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WO2025046537A1 - Méthodes de traitement du cancer à l'aide de futibatinib, de pembrolizumab et d'au moins un agent chimiothérapeutique supplémentaire - Google Patents

Méthodes de traitement du cancer à l'aide de futibatinib, de pembrolizumab et d'au moins un agent chimiothérapeutique supplémentaire Download PDF

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WO2025046537A1
WO2025046537A1 PCT/IB2024/058465 IB2024058465W WO2025046537A1 WO 2025046537 A1 WO2025046537 A1 WO 2025046537A1 IB 2024058465 W IB2024058465 W IB 2024058465W WO 2025046537 A1 WO2025046537 A1 WO 2025046537A1
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pharmaceutically acceptable
acceptable salt
day
cancer
administered
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Naoki Hirayama
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MSD International Holdings GmbH
MSD International GmbH
Taiho Pharmaceutical Co Ltd
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MSD International Holdings GmbH
MSD International GmbH
Taiho Pharmaceutical Co Ltd
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule

Definitions

  • FGF/FGFR fibroblast growth factor/fibroblast growth factor receptor
  • Fibroblast growth factors are expressed in various tissues and are one of the growth factors that regulate cell proliferation and differentiation.
  • the physiological activity of the FGFs is mediated by fibroblast growth factor receptors (FGFRs), which are specific cell surface receptors.
  • FGFRs belong to a receptor protein tyrosine kinase family and comprise an extracellular ligand-binding domain, a single transmembrane domain, 1 64309488-v1 155792.599942 and an intracellular tyrosine kinase domain.
  • FGFR1, FGFR2, FGFR3, and FGFR4 Four types of FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) have been heretofore identified.
  • FGFRs bind to FGFs to form dimers and are activated by phosphorylation. Activation of the receptors induces mobilization and activation of specific downstream signal transduction molecules, thereby developing physiological functions.
  • Some reports have been made about the relationship between aberrant FGF/FGFR signaling and various human tumors. Aberrant activation of FGF/FGFR signaling in human tumors is considered to be attributable to overexpression of FGFRs and/or gene amplification, gene mutation, chromosomal translocation, insertion, and inversion, gene fusion, or an autocrine or paracrine mechanism by overproduction of FGFs (ligands).
  • Futibatinib i.e., (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one
  • FGFR inhibitor see, e.g., WO2017/150725, which is incorporated by reference to its entirety.
  • Futibatinib is the first irreversible covalent inhibitor of FGFR that is being tested in humans.
  • cancer immunotherapy has progressed as a new cancer treatment method. Recent efforts have focused on therapies that specifically target the immune system, and promising results have been obtained with nivolumab, ipilimumab, pembrolizumab, and atezolizumab, for example. Therapeutic approaches to many types of cancers have thus changed dramatically. However, the survival benefit from these new agents remains limited, and many patients experience disease failure after clinical responses with them.
  • Activation of the adaptive immune response is initiated by the binding of antigenic peptide-MHC complexes to T-cell receptors (TCRs).
  • This binding is further defined by costimulation or coinhibition by binding between the costimulatory molecule B7 family and their receptor CD28 family. That is, in order for T cells to activate an antigen specifically, two characteristic signal transduction events are required, and T cells 2 64309488-v1 155792.599942 that have received only antigen stimulation without costimulation from the B7 family enter a state of anergy, and immune tolerance is induced. [0009] Taking advantage of this mechanism to suppress the activation of antigen-specific T cells, cancer cells escape from the immune surveillance system and continue to grow. Therefore, it is considered to be effective for cancer treatment to induce antitumor immune responses in the bodies of cancer patients by strengthening costimulation and blocking coinhibition and to prevent tumor immune escape.
  • nivolumab human IgG4 monoclonal antibody against human PD-1
  • PD-L1 and PD-L2 an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 with its ligands
  • pembrolizumab is used for the treatment of malignant melanoma and non-small cell lung cancer (see, e.g., N. Engl. J. Med., 366, 2443-2454 (2012)).
  • Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.
  • Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda ® (pembrolizumab) is indicated for the treatment of patients across a number of indications.
  • the tumor microenvironment (TME) has been recognized as an important factor in disease progression, attracting attention to trials for the development of new anticancer therapies targeting the TME (Breast Cancer Res: BCR.2011;13:227).
  • MDSCs bone marrow-derived immunosuppressor cells
  • Arthritis Rheumatol.2016;68:2717-2727; Tumour Biol.2016;37:1387-1406 3 64309488-v1 155792.599942
  • MDSCs are immature bone marrow cells that are recruited from the bone marrow and spleen into tumors in response to tumor-secreted chemotactic factors.
  • Activated MDSCs can enhance immunosuppression by stimulating the expression of regulatory T cells (Treg) and regulatory B cells (Breg) (Arthritis Rheumatol.2016;68:2717-2727; Immunology.2013;138:105-115).
  • Tregs inhibit the proliferation and activation of effector T cells by secreting interleukin (IL)-10 and transforming growth factor- ⁇ cytokines (Genes Immun.2014;15:511-5205) or act through PD-L1/PD-1-mediated intercellular adhesion (Immunological reviews.2010;236:219-242).
  • Breg inhibits the function of Th1, Th17, monocytes, dendritic cells, and CD8+ T cells while activating Tregs (Immunity.
  • Breg, MDSCs, and Tregs are immunosuppressor cells that control tissue immunosuppression via anti-inflammatory cytokines such as IL-10, IL-35, and transforming growth factor- ⁇ . These cytokines promote immunosuppression in TME because they regulate crosstalk between MDSCs, Tregs, and Bregs (Immunology. 2013;138:105-115; Immunity.2015;42:607-612; The Journal of Immunology. 2007;179:977-983). [0013] Recent studies have shown that the number of MDSCs in spleen cells and peripheral blood mononuclear cells decreases after administration of FGFR inhibitors to tumor-bearing mice.
  • anti-cancer agents having high therapeutic efficacy need to be carefully used, and it may not be possible to use them in some cases where, for example, an anti-cancer agent has severe side effects or is highly toxic. It is also known that anti- cancer agents may differ in effect among patients, or their efficacy may be reduced due to the long-term administration of the same agent. For example, it has been found that continued administration of certain immune checkpoint inhibitors can result in drug 4 64309488-v1 155792.599942 resistance. (see, e.g., Cell, 168, 707-723 (2017); N. Engl. J. Med., 375, 819-829 (2016); Sci. Transl. Med.9, eaal 3604 (2017)).
  • anti-cancer agents are often not effective for all patients, especially when administered individually. Thus, attempts have been made to increase the cure rate of such therapeutic anti-cancer agents by combining them. See, e.g., WO2020/175697 and WO2017/150725, both of which are incorporated by reference in their entireties. [0016] Despite the significant advancement in the treatment of cancer, improved therapies are still being sought. An object of the present disclosure is to provide a novel method for treating a cancer.
  • the present disclosure advances the state of the art by providing methods of treating a cancer comprising administering futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.
  • the present disclosure also provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg/m 2 , about 80 mg/m 2 , about 120 mg/m 2 , about 160 mg/m 2 , about 200 mg/m 2 , or about 240 mg/m 2 per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject 5 64309488-v1 155792.599942 about 400 mg/m 2 ,
  • the present disclosure also provides a kit for treating a cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.
  • the present disclosure also provides a pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.
  • the present disclosure also provides a use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer.
  • FIG.1 is a schematic of the study design expansion phase, according to embodiments of the disclosure. 6 64309488-v1 155792.599942
  • FIG.2A is a graphical representation showing overall response rate of Cohort D, according to embodiments of the disclosure.
  • FIG.2B is a graphical representation showing median duration of response of Cohort D, according to embodiments of the disclosure.
  • FIG.3A is a graphical representation showing overall response rate of Cohort A, according to embodiments of the disclosure.
  • FIG.3B is a graphical representation showing median duration of response of Cohort A, according to embodiments of the disclosure.
  • FIG.4A is a graphical representation showing overall response rate of Cohort B, according to embodiments of the disclosure.
  • FIG.4B is a graphical representation showing median duration of response of Cohort B, according to embodiments of the disclosure.
  • FIG.5A is a graphical representation showing overall survival of Cohorts A and B, according to embodiments of the disclosure.
  • FIG.5B is a graphical representation showing progression-free survival of Cohorts A and B, according to embodiments of the disclosure.
  • FIG.6 is a graphical representation showing certain adverse events of Cohorts A, B, and D, according to embodiments of the disclosure.
  • the present disclosure provides novel methods of treatment of a cancer including administering futibatinib or a pharmaceutically acceptable salt thereof and pembrolizumab or a pharmaceutically acceptable salt thereof in combination with at least one additional anti-cancer therapy agent which can advantageously maximize therapeutic efficacy.
  • the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.
  • Such combination therapies can be potent cancer treatments.
  • the novel methods of the disclosure can provide unexpectedly enhanced efficacy (e.g., an increased overall response rate) relative to administration of any of the anti-cancer therapy agents as a monotherapy or even a combination of only futibatinib and pembrolizumab.
  • efficacy of 7 64309488-v1 155792.599942 the methods using the combination therapy of the disclosure was unexpectedly increased without remarkably exacerbating toxicity.
  • doses of existing anti-cancer therapy agents e.g., chemotherapeutic agents
  • the present disclosure provides methods for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.
  • the futibatinib or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
  • the pembrolizumab or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
  • the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.
  • the at least one additional anti-cancer therapy agent is selected from the group consisting of: an antimetabolite, an alkaloid antitumor agent, a platinum-containing drug, a molecular targeting drug, an antitumor antibiotic, an alkylating agent, a hormonal therapy agent, a folic acid replenisher, an anti-androgen, and any combination thereof.
  • the at least one additional anti-cancer therapy agent is selected from the group consisting of 5- fluorouracil, cisplatin, oxaliplatin, calcium folinate hydrate, calcium levofolinate hydrate, and any combination thereof.
  • the method comprises administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of oxaliplatin or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, skin cancer, mesothelioma, and cancer of unknown primary.
  • the cancer is esophageal cancer.
  • the subject has not been previously treated with a chemotherapy agent and/or anti-PD-1/PD-L1 monoclonal antibody for the esophageal cancer. 9 64309488-v1 155792.599942 [0037]
  • the cancer is an advanced, metastatic, irreversible, resistant, or intractable cancer.
  • the subject is a human.
  • the administering is for at least one treatment cycle. In some embodiments, the treatment cycle is about 14 to about 28 days. In some embodiments, the treatment cycle is about 21 days. In some embodiments, the futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each day of the treatment cycle.
  • the pembrolizumab or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on consecutive days during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days during the treatment cycle.
  • the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 5 days during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle.
  • the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle. 10 64309488-v1 155792.599942 [0040] In some embodiments, the administering is for at least one additional treatment cycle. In some embodiments, an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is reduced during the at least one additional treatment cycle. [0041] In some embodiments, an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is about 4 mg to about 160 mg per dose, about 4 mg to about 24 mg per dose, about 12 mg to about 24 mg per dose, about 16 mg to about 24 mg per dose, or about 12 mg to about 20 mg per dose.
  • the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose. In some embodiments, the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 20 mg per dose. [0042] In some embodiments, an amount of the pembrolizumab or the pharmaceutically acceptable salt thereof being administered is about 100 mg to about 400 mg per dose or about 200 mg to about 400 mg per dose. In some embodiments, the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg or about 400 mg per dose. In some embodiments, the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg per dose.
  • an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 10 mg/m 2 to about 2000 mg/m 2 , about 10 mg/m 2 to about 1000 mg/m 2 , about 40 mg/m 2 to about 800 mg/m 2 , about 40 mg/m 2 to about 400 mg/m 2 , about 80 mg/m 2 to about 200 mg/m 2 , about 200 mg/m 2 to about 800 mg/m 2 , about 400 mg/m 2 to about 1600 mg/m 2 , or about 400 mg/m 2 to about 800 mg/m 2 per dose.
  • the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is about 40 mg/m 2 , about 80 mg/m 2 , about 120 mg/m 2 , about 160 mg/m 2 , about 200 mg/m 2 , about 240 mg/m 2 , about 300 mg/m 2 , about 400 mg/m 2 , about 500 mg/m 2 , about 600 mg/m 2 , about 700 mg/m 2 , about 800 mg/m 2 , about 900 mg/m 2 , about 1000 mg/m 2 , about 1100 mg/m 2 , about 1200 mg/m 2 , about 1300 mg/m 2 , about 1400 mg/m 2 , about 1500 mg/m 2 , or about 1600 mg/m 2 per dose.
  • the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable 11 64309488-v1 155792.599942 salt thereof is about 80 mg/m 2 per dose. In some embodiments, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is about 800 mg/m 2 per dose. [0044] In some embodiments, the futibatinib or the pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously.
  • the method achieves an overall response rate of equal to or greater than 50%. In some embodiments, the overall response rate is equal to or greater than 60%. In some embodiments, the overall response rate is equal to or greater than 70%. In some embodiments, the overall response rate is equal to or greater than 80%. In some embodiments, the method achieves an improved overall response rate relative to an overall response rate of administration of futibatinib or pembrolizumab alone. In some embodiments, the method achieves an improved overall response rate relative to an overall response rate of administration of a combination of futibatinib and pembrolizumab.
  • the present disclosure also provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg/m 2 , about 80 mg/m 2 , about 120 mg/m 2 , about 160 mg/m 2 , about 200 mg/m 2 , or about 240 mg/m 2 per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject about 400 mg/m 2 , about 500 mg/m 2 , about 600 mg/m 2
  • the present disclosure also provides a kit for treating cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.
  • the first composition further comprises a first pharmaceutically acceptable carrier.
  • the second composition further comprises a second pharmaceutically acceptable carrier.
  • the third composition further comprises a third pharmaceutically acceptable carrier.
  • the present disclosure also provides a use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer.
  • futibatinib or a pharmaceutically acceptable salt thereof pembrolizumab or a pharmaceutically acceptable salt thereof
  • at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer.
  • a range is from about 1 to about 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, 50 or any other value or range within the range.
  • the term “at least” includes the stated number, e.g., “at least 50” includes 50.
  • subject refers to an animal, preferably a mammal, including a human or a non-human animal including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment.
  • the subject is a human.
  • the subject is a human who has been diagnosed as needing a treatment for a cancer or a clinical symptom or medical state associated with a cancer.
  • the subject may be in need of, or desire, treatment for an existing cancer or may be in need of, or desire, prophylactic treatment to prevent or reduce the risk of occurrence of a cancer.
  • a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.
  • a subject “in need” of treatment includes a subject having a cancer and/or diagnosed with a cancer.
  • the term “active agent of the disclosure” or “active agent” or “therapeutic agent” or “pharmaceutical agent” refers to an agent or ingredient with a 14 64309488-v1 155792.599942 pharmacological effect, such as a therapeutic effect, at a relevant dose, and includes the pharmaceutically acceptable salt thereof.
  • anti-cancer therapy agents of the disclosure including futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.
  • active agent or any reference to a specific anti-cancer therapy agent of the disclosure (i.e., futibatinib, pembrolizumab, and the at least one additional anti-cancer therapy agent) is assumed to include the active agent or the pharmaceutically acceptable salt thereof.
  • the term “administration” and variants thereof (e.g., “administering”) in reference to an active agent of the disclosure means providing the active agent to a subject in need of treatment.
  • Administering of an active agent of the disclosure to the subject includes both self-administration and administration to the subject by another, including a medical professional.
  • Administration may be via any common route, and in forms suitable for each administration route.
  • routes include, but are not limited to, parenteral (e.g., subcutaneous, intramuscular, intraperitoneal or intravenous), oral, nasal, airway (e.g., aerosol), buccal, intradermal, transdermal, sublingual, rectal, and vaginal.
  • Treating cancer can include, for example, reduction in number of cancer cells, reduction in tumor size, reduction in rate of cancer cell infiltration into peripheral organs, reduction in rate of tumor metastasis or tumor growth, increase in overall survival (OS), increase in progression free survival (PFS), increase in disease free survival (DFS), complete response (CR), partial response (PR), stable disease (SD), improvement in duration of response (DOR), decrease in associated symptoms, and/or failure of tumors to reoccur after treatment has stopped.
  • OS overall survival
  • PFS progression free survival
  • DFS complete response
  • CR complete response
  • PR partial response
  • SD stable disease
  • DOR improvement in duration of response
  • Treatment can also mean prolonging survival as compared to expected survival in the absence of treatment. 15 64309488-v1 155792.599942 [0062] Positive therapeutic effects in cancer can be measured in a number of ways and would be understood by a person of skill in the art.
  • the treatment achieved by a therapeutically effective amount is any of progression free survival (PFS), disease free survival (DFS), or overall survival (OS).
  • PFS also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • DFS refers to the length of time during and after treatment that the patient remains free of disease.
  • OS typically refers to a time until death from the start of therapy.
  • Methods of the present invention may not be effective in achieving a positive therapeutic effect in every patient, but may do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi 2 - test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.
  • ORR all response rate
  • ORR is equal to the proportion of patients in an analysis population achieving a best overall response of partial or complete response (PR+CR). For example, ORR can be evaluated according to RECIST v1.1.
  • ORR is an acceptable measure of clinical benefit for screening new agents for evidence of anti-tumor effect, and agents that produce tumor shrinkage in a proportion of patients have a reasonable chance of subsequently demonstrating an improvement in OS.
  • “therapeutically effective” or “prophylactically effective” in reference to an amount refers to the amount necessary at the intended dosage to achieve the desired therapeutic and/or prophylactic effect for the period of time desired.
  • the desired effect may be, for example, the alleviation, amelioration, reduction or cessation of at least one symptom associated with the treated condition.
  • the “therapeutically effective amount” coincides with a daily dosage.
  • Amounts may vary, as the ordinarily skilled artisan will appreciate, according to various factors, including but not limited to the disease state and type, age, sex, and weight of the subject, and the ability of the active agent to elicit the desired effect in the individual. The response may be documented, for example, by in vitro assay, in vivo non-human animal studies, and/or further supported from clinical trials. 16 64309488-v1 155792.599942 [0065] Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect.
  • Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug interaction(s), reaction sensitivities, and tolerance/response to therapy.
  • An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • the term “combination” or “combination therapy” is intended to include administration of the active agents of the methods disclosed herein in a sequential manner, wherein each active agent is administered at a different time, as well as administration of these active agents, or at least two of the active agents concurrently or in a simultaneous manner.
  • “combination therapy”, “combination,” and the use of active agents “in combination” in the present disclosure may mean active agents administered as part of the same overall therapeutic regimen (e.g., during the same treatment cycle or period).
  • the dose of each of the active agents may be different: each may be administered simultaneously (including substantially simultaneously, e.g., at substantially the same time, or at different times.
  • the active agents of the combination may be administered sequentially (e.g., before or after) or simultaneously or substantially simultaneously, either in the same pharmaceutical formulation or pharmaceutical composition (i.e., formulated together) or in different pharmaceutical formulations or pharmaceutical compositions (i.e., formulated separately).
  • Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed or variable ratio of each therapeutic agent (i.e., simultaneous) or in multiple, single capsules or other dosage forms (e.g., injectable) for each of the therapeutic agents.
  • each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • Each of the active agents of the methods of the disclosure can be administered by the same route or by different routes.
  • one active agent(s) of the method may be administered by intravenous injection while at least one other 17 64309488-v1 155792.599942 active agent(s) of the method may be administered orally.
  • all active agents may be administered orally or all active agents may be administered by intravenous injection.
  • the sequence in which the active agents are administered can vary.
  • the terms “regimen” and “therapeutic regimen” refer to an administration plan or schedule that shows, in chronological order, the type and amount of therapeutic agents, the duration, and the procedure in drug treatment, and that shows the dose, administration method, administration order, and administration day of each drug.
  • the treatment in one therapeutic regimen is, for example, a method that starts administration of drugs to be combined, simultaneously or substantially simultaneously on the first day of a treatment cycle (i.e., treatment period).
  • the treatment in one therapeutic regimen also includes, for example, one treatment cycle with three weeks in which administration of drug A is started first, and administration of drug B is started one week later.
  • the “treatment cycle” or “treatment period” refers to the period of time during which the administration according to the methods of the disclosure takes place. During a treatment cycle, each of the active agents of the method is administered sequentially or simultaneously as described herein.
  • the term “q.d.” means one a day (from the Latin quaque die). The abbreviation is sometimes written without a period in capital letters as "QD” used to specify the frequency with which therapeutic agents are administered.
  • Q3W means once every three weeks and is used to specify the frequency with which therapeutic agents are administered.
  • This disclosure provides methods for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.
  • the present disclosure includes prodrugs, free-acid, free-base and pharmaceutically acceptable salts of the active agents described herein where applicable.
  • pharmaceutically acceptable salts refers to salts of the one or more compounds of the methods of the disclosure that are substantially non-toxic to 18 64309488-v1 155792.599942 living organisms, e.g., subjects in need of methods of treatment.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the one or more active components of the disclosure with an inorganic or organic acid, or an organic base, depending on the substituents present on the one or more active components of the disclosure.
  • the pharmaceutically acceptable salts of the present disclosure are not particularly limited, and include, for example, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, or with organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts; and the like.
  • Non-limiting examples of chemotherapeutic agents include antimetabolites, alkaloid antitumor agents (i.e., mitotic inhibitors and plant alkaloids), platinum-containing drugs (i.e., platinum analogs), molecular targeting drugs, antitumor antibiotics, alkylating agents, hormonal therapy agents, folic acid replenishers, anti- androgens, enzymes, topoisomerase inhibitors, retinoids, and aziridines.
  • Many anti- cancer agents can be classified within one or more of these groups. While certain anti- cancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art.
  • Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, nanoparticle albumin- bound paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; lurbinectedin, navelbine; noscapine; teniposide; thaliblastine; trabectedin, vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.
  • taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, nanoparticle albumin- bound paclitaxel, and tesetaxel
  • demecolcine epothilone
  • eribulin etoposide (VP- 16); e
  • alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophospha
  • Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. 20 64309488-v1 155792.599942 [0080] Non-limiting examples of enzymes include asparaginase and pegaspargase.
  • Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan (CPT-11), lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.
  • Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin (ATRA).
  • Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.
  • Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo- L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicin
  • Non-limiting examples of folic acid replenishers include calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4-hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, and exemestane.
  • Non-limiting examples of anti-androgens include flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, and ribocyclib.
  • Combination regimens of chemotherapy can be determined by those skilled in the art, and include, but are not limited to PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R- CHOP (rituxim
  • Cancers include solid and hematologic cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignancy (carcinoid).
  • cancers targeted by the methods of the present disclosure include, but are not limited to, head and neck cancer, digestive organ cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and cholangiocarcinoma), pancreatic cancer, urothelial cancer, small intestine cancer, large intestine cancer (e.g., colorectal cancer, colon cancer, and rectal cancer)), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma (e.g., malignant pleural mesothelioma, peritoneal mesothelioma, and pericardial mesothelioma)), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer, uterine body cancer, and endometrial cancer), etc.), renal cancer, bladder cancer, prostate cancer, testicular tumor,
  • digestive organ cancer
  • the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, skin cancer, mesothelioma, and cancer of unknown primary.
  • the cancer is an advanced, metastatic, irreversible, resistant, or intractable cancer.
  • dosage forms include oral preparations (e.g., tablets, coated tablets, powders, granules, capsules, solutions), injections, suppositories, patches, ointments, and the like. Such dosage forms can be formed by methods conventionally known to a person skilled in the art.
  • the active agents of the present disclosure may be formulated into a plurality of dosage forms, or may be formulated into a single dosage form, based on the administration form and administration schedule of each active agent. Further, formulations may be produced and sold in a single package suitable for combined administration, or formulations may be produced and sold in separate packages. The same applies to the embodiments of the pharmaceutical composition.
  • the subject is a treatment-naive human subject with esophageal cancer.
  • the subject is a treatment-naive human subject with advanced metastatic, irreversible, resistant, or intractable esophageal carcinoma.
  • the subject has not been previously treated for the esophageal cancer.
  • the subject has not been previously treated with an anti-PD-1/PD-L1 monoclonal antibody for the esophageal cancer.
  • the subject has not been previously treated with a chemotherapeutic agent for the esophageal cancer.
  • the subject is a treatment-na ⁇ ve human subject with non- small cell lung cancer.
  • the administration schedule and order of administration may be appropriately selected, for example, according to the type of cancer, the stage of cancer, and other various factors, including, but not limited to the age, sex, and weight of the subject, the ability of the active agent to elicit the desired effect in the subject, and adverse effects in the subject.
  • the active agents of the methods of the disclosure may be administered in any combination (e.g., separately or in a single dosage form and sequentially or concurrently).
  • At least two of active agents of the disclosure or all of the active agents of the disclosure may be administered in a single dosage formulation (e.g., a fixed dose drug combination) or in one or more separate dosage forms which allow for concurrent or sequential (or substantially sequential) administration of the active agents (co-administration of the separate active agents) to subjects.
  • the active agents of the disclosure are included in a pharmaceutical composition as described herein.
  • the methods of the disclosure also include administration of the active agents before or after a surgical procedure, or administration of the active agents during, before, or after radiation therapy.
  • futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are each administered separately.
  • futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered via a single pharmaceutical preparation further comprising at least one pharmaceutically acceptable carrier.
  • any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously.
  • futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered simultaneously.
  • futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously.
  • pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously.
  • any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are 33 64309488-v1 155792.599942 administered via a single pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier.
  • any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially.
  • futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered sequentially.
  • futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially.
  • pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered before pembrolizumab or the pharmaceutically acceptable salt thereof.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered after pembrolizumab or the pharmaceutically acceptable salt thereof.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered before pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered after pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.
  • futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.
  • futibatinib or the 34 64309488-v1 155792.599942 pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered before futibatinib or the pharmaceutically acceptable salt thereof.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered after futibatinib or the pharmaceutically acceptable salt thereof.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered before futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered after futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.
  • At least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are 35 64309488-v1 155792.599942 administered at the same frequency, either simultaneously or sequentially.
  • At least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered at the same frequency, but not simultaneously, e.g., once every 1 week or 2 weeks or 3 weeks but the administration of each therapy is separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, or 12 hours.
  • At least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered at different frequencies and each independently is administered every day, every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.
  • futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof are each administered every day or intermittently.
  • the administration according to the methods of the disclosure is for at least one treatment cycle.
  • each of the futibatinib or a pharmaceutically acceptable salt thereof, the pembrolizumab or a pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof is administered every day, intermittently, or once during a treatment cycle.
  • a treatment cycle is 1 – 365 days.
  • a treatment cycle is 1 day, 2 days, one week (i.e., 7 days), 2 weeks (i.e., 14 days), 3 weeks (i.e., 21 days), 4 weeks (i.e., 28 days), 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks, one month, months , months, 6 months or about one year.
  • a “week” means seven consecutive days.
  • the treatment cycle is about 14 to about 28 days.
  • the treatment cycle is about 21 days (i.e., 3 weeks).
  • administered every day or “daily” or “once a day” or “once a day on each day” includes an administration schedule based on a regimen in which dosing is performed on every day of a treatment cycle (i.e., treatment period).
  • an active ingredient may be administered every day (i.e., QD) of a 21-day treatment cycle.
  • a “drug holiday” may be provided as each treatment cycle ends.
  • an active agent is administer once during a 21-day treatment cycle (i.e, Q3W).
  • administered intermittently is not particularly limited as long as the conditions of at least twice during the treatment cycle and an administration interval of at least one day between dosing (the number of days between a certain day of administration and the next day of administration) are satisfied.
  • the administration is for 1 treatment cycle.
  • the administration is for at least one treatment cycle and one additional treatment cycle (i.e., at least two treatment cycles).
  • the administration is for at least 2 treatment cycles, or at least 3 treatment cycles, or at least 4 treatment cycles, or at least 5 treatment cycles, or at least 6 treatment cycles, or at least 7 treatment cycles, or at least 8 treatment cycles, or at least 9 treatment cycles, or at least 10 treatment cycles, or at least 11 treatment cycles, or at least 12 treatment cycles, or at least15 treatment cycles, or at least 20 treatment cycles, or at least 25 treatment cycles, or at least 30 treatment cycles, or at least 35 treatment cycles, or at least 40 treatment cycles.
  • the treatment is continuous until an endpoint which may be determined by a medical professional.
  • the administration is for less than or equal to 35 treatment cycles.
  • the administered amount of an active agent of the disclosure is held constant during one treatment cycle.
  • the administered amount of an active agent of the disclosure is held constant for at least one treatment cycle and at least one additional treatment cycle (i.e., more than one treatment cycle). In an embodiment, the administered amount of an active agent of the disclosure can be increased in a second or subsequent treatment cycle (i.e., an additional treatment cycle). In an embodiment, the administered amount of an active agent of the disclosure can be held constant for at least two treatment cycles and decreased in a third or subsequent 37 64309488-v1 155792.599942 treatment cycle. In an embodiment, the administered amount of an active agent of the disclosure can be held constant for at least two treatment cycles and increased in a third or subsequent treatment cycle.
  • an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg to about 160 mg per dose, about 4 mg to about 30 mg per dose, about 12 mg to about 24 mg per dose, about 16 mg to about 24 mg per dose, about 12 mg to about 20 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, about 24 mg, or about 30 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 12 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 16 mg per dose.
  • an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 20 mg per dose.
  • an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg to about 160 mg per dose once a day, about 4 mg to about 30 mg per dose once a day, about 12 mg to about 24 mg per dose once a day, about 16 mg to about 24 mg per dose once a day, or about 12 mg to about 20 mg per dose once a day.
  • an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, about 24 mg, or about 30 mg per dose once a day.
  • an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 12 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 16 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 20 mg per dose once a day. [00147] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each day of a treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg to about 160 mg per dose once a day on each day of a treatment cycle, about 4 mg to about 24 mg per dose once a day on each day of a treatment cycle, about 12 mg to about 38 64309488-v1 155792.599942 24 mg per dose once a day on each day of a treatment cycle, about 16 mg to about 24 mg per dose once a day on each day of a treatment cycle, or about 12 mg to about 20 mg per dose once a day on each day of a treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 12 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 16 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a treatment cycle.
  • the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is held constant during a second or subsequent treatment cycle. In an embodiment, the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is increased during a second or subsequent treatment cycle. In an embodiment, the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is decreased during a second or subsequent treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a first treatment cycle and in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a second or subsequent treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a first treatment cycle and in an amount of about 16 mg per dose once a day on each day of a second or subsequent treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a first treatment cycle and in an amount of about 16 mg per dose once a day on each day of a second treatment cycle and in an amount of about 12 mg per dose once a day on each day of a third or subsequent treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-14 of a 14-day treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-21 of a 21-day treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-28 of a 28-day treatment cycle. [00151] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least one 21-day treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least two 21-day treatment cycles. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least three 21-day treatment cycles. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during each additional 21-day treatment cycle up to thirty five (35) consecutive 21-day treatment cycles.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle.
  • futibatinib or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle in an amount of about 2 to 1000 mg per dose, about 10 to 500 mg per dose, about 20 to 200 mg per dose, or about 50 to 160 mg per dose.
  • intermittent administration is according to an administration schedule based on a 1-week (7 day) treatment cycle, in which futibatinib or a pharmaceutically acceptable salt thereof is administered at least twice every one to three days per treatment cycle (with an interval between a certain day of administration and the next day of administration of 1 to 3 days), and this cycle is performed once or repeated twice or more.
  • intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which futibatinib or a pharmaceutically acceptable salt thereof is administered 4 to 7 times every one to three days per treatment cycle (with an interval between a certain day of administration and the next day of administration of 1 to 3 days), and this cycle is performed once or repeated twice or more.
  • intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days 40 64309488-v1 155792.599942 contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 4, 8, and 11.
  • intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13.
  • intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 8, 10, and 12.
  • an example of the administration schedule is such that 160 mg of futibatinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1, 3, 5, 8, 10, and 12.
  • an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose, or about 200 mg to about 400 mg per dose, or about 100 mg to 200 mg per dose, or about 150 mg to 200 mg per dose, or about 200 mg to 300 mg per dose, or about 250 mg to 300 mg per dose, or about 300 mg to 400 mg per dose, or about 350 mg to 400 mg per dose.
  • an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose, or about 200 mg to about 400 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg or about 400 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 1.0 to 2.0 mg/kg (body weight) per dose, or 2.0 mg/kg (body weight) per dose.
  • an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose once a day, or about 200 mg to about 400 mg per dose once a day, or about 100 mg to 200 mg per dose once a day, or about 150 mg to 200 mg per dose once a day, or about 200 mg to 300 mg per dose once a day, or about 250 mg to 300 mg per dose once a day, or about 300 mg to 400 mg per dose once a day, or about 350 mg to 400 mg per dose once a day.
  • an amount of pembrolizumab or the pharmaceutically acceptable salt 41 64309488-v1 155792.599942 thereof administered is about 100 mg to about 400 mg per dose once a day, or about 200 mg to about 400 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg or about 400 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 1.0 to 2.0 mg/kg (body weight) per dose, or 2.0 mg/kg (body weight) per dose once a day.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered once a day on each day of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered once during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered more than once during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on at least day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, or day 10 of a treatment cycle.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, and day 5 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 2 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 3 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 4 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 5 of a treatment cycle.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 6 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 7 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 8 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is 42 64309488-v1 155792.599942 administered on day 9 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 10 of a treatment cycle. [00157] In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least one 21-day treatment cycle.
  • pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least two 21-day treatment cycles. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least three 21-day treatment cycles. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of each additional 21- day treatment cycle up to thirty five (35) consecutive 21-day treatment cycles. [00158] In an embodiment, the amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is held constant during a second or subsequent treatment cycle. In an embodiment, the amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is increased during a second or subsequent treatment cycle.

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Abstract

La présente divulgation concerne des méthodes de traitement d'un cancer chez un sujet en ayant besoin, comprenant l'administration au sujet de futibatinib ou d'un sel pharmaceutiquement acceptable de celui-ci, de pembrolizumab ou d'un sel pharmaceutiquement acceptable de celui-ci, et d'au moins un agent thérapeutique anticancéreux supplémentaire ou d'un sel pharmaceutiquement acceptable de celui-ci. Dans certains modes de réalisation, l'au moins un agent thérapeutique anticancéreux supplémentaire est un agent chimiothérapeutique.
PCT/IB2024/058465 2023-08-31 2024-08-30 Méthodes de traitement du cancer à l'aide de futibatinib, de pembrolizumab et d'au moins un agent chimiothérapeutique supplémentaire Pending WO2025046537A1 (fr)

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