments, the cancer is a non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC), urothelial cancer (mUC) or another solid tumor. In some embodiments, the patient is administered at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, or more treatment cycles. In some embodiments, the patient is administered a treatment cycle until disease progression.
In some alternative embodiments, the additional immune checkpoint inhibitor administered in combination with trilaciclib and a PD-1 or PD-L1 inhibitor is selected from an inhibitor of program death-ligand 2 (PD-L2), CTLA-4, and V-domain Ig suppressor of T-cell activation (VISTA), B7-H3/CD276, indoleamine 2,3 -dioxygenase (IDO), killer immunoglobulin-like receptors (KIRs), carcinoembryonic antigen cell adhesion molecules (CEACAM) such as CEACAM-1, CEACAM-3, and CEACAM-5, sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15), and B and T lymphocyte attenuator (BTLA) protein. In an alternative embodiment to the embodiments above, the treatment protocol provides for the administration of trilaciclib and the PD-1 or PD-L1 as described herein, and a multiple tyrosine kinase (MTK) inhibitor instead of an additional immune checkpoint inhibitor, for example, but not limited to, lenvatinib, sitravatinib, and cabozantinib.
Non-Small Cell Lung Cancer
Non-small cell lung cancer makes up nearly 85% of all lung cancers diagnosed. Common non-small cell lung cancer types include adenocarcinoma, which generally presents with glandular differentiation, squamous cell carcinoma, which generally presents with squamous differentiation (keratinization), and large cell carcinoma, which generally presents as large and poorly- differentiated. These patients should undergo molecular testing for oncogenes and programmed death ligand 1 (PD-L1). Patients with advanced or recurrent disease with actionable oncogenes should be considered for treatment with targeted therapy. Patients without an actionable genetic alteration should be treated with trilaciclib and chemotherapy alone, trilaciclib, chemotherapy with immunotherapy, or trilaciclib and immunotherapy alone. Patients with poor performance status or co-morbidities can be considered for single-agent chemotherapy, immunotherapy, or (if they have an actionable oncogene) targeted therapy.
Sciuamous NSCLC
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor. In some embodiments, the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor expressing PD-L1 as determined by an FDA-approved, or CE Mark test.
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for example, but not limited to, a squamous cell NSCLC first- or second-line treatment protocol such as, but not limited to: single agent chemotherapy or combination chemotherapy. Non-limiting examples of single agent chemotherapy regimens for the first-line treatment of locally advanced or metastatic squamous cell NSCLC include cisplatin 50 mg/m2 IV on days 1, 8, 29, and 36 plus etoposide 50 mg/m2 IV on days 1-5 and days 29-33; cisplatin 100 mg/m2 IV on days 1 and 29 plus vinblastine 5 mg/m2/weekly IV for 5 wks.; carboplatin AUC 2 IV weekly for 7 wks. plus paclitaxel 45-50 mg/m2 IV weekly for 7 wks. followed by two cycles of consolidation chemotherapy with carboplatin AUC 6 IV on day 1 plus paclitaxel 200 mg/m2 IV on day 1 every 21 wks.; paclitaxel 200 mg/m2 IV every 21 days, docetaxel 35 mg/m2 IV weekly for 3 wks. every 28 days, docetaxel 75 mg/m2 IV every 21 days, gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 wks., gemcitabine 1250 mg/m2 IV on days 1 and 8 every 21 days, vinorelbine 25 mg/m2 IV weekly, vinorelbine 30 mg/m2 IV on days 1 and 8 every 21 days. Non-limiting examples of combination chemotherapy regimens for the first-line treatment of locally advanced or metastatic squamous cell NSCLC include cisplatin 75 mg/m2 IV on day 1 plus paclitaxel 175 mg/m2 IV on day 1 every 21 days, cisplatin 100 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 28 days, cisplatin 60 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1 and 8 every 21 days, cisplatin 75 mg/m2 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m2 IV on days 1, 8, and 15 every 28 days, protein-bound paclitaxel 100 mg/m2 IV on days 1, 8, and 15 of every 21 days plus carboplatin AUC 6 IV on day 1, carboplatin AUC 6 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 days, carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m2 IV on days 1 and 8 every 21 days, cisplatin 100 mg/m2 IV on day 1 every 28 days plus vinorelbine 25 mg/m2 IV weekly, cisplatin 40 mg/m2 IV on day 1 plus vinorelbine 25 mg/m2 IV on days 1 and 8 every 21 days, or carboplatin AUC 5 IV on day 1 plus vinorelbine 30 mg/m2 IV on days 1 and 8 every 21 days. Non-limiting examples of chemotherapy regimens for the second-line treatment of locally advanced or metastatic squamous cell NSCLC include Docetaxel 75 mg/m2 IV on day 1 every 21 days for four to six cycles +/- ramucirumab 10 mg/kg IV.
In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes. In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti -PD-LI bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche). In some embodiments, trilaciclib, the PD-1 or PD-L1 inhibitor, and the TIM-3 inhibitor are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle. In some embodiments, the PD-1 or PD-L1 inhibitor comprises PD-1 inhibitor dostarlimab. In some embodiments, the TIM-3 inhibitor comprises cobolimab. In some embodiments, trilaciclib, dostarlimab, and cobolimab are administered on day 1 of each 21-day cycle, and trilaciclib is administered again on day 7 and day 14 of each 21-day cycle. In some embodiments, the 21-day cycle is repeated in the absence of disease progression or unacceptable toxicity. In some embodiments, dostarlimab and cobolimab are administered intravenously over 30 minutes. In some embodiments, dostarlimab is administered at a dose of about 500 mg. In some embodiments, cobolimab is administered at a dose of about 300 mg.
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Non-sciuamous NSCLC
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic non-squamous cell NSCLC in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and multiple tyrosine kinase (MTK) inhibitor. In some embodiments, the MTK inhibitor is selected from lenvatinib, sitravatinib, or crizotinib. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor expressing PD-L1 as determined by an FDA-approved, or CE Mark test.
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for example, but not limited to, a squamous cell NSCLC first- or second-line treatment protocol such as, but not limited to: single agent chemotherapy or combination chemotherapy. A non-limiting example of a single agent chemotherapy regimen is pemetrexed 500 mg/m2 IV every 21 days. Nonlimiting examples of combination chemotherapy regimens include carboplatin AUC 5 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 every 21 days for four cycles; cisplatin 75 mg/m2 IV on day 1 plus pemetrexed 500 mg/m2 IV on day 1 every 21 days for three cycles, cisplatin 75 mg/m2 IV on day 1 plus paclitaxel 175 mg/m2 IV on day 1 every 21 days, cisplatin 100 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 28 days, cisplatin 60 mg/m2 IV on day 1 plus gemcitabine 1000 mg/m2 IV on days 1 and 8 every 21 days, cisplatin 75 mg/m2 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 175-225 mg/m2 IV on day 1 every 21 days, carboplatin AUC 6 IV on day 1 plus paclitaxel 90 mg/m2 IV on days 1, 8, and 15 every 28 days, protein-bound paclitaxel 100 mg/m2 IV on days 1, 8, and 15 of every 21 days plus carboplatin AUC 6 IV on day 1, carboplatin AUC 6 IV on day 1 plus docetaxel 75 mg/m2 IV on day 1 every 21 days, carboplatin AUC 5 IV on day 1 plus gemcitabine 1250 mg/m2 IV on days 1 and 8 every 21 days, cisplatin 100 mg/m2 IV on day 1 every 28 days plus vinorelbine 25 mg/m2 IV weekly, cisplatin 40 mg/m2 IV on day 1 plus vinorelbine 25 mg/m2 IV on days 1 and 8 every 21 days, or carboplatin AUC 5 IV on day 1 plus vinorelbine 30 mg/m2 IV on days 1 and 8 every 21 days. \ In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg. In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (OPDUALAG®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Triple Negative Breast Cancer
Triple-negative Breast Cancer (TNBC) is a highly aggressive breast cancer subtype that accounts for 15-20% of breast cancer cases annually and 25% of all breast cancer deaths. TNBC has been characterized by several aggressive clinicopathologic features, including onset at a younger age; large, high-grade tumors; and a propensity for visceral metastasis (Cheang et al., Basal-like breast cancer defined by five biomarkers has superior prognostic value than triplenegative phenotype. Clin Cancer Res. 2008; 14(5): 1368-76.; Foulkes et al., Triple-negative breast cancer. N Engl J Med. 2010 Nov 11; 363(20): 1938-48).
A breast cancer is generally classified as TNBC based on local ER-negative, progesterone receptor (PR)-negative, HER2-negative status, which can be determined through a histological or cytological hormone receptor immunohistochemistry (H4C) assessment for estrogen and progesterone (defined as <1% nuclei staining), and by IHC [0 or 1+] OR in situ hybridization [ratio <2.0] OR average gene copy number of <4 signals/nucleus) for HER2 -negative, non- overexpression (per 2018 American Society of Clinical Oncology and the College of American Pathologists (ASCO CAP) criteria).
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a second- line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic triple negative breast cancer (TNBC) in a second- line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for example, but not limited to, a metastatic TNBC treatment protocol such as, but not limited to: first line adjuvant therapy, first-line chemotherapy for metastatic TNBC, and second-line chemotherapy for metastatic TNBC. Non-limiting examples of first-line adjuvant therapy for metastatic TNBC include: Capecitabine 1,000-1,250 mg/m2 orally twice daily on days 1-14, repeat cycle every 3 weeks; Carboplatin AUC 6 IV over 30 minutes on day 1, repeat cycle every 3 or 4 weeks; Cisplatin 75 mg/m2 IV over 60 minutes on day 1, repeat cycle every 3 weeks; Doxorubicin 60-75 mg/m2 IV push on day 1, repeat cycle every 3 weeks or Doxorubicin 20 mg/m2 IV push on day 1, repeat cycle weekly; Eribulin 1.4 mg/m2 IV push on days 1 and 8, repeat cycle every 3 weeks; Gemcitabine 800-1,200 mg/m2 IV over 30 minutes on days 1, 8, and 15, repeat cycle every 4 weeks; Liposomal Doxorubicin 40-50 mg/m2 IV on day 1, repeat cycle every 4 weeks; Paclitaxel 175 mg/m2 IV over 3 hours on day 1, repeat cycle every 3 weeks or Paclitaxel 80 mg/m2 IV over 60 minutes on day 1, repeat cycle weekly; Vinorelbine 25 mg/m2 over 5-10 minutes on day 1, repeat cycle weekly; Albumin-bound paclitaxel 260 mg/m2 IV over 30 minutes on day 1, repeat cycle every 3 weeks or Albumin-bound paclitaxel 100 mg/m2 IV over 30 minutes on days 1, 8 and 15, repeat cycle every 4 weeks or Albumin-bound paclitaxel 125 mg/m2 IV over 30 minutes on days 1, 8 and 15, repeat cycle every 4 weeks; Cyclophosphamide 50 mg orally once daily on days 1-21, repeat cycle every 4 weeks; Docetaxel 60-100 mg/m2 IV over 60 minutes on day 1, repeat cycle every 3 weeks or Docetaxel 35 mg/m2 IV over 60 minutes on days 1, 8, 15, 22, 29, and 36; Epirubicin 60-90 mg/m2 IV push on day 1, repeat cycle every 3 weeks; Ixabepilone 40 mg/m2 (max 88 mg) IV over 3 hours on day 1, repeat cycle every 3 weeks; Days 1,15: Atezolizumab 840 mg IV over 60 minutes on days 1 and 15, followed by: Albumin-bound Paclitaxel 100 mg/m2 IV on days 1, 8, and 15, repeat cycle every 4 weeks.
In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Colorectal Cancer (CRC)
Colorectal cancer (CRC) is one of the prevalent malignancies with a high mortality rate worldwide. CRC incidence is increasing, and it is estimated that the number of CRC patients will reach 2.5 million by 2035. CRC is an invasive cancer, the initiation and progression of which involve both hereditary and environmental factors. The current therapeutic approach at the early stages of CRC is surgery, followed by radiotherapy and chemotherapy. These common treatments may give rise to several challenges, such as their side effects, and are often associated with the development of drug resistance. In order to overcome these obstacles, other therapeutic approaches and common therapies aiming to achieve better results are required. Checkpoint inhibitors can be used for people whose colorectal cancer cells have tested positive for specific gene changes, such as a high level of microsatellite instability (MSI-H), or changes in one of the mismatch repair (MMR) genes.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic and unresectable colorectal cancer in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the patient has a tumor shown by an FDA-approved test to be microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for example, but not limited to, a metastatic colorectal cancer treatment protocol such as, but not limited to: postoperative adjuvant chemotherapy for colorectal cancer, first-line chemotherapy for colorectal cancer, and second-line chemotherapy for colorectal cancer. Non-limiting examples of first-line chemotherapy for colorectal cancer include: FOLFIRI - 180 mg/m2 irinotecan day 1, 400 mg/m2 leucovorin over two hours day 1, Fluorouracil 400 mg/m2 bolus day 1, followed by 2400 to 3000 mg/m2 over 46 hours, continuous infusion; repeat cycle every two weeks; Douillard regimen - 180 mg/m2 irinotecan day 1, 200 mg/m2 leucovorin over two hours days 1 and 2 before fluorouracil, Fluorouracil 400 mg/m2 bolus then 600 mg/m2 over 22 hours days 1 and 2; repeat cycle every 2 weeks; FOLFOX 4 - 85 mg/m2 oxaliplatin day 1, 400 mg/m2 leucovorin over two hours days 1 and 2 before fluorouracil, Fluorouracil 400 mg/m2 bolus, then 600 mg/m2 over 22 hours days 1 and 2; repeat cycle every two weeks; FOLFOX 6 - 100 mg/m2 oxaliplatin day 1, 400 mg/m2 leucovorin over two hours day 1, fluorouracil 400 mg/m2 bolus day 1, followed by 2400 to 3000 mg/m2 over 46 hours, continuous infusion, repeat cycle every two weeks; Modified FOLFOX 6 - 85 mg/m2 oxaliplatin day 1, 350 mg total dose leucovorin over two hours day 1, fluorouracil 400 mg/m2 bolus day 1, followed by 2400 mg/m2 over 46 hours, continuous infusion, repeat cycle every two weeks; FOLFOX 7 - 130 mg/m2 oxaliplatin day 1, 400 mg/m2 leucovorin over two hours day 1, fluorouracil 400 mg/m2 bolus day 1, followed by 2400 mg/m2 over 46 hours, continuous infusion, repeat cycle every two weeks; Modified FOLFOX7 - 85 mg/m2 oxaliplatin day 1, 200 mg/m2 leucovorin over two hours day 1, fluorouracil 2400 mg/m2 over 46 hours, continuous infusion, repeat cycle every two weeks; XELOX - 130 mg/m2 oxaliplatin day 1, Capecitabine 1000 mg/m2 orally twice per day on days 1 to 14, repeat cycle every 3 weeks; FOLFOXIRI - 165 mg/m2 irinotecan day 1, 85 mg/m2 oxaliplatin day 1, 400 mg/m2 leucovorin over two hours day 1, Fluorouracil 3200 mg/m2 over 48 hours, repeat cycle every two weeks.
In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti -PD-LI bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical). In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences). Metastatic Urothelial Carcinoma
Metastatic urothelial (transitional cell) carcinoma (mUC) is the predominant histologic type of bladder cancer in the United States and Europe, where it accounts for 90 percent of all bladder cancers. Bladder cancer is the 6th most commonly occurring cancer in men and the 17th most commonly occurring cancer in women globally. Bladder cancer is the most common malignancy involving the urinary system. Bladder cancer can be categorized as non-muscle invasive, muscle invasive, or metastatic. Approximately 25 percent of patients will have muscle- invasive disease and either present with or later develop metastases. Systemic chemotherapy is the standard approach for the initial treatment of patients with inoperable locally advanced or metastatic urothelial malignancies. Although initial response rates are high, the median survival with multiagent chemotherapy is approximately 15 months.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic urothelial carcinoma (mUC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic urothelial carcinoma (mUC) in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic urothelial carcinoma (mUC) in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic urothelial carcinoma (mUC) in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1.
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for example, but not limited to, a metastatic urothelial carcinoma treatment protocol such as, but not limited to: postoperative adjuvant intravesical chemotherapy for metastatic urothelial carcinoma, first-line chemotherapy for metastatic urothelial carcinoma, and second-line chemotherapy for metastatic urothelial carcinoma. Non-limiting examples of first-line chemotherapy for metastatic urothelial carcinoma include: gemcitabine 1000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2 repeating cycle every 28 days for a maximum of six cycles; dosing methotrexate 30 mg/m2 IV on days 1, 15, and 22 plus vinblastine 3 mg/m2 IV on days 2, 15, and 22 plus doxorubicin 30 mg/m2 IV on day 2 plus cisplatin 70 mg/m2 IV on day 2, repeat cycle every 28d for a total of six cycles; paclitaxel (80 mg/m2 before gemcitabine and cisplatin on days 1 and 8), gemcitabine (1000 mg/m2 on days 1 and 8), and cisplatin (70 mg/m2 on day 1), repeated every 21 days for a maximum of six cycles; and dose-dense regimens of the above administered along with doses of growth factor stimulants.
In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes.
In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB 154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti-PD-Ll bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Solid Tumors
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic solid tumor in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic solid tumor in a first-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic solid tumor in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a chemotherapeutic agent, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM- 3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability-high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test.
In one aspect, the improved methods of treatment described herein are administered to a patient having locally advanced or metastatic solid tumor in a second-line advanced/metastatic setting, wherein the patient is administered trilaciclib, a PD-1 or PD-L1 inhibitor, and an additional immune checkpoint inhibitor selected from a TIGIT inhibitor, a TIM-3 inhibitor, a LAG-3 inhibitor or a CD73 inhibitor. In some embodiments, the patient has a tumor expressing PD-L1. In some embodiments, the solid tumor is selected from a cervical cancer, a squamous cell carcinoma of the head and neck (SCCHN), a cutaneous squamous cell carcinoma (cSCC), a Merkel cell carcinoma, a basal cell carcinoma, a small cell lung cancer (SCLC), a melanoma, a malignant pleural mesothelioma, a renal cell carcinoma, a hepatocellular carcinoma, a microsatellite instability -high or mismatch repair deficient cancer, an endometrial carcinoma, a tumor mutational burden-high (TMB-H) cancer, a gastric cancer, a gastroesophageal junction cancer, an esophageal adenocarcinoma, or an esophageal cancer. In some embodiments, the patient has a tumor which expresses PD-L1, as determined by an FDA-approved, or CE Mark test.
In one embodiment, a CDK4/6 inhibitor, in combination with a PD-1 or PD-L1 checkpoint inhibitor, and an additional immune checkpoint inhibitor (ICI) selected from a T cell immunoreceptor with Ig and ITIM domains (TIGIT) checkpoint inhibitor, a T-cell immunoglobulin mucin-3 (TIM-3) checkpoint inhibitor, a Lymphocyte-activation gene 3 (LAG- 3) checkpoint inhibitor or a Cluster of Differentiation 73 (CD73) checkpoint inhibitor can be used in conjunction with a number of standard of care chemotherapeutic treatment regimens for the treatment of a solid tumor.
In one embodiment, the CDK4/6 inhibitor is trilaciclib. In some embodiments, trilaciclib is administered less than 4 hours prior to the administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered about one hour or less, for example, about 45 minutes, about 40 minutes, about 35 minutes, or about 30 minutes, prior to administration of the first-line chemotherapeutic regimen. In some embodiments, trilaciclib is administered to the patient intravenously between about 190 and 280 mg/m2. In some embodiments, the trilaciclib is administered at about 240 mg/m2.
In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the immune checkpoint inhibitor is a PD-1 inhibitor selected from a group consisting of nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®) and dostarlimab (JEMPERLI®). In one embodiment, the PD-1 inhibitor is nivolumab. In some embodiments, nivolumab is administered at 360 mg with a platinum-containing chemotherapy on the same day every 3 weeks for 3 cycles. In some embodiments, nivolumab is administered at 240 mg every 2 weeks or 480 mg every 4 weeks. In one embodiment, the PD-1 inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at 200 mg every 3 weeks or 400 mg every 6 weeks. In one embodiment, the PD-1 inhibitor is cemiplimab. In some embodiments cemiplimab is administered at 350 mg as an intravenous infusion over 30 minutes every 3 weeks. In one embodiment, the PD-1 inhibitor is dostarlimab. In some embodiments dostarlimab is administered at 500 mg every 3 weeks for Dose 1-4 and then 1,000 mg every 6 weeks as an intravenous infusion over 30 minutes. In one embodiment, the immune checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is selected from a group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®). In one embodiment, the PD-LI inhibitor is atezolizumab. In some embodiments, atezolizumab is administered at as 840 mg every 2 weeks, 1200 mg every 3 weeks or 1680 mg every 4 weeks for up to 1 year. In some embodiments, the PD-LI inhibitor is avelumab. In some embodiments, avelumab is administered at 800 mg every 2 weeks as an intravenous infusion over 60 minutes. In one embodiment, the PD-LI inhibitor is durvalumab. In some embodiments, durvalumab is administered at 10 mg/kg every 2 weeks or 1500 mg every 4 weeks for patients that weigh more than 30 kg and 10 mg/kg every 2 weeks for patients that weigh less than 30 kg.
In one embodiment the additional checkpoint inhibitor is a TIGIT checkpoint inhibitor. In one embodiment, the TIGIT checkpoint inhibitor is selected from a group consisting of Vibostolimab (MK-7684; Merck), Etigilimab/OMP-313 M32 (OncoMed), Tiragolumab (MTIG7192A/RG-6058; Roche/Genentech), ociperlimab (BGB-A1217; Beigene), BMS-986207 (BMS), COM902 (Compugen), M6223 (Merck KGaA), domvanalimab (AB- 154; Arcus Biosciences), AZD2936 (AstraZeneca), JS006 (Shanghai Junshi Bioscience), IBI139 (Innovent Biologies), ASP-8374 (Astellas/Potenza), BAT6021 (Bio-Thera Solutions), TAB006 (Shanghai Junshi Bioscience), Domvanalimab (AB154; Arcus Biosciences), EOS884448 (EOS-448; iTeos), SEA-TGT (Seattle Genetics), mAb-7 (Stanwei Biotech); SHR-1708 (Hengrui Medicine), GS02 (Suzhou Zelgen/Qilu Pharma), RXI-804 (Rxi Pharmaceuticals), NB6253 (Northern Biologies), ENUM009 (Enumreal Biomedical), CASC-674 (Cascadian Therapeutics), AJUD008 (AJUD Biopharma), AGEN1777 (Agenus, Bristol-Myers Squibb), HLX53 (Shanghai Henlius Biotech), BAT6005 (Bio-Thera Solutions), the anti-TIGIT/anti -PD-LI bispecific antibody HLX301 (Shanghai Henlius Biotech) and the anti-TIGIT/anti-PD-Ll antibody HB0036 (Shanghai Huaota Biopharmaceutical).
In one embodiment the additional checkpoint inhibitor is a TIM-3 checkpoint inhibitor. In one embodiment, the TIM-3 checkpoint inhibitor is selected from a group consisting of Cobolimab (TSR-022; Tesaro), RG7769 (Genentech), MAS825 (Novartis), sabatolimab (MBG453; Novartis), Sym023 (Symphogen), INCAGN2390 (Incyte), LY3321367 (Eli Lilly and Company), BMS- 986258 (BMS), SHR-1702 (Jiangsu HengRui), AZD7789 (AstraZeneca); TQB2618 (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.); and NB002 (Neologies Bioscience), BGBA425 (Beigene) and the Tim-3 and PD-1 bispecific RO7121661 (Roche).
In one embodiment the additional checkpoint inhibitor is a LAG-3 checkpoint inhibitor. In one embodiment, the LAG-3 checkpoint inhibitor is selected from a group consisting of relatlimab (Opdualag®; BMS-986016; Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), eftilagimod alpha (IMP321; Prima BioMed), leramilimab (LAG525; Novartis), favezelimab (MK- 4280; Merck), fianlimab (REGN3767; Regeneron), TSR-033 (Tesaro/GSK), BI754111 (Boehringer Ingelheim), Sym022 (Symphogen), LBL-007 (Nanjing Leads Biolabs), IBI110 (Innovent Biologies), IB 1323 (Innovent Biologies), INCAGN02385 (Incyte Corporation), AVA021 (Avacta), MGD013 (Macrogenics), RO7247669 (Hoffman-LaRoche), EMB-02 (Shanghai Epimab Biotherapeutics), XmAb841 (Xencor), the dual PD-1 and LAG-3 inhibitor tebotelimab (MGD013; MacroGenics), CB213 (Crescendo Biologies), and SNA-03 (Microbio Group) and the dual PD-L1 and LAG-3 inhibitor FS118 (F-Star).
In one embodiment the additional checkpoint inhibitor is a CD73 checkpoint inhibitor. In one embodiment, the CD73 checkpoint inhibitor is selected from a group consisting of HLX23 (Shanghai Henlius Biotech), LY3475070 (Eli Lilly and Company), IPH5301 (Innate Pharma, AstraZeneca), AK119 (Akesobio Australia Pty Ltd.), PT199 (Phanes Therapeutics), mupadolimab (CPI-006; Corvus Pharmaceuticals), Sym024 (Symphogen), oleclumab (MEDI9447; Astra Zeneca), IBI325 (Innovent Biologies), ORIC-533 (Oric Pharmaceuticals), JAB-BX102 (Jacobio Pharmaceuticals), TJ004309 (Tracon Pharmaceuticals), AB680 (Arcus Biosciences), NZV930 (Novartis), BMS-986179 (Bristol Myers Squibb), INCA00186 (Incyte Corporation), and the Anti- CD73-TGFP-Trap Bifunctional Antibody dalutrafusp alfa (Gilead Sciences).
Pharmaceutical Compositions and Dosage Forms
The active compounds described herein for use in the methods described herein, or its salt, isotopic analog, or prodrug can be administered in an effective amount to a subject using any suitable approach which achieves the desired therapeutic result. The amount and timing of the active compounds administered will, of course, be dependent on the subject being treated, the instructions of the supervising medical specialist, on the time course of the exposure, on the manner of administration, on the pharmacokinetic properties of the particular active compound, and on the judgment of the prescribing physician. Thus, because of host to host variability, the dosages given below are a guideline and the physician can titrate doses of the active compounds to achieve the treatment that the physician considers appropriate for the host. In considering the degree of treatment desired, the physician can balance a variety of factors such as age and weight of the host, presence of preexisting disease, as well as presence of other diseases. General administration dosages for CDK4/6 inhibitors such as Compound I have been previously described in WO 2016/126889, incorporated herein by its entirety.
The pharmaceutical compositions may be administered in a therapeutically effective amount by any desired mode of administration, but is typically administered as an intravenous injection or infusion. In alternative embodiments, the compounds or pharmaceutically acceptable salts are delivered in an effective amount with a pharmaceutically acceptable carrier for oral delivery. As more general non-limiting examples, the pharmaceutical composition one suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous), injections, inhalation or spray, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, or by other means of administration containing conventional pharmaceutically acceptable carriers.
The therapeutically effective dosage of any active compound described herein will be determined by the health care practitioner depending on the condition, size and age of the patient as well as the route of delivery. In one non-limited embodiment, a dosage from about 0.1 to about 200 mg/kg has therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed. In some embodiments, the dosage may be the amount of compound needed to provide a serum concentration of the active compound of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 pM, 5 pM, 10 pM, 20 pM, 30 pM, or 40 pM.
In certain embodiments, the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples of dosage forms with at least 0.01, 0.05, 0.1, 1, 5, 10, 15, 20, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent, in a ratio that achieves the desired results.
An effective amount of the disclosed compounds or their salts may be administered based on the weight, size or age of the patient. For example, a therapeutic amount may, for example, be in the range of about 0.01 mg/kg to about 250 mg/kg body weight, or about 0.1 mg/kg to about 10 mg/kg, in at least one dose. The patient can be administered as many doses as are required to reduce and/or alleviate and/or cure the disorder in question. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
In certain embodiments the dose ranges from about 0.01-500 mg/kg of patient body weight, for example about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 105 mg/kg, about 110 mg/kg, about 115 mg/kg, about 120 mg/kg, about 125 mg/kg, about 130 mg/kg, about 135 mg/kg, about 140 mg/kg, about 145 mg/kg, about 150 mg/kg, about 155 mg/kg, about 160 mg/kg, about 165 mg/kg, about 170 mg/kg, about 175 mg/kg, about 180 mg/kg, about 185 mg/kg, about 190 mg/kg, about 195 mg/kg, 200 mg/kg, about 205 mg/kg, about 210 mg/kg, about 215 mg/kg, about 220 mg/kg, about 225 mg/kg, about 230 mg/kg, about 235 mg/kg, about 240 mg/kg, about 245 mg/kg, about 250 mg/kg, about 255 mg/kg, about 260 mg/kg, about 265 mg/kg, about 270 mg/kg, about 275 mg/kg, about 280 mg/kg, about 285 mg/kg, about 290 mg/kg, about 295 mg/kg, 300 mg/kg, about 305 mg/kg, about 310 mg/kg, about 315 mg/kg, about 320 mg/kg, about 325 mg/kg, about 330 mg/kg, about 335 mg/kg, about 340 mg/kg, about 345 mg/kg, about 350 mg/kg, about 355 mg/kg, about 360 mg/kg, about 365 mg/kg, about 370 mg/kg, about 375 mg/kg, about 380 mg/kg, about 385 mg/kg, about 390 mg/kg, about 395 mg/kg, 400 mg/kg, about 405 mg/kg, about 410 mg/kg, about 415 mg/kg, about 420 mg/kg, about 425 mg/kg, about 430 mg/kg, about 435 mg/kg, about 440 mg/kg, about 445 mg/kg, about 450 mg/kg, about 455 mg/kg, about 460 mg/kg, about 465 mg/kg, about 470 mg/kg, about 475 mg/kg, about 480 mg/kg, about 485 mg/kg, about 490 mg/kg, about 495 mg/kg, or about 500 mg/kg.
In one embodiment, the CDK4/6 inhibitor administered is trilaciclib, which is administered at a dosage of about 180 mg/m2 to about 280 mg/m2. In one embodiment, trilaciclib is administered at about 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, or about 280 mg/m2. In one embodiment, trilaciclib is administered at a dose of about 200 mg/m2. In one embodiment, trilaciclib is administered at a dose of about 240 mg/m2.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
In certain embodiments the compounds for administration are administered as a pharmaceutically acceptable salt. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
Compounds disclosed herein or used as described herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intravenous, intramuscular, inhalation, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcomeal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device.
In accordance with the presently disclosed methods, an oral administration can be in any desired form such as a solid, gel or liquid, including a solution, suspension, or emulsion. In some embodiments, the compounds or salts are administered by inhalation, intravenously, or intramuscularly as a liposomal suspension. When administered through inhalation the active compound or salt may be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, from about 0.01, 0.1 or 0.5 to about 5, 10, 20 or more microns, and optionally from about 1 to about 2 microns. Compounds as disclosed in the present invention have demonstrated good pharmacokinetic and pharmacodynamics properties, for instance when administered by the oral or intravenous routes.
The pharmaceutical formulations can comprise an active compound described herein or a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water may sometimes be the carrier of choice for water-soluble compounds or salts. With respect to the water-soluble compounds or salts, an organic vehicle, such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, can be suitable. In the latter instance, the organic vehicle can contain a substantial amount of water. The solution in either instance can then be sterilized in a suitable manner known to those in the art, and for illustration by filtration through a 0.22-micron filter. Subsequent to sterilization, the solution can be dispensed into appropriate receptacles, such as depyrogenated glass vials. The dispensing is optionally done by an aseptic method. Sterilized closures can then be placed on the vials and, if desired, the vial contents can be lyophilized.
Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
In addition to the active compounds or their salts, the pharmaceutical formulations can contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the formulations can contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. An antimicrobial preservative is typically employed when the formulations is placed in a vial designed for multi-dose use. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.
For oral administration, a pharmaceutical composition can take the form of a solution suspension, tablet, pill, capsule, powder, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate, and talc are often very useful for tableting purposes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules. Materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of the presently disclosed host matter can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
In yet another embodiment of the host matter described herein, there are provided injectable, stable, sterile formulations comprising an active compound as described herein, or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate, which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form liquid formulation suitable for injection thereof into a host. When the compound or salt is substantially water-insoluble, a sufficient amount of emulsifying agent, which is physiologically acceptable, can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier. Particularly useful emulsifying agents include phosphatidyl cholines and lecithin.
Additional embodiments provided herein include liposomal formulations of the active compounds disclosed herein. The technology for forming liposomal suspensions is well known in the art. When the compound is an aqueous-soluble salt, using conventional liposome technology, the same can be incorporated into lipid vesicles. In such an instance, due to the water solubility of the active compound, the active compound can be substantially entrained within the hydrophilic center or core of the liposomes. The lipid layer employed can be of any conventional composition and can either contain cholesterol or can be cholesterol-free. When the active compound of interest is water-insoluble, again employing conventional liposome formation technology, the salt can be substantially entrained within the hydrophobic lipid bilayer that forms the structure of the liposome. In either instance, the liposomes that are produced can be reduced in size, as through the use of standard sonication and homogenization techniques. The liposomal formulations comprising the active compounds disclosed herein can be lyophilized to produce a lyophilizate, which can be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
Pharmaceutical formulations also are provided which are suitable for administration as an aerosol by inhalation. These formulations comprise a solution or suspension of a desired compound described herein or a salt thereof, or a plurality of solid particles of the compound or salt. The desired formulations can be placed in a small chamber and nebulized. Nebulization can be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the compounds or salts. The liquid droplets or solid particles may for example have a particle size in the range of about 0.5 to about 10 microns, and optionally from about 0.5 to about 5 microns. In one embodiment, the solid particles provide for controlled release through the use of a degradable polymer. The solid particles can be obtained by processing the solid compound or a salt thereof, in any appropriate manner known in the art, such as by micronization. Optionally, the size of the solid particles or droplets can be from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose. The compounds can be administered via an aerosol suspension of respirable particles in a manner set forth in U.S. Pat. No. 5,628,984, the disclosure of which is incorporated herein by reference in its entirety.
Pharmaceutical formulations also are provided which provide a controlled release of a compound described herein, including through the use of a degradable polymer, as known in the art.
When the pharmaceutical formulations suitable for administration as an aerosol is in the form of a liquid, the formulations can comprise a water-soluble active compound in a carrier that comprises water. A surfactant can be present, which lowers the surface tension of the formulations sufficiently to result in the formation of droplets within the desired size range when hosted to nebulization.
The term "pharmaceutically acceptable salts" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with hosts (e.g., human hosts) without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the presently disclosed host matter.
Thus, the term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the presently disclosed compounds. These salts can be prepared during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Basic compounds are capable of forming a wide variety of different salts with various inorganic and organic acids. Acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ from their respective salt forms in certain physical properties such as solubility in polar solvents. Pharmaceutically acceptable base addition salts may be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations, include, but are not limited to, sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include, but are not limited to, N,N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-m ethylglucamine, and procaine. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms may differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents.
Salts can be prepared from inorganic acids sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, laurylsulphonate and isethionate salts, and the like. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts can include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like. See, for example, Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
Embodiments
Provided herein are at least the following embodiments:
1. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000155_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
2. The use of embodiment 1, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
3. The use of embodiment 1 or 2, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma. 4. The use of any of embodiments 1-3, wherein the solid cancer is small cell lung cancer.
5. The use of any of embodiments 1-3, wherein the solid cancer is non-small cell lung cancer.
6. The use of any of embodiments 1-3, wherein the solid cancer is triple negative breast cancer.
7. The use of any of embodiments 1-3, wherein the solid cancer is colorectal cancer.
8. The use of any of embodiments 1-3, wherein the solid cancer is urothelial cancer.
9. The use of any of embodiments 1-3, wherein the solid cancer is cervical cancer.
10. The use of any of embodiments 1-3, wherein the solid cancer is esophageal cancer.
11. The use of any of embodiments 1-3, wherein the solid cancer is melanoma.
12. The use of any of embodiments 1-3, wherein the solid cancer is head and neck squamous cell carcinoma.
13. The use of any of embodiments 1-12, wherein the treatment is administered to the human in a first-line setting.
14. The use of any of embodiments 1-12, wherein the treatment is administered to the human in a second-line setting.
15. The use of embodiment 14, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
16. The use of any of embodiments 1-15, wherein the human is administered an effective amount of a PD-1 inhibitor.
17. The use of embodiment 16, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
18. The use of embodiment 17, wherein the PD-1 inhibitor is nivolumab.
19. The use of any of embodiments 1-15, wherein the human is administered an effective amount of a PD-L1 inhibitor.
20. The use of embodiment 19, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333. 21. The use of any of embodiments 1-20, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
22. The use of embodiment 21, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
23. The use of embodiment 22, wherein the LAG-3 inhibitor is relatlimab.
24. The use of any of embodiments 1-20, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
25. The use of embodiment 24, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
26. The use of any of embodiments 1-20, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
27. The use of embodiment 26, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
28. The use of any of embodiments 1-20, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
29. The use of embodiment 28, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
30. The use of any of embodiments 1-29, wherein trilaciclib is administered once a week.
31. The use of any of embodiments 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
32. The use of any of embodiments 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks. 33. The use of any of embodiments 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
34. The use of any of embodiments 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
35. The use of any of embodiments 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
36. The use of any of embodiments 2-35, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
37. The use of any of embodiment 36, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
38. The use of embodiment 36 or 37, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
39. The use of embodiment 36 or 37, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
40. The use of any of embodiments 1-39, wherein the solid cancer expresses PD-L1. 41. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000159_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
42. The use of embodiment 41, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
43. The use of embodiment 41 or 42, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
44. The use of any of embodiments 41-43, wherein the solid cancer is colorectal cancer.
45. The use of any of embodiments 41-43, wherein the solid cancer is small cell lung cancer.
46. The use of any of embodiments 41-43, wherein the solid cancer is non-small cell lung cancer.
47. The use of any of embodiments 41-43, wherein the solid cancer is triple negative breast cancer.
48. The use of any of embodiments 41-43, wherein the solid cancer is urothelial cancer.
49. The use of any of embodiments 41-43, wherein the solid cancer is cervical cancer.
50. The use of any of embodiments 41-43, wherein the solid cancer is esophageal cancer.
51. The use of any of embodiments 41-43, wherein the solid cancer is melanoma. 52. The use of any of embodiments 41-43, wherein the solid cancer is head and neck squamous cell carcinoma.
53. The use of any of embodiments 41 -52, wherein the treatment is administered to the human in a first-line setting.
54. The use of any of embodiments 41-52, wherein the treatment is administered to the human in a second-line setting.
55. The use of embodiment 54, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
56. The use of any of embodiments 41-55, wherein the human is administered an effective amount of a PD-1 inhibitor.
57. The use of embodiment 56, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
58. The use of any of embodiments 41-55, wherein the human is administered an effective amount of a PD-L1 inhibitor.
59. The use of embodiment 58, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
60. The use of embodiments 41-59, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
61. The use of any of embodiments 41-60, wherein trilaciclib is administered once a week.
62. The use of any of embodiments 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
63. The use of any of embodiments 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
64. The use of any of embodiments 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every four weeks. 65. The use of any of embodiments 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every six weeks.
66. The use of any of embodiments 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
67. The use of any of embodiments 42-66, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
68. The use of embodiment 67, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
69. The use of embodiment 67 or 68, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
70. The use of embodiment 67 or 68, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
71. The use of any of embodiments 41-70, wherein the solid cancer expresses PD-L1. 72. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000162_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG- 3) inhibitor.
73. The use of embodiment 72, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
74. The use of embodiment 72 or 73, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
75. The use of any of embodiments 72-74, wherein the solid cancer is colorectal cancer.
76. The use of any of embodiments 72-74, wherein the solid cancer is small cell lung cancer.
77. The use of any of embodiments 72-74, wherein the solid cancer is non-small cell lung cancer.
78. The use of any of embodiments 72-74, wherein the solid cancer is triple negative breast cancer.
79. The use of any of embodiments 72-74, wherein the solid cancer is urothelial cancer.
80. The use of any of embodiments 72-74, wherein the solid cancer is cervical cancer.
81. The use of any of embodiments 72-74, wherein the solid cancer is esophageal cancer.
82. The use of any of embodiments 72-74, wherein the solid cancer is melanoma. 83. The use of embodiment 82, wherein the melanoma is unresectable or metastatic melanoma.
84. The use of any of embodiments 72-74, wherein the solid cancer is head and neck squamous cell carcinoma.
85. The use of any of embodiments 72-84, wherein the treatment is administered to the human in a first-line setting.
86. The use of any of embodiments 72-84, wherein the treatment is administered to the human in a second-line setting.
87. The use of embodiment 86, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
88. The use of any of embodiments 72-87, wherein the human is administered an effective amount of a PD-1 inhibitor.
89. The use of embodiment 88, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
90. The use of embodiment 89, wherein the PD-1 inhibitor is nivolumab.
91. The use of any of embodiments 72-87, wherein the human is administered an effective amount of a PD-L1 inhibitor.
92. The use of embodiment 91, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
93. The use of any of embodiments 72-92, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
94. The use of embodiment 93, wherein the LAG-3 inhibitor is relatlimab.
95. The use of any of embodiments 68-86, wherein trilaciclib is administered once a week.
96. The use of any of embodiments 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks. 97. The use of any of embodiments 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks.
98. The use of any of embodiments 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
99. The use of any of embodiments 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every six weeks.
100. The use of any of embodiments 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
101. The use of any of embodiments 73-100, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
102. The use of embodiment 101, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
103. The use of embodiment 101 or 102, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
104. The use of embodiment 101 or 102, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
105. The use of any of embodiments 72-104, wherein the solid cancer PD-L1.
106. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000165_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
107. The use of embodiment 106, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
108. The use of embodiment 106 or 107, wherein the treatment is administered to the human in a first-line setting.
109. The use of embodiment 106 or 107, wherein the treatment is administered to the human in a second-line setting.
110. The use of embodiment 109, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
111. The use of any of embodiments 106-110, wherein trilaciclib is administered once a week.
112. The use of any of embodiments 106-111, wherein nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
113. The use of embodiment 112, wherein nivolumab and relatlimab are administered once every four weeks. 114. The use of any of embodiments 106-111, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, herein the duration of the first cycle is different than the duration of the second cycle.
115. The use of any of embodiments 107-114, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
116. The use of any of embodiment 115, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
117. The use of embodiment 115 or 116, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
118. The use of embodiment 115 or 116, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
119. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000167_0001
or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a Cluster of Differentiation 73 (CD73) inhibitor.
120. The use of embodiment 119, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
121. The use of embodiment 119 or 120, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
122. The use of any of embodiments 119-121, wherein the solid cancer is colorectal cancer.
123. The use of any of embodiments 119-121, wherein the solid cancer is small cell lung cancer.
124. The use of any of embodiments 119-121, wherein the solid cancer is non-small cell lung cancer.
125. The use of any of embodiments 119-121, wherein the solid cancer is triple negative breast cancer.
126. The use of any of embodiments 119-121, wherein the solid cancer is urothelial cancer.
127. The use of any of embodiments 119-121, wherein the solid cancer is cervical cancer.
128. The use of any of embodiments 119-121, wherein the solid cancer is esophageal cancer.
129. The use of any of embodiments 119-121, wherein the solid cancer is melanoma.
130. The use of any of embodiments 119-121, wherein the solid cancer is head and neck squamous cell carcinoma.
131. The use of any of embodiments 119-130, wherein the treatment is administered to the human in a first-line setting. 132. The use of any of embodiments 119-130, wherein the treatment is administered to the human in a second-line setting.
133. The use of embodiments 132, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
134. The use of any of embodiments 116-133, wherein the human is administered an effective amount of a PD-1 inhibitor.
135. The use of embodiment 134, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
136. The use of any of embodiments 116-133, wherein the human is administered an effective amount of a PD-L1 inhibitor.
137. The use of embodiment 136, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
138. The use of any of embodiments 116-137, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
139. The use of any of embodiments 116-138, wherein trilaciclib is administered once a week.
140. The use of any of embodiments 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
141. The use of any of embodiments 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks.
142. The use of any of embodiments 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
143. The use of any of embodiments 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks. 144. The use of any of embodiments 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
145. The use of any of embodiments 117-144, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
146. The use of any of embodiment 145, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
147. The use of embodiment 145 or 146, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
148. The use of embodiment 145 or 146, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
149. The use of any of embodiments 116-148, wherein the solid cancer expresses PD-L1.
150. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000170_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the patient an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
151. The use of embodiment 150, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
152. The use of embodiment 150 or 151, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
153. The use of any of embodiments 150-152, wherein the treatment is administered to the patient in a first-line setting.
154. The use of any of embodiments 150-152, wherein the treatment is administered to the patient in a second-line setting.
155. The use of embodiment 154, wherein the patient has previously received a PD-1 or PD- L1 inhibitor and has experienced disease progression.
156. The use of any of embodiments 150-155, wherein the patient is administered an effective amount of a PD-1 inhibitor.
157. The use of embodiment 156, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
158. The use of any of embodiments 150-155, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
159. The use of embodiment 158, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
160. The use of any of embodiments 150-159, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
161. The use of embodiment 160, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
162. The use of any of embodiments 150-159, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
163. The use of embodiment 162, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
164. The use of any of embodiments 150-159, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
165. The use of embodiment 164, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223 or HB0036.
166. The use of embodiments any of embodiments 150-159, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
167. The use of embodiment 166, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa. 168. The use of any of embodiments 150-167, wherein trilaciclib is administered once a week.
169. The use of any of embodiments 150-168, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
170. The use of any of embodiments 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
171. The use of any of embodiments 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
172. The use of any of embodiments 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
173. The use of any of embodiments 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
174. The use of embodiment 150, wherein a PD-1 inhibitor is administered and a LAG-3 inhibitor is administered, and wherein the PD-1 inhibitor is nivolumab and the LAG-3 inhibitor is relatlimab.
175. The use of embodiments 151-173, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
176. The use of embodiment 175, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
177. The use of embodiment 175 or 176, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
178. The use of embodiment 175 or 176, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
179. The use of any of embodiments 150-178, wherein the solid cancer expresses PD-L1.
180. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the
CDK4/6 inhibitor has the structure:
Figure imgf000173_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a TIM-3 inhibitor.
181. The use of embodiment 180, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
182. The use of embodiment 180 or 181, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
183. The use of any of embodiments 180-182, wherein the treatment is administered to the patient in a first-line setting. 184. The use of any of embodiments 180-182, wherein the treatment is administered to the patient in a second-line setting.
185. The use of embodiment 184, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
186. The use of any of embodiments 180-185, wherein the patient is administered an effective amount of a PD-1 inhibitor.
187. The use of embodiment 186, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
188. The use of any of embodiments 180-185, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
189. The use of embodiment 188, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
190. The use of any of embodiments 180-189, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
191. The use of any of embodiments 180-190, wherein trilaciclib is administered once a week.
192. The use of any of embodiments 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
193. The use of any of embodiments 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
194. The use of any of embodiments 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every four weeks.
195. The use of any of embodiments 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every six weeks.
196. The use of any of embodiments 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
197. The use of any of embodiments 181-196, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
198. The use of embodiment 197, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
199. The use of embodiment 197 or 198, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
200. The use of embodiment 197 or 198, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
201. The use of embodiments 181-200, wherein the solid cancer expresses PD-L1.
202. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000176_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a LAG-3 inhibitor.
203. The use of embodiment 202, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
204. The use of embodiment 202 or 203, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
205. The use of any of embodiments 202-204, wherein the treatment is administered to the patient in a first-line setting.
206. The use of any of embodiments 202-204, wherein the treatment is administered to the patient in a second-line setting.
207. The use of embodiment 206, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
208. The use of any of embodiments 202-207, wherein the patient is administered an effective amount of a PD-1 inhibitor.
209. The use of embodiment 208, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
210. The use of embodiment 209, wherein the PD-1 inhibitor is nivolumab.
211. The use of any of embodiments 202-207, wherein the patient is administered an effective amount of a PD-L1 inhibitor. 212. The use of embodiment 211, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
213. The use of any of embodiments 202-212, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
214. The use of embodiment 213, wherein the LAG-3 inhibitor is relatlimab.
215. The use of any of embodiments 202-214, wherein trilaciclib is administered once a week.
216. The use of any of embodiments 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks.
217. The use of any of embodiments 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks.
218. The use of any of embodiments 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
219. The use of any of embodiments 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every six weeks.
220. The use of any of embodiments 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
221. The use of any of embodiments 203-220, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
222. The use of embodiment 221, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent. 223. The use of embodiment 221 or 222, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
224. The use of embodiment 221 or 222, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
225. The use of any of embodiments 202-224, wherein the solid cancer PD-L1.
226. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000178_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a CD73 inhibitor.
227. The use of embodiment 226, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent. 228. The use of embodiment 226 or 227, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, or head and neck squamous cell carcinoma.
229. The use of any of embodiments 226-228, wherein the treatment is administered to the patient in a first-line setting.
230. The use of any of embodiments 226-228, wherein the treatment is administered to the patient in a second-line setting.
231. The use of embodiment 230, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
232. The use of any of embodiments 226-231, wherein the patient is administered an effective amount of a PD-1 inhibitor.
233. The use of embodiment 232, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
234. The use of any of embodiments 226-231, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
235. The use of embodiment 234, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
236. The use of any of embodiments 226-235, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
237. The use of any of embodiments 226-236, wherein trilaciclib is administered once a week.
238. The use of any of embodiments 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
239. The use of any of embodiments 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks. 240. The use of any of embodiments 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
241. The use of any of embodiments 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks.
242. The use of any of embodiments 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
243. The use of any of embodiments 227-242, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
244. The use of embodiment 243, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
245. The use of embodiment 243 or 244, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
246. The use of embodiment 243 or 244, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
247. The use of any of embodiments 226-246, wherein the solid cancer expresses PD-L1. 248. A composition for use for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the composition for use comprises a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000181_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; and, wherein the treatment comprises: a. administering to the patient an effective amount of trilaciclib, b. administering to the patient an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the patient an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
249. The composition of embodiment 248, wherein the treatment further comprises administering to the patient an effective amount of a chemotherapeutic agent.
250. The composition of embodiment 248 or 249, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
251. The composition of any of embodiments 248-250, wherein the treatment is administered to the patient in a first-line setting.
252. The composition of any of embodiments 248-250, wherein the treatment is administered to the patient in a second-line setting.
253. The composition of embodiment 252, wherein the patient has previously received a PD- 1 or PD-L1 inhibitor and has experienced disease progression. 254. The composition of any of embodiments 248-253, wherein the patient is administered an effective amount of a PD-1 inhibitor.
255. The composition of embodiment 254, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP-224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
256. The composition of embodiment 255, wherein the PD-1 inhibitor is nivolumab.
257. The composition of any of embodiments 248-253, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
258. The composition of embodiment 257, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
259. The composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
260. The composition of embodiment 259, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
261. The composition of embodiment 260, wherein the LAG-3 inhibitor is relatlimab.
262. The composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
263. The composition of embodiment 262, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
264. The composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
265. The composition of embodiment 264, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223 or HB0036.
266. The composition of any of embodiments 248-258, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
267. The composition of embodiment 266, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
268. The composition of any of embodiments 248-267, wherein trilaciclib is administered once a week.
269. The composition of any of embodiments 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
270. The composition of any of embodiments 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
271. The composition of any of embodiments 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
272. The composition of any of embodiments 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
273. The composition of any of embodiments 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
274. The composition of embodiment 248, wherein a PD-1 inhibitor is administered and a LAG-3 inhibitor is administered, and wherein the PD-1 inhibitor is nivolumab and the LAG-3 inhibitor is relatlimab. 275. The composition of any of embodiments 249-273, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
276. The composition of embodiment 275, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
277. The composition of embodiment 275 or 276, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
278. The composition of embodiment 275 or 276, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin- stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5 -fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
279. The composition of any of embodiments 248-278, wherein the solid cancer expresses
PD-L1.
280. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000184_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
281. The method of embodiment 280, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
282. The method of embodiment 280 or 281, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
283. The method of any of embodiments 280-282, wherein the solid cancer is small cell lung cancer.
284. The method of any of embodiments 280-282, wherein the solid cancer is non-small cell lung cancer.
285. The method of any of embodiments 280-282, wherein the solid cancer is triple negative breast cancer.
286. The method of any of embodiments 280-282, wherein the solid cancer is colorectal cancer.
287. The method of any of embodiments 280-282, wherein the solid cancer is urothelial cancer.
288. The method of any of embodiments 280-282, wherein the solid cancer is cervical cancer.
289. The method of any of embodiments 280-282, wherein the solid cancer is esophageal cancer.
290. The method of any of embodiments 280-282, wherein the solid cancer is melanoma.
291. The method of any of embodiments 280-282, wherein the solid cancer is head and neck squamous cell carcinoma. 292. The method of any of embodiments 280-291, wherein the treatment is administered to the human in a first-line setting.
293. The method of any of embodiments 280-291, wherein the treatment is administered to the human in a second-line setting.
294. The method of embodiment 293, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
295. The method of any of embodiments 280-294, wherein the human is administered an effective amount of a PD-1 inhibitor.
296. The method of embodiment 295, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
297. The method of embodiment 296, wherein the PD-1 inhibitor is nivolumab.
298. The method of any of embodiments 280-294, wherein the human is administered an effective amount of a PD-L1 inhibitor.
299. The method of embodiment 298, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
300. The method of any of embodiments 280-299, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
301. The method of embodiment 300, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
302. The method of embodiment 301, wherein the LAG-3 inhibitor is relatlimab.
303. The method of any of embodiments 280-299, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
304. The method of embodiment 303, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS- 986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661. 305. The method of any of embodiments 280-299, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
306. The method of embodiment 305, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
307. The method of any of embodiments 280-299, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
308. The method of embodiment 307, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
309. The method of any of embodiments 280-308, wherein trilaciclib is administered once a week.
310. The method of any of embodiments 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
311. The method of any of embodiments 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
312. The method of any of embodiments 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
313. The method of any of embodiments 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
314. The method of any of embodiments 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle. 315. The method of any of embodiments 281-314, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
316. The method of any of embodiment 315, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
317. The method of embodiment 314 or 315, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
318. The method of embodiment 314 or 315, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
319. The method of any of embodiments 280-318, wherein the solid cancer expresses PD-L1.
320. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000188_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
321. The method of embodiment 320, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
322. The method of embodiment 320 or 321, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
323. The method of any of embodiments 320-322, wherein the solid cancer is colorectal cancer.
324. The method of any of embodiments 320-322, wherein the solid cancer is small cell lung cancer.
325. The method of any of embodiments 320-322, wherein the solid cancer is non-small cell lung cancer.
326. The method of any of embodiments 320-322, wherein the solid cancer is triple negative breast cancer.
327. The method of any of embodiments 320-322, wherein the solid cancer is urothelial cancer.
328. The method of any of embodiments 320-322, wherein the solid cancer is cervical cancer.
329. The method of any of embodiments 320-322, wherein the solid cancer is esophageal cancer.
330. The method of any of embodiments 320-322, wherein the solid cancer is melanoma.
331. The method of any of embodiments 320-322, wherein the solid cancer is head and neck squamous cell carcinoma.
332. The method of any of embodiments 320-331, wherein the treatment is administered to the human in a first-line setting.
333. The method of any of embodiments 320-331, wherein the treatment is administered to the human in a second-line setting.
334. The method of embodiment 333, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression. 335. The method of any of embodiments 320-334, wherein the human is administered an effective amount of a PD-1 inhibitor.
336. The method of embodiment 335, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
337. The method of any of embodiments 320-334, wherein the human is administered an effective amount of a PD-L1 inhibitor.
338. The method of embodiment 337, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
339. The method of embodiments 320-338, wherein the TIM-3 inhibitor is selected from
Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS- 986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
340. The method of any of embodiments 320-339, wherein trilaciclib is administered once a week.
341. The method of any of embodiments 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
342. The method of any of embodiments 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
343. The method of any of embodiments 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every four weeks.
344. The method of any of embodiments 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every six weeks.
345. The method of any of embodiments 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
346. The method of any of embodiments 321-345, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
347. The method of embodiment 346, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
348. The method of embodiment 346 or 347, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
349. The method of embodiment 346 or 347, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
350. The method of any of embodiments 320-349, wherein the solid cancer expresses PD-L1.
351. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000191_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG- 3) inhibitor.
352. The method of embodiment 351, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
353. The method of embodiment 351 or 352, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
354. The method of any of embodiments 351-353, wherein the solid cancer is colorectal cancer.
355. The method of any of embodiments 351-353, wherein the solid cancer is small cell lung cancer.
356. The method of any of embodiments 351-353, wherein the solid cancer is non-small cell lung cancer.
357. The method of any of embodiments 351-353, wherein the solid cancer is triple negative breast cancer.
358. The method of any of embodiments 351-353, wherein the solid cancer is urothelial cancer.
359. The method of any of embodiments 351-353, wherein the solid cancer is cervical cancer.
360. The method of any of embodiments 351-353, wherein the solid cancer is esophageal cancer.
361. The method of any of embodiments 351-353, wherein the solid cancer is melanoma.
362. The method of embodiment 361, wherein the melanoma is unresectable or metastatic melanoma.
363. The method of any of embodiments 351-353, wherein the solid cancer is head and neck squamous cell carcinoma. 364. The method of any of embodiments 351-353, wherein the treatment is administered to the human in a first-line setting.
365. The method of any of embodiments 351-353, wherein the treatment is administered to the human in a second-line setting.
366. The method of embodiment 365, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
367. The method of any of embodiments 351-366, wherein the human is administered an effective amount of a PD-1 inhibitor.
368. The method of embodiment 367, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
369. The method of embodiment 368, wherein the PD-1 inhibitor is nivolumab.
370. The method of any of embodiments 351-366, wherein the human is administered an effective amount of a PD-L1 inhibitor.
371. The method of embodiment 370, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
372. The method of any of embodiments 351-371, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
373. The method of embodiment 372, wherein the LAG-3 inhibitor is relatlimab.
374. The method of any of embodiments 351-373, wherein trilaciclib is administered once a week.
375. The method of any of embodiments 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks.
376. The method of any of embodiments 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks. 377. The method of any of embodiments 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
378. The method of any of embodiments 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every six weeks.
379. The method of any of embodiments 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
380. The method of any of embodiments 352-379, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
381. The method of embodiment 380, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
382. The method of embodiment 380 or 381, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
383. The method of embodiment 380 or 381, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
384. The method of any of embodiments 351-383, wherein the solid cancer PD-L1. 385. A method of treating a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000195_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
386. The method of embodiment 385, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
387. The method of embodiment 385 or 386, wherein the treatment is administered to the human in a first-line setting.
388. The method of embodiment 385 or 386, wherein the treatment is administered to the human in a second-line setting.
389. The method of embodiment 388, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
390. The method of any of embodiments 385-389, wherein trilaciclib is administered once a week.
391. The method of any of embodiments 385-390, wherein nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
392. The method of embodiment 391, wherein nivolumab and relatlimab are administered once every four weeks.
393. The method of any of embodiments 385-392, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
394. The method of any of embodiments 386-393, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
395. The method of any of embodiment 394, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
396. The method of embodiment 394 or 395, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
397. The method of embodiment 394 or 395, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
398. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000197_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a Cluster of Differentiation 73 (CD73) inhibitor.
399. The method of embodiment 398, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
400. The method of embodiment 398 or 399, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
401. The method of any of embodiments 398-400, wherein the solid cancer is colorectal cancer.
402. The method of any of embodiments 398-400, wherein the solid cancer is small cell lung cancer.
403. The method of any of embodiments 398-400, wherein the solid cancer is non-small cell lung cancer.
404. The method of any of embodiments 398-400, wherein the solid cancer is triple negative breast cancer.
405. The method of any of embodiments 398-400, wherein the solid cancer is urothelial cancer.
406. The method of any of embodiments 398-400, wherein the solid cancer is cervical cancer.
407. The method of any of embodiments 398-400, wherein the solid cancer is esophageal cancer.
408. The method of any of embodiments 398-400, wherein the solid cancer is melanoma. 409. The method of any of embodiments 398-400, wherein the solid cancer is head and neck squamous cell carcinoma.
410. The method of any of embodiments 398-409, wherein the treatment is administered to the human in a first-line setting.
411. The method of any of embodiments 398-409, wherein the treatment is administered to the human in a second-line setting.
412. The method of embodiments 411, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
413. The method of any of embodiments 398-412, wherein the human is administered an effective amount of a PD-1 inhibitor.
414. The method of embodiment 413, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
415. The method of any of embodiments 398-412, wherein the human is administered an effective amount of a PD-L1 inhibitor.
416. The method of embodiment 415, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
417. The method of any of embodiments 398-416, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
418. The method of any of embodiments 398-417, wherein trilaciclib is administered once a week.
419. The method of any of embodiments 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
420. The method of any of embodiments 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks. 421. The method of any of embodiments 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
422. The method of any of embodiments 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks.
423. The method of any of embodiments 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
424. The method of any of embodiments 399-423, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
425. The method of any of embodiment 424, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
426. The method of embodiment 424 or 425, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
427. The method of embodiment 424 or 425, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
428. The method of any of embodiments 398-427, wherein the solid cancer expresses PD-L1. Examples
The claimed invention is further described by way of the following non-limiting examples. Further aspects and embodiments of the present invention will be apparent to those of ordinary skill in the art, in view of the above disclosure and following experimental exemplification, included by way of illustration and not limitation, and with reference to the attached figures.
Example 1. Effect of Trilaciclib alone or in combination with LAG-3 on IFN-y production by exhausted T cells upon restimulation.
Splenocytes from MBP-tracker mice were stimulated with WT-MBP or APL-MBP for 72 hours to generate non-exhausted and exhausted cells, respectively. T cells were purified and rested before being re-stimulated in the presence of increasing concentrations of Trilaciclib or vehicle control +/- anti-LAG-3 (lOug/mL). Cell supernatants were collected at the end of culture to assess IFN-g production by ELISA. Data are presented as mean +/- SEM. Results are shown in Figure 1.
Example 2. In vivo tumor studies with chemotherapy/ICI inhibitor +/- trilaciclib.
Nine-week-old female C57BL/6 (C57BL/6NCrl) and BALB/c mice were implanted subcutaneously with 5* 105 MC3822 or CT26 American Type Culture Collection (ATCC) tumor cells, respectively (cell lines supplied by Charles River Laboratories). Two to three weeks after tumor injection and prior to treatment start (day 1 of the study), animals with individual tumor volumes from 80 to 120mm3 were sorted into the appropriate number of treatment groups, with group mean tumor volumes of 100 mm3. Trilaciclib (lOOmg/kg), oxaliplatin (lOmg/kg; Fresenius Kabi USA, Lot 8760467A01) or 5 -fluorouracil (5-FU; 75mg/kg, Fresenius Kabi USA, Lot 6113613) were administered intraperitoneally (IP) once weekly for 3 weeks. Anti-PD-Ll (BioXCell, Cat. No. BE0101, clone 10F.9G2, lOOpg/animal, IP) or anti -programmed death-1 (PD- 1; BioXCell, Cat. No. BE0146, clone RMP1-14, 5mg/ kg, IP) were given twice per week. Tumors were measured using calipers twice per week. Each animal was euthanized when its tumor volume reached the 1000 mm3 end point or at last day of the study. A partial response (PR) indicated that the tumor volume was <50% of its day 1 volume for three consecutive measurements during the course of the study, and >13.5mm3 for at least one of these three measurements. A complete response (CR) indicated that the tumor volume was <13.5mm3 for three consecutive measurements during the course of the study. Animals were scored only once during the study for a PR or CR event, and only as CR if both PR and CR criteria were satisfied. Results are shown for MC38 treated mice in Figures 2A-4B and for CT26 treated mice in Figures 5A-5B. Results show that Trilaciclib in combination with chemotherapy + anti-PD-1 enhances survival and suppresses tumor growth. Results were previously published (Anne Y Lai et al. J Immunother Cancer 2020; 8: e000847).
Example 3. Transient G1 arrest alters the proportion of intratumor T-cell subsets favoring effector T-cell function.
Tumors and spleens were harvested on days 5 and 9 from OP-treated and TOP -treated MC38 mice following the induction plus maintenance (IM) treatment schedule. Mouse tumor samples were dissociated according to the manufacturer’s instructions using the gentleMACS protocol Tumor Dissociation Kit (Miltenyi Biotech; catalog number 130-096-730). Single-cell suspensions were subsequently stained with LIVE/DEAD Fixable Aqua Dead Cell Stain Kit (Life Technologies) and Fragment crystallizable receptors were blocked using TruStain FcX (Biolegend) before staining with antibodies for cell surface markers: CD8+ T cells (CD45+ CD3+ CD1 lb-CD8+ CD4- ), CD4+ T cells (CD45+ CD3+ CD1 lb-CD8- CD4+ ), Tregs (CD45+ CD3+ CDl lb-CD8- CD4+ CD25+ FoxP3+), mMDSC (CDl lb+ CD3- Ly6C+ Ly6G-), gMDSC (CD1 lb+ CD3- Ly6C+ Ly6G+) and macrophages (CD1 lb+ CD3- Ly6C-Ly6G-). The proportion of Tregs in total tumor or spleen CD4+ T cells treated with vehicle, oxaliplatin/PD-1, or trilaciclib/oxaliplatin/PD-1 on days 5 and 9 is shown in Figure 6. The ratio of CD8+ T cells to Tregs (% CD8+ T cells/% Tregs) in the CD45+ population (n=5-8 tumors analyzed per treatment group and time point) are shown in Figure 7. Results show that the addition of trilaciclib reduces Tregs and leads to higher CD8: Treg ratios and Trilaciclib promotes CD8 T cell activation. For FoxP3 staining, cells were permeabilized with Transcription Factor Fixation/Permeabilization buffer (eBioscience) and incubated with anti-FoxP3 antibody. Spleens were processed to singlecell suspension, lysed with ammonium-chloride-potassium buffer to remove RBCs and stained with antibodies: activated CD8+ T cells (CD8+ CD4- CD69+), activated CD4+ T cells (CD4+ CD8- CD69+) and Tregs (CD4+ CD25+ FoxP3+). The proportion of activated (% CD69+) cells in CD8+ T cells is shown in Figure 8. Dead cells were excluded by propidium iodide staining. Antibody clones and vendor information are listed in the online supplemental methods. Data were collected on a FACSCanto II (BD Biosciences) and analyzed with FlowJo software (Tree Star). Results were previously published (Anne Y Lai et al. J Immunother Cancer 2020; 8: e000847).
Example 4. CDK4/6 inhibition augments anti-PD-1 antibody induced anti-tumor immunity.
MC38 and CT26 cells were injected into 6-8 wks C57BL/6 or Balb/c female mice subcutaneously, respectively. Vehicle control, CDK4/6 inhibitors (trilaciclib) were treated alone or together with PD-1 antibody starting at the indicated time point, using an intermittent dosing schedule of 3 days on, 4 days off until experimental endpoint. PD-1 antibody was administered 3 times a week (Monday, Wednesday and Friday) at 200 pg/mouse through I.P. injection. Tumor volumes were monitored every 2~3 days. Tumor growth curves of MC38 treated with CDK4/6 inhibitor or PD-1 antibody alone or in combination are shown in Figure 9. Naive or KP tumor bearing C57BL/6 mice were sacrificed and total splenocytes were harvested. Spleens were digested with collagenase D (Roche) and DNase I (Roche) at 37 °C for 30 min, followed by 1 x ACS lysis buffer (Biolegend) incubation to lyse red blood cells. The collected total splenocytes were stained with the fluorochome-conjugated cell surface markers CD3, CD4, CD8 and CD25 to isolate different T cell subpopulations, including conventional T cell Tconv (CD3+CD4+CD25-), Treg (CD3+CD4+CD25+), and CD8+ (CD3+CD8+) using BD FACSAria II SORP cell sorter (BD Bioscience). DAPI (4', 6- diamidino-2-phenylindole) staining was used to exclude dead cells. Sorted cells were cultured in 96-well plates pre-coated with CD3 antibody (eBioscience) and treated with trilaciclib in the presence of CD28 (eBioscience). Cells were collected 3 days after culturing and cytokine production of IFNy and IL-2 was determined by intracellular staining and analyzed on BD LSRFortessa (BD Bioscience). At the end of the treatment (day 17), mice were sacrificed and TILs were isolated from the tumor for cytokine analysis for IL-2 from CD4+ T cells (left panel) and IFNY from CD8+ T cells (right panel). (*p<0.001). The results are shown in Figures 10A-10B. This shows that Trilaciclib works synergistically with anti-PD-1 to enhance IL-2 production by CD4+ T cells and that Trilaciclib alone enhances IFN-y production in CD8+ T cells, and acts synergistically with anti-PD-1 Results were previously published (Deng J, Wang ES, Jenkins RW, et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2018 Feb;8(2):216-233). Example 5. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIGIT in the MMTV- PyMT Triple Negative Breast Cancer model.
5* 105 MMTV-PyMT tumor cells were implanted subcutaneously into the fourth inguinal mammary fat pads of nine-week-old female BALB/c mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk)
5. anti-TIGIT (10 mg/kg 2x qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
7. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1. Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody led to decreased tumor growth overall (Fig. 11 A) and fold change (Fig. 1 IB) in mice xenotransplanted with MMTV-PyMT tumor cells, which translated into gains in overall survival (Fig. 11C). The individual tumor growth curves for each treatment group were also plotted separately (Figs. 11D-11K).
Example 6. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIGIT in the CT26 colorectal cancer model.
5* 105 CT26 tumor cells were implanted subcutaneously into the axilla of nine-week-old female BALB/c mice. Two separate experiments were run to compare the results when drug dosing was initiated at either 7 days or 10 days after tumor cell injection. Prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations for the experiment where treatment was initiated after 7 days included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk)
5. anti-TIGIT (10 mg/kg 2x qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
7. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 7 post tumor cell injection). Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Drug treatment was discontinued at Day 63.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody on day 7 led to decreased tumor growth overall (Fig. 12A) and fold change (Fig. 12B) in mice xenotransplanted with CT26 tumor cells, which translated into gains in overall survival (Fig. 12C). The individual tumor growth curves for each treatment group were also plotted separately (Figs. 12D-12K).
The treatment combinations for the experiment where treatment was initiated after 10 days included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
5. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 10 post tumor cell injection). Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody on day 10 led to decreased tumor growth (fold change) (Fig. 13 A) in mice xenotransplanted with CT26 tumor cells, which translated into gains in overall survival (Fig. 13B). The individual tumor growth curves for each treatment group were also plotted separately (Figs. 13C-13H).
In comparing the two experiments, it is clear that the efficacy of combinations including anti-TIGIT therapy is dependent on tumor size and that delayed treatment with anti-TIGIT therapy could lead to negative consequences (Figs. 14A-C).
Example 7. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIM3 or a-LAG3 in the CT26 colorectal cancer model.
5* 105 CT26 tumor cells were implanted subcutaneously into the axilla of nine-week-old female BALB/c mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into 12 groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-PD-1 (5 mg/kg 2x qwk)
4. anti-Lag3 (10 mg/kg 2x qwk)
5. anti-Tim3 (5 mg/kg 2x qwk)
6. anti-PD-1 (5 mg/kg 2x qwk) + anti-Lag3 (10 mg/kg 2x qwk)
7. anti-PD-1 (5 mg/kg 2x qwk) + anti-Tim3 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
9. Trilaciclib (100 mg/kg qwk) + anti-Lag3 (10 mg/kg 2x qwk)
10. Trilaciclib (100 mg/kg qwk) + anti-Tim3 (5 mg/kg 2x qwk)
11. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-Lag3 (10 mg/kg 2x qwk)
12. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-Tim3 (5 mg/kg 2x qwk) Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1. Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-Lag3 or anti- Tim3 antibody on day 7 led to decreased tumor growth (fold change) (Fig. 15A-15C) and survival increases (FIG. 15D-E) in mice xenotransplanted with CT26 tumor cells. Median TTE for or a- PD-1 plus a-LAG3 was 55.5 days versus >70 days with the addition of trilaciclib (FIG. 15D). Median time-to-endpoint (TTE) for a-PD-1 plus a-TIM3, with or without trilaciclib, was not reached (FIG. 15E). The individual tumor growth curves for each treatment group were also plotted separately (Figs. 15F-15Q).
Example 8. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIGIT in the CT26 colorectal cancer model.
5* 105 CT26 tumor cells were implanted subcutaneously into the axilla of nine-week-old female BALB/c mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk)
5. anti-TIGIT (10 mg/kg 2x qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
7. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 7 post tumor cell injection). Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody on day 7 led to decreased tumor volume (Fig. 16A) and extended overall survival (Fig. 16B) with the combination of Trilaciclib and anti-PDl antibody resulting in the greatest reduction in tumor volume.
Example 9. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIGIT in the AT3- OVA breast cancer model.
5* 105 AT3-OVA tumor cells were implanted subcutaneously into the fourth inguinal mammary fat pads of nine-week-old female C57BL/6 mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk)
5. anti-TIGIT (10 mg/kg 2x qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
7. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 7 post tumor cell injection). Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody on day 7 led to decreased tumor volume (Fig. 17A) and extended overall survival (Fig. 17B) with the combination of Trilaciclib and anti-PD-1 antibody resulting in the greatest reduction in tumor volume. The combination of Trilaciclib and anti-PD-1 antibody and anti-TIGIT antibody led to the greatest increase in overall survival. Example 10. Evaluating Trilaciclib and a-PD-1 in Combination with a-TIGIT in the S2WTP3 breast cancer model.
5* 105 S2WTP3 tumor cells were implanted subcutaneously into the fourth inguinal mammary fat pads of nine-week-old female BALB/c mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer)
2. Trilaciclib (100 mg/kg qwk)
3. anti-TIGIT (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk)
5. anti-TIGIT (10 mg/kg 2x qwk) + anti-PD-1 (5 mg/kg 2x qwk)
6. Trilaciclib (100 mg/kg qwk) + anti-TIGIT (10 mg/kg 2x qwk)
7. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-TIGIT (10 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 7 post tumor cell injection). Checkpoint inhibitor administration occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-TIGIT antibody on day 7 led to decreased tumor volume (Fig. 18) with the combination of Trilaciclib and anti-PDl antibody resulting in the greatest reduction in tumor volume.
Example 11. Evaluating Trilaciclib and a-PD-1 in Combination with a-CD73 in the CT-26 Colorectal Cancer Model
5* 105 CT26 tumor cells were implanted subcutaneously into the axilla of six- to eight- week-old female BALB/c mice. One week after tumor cell injection and prior to treatment start (day 0 of the study), animals were divided into eight groups (N=8 per group) according to treatment. Tumors ranged in size of 80-120 mm3. The treatment combinations included:
1. Vehicle (Citrate Buffer + rIgG2a isotype control)
2. Trilaciclib (100 mg/kg qwk) + rIgG2a isotype control (10 mg/kg 2x qwk) 3. anti-CD73 (5 mg/kg 2x qwk) + vehicle + rIgG2a isotype control (10 mg/kg 2x qwk)
4. anti-PD-1 (5 mg/kg 2x qwk) + vehicle + r!gG2a isotype control (10 mg/kg 2x qwk)
5. Trilaciclib (100 mg/kg qwk) + anti-CD73 (5 mg/kg 2x qwk) + r!gG2a isotype control (10 mg/kg 2x qwk) 6. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + r!gG2a isotype control (10 mg/kg
2x qwk)
7. Vehicle + anti-PD-1 (5 mg/kg 2x qwk) + anti-CD73 (5 mg/kg 2x qwk)
8. Trilaciclib (100 mg/kg qwk) + anti-PD-1 (5 mg/kg 2x qwk) + anti-CD73 (5 mg/kg 2x qwk)
Trilaciclib (100 mg/kg) was dosed weekly (qwk) on day 1 (Day 7 post tumor cell injection). InVivoMAb anti -mouse CD73 clone TY/23 (BioXcell) and inVivoMAb anti-mouse PD-1 clone RMP1-14 (BioXcell) occurred twice weekly (2x qwk) on day 1 (after trilaciclib administration) and day 4 at the concentrations listed above. Treatment occurred for six weeks.
Table 1. Summary of treatment group tumor growth and survival
Figure imgf000209_0001
Figure imgf000210_0001
italicized p-values are significant (p-val.<0.05). IRI, Inhibitory Receptor Immunotherapy.
Trilaciclib administered in combination with anti-PD-1 antibody and/or anti-CD73 antibody on day 7 led to decreased tumor growth (tumor volume) (Fig. 20A) in mice xenotransplanted with CT26 tumor cells, which translated into gains in overall survival (Fig. 20B).
Based on the additive model, anti-PD-1 treatment has a significant effect (2.56 e-11) on tumor growth on D19 when adjusted for anti-CD73 and Trilaciclib. Similarly, Trilaciclib has a significant effect (0.0339) on tumor growth on D19 when adjusted for anti-CD73 and anti-PD-1. No significant interaction/synergistic effect was identified between any combination of drugs for tumor growth on D 17 or D 19.
Based on the additive model, anti-PD-1 treatment has a significant effect (1.37 e-10) on survival on D19 when adjusted for anti-CD73 and Trilaciclib. Similarly, anti-CD73 has a significant effect (0.0455) on survival on D19 when adjusted for Trilaciclib and anti-PD-1. No significant interaction/synergistic effect was identified between any combination of drugs for survival on D17 or D19.

Claims

CLAIMS What is claimed is:
1. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000211_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
2. The use of claim 1, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
3. The use of claim 1 or 2, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
4. The use of any of claims 1-3, wherein the solid cancer is small cell lung cancer.
5. The use of any of claims 1-3, wherein the solid cancer is non-small cell lung cancer.
6. The use of any of claims 1-3, wherein the solid cancer is triple negative breast cancer.
7. The use of any of claims 1-3, wherein the solid cancer is colorectal cancer.
8. The use of any of claims 1-3, wherein the solid cancer is urothelial cancer.
9. The use of any of claims 1-3, wherein the solid cancer is cervical cancer.
10. The use of any of claims 1-3, wherein the solid cancer is esophageal cancer.
11. The use of any of claims 1-3, wherein the solid cancer is melanoma.
12. The use of any of claims 1-3, wherein the solid cancer is head and neck squamous cell carcinoma.
13. The use of any of claims 1-12, wherein the treatment is administered to the human in a first-line setting.
14. The use of any of claims 1-12, wherein the treatment is administered to the human in a second-line setting.
15. The use of claim 14, wherein the human has previously received a PD-1 orPD-Ll inhibitor and has experienced disease progression.
16. The use of any of claims 1-15, wherein the human is administered an effective amount of a PD-1 inhibitor.
17. The use of claim 16, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
18. The use of claim 17, wherein the PD-1 inhibitor is nivolumab.
19. The use of any of claims 1-15, wherein the human is administered an effective amount of a PD-L1 inhibitor.
20. The use of claim 19, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
21. The use of any of claims 1-20, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
22. The use of claim 21, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
23. The use of claim 22, wherein the LAG-3 inhibitor is relatlimab.
24. The use of any of claims 1-20, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
25. The use of claim 24, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
26. The use of any of claims 1-20, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
27. The use of claim 26, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA-TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
28. The use of any of claims 1-20, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
29. The use of claim 28, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
30. The use of any of claims 1-29, wherein trilaciclib is administered once a week.
31. The use of any of claims 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
32. The use of any of claims 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
33. The use of any of claims 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
34. The use of any of claims 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
35. The use of any of claims 1-30, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
36. The use of any of claims 2-35, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
37. The use of any of claim 36, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
38. The use of claim 36 or 37, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
39. The use of claim 36 or 37, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5- fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
40. The use of any of claims 1-39, wherein the solid cancer expresses PD-L1.
41. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
212
Figure imgf000215_0001
or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
42. The use of claim 41, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
43. The use of claim 41 or 42, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
44. The use of any of claims 41-43, wherein the solid cancer is colorectal cancer.
45. The use of any of claims 41-43, wherein the solid cancer is small cell lung cancer.
46. The use of any of claims 41-43, wherein the solid cancer is non-small cell lung cancer.
47. The use of any of claims 41-43, wherein the solid cancer is triple negative breast cancer.
48. The use of any of claims 41-43, wherein the solid cancer is urothelial cancer.
49. The use of any of claims 41-43, wherein the solid cancer is cervical cancer.
50. The use of any of claims 41-43, wherein the solid cancer is esophageal cancer.
51. The use of any of claims 41-43, wherein the solid cancer is melanoma.
52. The use of any of claims 41-43, wherein the solid cancer is head and neck squamous cell carcinoma.
53. The use of any of claims 41-52, wherein the treatment is administered to the human in a first-line setting.
54. The use of any of claims 41-52, wherein the treatment is administered to the human in a second-line setting.
213
55. The use of claim 54, wherein the human has previously received a PD-1 inhibitor or PD- L1 inhibitor and has experienced disease progression.
56. The use of any of claims 41-55, wherein the human is administered an effective amount of a PD-1 inhibitor.
57. The use of claim 56, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
58. The use of any of claims 41-55, wherein the human is administered an effective amount of a PD-L1 inhibitor.
59. The use of claim 58, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
60. The use of claims 41-59, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
61. The use of any of claims 41-60, wherein trilaciclib is administered once a week.
62. The use of any of claims 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
63. The use of any of claims 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
64. The use of any of claims 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the
TIM-3 inhibitor are administered once every four weeks.
65. The use of any of claims 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-
3 inhibitor are administered once every six weeks.
66. The use of any of claims 41-61, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks;
214 wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
67. The use of any of claims 42-66, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
68. The use of claim 67, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
69. The use of claim 67 or 68, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
70. The use of claim 67 or 68, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5- fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
71. The use of any of claims 41-70, wherein the solid cancer expresses PD-L1.
72. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
215
Figure imgf000218_0001
or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG- 3) inhibitor.
73. The use of claim 72, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
74. The use of claim 72 or 73, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
75. The use of any of claims 72-74, wherein the solid cancer is colorectal cancer.
76. The use of any of claims 72-74, wherein the solid cancer is small cell lung cancer.
77. The use of any of claims 72-74, wherein the solid cancer is non-small cell lung cancer.
78. The use of any of claims 72-74, wherein the solid cancer is triple negative breast cancer.
79. The use of any of claims 72-74, wherein the solid cancer is urothelial cancer.
80. The use of any of claims 72-74, wherein the solid cancer is cervical cancer.
81. The use of any of claims 72-74, wherein the solid cancer is esophageal cancer.
82. The use of any of claims 72-74, wherein the solid cancer is melanoma.
83. The use of claim 82, wherein the melanoma is unresectable or metastatic melanoma.
84. The use of any of claims 72-74, wherein the solid cancer is head and neck squamous cell carcinoma.
85. The use of any of claims 72-84, wherein the treatment is administered to the human in a first-line setting.
86. The use of any of claims 72-84, wherein the treatment is administered to the human in a second-line setting.
216
87. The use of claim 86, wherein the human has previously received a PD-1 inhibitor or PD- L1 inhibitor and has experienced disease progression.
88. The use of any of claims 72-87, wherein the human is administered an effective amount of a PD-1 inhibitor.
89. The use of claim 88, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
90. The use of claim 89, wherein the PD-1 inhibitor is nivolumab.
91. The use of any of claims 72-87, wherein the human is administered an effective amount of a PD-L1 inhibitor.
92. The use of claim 91, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
93. The use of any of claims 72-92, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
94. The use of claim 93, wherein the LAG-3 inhibitor is relatlimab.
95. The use of any of claims 68-86, wherein trilaciclib is administered once a week.
96. The use of any of claims 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks.
97. The use of any of claims 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks.
98. The use of any of claims 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
99. The use of any of claims 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG- 3 inhibitor are administered once every six weeks.
217
100. The use of any of claims 72-95, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
101. The use of any of claims 73-100, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
102. The use of claim 101, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
103. The use of claim 101 or 102, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
104. The use of claim 101 or 102, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
105. The use of any of claims 72-104, wherein the solid cancer PD-L1.
106. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises:
218 a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000221_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
107. The use of claim 106, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
108. The use of claim 106 or 107, wherein the treatment is administered to the human in a first- line setting.
109. The use of claim 106 or 107, wherein the treatment is administered to the human in a second-line setting.
110. The use of claim 109, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
111. The use of any of claims 106-110, wherein trilaciclib is administered once a week.
112. The use of any of claims 106-111, wherein nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
113. The use of claim 112, wherein nivolumab and relatlimab are administered once every four weeks.
114. The use of any of claims 106-111, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and,
219 herein the duration of the first cycle is different than the duration of the second cycle.
115. The use of any of claims 107-114, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
116. The use of any of claim 115, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
117. The use of claim 115 or 116, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
118. The use of claim 115 or 116, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
119. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor for the treatment of a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000222_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof;
220 b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a Cluster of Differentiation 73 (CD73) inhibitor.
120. The use of claim 119, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
121. The use of claim 119 or 120, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
122. The use of any of claims 119-121, wherein the solid cancer is colorectal cancer.
123. The use of any of claims 119-121, wherein the solid cancer is small cell lung cancer.
124. The use of any of claims 119-121, wherein the solid cancer is non-small cell lung cancer.
125. The use of any of claims 119-121, wherein the solid cancer is triple negative breast cancer.
126. The use of any of claims 119-121, wherein the solid cancer is urothelial cancer.
127. The use of any of claims 119-121, wherein the solid cancer is cervical cancer.
128. The use of any of claims 119-121, wherein the solid cancer is esophageal cancer.
129. The use of any of claims 119-121, wherein the solid cancer is melanoma.
130. The use of any of claims 119-121, wherein the solid cancer is head and neck squamous cell carcinoma.
131. The use of any of claims 119-130, wherein the treatment is administered to the human in a first-line setting.
132. The use of any of claims 119-130, wherein the treatment is administered to the human in a second-line setting.
133. The use of claims 132, wherein the human has previously received a PD-1 inhibitor or PD- L1 inhibitor and has experienced disease progression.
134. The use of any of claims 116-133, wherein the human is administered an effective amount of a PD-1 inhibitor.
135. The use of claim 134, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab,
221 sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
136. The use of any of claims 116-133, wherein the human is administered an effective amount of a PD-L1 inhibitor.
137. The use of claim 136, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
138. The use of any of claims 116-137, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
139. The use of any of claims 116-138, wherein trilaciclib is administered once a week.
140. The use of any of claims 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
141. The use of any of claims 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks.
142. The use of any of claims 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
143. The use of any of claims 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks.
144. The use of any of claims 116-139, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
145. The use of any of claims 117-144, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
222
146. The use of any of claim 145, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
147. The use of claim 145 or 146, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
148. The use of claim 145 or 146, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
149. The use of any of claims 116-148, wherein the solid cancer expresses PD-L1.
150. Use of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount of the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000225_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and,
223 c. administering to the patient an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
151. The use of claim 150, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
152. The use of claim 150 or 151, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
153. The use of any of claims 150-152, wherein the treatment is administered to the patient in a first-line setting.
154. The use of any of claims 150-152, wherein the treatment is administered to the patient in a second-line setting.
155. The use of claim 154, wherein the patient has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
156. The use of any of claims 150-155, wherein the patient is administered an effective amount of a PD-1 inhibitor.
157. The use of claim 156, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
158. The use of any of claims 150-155, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
159. The use of claim 158, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
160. The use of any of claims 150-159, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
224
161. The use of claim 160, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
162. The use of any of claims 150-159, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
163. The use of claim 162, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
164. The use of any of claims 150-159, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
165. The use of claim 164, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223 or HB0036.
166. The use of claims any of claims 150-159, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
167. The use of claim 166, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
168. The use of any of claims 150-167, wherein trilaciclib is administered once a week.
169. The use of any of claims 150-168, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
170. The use of any of claims 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
171. The use of any of claims 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
172. The use of any of claims 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
225
173. The use of any of claims 150-169, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
174. The use of claim 150, wherein a PD-1 inhibitor is administered and a LAG-3 inhibitor is administered, and wherein the PD-1 inhibitor is nivolumab and the LAG-3 inhibitor is relatlimab.
175. The use of claims 151-173, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
176. The use of claim 175, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
177. The use of claim 175 or 176, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
178. The use of claim 175 or 176, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
179. The use of any of claims 150-178, wherein the solid cancer expresses PD-L1.
226
180. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000229_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a TIM-3 inhibitor.
181. The use of claim 180, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
182. The use of claim 180 or 181, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
183. The use of any of claims 180- 182, wherein the treatment is administered to the patient in a first-line setting.
184. The use of any of claims 180-182, wherein the treatment is administered to the patient in a second-line setting.
185. The use of claim 184, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
186. The use of any of claims 180-185, wherein the patient is administered an effective amount of a PD-1 inhibitor.
187. The use of claim 186, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab,
227 sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
188. The use of any of claims 180-185, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
189. The use of claim 188, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
190. The use of any of claims 180-189, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
191. The use of any of claims 180-190, wherein trilaciclib is administered once a week.
192. The use of any of claims 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
193. The use of any of claims 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
194. The use of any of claims 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every four weeks.
195. The use of any of claims 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every six weeks.
196. The use of any of claims 180-191, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
197. The use of any of claims 181-196, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
228
198. The use of claim 197, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
199. The use of claim 197 or 198, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
200. The use of claim 197 or 198, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
201. The use of claims 181-200, wherein the solid cancer expresses PD-L1.
202. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the
CDK4/6 inhibitor has the structure:
Figure imgf000231_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a LAG-3 inhibitor.
229
203. The use of claim 202, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
204. The use of claim 202 or 203, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
205. The use of any of claims 202-204, wherein the treatment is administered to the patient in a first-line setting.
206. The use of any of claims 202-204, wherein the treatment is administered to the patient in a second-line setting.
207. The use of claim 206, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
208. The use of any of claims 202-207, wherein the patient is administered an effective amount of a PD-1 inhibitor.
209. The use of claim 208, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
210. The use of claim 209, wherein the PD-1 inhibitor is nivolumab.
211. The use of any of claims 202-207, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
212. The use of claim 211, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
213. The use of any of claims 202-212, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
214. The use of claim 213, wherein the LAG-3 inhibitor is relatlimab.
215. The use of any of claims 202-214, wherein trilaciclib is administered once a week.
230
216. The use of any of claims 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks.
217. The use of any of claims 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks.
218. The use of any of claims 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
219. The use of any of claims 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every six weeks.
220. The use of any of claims 202-215, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
221. The use of any of claims 203-220, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
222. The use of claim 221, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
223. The use of claim 221 or 222, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
224. The use of claim 221 or 222, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
225. The use of any of claims 202-224, wherein the solid cancer PD-L1.
226. Use of a CDK4/6 inhibitor in the manufacture of a medicament for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the patient an effective amount the CDK4/6 inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000234_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the patient an effective amount of a PD-1 inhibitor or a PD-L1 inhibitor; and, c. administering to the patient an effective amount of a CD73 inhibitor.
227. The use of claim 226, wherein the method further comprises administering to the patient an effective amount of a chemotherapeutic agent.
228. The use of claim 226 or 227, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, or head and neck squamous cell carcinoma.
229. The use of any of claims 226-228, wherein the treatment is administered to the patient in a first-line setting.
230. The use of any of claims 226-228, wherein the treatment is administered to the patient in a second-line setting.
231. The use of claim 230, wherein the patient has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
232. The use of any of claims 226-231, wherein the patient is administered an effective amount of a PD-1 inhibitor.
233. The use of claim 232, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
234. The use of any of claims 226-231, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
235. The use of claim 234, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
236. The use of any of claims 226-235, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
237. The use of any of claims 226-236, wherein trilaciclib is administered once a week.
238. The use of any of claims 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
239. The use of any of claims 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks.
240. The use of any of claims 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
241. The use of any of claims 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks.
242. The use of any of claims 226-237, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and
233 wherein the duration of the first cycle is different than the duration of the second cycle.
243. The use of any of claims 227-242, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
244. The use of claim 243, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
245. The use of claim 243 or 244, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
246. The use of claim 243 or 244, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
247. The use of any of claims 226-246, wherein the solid cancer expresses PD-L1.
248. A composition for use for the treatment of a human patient with cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the composition for use comprises a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000236_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; and, wherein the treatment comprises: a. administering to the patient an effective amount of trilaciclib,
234 b. administering to the patient an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the patient an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
249. The composition of claim 248, wherein the treatment further comprises administering to the patient an effective amount of a chemotherapeutic agent.
250. The composition of claim 248 or 249, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
251. The composition of any of claims 248-250, wherein the treatment is administered to the patient in a first-line setting.
252. The composition of any of claims 248-250, wherein the treatment is administered to the patient in a second-line setting.
253. The composition of claim 252, wherein the patient has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
254. The composition of any of claims 248-253, wherein the patient is administered an effective amount of a PD-1 inhibitor.
255. The composition of claim 254, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab or JTX-4014.
256. The composition of claim 255, wherein the PD-1 inhibitor is nivolumab.
257. The composition of any of claims 248-253, wherein the patient is administered an effective amount of a PD-L1 inhibitor.
258. The composition of claim 257, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170 or BGB-A333.
235
259. The composition of any of claims 248-258, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
260. The composition of claim 259, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213 or SNA-03.
261. The composition of claim 260, wherein the LAG-3 inhibitor is relatlimab.
262. The composition of any of claims 248-258, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
263. The composition of claim 262, wherein the TIM-3 inhibitor is selected from cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425 or RO7121661.
264. The composition of any of claims 248-258, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
265. The composition of claim 264, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223 or HB0036.
266. The composition of any of claims 248-258, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
267. The composition of claim 266, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
268. The composition of any of claims 248-267, wherein trilaciclib is administered once a week.
269. The composition of any of claims 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
270. The composition ofany ofclaims 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
236
271. The composition of any of claims 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
272. The composition ofany ofclaims 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
273. The composition ofany ofclaims 248-268, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
274. The composition of claim 248, wherein a PD-1 inhibitor is administered and a LAG-3 inhibitor is administered, and wherein the PD-1 inhibitor is nivolumab and the LAG-3 inhibitor is relatlimab.
275. The composition of any of claims 249-273, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
276. The composition of claim 275, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
277. The composition of claim 275 or 276, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
278. The composition of claim 275 or 276, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab
237 vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or combinations thereof.
279. The composition of any of claims 248-278, wherein the solid cancer expresses PD-L1.
280. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000240_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD- 1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of an additional immune checkpoint inhibitor selected from a T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor, a lymphocyte activation gene-3 (LAG-3) inhibitor, or a Cluster of Differentiation 73 (CD73) inhibitor.
281. The method of claim 280, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
282. The method of claim 280 or 281, wherein the solid cancer is selected from small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, colorectal cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
283. The method of any of claims 280-282, wherein the solid cancer is small cell lung cancer.
284. The method of any of claims 280-282, wherein the solid cancer is non-small cell lung cancer.
285. The method of any of claims 280-282, wherein the solid cancer is triple negative breast cancer.
238
286. The method of any of claims 280-282, wherein the solid cancer is colorectal cancer.
287. The method of any of claims 280-282, wherein the solid cancer is urothelial cancer.
288. The method of any of claims 280-282, wherein the solid cancer is cervical cancer.
289. The method of any of claims 280-282, wherein the solid cancer is esophageal cancer.
290. The method of any of claims 280-282, wherein the solid cancer is melanoma.
291. The method of any of claims 280-282, wherein the solid cancer is head and neck squamous cell carcinoma.
292. The method of any of claims 280-291, wherein the treatment is administered to the human in a first-line setting.
293. The method of any of claims 280-291, wherein the treatment is administered to the human in a second-line setting.
294. The method of claim 293, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
295. The method of any of claims 280-294, wherein the human is administered an effective amount of a PD-1 inhibitor.
296. The method of claim 295, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
297. The method of claim 296, wherein the PD-1 inhibitor is nivolumab.
298. The method of any of claims 280-294, wherein the human is administered an effective amount of a PD-L1 inhibitor.
299. The method of claim 298, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
300. The method of any of claims 280-299, wherein the additional immune checkpoint inhibitor administered is a LAG-3 inhibitor.
301. The method of claim 300, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111,
239 Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
302. The method of claim 301, wherein the LAG-3 inhibitor is relatlimab.
303. The method of any of claims 280-299, wherein the additional immune checkpoint inhibitor administered is a TIM-3 inhibitor.
304. The method of claim 303, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
305. The method of any of claims 280-299, wherein the additional immune checkpoint inhibitor administered is a TIGIT inhibitor.
306. The method of claim 305, wherein the TIGIT inhibitor is selected from BAT6005Vibostolimab, Etigilimab, Tiragolumab, ociperlimab, BMS-986207, COM902, M6223, domvanalimab, AZD2936, JS006, IBI139, ASP-8374, BAT6021, TAB006, EOS884448, SEA- TGT, mAb-7, SHR-1708, GS02, RXI-804, NB6253, ENUM009, CASC-674, AJUD008, AGEN1777, HLX301, HLX53, M6223, or HB0036.
307. The method of any of claims 280-299, wherein the additional immune checkpoint inhibitor administered is a CD73 inhibitor.
308. The method of claim 307, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
309. The method of any of claims 280-308, wherein trilaciclib is administered once a week.
310. The method of any of claims 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every two weeks.
311. The method of any of claims 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every three weeks.
312. The method of any of claims 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every four weeks.
313. The method of any of claims 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor and the additional immune checkpoint inhibitor are administered once every six weeks.
240
314. The method of any of claims 280-309, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the additional immune checkpoint inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
315. The method of any of claims 281-314, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
316. The method of any of claim 315, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
317. The method of claim 314 or 315, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
318. The method of claim 314 or 315, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
319. The method of any of claims 280-318, wherein the solid cancer expresses PD-L1.
320. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
241
Figure imgf000244_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a T-cell immunoglobulin and mucin domain 3 (TIM-3) inhibitor.
321. The method of claim 320, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
322. The method of claim 320 or 321, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
323. The method of any of claims 320-322, wherein the solid cancer is colorectal cancer.
324. The method of any of claims 320-322, wherein the solid cancer is small cell lung cancer.
325. The method of any of claims 320-322, wherein the solid cancer is non-small cell lung cancer.
326. The method of any of claims 320-322, wherein the solid cancer is triple negative breast cancer.
327. The method of any of claims 320-322, wherein the solid cancer is urothelial cancer.
328. The method of any of claims 320-322, wherein the solid cancer is cervical cancer.
329. The method of any of claims 320-322, wherein the solid cancer is esophageal cancer.
330. The method of any of claims 320-322, wherein the solid cancer is melanoma.
331. The method of any of claims 320-322, wherein the solid cancer is head and neck squamous cell carcinoma.
332. The method of any of claims 320-331, wherein the treatment is administered to the human in a first-line setting.
242
333. The method of any of claims 320-331, wherein the treatment is administered to the human in a second-line setting.
334. The method of claim 333, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
335. The method of any of claims 320-334, wherein the human is administered an effective amount of a PD-1 inhibitor.
336. The method of claim 335, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
337. The method of any of claims 320-334, wherein the human is administered an effective amount of a PD-L1 inhibitor.
338. The method of claim 337, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
339. The method of claims 320-338, wherein the TIM-3 inhibitor is selected from Cobolimab, RG7769, MAS825, sabatolimab, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, AZD7789, TQB2618, NB002, BGBA425, or RO7121661.
340. The method of any of claims 320-339, wherein trilaciclib is administered once a week.
341. The method of any of claims 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every two weeks.
342. The method of any of claims 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every three weeks.
343. The method of any of claims 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every four weeks.
344. The method of any of claims 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor and the TIM-3 inhibitor are administered once every six weeks.
345. The method of any of claims 320-340, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the TIM-3 inhibitor is administered once over a duration of a second cycle;
243 wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
346. The method of any of claims 321-345, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
347. The method of claim 346, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
348. The method of claim 346 or 347, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
349. The method of claim 346 or 347, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
350. The method of any of claims 320-349, wherein the solid cancer expresses PD-L1.
351. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
244
Figure imgf000247_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and, c. administering to the human an effective amount of a lymphocyte activation gene-3 (LAG-
3) inhibitor.
352. The method of claim 351, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
353. The method of claim 351 or 352, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
354. The method of any of claims 351-353, wherein the solid cancer is colorectal cancer.
355. The method of any of claims 351-353, wherein the solid cancer is small cell lung cancer.
356. The method of any of claims 351-353, wherein the solid cancer is non-small cell lung cancer.
357. The method of any of claims 351-353, wherein the solid cancer is triple negative breast cancer.
358. The method of any of claims 351-353, wherein the solid cancer is urothelial cancer.
359. The method of any of claims 351-353, wherein the solid cancer is cervical cancer.
360. The method of any of claims 351-353, wherein the solid cancer is esophageal cancer.
361. The method of any of claims 351-353, wherein the solid cancer is melanoma.
362. The method of claim 361, wherein the melanoma is unresectable or metastatic melanoma.
363. The method of any of claims 351-353, wherein the solid cancer is head and neck squamous cell carcinoma.
364. The method of any of claims 351-353, wherein the treatment is administered to the human in a first-line setting.
245
365. The method of any of claims 351-353, wherein the treatment is administered to the human in a second-line setting.
366. The method of claim 365, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
367. The method of any of claims 351-366, wherein the human is administered an effective amount of a PD-1 inhibitor.
368. The method of claim 367, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab, sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
369. The method of claim 368, wherein the PD-1 inhibitor is nivolumab.
370. The method of any of claims 351-366, wherein the human is administered an effective amount of a PD-L1 inhibitor.
371. The method of claim 370, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
372. The method of any of claims 351-371, wherein the LAG-3 inhibitor is selected from relatlimab, GSK2831781, eftilagimod alpha, leramilimab, favezelimab, fianlimab, TSR-033, BI754111, Sym022, LBL-007, IBI110, IBI323, INCAGN02385, AVA021, MGD013, RO7247669, EMB-02, AVA-0017, XmAb841, tebotelimab, FS118, CB213, or SNA-03.
373. The method of claim 372, wherein the LAG-3 inhibitor is relatlimab.
374. The method of any of claims 351-373, wherein trilaciclib is administered once a week.
375. The method of any of claims 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every two weeks.
376. The method of any of claims 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every three weeks.
377. The method of any of claims 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every four weeks.
378. The method of any of claims 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor and the LAG-3 inhibitor are administered once every six weeks.
246
379. The method of any of claims 351-374, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the LAG-3 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
380. The method of any of claims 352-379, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
381. The method of claim 380, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
382. The method of claim 380 or 381, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
383. The method of claim 380 or 381, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
384. The method of any of claims 351-383, wherein the solid cancer PD-L1.
385. A method of treating a human having melanoma, wherein the melanoma is unresectable or metastatic melanoma, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
247
Figure imgf000250_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of nivolumab; and, c. administering to the human an effective amount of relatlimab.
386. The method of claim 385, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
387. The method of claim 385 or 386, wherein the treatment is administered to the human in a first-line setting.
388. The method of claim 385 or 386, wherein the treatment is administered to the human in a second-line setting.
389. The method of claim 388, wherein the human has previously received a PD-1 or PD-L1 inhibitor and has experienced disease progression.
390. The method of any of claims 385-389, wherein trilaciclib is administered once a week.
391. The method of any of claims 385-390, wherein nivolumab and relatlimab are administered once a week, every two weeks, every three weeks, every four weeks, every six weeks, or every twelve weeks.
392. The method of claim 391, wherein nivolumab and relatlimab are administered once every four weeks.
393. The method of any of claims 385-392, wherein nivolumab is administered once over a duration of a first cycle and relatlimab is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and, wherein the duration of the first cycle is different than the duration of the second cycle.
248
394. The method of any of claims 386-393, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
395. The method of any of claim 394, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
396. The method of claim 394 or 395, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
397. The method of claim 394 or 395, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
398. A method of treating a human having cancer, wherein the cancer is an advanced or metastatic solid cancer, and wherein the treatment comprises: a. administering to the human an effective amount of a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, wherein the CDK4/6 inhibitor has the structure:
Figure imgf000251_0001
(trilaciclib), or a pharmaceutically acceptable salt thereof; b. administering to the human an effective amount of a programmed cell death protein-1 (PD-
1) inhibitor or a programmed death-ligand- 1 (PD-L1) inhibitor; and,
249 c. administering to the human an effective amount of a Cluster of Differentiation 73 (CD73) inhibitor.
399. The method of claim 398, wherein the treatment further comprises administering to the human an effective amount of a chemotherapeutic agent.
400. The method of claim 398 or 399, wherein the solid cancer is selected from colorectal cancer, small cell lung cancer, non-small cell lung cancer, triple negative breast cancer, urothelial cancer, cervical cancer, esophageal cancer, melanoma, or head and neck squamous cell carcinoma.
401. The method of any of claims 398-400, wherein the solid cancer is colorectal cancer.
402. The method of any of claims 398-400, wherein the solid cancer is small cell lung cancer.
403. The method of any of claims 398-400, wherein the solid cancer is non-small cell lung cancer.
404. The method of any of claims 398-400, wherein the solid cancer is triple negative breast cancer.
405. The method of any of claims 398-400, wherein the solid cancer is urothelial cancer.
406. The method of any of claims 398-400, wherein the solid cancer is cervical cancer.
407. The method of any of claims 398-400, wherein the solid cancer is esophageal cancer.
408. The method of any of claims 398-400, wherein the solid cancer is melanoma.
409. The method of any of claims 398-400, wherein the solid cancer is head and neck squamous cell carcinoma.
410. The method of any of claims 398-409, wherein the treatment is administered to the human in a first-line setting.
411. The method of any of claims 398-409, wherein the treatment is administered to the human in a second-line setting.
412. The method of claims 411, wherein the human has previously received a PD-1 inhibitor or PD-L1 inhibitor and has experienced disease progression.
413. The method of any of claims 398-412, wherein the human is administered an effective amount of a PD-1 inhibitor.
414. The method of claim 413, wherein the PD-1 inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, pidilizumab, AMP -224, AMP-514, sintilimab,
250 sasanlimab, spartalizumab, retifanlimab, tislelizumab, toripalimab, camrelizumab, CS1003, zimberelimab, or JTX-4014.
415. The method of any of claims 398-412, wherein the human is administered an effective amount of a PD-L1 inhibitor.
416. The method of claim 415, wherein the PD-L1 inhibitor is selected from atezolizumab, durvalumab, avelumab, envafolimab, BMS-936559, BMS-986189, lodapolimab, cosibelimab, sugemalimab, adebrelimab, CBT-502, AUNP12, CA-170, or BGB-A333.
417. The method of any of claims 398-416, wherein the CD73 inhibitor is selected from HLX23, LY3475070, IPH5301, AK119, PT199, mupadolimab, Sym024, oleclumab, IBI325, ORIC-533, JAB-BX102, TJ004309, AB680, NZV930, BMS-986179, INCA00186, or dalutrafusp alfa.
418. The method of any of claims 398-417, wherein trilaciclib is administered once a week.
419. The method of any of claims 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every two weeks.
420. The method of any of claims 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every three weeks.
421. The method of any of claims 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every four weeks.
422. The method of any of claims 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor and the CD73 inhibitor are administered once every six weeks.
423. The method of any of claims 398-418, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered once over a duration of a first cycle and the CD73 inhibitor is administered once over a duration of a second cycle; wherein the duration of the first cycle is selected from two weeks, three weeks, four weeks, or six weeks; wherein the duration of the second cycle is selected from two weeks, three weeks, four weeks, or six weeks; and wherein the duration of the first cycle is different than the duration of the second cycle.
424. The method of any of claims 399-423, wherein trilaciclib is administered about 8 hours or less prior to the administration of the chemotherapeutic agent.
251
425. The method of any of claim 424, wherein trilaciclib is administered about 4 hours or less prior to administration of the chemotherapeutic agent.
426. The method of claim 424 or 425, wherein the chemotherapeutic agent is selected from a platinum drug, a taxane, a topoisomerase inhibitor, an alkylating agent, a cytotoxic antibiotic, an antimetabolite, or a vinca alkaloid.
427. The method of claim 424 or 425, wherein the chemotherapeutic agent is selected from carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, paclitaxel albumin-stabilized nanoparticle formulation (nab -paclitaxel), topotecan, campothecin, irinotecan, belotecan, doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, teniposide, cyclophosphamide, vinblastine, gemcitabine, 5-fluoruracil, eribulin, premetrexed, mitomycin; sacituzumab govitecan, valrubicin, vinorelbine tartrate, trabectedin, temozolomide, melphalan, dacarbazine, methotrexate, mitroxantrone, bleomycin, irinotecan, cabazitaxel, bortezomib, vincristine, vindesine, diaziquone; mechlorethamine; mitomycin C; fludarabine; cytosine arabinoside, ixabepilone, enfortumab vedotin, ifosfamide, and capectabine, or pharmaceutically acceptable salts of any thereof; or a combination thereof.
428. The method of any of claims 398-427, wherein the solid cancer expresses PD-L1.
252
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