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WO2025049277A1 - Méthodes et compositions pour le traitement du cancer du poumon non à petites cellules comprenant un anticorps antagoniste anti-tigit et un antagoniste de liaison de l'axe pd-1 - Google Patents

Méthodes et compositions pour le traitement du cancer du poumon non à petites cellules comprenant un anticorps antagoniste anti-tigit et un antagoniste de liaison de l'axe pd-1 Download PDF

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Publication number
WO2025049277A1
WO2025049277A1 PCT/US2024/043565 US2024043565W WO2025049277A1 WO 2025049277 A1 WO2025049277 A1 WO 2025049277A1 US 2024043565 W US2024043565 W US 2024043565W WO 2025049277 A1 WO2025049277 A1 WO 2025049277A1
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administered
atezolizumab
tiragolumab
subject
nsclc
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WO2025049277A9 (fr
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Christina Jeanne MATHENY
Maya Nicole WHITE
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Genentech Inc
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Genentech Inc
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    • 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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • 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
    • 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
    • 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
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the treatment of non-small cell lung cancer (NSCLC). More specifically, the invention relates to the treatment of patients having an NSCLC by administering a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) following surgical resection and adjuvant chemotherapy or by administering a treatment regimen that includes an adjuvant chemotherapy, an anti-TIGIT antagonist antibody (e.g., tiragolumab), and a PD-1 axis binding antagonist (e.g., atezolizumab) following surgical resection.
  • a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) following surgical resection.
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • Lung cancer remains the leading cause of cancer deaths worldwide and is one of the most common cancers in both men and women. In 2023 in the United States, it is estimated that there will be 238,340 new cases of lung cancer and 127,070 lung cancer deaths. Data from Europe estimate that in 2023 there will be 159,057 lung cancer deaths.
  • Non-small cell lung cancer is the predominant subtype of lung cancer, accounting for approximately 80%-85% of all cases.
  • NSCLC can be divided into two major histologic types: adenocarcinoma and squamous cell carcinoma.
  • Adenocarcinoma histology accounts for approximately 40%-50% of all NSCLC, while squamous cell histology accounts for approximately 20%-30% of NSCLC.
  • the remaining cases of NSCLC are represented by large cell carcinoma, neuroendocrine tumors, and sarcomatoid carcinoma, and are of poorly differentiated histology.
  • NSCLC Newcastle disease virus
  • curative intent 30%-70% of patients undergoing resection develop recurrence and die as a result of disease progression.
  • Radiation therapy is no longer recommended after surgery as an adjuvant treatment option for spatients with Stage I and II NSCLC because it has been shown to have a deleterious effect on long-term survival.
  • the invention provides a method of treating a subject having a non-small cell lung cancer (NSCLC), the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.
  • NSCLC non-small cell lung cancer
  • the subject has received between one and four dosing cycles of the adjuvant chemotherapy (e.g., has received four dosing cycles of the adjuvant chemotherapy).
  • the invention provides a method of treating a subject having a non-small cell lung cancer (NSCLC), the method comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.
  • NSCLC non-small cell lung cancer
  • the method comprises administering to the subject between one and four dosing cycles of the adjuvant chemotherapy (e.g., comprises administering to the subject four dosing cycles of the adjuvant chemotherapy).
  • administration of the one or more dosing cycles of tiragolumab and atezolizumab is initiated within ten weeks of the last administered dose of the adjuvant chemotherapy.
  • the method comprises administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.
  • the method comprises administering to the subject tiragolumab at a fixed dose of about 840 mg every four weeks.
  • the length of each of the one or more dosing cycles of tiragolumab and atezolizumab is 28 days.
  • the method comprises administering to the subject atezolizumab and/or tiragolumab on about Day 1 of each 28-day dosing cycle.
  • the method comprises co-administering to the subject atezolizumab and tiragolumab. In some aspects, the method comprises co-administering to the subject atezolizumab and tiragolumab by intravenous co-infusion. In some aspects, atezolizumab and tiragolumab are formulated together and are administered intravenously as a fixed dose combination (FDC).
  • FDC fixed dose combination
  • the method comprises (i) administering (e.g., intravenously administering) to the subject atezolizumab before tiragolumab or (ii) administering (e.g., intravenously administering) to the subject tiragolumab before atezolizumab.
  • up to 13 dosing cycles of tiragolumab and atezolizumab are administered to the subject.
  • dosing cycles of tiragolumab and atezolizumab are administered to the subject for up to one year.
  • the invention provides a method of treating a subject having an NSCLC, the method comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) a Stage I IB NSCLC; (b) a Stage IIIA NSCLC; or (c) a T3N2 Stage IIIB NSCLC.
  • the invention provides a method of treating a subject having an NSCLC, the method comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) a Stage IIB NSCLC; (b) a Stage 11 IA NSCLC; or (c) a T3N2 Stage I IIB NSCLC.
  • the invention provides use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.
  • the invention provides use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.
  • the invention provides tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy.
  • the invention provides tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject an adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected.
  • the subject has received between one and four dosing cycles of the adjuvant chemotherapy (e.g., has received four dosing cycles of the adjuvant chemotherapy).
  • between one and four dosing cycles of the adjuvant chemotherapy are to be administered to the subject (e.g., four dosing cycles of the adjuvant chemotherapy are to be administered to the subject).
  • administration of the one or more dosing cycles of tiragolumab and atezolizumab is to be initiated within ten weeks of the last administered dose of the adjuvant chemotherapy.
  • Atezolizumab is to be administered at a fixed dose of about 1680 mg every four weeks. In some aspects, tiragolumab is to be administered at a fixed dose of about 840 mg every four weeks.
  • the length of each of the one or more dosing cycles of tiragolumab and atezolizumab is 28 days. In some aspects, atezolizumab and/or tiragolumab is to be administered to the subject on about Day 1 of each 28-day dosing cycle.
  • Atezolizumab and tiragolumab are to be co-administered to the subject. In some aspects, atezolizumab and tiragolumab are to be co-administered to the subject by intravenous coinfusion. In some aspects, atezolizumab and tiragolumab are to be formulated together and administered intravenously as a fixed dose combination (FDC). In other aspects, (i) atezolizumab is to be administered (e.g., intravenously administered) to the subject before tiragolumab or (ii) tiragolumab is to be administered (e.g., intravenously administered) to the subject before atezolizumab.
  • FDC fixed dose combination
  • up to 13 dosing cycles of tiragolumab and atezolizumab are to be administered to the subject. In some aspects, dosing cycles of tiragolumab and atezolizumab are to be administered to the subject for up to one year.
  • the invention provides use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) a Stage IIB NSCLC; (b) a Stage IIIA NSCLC; or (c) a T3N2 Stage I IIB NSCLC.
  • the invention provides use of tiragolumab and/or atezolizumab in the manufacture of a medicament for the treatment of a subject having an NSCLC, the treatment comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) a Stage IIB NSCLC; (b) a Stage IIIA NSCLC; or (c) a T3N2 Stage IIIB NSCLC.
  • the invention provides tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the subject has received between one and four cycles of a platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) a Stage IIB NSCLC; (b) a Stage IIIA NSCLC; or (c) a T3N2 Stage IIIB NSCLC.
  • the invention provides tiragolumab and/or atezolizumab for use in treating a subject having an NSCLC, the treating comprising administering to the subject between one and four cycles of a platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) a Stage IIB NSCLC; (b) a Stage IIIA NSCLC; or (c) a T3N2 Stage IIIB NSCLC.
  • the complete resection was a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy. In some aspects, the complete resection was a resection resulting in (i) no residual tumor and (ii) all surgical margins negative for invasive carcinoma.
  • the adjuvant chemotherapy is a platinum-based adjuvant chemotherapy.
  • the platinum-based adjuvant chemotherapy comprises cisplatin.
  • the platinum-based adjuvant chemotherapy comprises carboplatin.
  • the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents.
  • the one or more additional chemotherapeutic agents comprises a vinca alkaloid (e.g., vinorelbine), a taxane (e.g., docetaxel or paclitaxel), an antimetabolite (e.g., gemcitabine or pemetrexed), a topoisomerase II inhibitor (e.g., etoposide), or a combination thereof.
  • the platinum-based adjuvant chemotherapy is a platinum-based adjuvant doublet chemotherapy.
  • the platinum-based adjuvant doublet chemotherapy comprises (i) cisplatin and pemetrexed administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75 mg/m 2 intravenously on Day 1 of each 21 -day dosing cycle and pemetrexed is administered at a dose of about 500 mg/m 2 on Day 1 of each 21 -day dosing cycle; (ii) cisplatin and gemcitabine administered in one or more 21 -day dosing cycles, wherein cisplatin is administered at a dose of about 75 mg/m 2 intravenously on Day 1 of each 21 -day dosing cycle and gemcitabine is administered at a dose of about 1250 mg/m 2 on Days 1 and 8 of each 21 -day dosing cycle; (iii) cisplatin and docetaxel administered in one or more 21
  • the subject has not experienced recurrence of the NSCLC following the complete resection.
  • the subject has not experienced recurrence of the NSCLC following the adjuvant chemotherapy.
  • the NSCLC is (a) a Stage I IB NSCLC; (b) a Stage I HA NSCLC; or (c) a T3N2 Stage II IB NSCLC.
  • NSCLC staging is per the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8 th edition.
  • the NSCLC is squamous NSCLC. In other aspects, the NSCLC is non- squamous NSCLC.
  • the PD-L1 -positive tumor cell fraction of a tumor sample obtained from the subject has been determined by an immunohistochemical (IHC) assay.
  • the PD-L1 - positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8 (e.g., is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay).
  • the PD-L1 -positive tumor cell fraction has been determined using a Ventana SP263 IHC assay.
  • the tumor sample obtained from the subject has been determined to have a percentage of tumor cells with any membrane staining above background (TC) of equal to or greater than 1%.
  • the tumor sample obtained from the subject has been determined to have a TC of equal to or greater than 50%.
  • the subject does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • the subject has a squamous NSCLC and has not been assessed for an EGFR or ALK genomic tumor aberration.
  • the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.
  • the treating results in an increase in the duration of disease-free survival (DFS) as compared to a reference DFS duration (e.g., the mean or median DFS duration of a population of subjects who have received a control treatment (e.g., atezolizumab monotherapy)).
  • DFS disease-free survival
  • the treating results in an increase in the duration of overall survival (OS) as compared to a reference OS duration (e.g., the mean or median OS duration of a population of subjects who have received a control treatment (e.g., atezolizumab monotherapy)).
  • OS overall survival
  • a reference OS duration e.g., the mean or median OS duration of a population of subjects who have received a control treatment (e.g., atezolizumab monotherapy)
  • the treating results in an increase in the DFS rate as compared to a reference DFS rate (e.g., the DFS rate of a population of subjects who have received a control treatment (e.g., atezolizumab monotherapy)).
  • a reference DFS rate e.g., the DFS rate of a population of subjects who have received a control treatment (e.g., atezolizumab monotherapy)
  • the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.
  • the subject is a human.
  • FIG. 1 is a schematic diagram showing the overall design of the G045006 study.
  • NSCLC nonsmall cell lung cancer.
  • Q4W every four weeks.
  • a PD-L1 status of “1 -49%” refers to a PD-L1 membrane staining above background (TC) of equal to or greater than 1% and less than 50%.
  • platinum-based adjuvant chemotherapy refers to an adjuvant chemotherapy regimen that includes a platinum-based chemotherapeutic agent.
  • an adjuvant platinum-based chemotherapy may include a platinum-based chemotherapeutic agent (e.g., cisplatin or carboplatin) in combination with one or more additional chemotherapeutic agents, e.g., a vinca alkaloid (e.g., vinorelbine), a taxane (e.g., docetaxel), an anti-metabolite (e.g., gemcitabine or pemetrexed), or a combination thereof.
  • a platinum-based chemotherapeutic agent e.g., cisplatin or carboplatin
  • additional chemotherapeutic agents e.g., a vinca alkaloid (e.g., vinorelbine), a taxane (e.g., docetaxel), an anti-metabolite (e.g., gemcitabine or pemetrexed),
  • the adjuvant platinum-based chemotherapy is a platinum-based doublet chemotherapy, e.g., a chemotherapy comprising a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and an additional therapeutic agent (e.g., pemetrexed, docetaxel, gemcitabine, vinorelbine, paclitaxel, or nab-paclitaxel).
  • adjuvant chemotherapy is a chemotherapy (e.g., a chemotherapy regimen) that is administered to a subject after a primary or initial therapy (e.g., is administered after surgical resection of a cancer).
  • “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer.
  • chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitinib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Si
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, es
  • Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (let
  • Chemotherapeutic agents also include “platinum-based” chemotherapeutic agents, also referred to herein as “platinum agents,” which comprise an organic compound which contains platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes called “platins” in the art. Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin.
  • Platinum-based chemotherapeutic agents may be administered in combination with one or more additional chemotherapeutic agents, e.g., a nucleoside analog (e.g., gemcitabine), an antimetabolite (e.g., pemetrexed or gemcitabine), or a taxane (e.g., paclitaxel or nab- paclitaxel).
  • a nucleoside analog e.g., gemcitabine
  • an antimetabolite e.g., pemetrexed or gemcitabine
  • a taxane e.g., paclitaxel or nab- paclitaxel
  • eligible for treatment with a platinum-based chemotherapy means that the subject is eligible for treatment with a platinum-based chemotherapy, either in the attending clinician’s judgment or according to standardized criteria for eligibility for platinum-based chemotherapy that are known in the art.
  • Chemotherapeutic agents also include “non-platinum-based chemotherapeutic agents,” which, as used herein, refer to chemotherapeutic agents that are not “platinum-based.” As used herein, the terms “non-platinum-based chemotherapeutic agents” and “non-platinum agents” are used interchangeably.
  • non-platinum-based chemotherapeutic agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331 ), taxanes (e.g., paclitaxel (e.g., albumin-engineered paclitaxel, also referred to as nanoparticle-albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).
  • exemplary non-platinum-based chemotherapeutic agents also include alkylating agents (e.g., cyclophosphamide).
  • nucleoside analog refers to a nucleoside that includes a nucleic acid analog and a sugar. Nucleoside analogs may function as antimetabolites. Exemplary nucleoside analogues include but are not limited to gemcitabine, cytarabine, fludarabine, and cladribine.
  • Taxanes as used herein is a diterpene which may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization.
  • Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof.
  • Exemplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS # 33069-62-4), docetaxel (i.e., TAXOTERE®, CAS # 114977-28- 5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel.
  • the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., ABRAXANE® and/or nab-docetaxel, ABI-008).
  • the taxane is nab-paclitaxel (ABRAXANE®).
  • the taxane is formulated in CREMAPHOR® (e.g., TAXOL®) and/or in Tween such as polysorbate 80 (e.g., TAXOTERE®).
  • the taxane is liposome-encapsulated taxane.
  • the taxane is a prodrug form and/or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleyl carbonate-paclitaxel).
  • the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR and/or Tween-such as TOCOSOL® paclitaxel).
  • an “antimetabolite” as used herein is a chemotherapeutic agent that interferes with and inhibits (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell).
  • Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.
  • Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa- 2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin
  • Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17- butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective
  • Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic, and anti-inflammatory effects.
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumi
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • Chemotherapeutic agents also include “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include small molecules that bind to EGFR.
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521 ,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041 , 6,002,008, and 5,747,498, as well as the following PCT publications: WO98/14451 , W098/50038, W099/09016, and WO99/24037.
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2- propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 -methyl
  • Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Aik) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP261 13, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR- overexpressing cells; lapatini
  • anthracycline relates to a chemotherapeutic agent, an anticancer agent for inducing apoptosis, preferably by inhibiting the rebinding of DNA in topoisomerase II.
  • examples include doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, rhodomycin, pyrarubicin, valrubicin, N-trifluoro-acetyl doxorubicin-14-valerate, aclacinomycin, morpholinodoxorubicin (morpholino- DOX), cyanomorpholino-doxorubicin (cyanomorpholino-DOX), 2-pyrrolino-doxorubicin (2-PDOX), 5- iminodaunomycin, mitoxantrone and aclacinomycin A (aclarubicin).
  • the anthracycline is administered in combination with an alkyl
  • alkylating agent as used herein is a chemotherapeutic agent which causes DNA damage by attaching an alkyl group to DNA.
  • Alkylating agents include cyclophosphamide and N,N',N"- triethylenethiophosphoramide.
  • a comparator arm refers to a reference (e.g., a reference population of patients) used as a basis of comparison for a treatment or treatment arm in a study, e.g., a clinical trial.
  • a comparator arm may be a control arm in a clinical trial.
  • the comparator arm may include a population of patients who have received a control treatment, such as one or more previously approved treatments or marketed products.
  • a “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject.
  • healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue e.g., cells or tissue adjacent to a tumor.
  • a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of a subject who is not the subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject.
  • TIGIT or “T-cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM.
  • the term encompasses “full-length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 31 ).
  • the term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1 .
  • tiragolumab is a fully human lgG1/kappa MAb-derived in Open Monoclonal Technology (OMT) rats that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 33 and the light chain sequence of SEQ ID NO: 34.
  • Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 1 17, Vol. 31 , No. 2, published June 9, 2017 (see page 343).
  • anti-TIGIT antagonist antibody refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT.
  • an anti-TIGIT antagonist antibody may block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation.
  • an anti-TIGIT antagonist antibody may block signaling through PVR without impacting PVR- CD226 interaction.
  • an anti- TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity.
  • an anti-TIGIT antagonist antibody for use in certain of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions.
  • the extent of binding of an anti-TIGIT antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT as measured, e.g., by a radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • an anti-TIGIT antagonist antibody that binds to TIGIT has a dissociation constant (KD) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • KD dissociation constant
  • an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT from different species or an epitope on TIGIT that allows for cross-species reactivity.
  • the anti-TIGIT binding antibody has intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EOS084448, or TJ-T6). In some aspects, the anti-TIGIT binding antibody has enhanced Fc- mediated effector function (e.g., SGN-TGT). In other aspects, the anti-TIGIT binding antibody lacks Fc- mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902).
  • the anti-TIGIT binding antibody is an IgG 1 class antibody (e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308).
  • the anti-TIGIT binding antibody is an lgG4 class antibody (e.g., ASP8374 or COM902).
  • the anti-TIGIT antagonist antibody is tiragolumab.
  • the terms “programmed death ligand 1 ” and “PD-L1” refer herein to native sequence human PD- L1 polypeptide.
  • Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7.
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-1 (isoform 1 ) (SEQ ID NO: 32).
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-2 (isoform 2).
  • the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No.
  • PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”
  • atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG 1 kappa immunoglobulin that binds PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 1 and the light chain sequence of SEQ ID NO: 2.
  • Atezolizumab comprises a single amino acid substitution (asparagine to alanine) at position 297 on the heavy chain (N297A) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc receptors.
  • Atezolizumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 112, Vol. 28, No. 4, published January 16, 2015 (see page 485).
  • PD-1 axis binding antagonist refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing).
  • a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.
  • the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist.
  • the PD-1 axis binding antagonist is a PD-L1 binding antagonist.
  • PD-L1 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1 .
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners.
  • the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 .
  • the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and/or B7-1 .
  • a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-L1 binding antagonist binds to PD-L1 .
  • a PD- L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody).
  • anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK- 106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636
  • the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab).
  • the PD-L1 binding antagonist is MDX-1105.
  • the PD-L1 binding antagonist is MEDI4736 (durvalumab).
  • the PD-L1 binding antagonist is MSB0010718C (avelumab).
  • the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally.
  • Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003.
  • the PD-L1 binding antagonist is atezolizumab.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2.
  • PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2.
  • a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T- cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-1 binding antagonist binds to PD-1 .
  • the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody).
  • anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI
  • a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108.
  • a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab.
  • Other additonal exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.
  • PD-L2 binding antagonist refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 .
  • PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.”
  • An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51 .
  • a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners.
  • the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 .
  • Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 .
  • a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition).
  • the PD-L2 binding antagonist binds to POUT
  • a PD-L2 binding antagonist is an immunoadhesin.
  • a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.
  • cancer refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body.
  • the cancer is lung cancer, e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage II IB NSCLC.
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre
  • tumor cell refers to any tumor cell present in a tumor or a sample thereof. Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and/or described herein.
  • treating comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab); an anti-TIG IT antagonist antibody (e.g., tiragolumab); and/or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent)).
  • a therapeutic agent e.g., a PD-1 axis binding antagonist (e.g., atezolizumab); an anti-TIG IT antagonist antibody (e.g., tiragolumab); and/or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent)).
  • Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy.
  • the treatment may be first-line treatment (e.g., the patient may be previously untreated
  • an “effective amount” of a compound for example, a PD-1 axis binding antagonist (e.g., atezolizumab); an anti-TIGIT antagonist antibody (e.g., tiragolumab); and/or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent), is at least the minimum amount required to achieve the desired therapeutic result, such as a measurable increase in overall survival or progression-free survival of a particular disease or disorder (e.g., cancer, e.g., NSCLC, e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage 11 IB NSCLC).
  • a particular disease or disorder e.g., cancer, e.g., NSCLC, e.g., a Stage I IB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage 11 IB NSCLC.
  • an effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the subject.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSE), reduction in symptoms per the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or general level of physical emotional, cognitive, or social functioning), reduction in pain as measured by, e.g., the 10-point pain severity (measured at its worst) numerical rating scale (NRS), and/or reduction in symptoms associated with lung cancer per the health-related quality of life (HRQoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspnea and chest pain), increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting
  • progression-free survival or radiographic progression-free survival rPFS
  • delay of unequivocal clinical progression e.g., cancer-related pain progression, symptomatic skeletal-related event, deterioration in Eastern Cooperative Group Oncology Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily living abilities of the patient), and/or initiation of next systemic anti-cancer therapy), and/or delaying time to lung-specific antigen progression
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e.
  • an effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • survival refers to the patient remaining alive, and includes overall survival as well as progression-free survival.
  • Disease-free survival and “DFS” refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer, e.g., NSCLC) to the occurrence of local or distant recurrence of the disease (e.g., cancer, e.g., NSCLC), new primary disease (e.g., cancer, e.g., NSCLC), or death from any cause.
  • a disease e.g., cancer, e.g., NSCLC
  • new primary disease e.g., cancer, e.g., NSCLC
  • death from any cause e.g., NSCLC
  • DFS may be defined as the time from first study treatment to to the occurrence of local or distant recurrence of the disease, new primary disease, or death from any cause.
  • overall survival and “OS” refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer) that the patient is still alive.
  • OS may be defined as the time from first study treatment to death from any cause.
  • partial response and “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD prior to treatment.
  • progressive disease and “PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest sum on study (nadir), including baseline.
  • stable disease and “SD” refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
  • subject or “individual” is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human. Patients are also subjects herein.
  • a “PD-L1 -positive tumor cell fraction” is the percentage of viable tumor cells showing partial or complete membrane staining (exclusive of cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample, following staining of the sample in the context of an immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using the antibody SP142, SP263, 22C3, or 28-8.
  • IHC immunohistochemical
  • non-tumor cells e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris
  • any given diagnostic PD-L1 antibody may correspond with a particular IHC assay protocol and/or scoring terminology that can be used to derive a PD-L1 -positive tumor cell fraction.
  • a PD- L1 -positive tumor cell fraction can be derived from a tumor cell sample stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW® detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTIVIEW® detection and amplification on Benchmark ULTRA, or EnVision Flex on AutostainerLink 48, respectively.
  • Ventana SP142 IHC assay is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • Ventana SP263 IHC assay is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • the “pharmDx 22C3 IHC assay” is conducted according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.
  • the “pharmDx 28-8 IHC assay” is conducted according to the PD-L1 IHC 28-8 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.
  • the term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.
  • “in combination with” refers to administration of one treatment modality in addition to another treatment modality, for example, a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab).
  • a treatment regimen that includes administration of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab).
  • “in combination with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the patient.
  • a drug that is administered “concurrently” with one or more other drugs is administered during the same treatment cycle, on the same day of treatment, as the one or more other drugs, and, optionally, at the same time as the one or more other drugs.
  • the concurrently administered drugs are each administered on Day 1 of each four-week (28-day) dosing cycle.
  • antibody herein specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity.
  • the antibody is a full-length monoclonal antibody.
  • IgG immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.
  • antibodies can be assigned to different classes.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, e, y, and p, respectively.
  • An antibody may be part of a larger fusion molecule, formed by covalent or non- covalent association of the antibody with one or more other proteins or peptides.
  • full-length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below.
  • the terms refer to an antibody comprising an Fc region.
  • Fc region herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region.
  • the term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C- terminus of the heavy chain.
  • an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C- terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present.
  • a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447).
  • a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein comprises an additional C-terminal glycine residue (G446).
  • a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein comprises an additional C-terminal lysine residue (K447).
  • the Fc region contains a single amino acid substitution N297A of the heavy chain.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 .
  • the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1 -107 of the light chain and residues 1 -113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991 )).
  • the “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra).
  • the “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.
  • naked antibody refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel.
  • the naked antibody may be present in a pharmaceutical composition.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.
  • hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example “complementarity determining regions” (“CDRs”).
  • CDRs complementarity determining regions
  • antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3).
  • Exemplary CDRs herein include:
  • CDRs are determined according to Kabat et al., supra.
  • CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.
  • “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs).
  • the FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -CDR-H1 (CDR-L1 )-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.
  • variable domain residue numbering as in Kabat or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain.
  • a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc., according to Kabat) after heavy chain FR residue 82.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.
  • the term “monospecific” antibody as used herein denotes an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen.
  • the term “bispecific” antibody as used herein means that the antibody is able to specifically bind to at least two distinct antigens, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) binding to different antigens or to different epitopes on the same antigen.
  • VH antibody heavy chain variable domain
  • VL antibody light chain variable domain
  • Such a bispecific antibody is an 1 +1 format.
  • bispecific antibody formats are 2+1 formats (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 formats (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope).
  • a bispecific antibody comprises two antigen binding sites, each of which is specific for a different antigen.
  • bispecific antibodies according to the invention are at least “bivalent” and may be “trivalent” or “multivalent” (e.g., “tetravalent” or “hexavalent”).
  • the antibodies of the present invention have two or more binding sites and are bispecific. That is, the antibodies may be bispecific even in cases where there are more than two binding sites (i.e.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies, triabodies, tetrabodies, cross-Fab fragments; linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibodies formed from antibody fragments and single domain antibodies.
  • Diabodies are antibody fragments with two antigen-binding domains that may be bivalent or bispecific, see, for example, EP 404,097; WO 1993/01161 ; Hudson et al., Nat Med 9, 129-134 (2003); and Hollinger et al., Proc Natl Acad Sci USA 90, 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat Med 9, 129-134 (2003).
  • Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody.
  • a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see e.g., U.S. Patent No. 6,248,516 B1 ).
  • antibody fragments comprise single chain polypeptides having the characteristics of a VH domain, namely being able to assemble together with a VL domain, or of a VL domain, namely being able to assemble together with a VH domain to a functional antigen binding site and thereby providing the antigen binding property of full-length antibodies.
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.
  • Papain digestion of intact antibodies produces two identical antigen-binding fragments, called “Fab” fragments containing each the heavy- and light-chain variable domains and also the constant domain of the light chain and the first constant domain (CH1 ) of the heavy chain.
  • Fab fragment refers to an antibody fragment comprising a light chain fragment comprising a VL domain and a constant domain of a light chain (CL), and a VH domain and a first constant domain (CH1 ) of a heavy chain.
  • Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteins from the antibody hinge region.
  • Fab’-SH are Fab’ fragments wherein the cysteine residue(s) of the constant domains bear a free thiol group. Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites (two Fab fragments) and a part of the Fc region.
  • cross-Fab fragment or “xFab fragment” or “crossover Fab fragment” refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged.
  • Two different chain compositions of a crossover Fab molecule are possible and comprised in the bispecific antibodies of the invention: On the one hand, the variable regions of the Fab heavy and light chain are exchanged, i.e. , the crossover Fab molecule comprises a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1 ), and a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL).
  • This crossover Fab molecule is also referred to as CrossFab (VLVH).
  • the crossover Fab molecule comprises a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL), and a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1 ).
  • This crossover Fab molecule is also referred to as CrossFab ⁇ CLCHI).
  • a “single chain Fab fragment” or “scFab” is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1 ), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CH1 -linker-VL-CL, b) VL-CL-linker-VH-CH1 , c) VH-CL-linker-VL-CH1 or d) VL-CH1 -linker-VH-CL; and wherein said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids.
  • Said single chain Fab fragments are stabilized via the natural disulfide bond between the CL domain and the CH1 domain.
  • these single chain Fab molecules might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).
  • a “crossover single chain Fab fragment” or “x-scFab” is a is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1 ), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CL- linker-VL-CH1 and b) VL-CH1 -linker-VH-CL; wherein VH and VL form together an antigen-binding domain which binds specifically to an antigen and wherein said linker is a polypeptide of at least 30 amino acids.
  • these x-scFab molecules might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).
  • a “single-chain variable fragment (scFv)” is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of an antibody, connected with a short linker peptide of ten to about 25 amino acids.
  • the linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original antibody, despite removal of the constant regions and the introduction of the linker.
  • scFv antibodies are, e.g., described in Houston, J.S., Methods in Enzymol. 203 (1991 ) 46- 96).
  • antibody fragments comprise single chain polypeptides having the characteristics of a VH domain, namely being able to assemble together with a VL domain, or of a VL domain, namely being able to assemble together with a VH domain to a functional antigen binding site and thereby providing the antigen binding property of full-length antibodies.
  • effector functions refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype.
  • antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.
  • an “activating Fc receptor” is an Fc receptor that following engagement by an Fc region of an antibody elicits signaling events that stimulate the receptor-bearing cell to perform effector functions. Activating Fc receptors include FcyRllla (CD16a), FcyRI (CD64), FcyRlla (CD32), and FcaRI (CD89). A particular activating Fc receptor is human FcyRllla (see UniProt accession no. P08637, version 141).
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087.
  • the ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code.
  • the ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.
  • % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows:
  • a subject e.g., a human subject having a non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • a subject e.g., a human subject having a non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • administering comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab)
  • an adjuvant chemotherapy e.g., an adjuvant platinum-based chemotherapy.
  • a subject e.g., a human subject
  • an NSCLC e.g., a Stage IIB NSCLC, a Stage I HA NSCLC, or a T3N2 Stage HIES NSCLC
  • administering to the subject one or more dosing cycles of tiragolumab and atezolizumab, wherein, prior to the administration of tiragolumab and atezolizumab, the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy).
  • an adjuvant chemotherapy e.g., an adjuvant platinum-based chemotherapy
  • an adjuvant chemotherapy e.g., an adjuvant platinum-based chemotherapy
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g.,
  • a subject e.g., a human subject having an NSCLC (e.g., a Stage IIB NSCLC, a Stage I HA NSCLC, or a T3N2 Stage IIIB NSCLC) comprising administering to the subject an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy) followed by one or more dosing cycles of tiragolumab and atezolizumab, wherein, prior to the administration of the adjuvant chemotherapy and tiragolumab and atezolizumab, the NSCLC has been completely resected.
  • an adjuvant chemotherapy e.g., an adjuvant platinum-based chemotherapy
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • the invention provides a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti- TIGIT antagonist antibody (e.g., tiragolumab) for use in a method of treating a subject (e.g., a human subject) having an NSCLC (e.g., a Stage IIB NSCLC, a Stage 11 IA NSCLC, or a T3N2 Stage IIIB NSCLC) comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab), wherein, prior to the administration of the NSCLC (e.g., a Stage IIB NSCLC, a Stage 11 I
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • the present disclosure provides methods of adjuvant treatment for subjects who have had complete surgical resection of an NSCLC (e.g., resection resulting in no residual tumor and all surgical margins negative for invasive carcinoma).
  • the surgical resection may have been, e.g., a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy.
  • the surgically resected NSCLC is a Stage I IB NSCLC, a Stage IIIA NSCLC, or a T3N2 Stage II IB NSCLC according to the Union Internationale Contre le Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8 th edition (Detterbeck et al., Chest, 151 : 193-203, 2017).
  • UICC/AJCC Union Internationale Contre le Cancer/American Joint Committee on Cancer
  • the NSCLC is a squamous NSCLC. In other aspects, the NSCLC is a non- squamous NSCLC.
  • the subject does not have an epidermal growth factor receptor (EGFR) genomic tumor aberration (e.g., does not have a mutation in the EGFR gene) and does not have an anaplastic lymphoma kinase (ALK) genomic tumor aberration (e.g., does not have an ALK fusion oncogene).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase genomic tumor aberration
  • the surgically resected NSCLC is tested for EGFR and ALK aberrations and is found not to have such aberrations.
  • the subject has an unknown EGFR and/or ALK status (e.g., a tumor sample from the subject has not been tested for EGFR and/or ALK genomic tumor aberrations).
  • the NSCLC is a squamous NSCLC and has not been assessed for an EGFR or ALK genomic tumor aberration.
  • the PD-L1 -positive tumor cell fraction of a tumor sample (e.g., NSCLC sample) obtained from the subject has been determined by an immunohistochemical (IHC) assay.
  • IHC immunohistochemical
  • the PD-L1 -positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8 (e.g., the PD-L1 -positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay).
  • the PD-L1 -positive tumor cell fraction of the tumor sample obtained from the subject has been determined using a Ventana SP263 IHC assay.
  • the tumor sample obtained from the subject has been determined to have a percentage of tumor cells with any PD-L1 membrane staining above background (TC) of equal to or greater than 1 % (> 1 % TC), as measured using the Ventana SP263 IHC assay (e.g., the TC of the tumor sample is at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%).
  • the tumor sample obtained from the subject has been determined to have a TC that is equal to or greater than 1 % and less than 50% (e.g., has been determined to have a TC of about 1 -5%, 5-10%, 10-15%, 15-20%, 20- 25%, 25-30%, 30-35%, 35-40%, 40-45%, or 45-49.99%).
  • the tumor sample obtained from the subject has been determined to have a TC of equal to or greater than 50% (> 50% TC), as measured using the Ventana SP263 IHC assay (e.g., the TC of the tumor sample is at least 50%, 55%, 60%, 65%, 70%, or 75%).
  • the tumor sample obtained from the subject has been determined to have a TC of less than or equal to 1 %.
  • Prior treatment e.g., has been determined to have a TC of about 1 -5%, 5-10%, 10-15%, 15-20%, 20- 25%, 25-30%, 30-35%, 35-40%, 40-45%, or 45-49.99%)
  • the subject had not been treated for the NSCLC prior to the surgery (e.g., has not received an anti-cancer therapy prior to the surgery, e.g., has not received a chemotherapy or a cancer immunotherapy prior to the surgery).
  • subjects treated according to the methods provided herein are administered an adjuvant chemotherapy.
  • the adjuvant chemotherapy may be administered in one or more dosing cycles. In some aspects, between one and four dosing cycles of the adjuvant chemotherapy are administered to the subject (e.g., one, two, three, or four dosing cycles are administered to the subject). Accordingly, in some aspects, the subject has received between one and four dosing cycles of the adjuvant chemotherapy prior to the one or more dosing cycles of tiragolumab and atezolizumab. In some aspects, the subject has received four dosing cycles of the adjuvant chemotherapy prior to the one or more dosing cycles of tiragolumab and atezolizumab. Alternatively, in some aspects, more than four dosing cycles (e.g., 5, 6, 7, 8, 9, 10, or more than 10 dosing cycles) are administered to the subject.
  • more than four dosing cycles e.g., 5, 6, 7, 8, 9, 10, or more than 10 dosing cycles
  • the adjuvant chemotherapy is an adjuvant platinum-based chemotherapy.
  • the adjuvant platinum-based chemotherapy may be an adjuvant platinum-based doublet chemotherapy.
  • Platinum-based doublet chemotherapies include, but are not limited to, chemotherapies comprising (a) carboplatin or cisplatin and (b) pemetrexed, gemcitabine, docetaxel, vinorelbine, etoposide, or paclitaxel.
  • the adjuvant chemotherapy is a platinum-based doublet chemotherapy comprising cisplatin.
  • the adjuvant chemotherapy is a platinum-based doublet chemotherapy comprising carboplatin.
  • the adjuvant chemotherapy may be histology-based, e.g., may be selected based on whether the NSCLC of the subject has squamous or non-squamous histology.
  • Exemplary platinum-based doublet chemotherapies are described, e.g., in Azzoli et al., J Clin Oncol, 27(36): 6251 -6266, 2009; the NCCN/ESMO guidelines (National Comprehensive Cancer Network. NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, 2023); and Table 1 , below.
  • Other dosing regimens can be considered (e.g., if consistent with approved drug labels specific for adjuvant treatment of NSCLC).
  • the adjuvant platinum-based chemotherapy comprises cisplatin.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, and the cisplatin is administered at a dose of about 75-80 mg/m 2 (e.g., at a dose of about 75 mg/m 2 ) intravenously on Day 1 of each 21 -day dosing cycle.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, and the cisplatin is administered at a dose of about 50 mg/m 2 on Days 1 and 8 of each 28-day dosing cycle or at a dose of 50 mg/m 2 on Day 1 of each 28-day dosing cycle.
  • the adjuvant platinum-based chemotherapy comprises carboplatin.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, and the carboplatin is administered at a target dose of about area under the free carboplatin plasma concentration versus time curve (AUC) 5 or AUC 6 intravenously on Day 1 of each 21 -day dosing cycle.
  • the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents, e.g., a vinca alkaloid, a taxane, an anti-metabolite, or a combination thereof.
  • a vinca alkaloid is vinorelbine; the taxane is docetaxel; or the anti-metabolite is gemcitabine or pemetrexed.
  • the subject has a non-squamous NSCLC
  • the platinum-based adjuvant chemotherapy comprises cisplatin and pemetrexed.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m 2 intravenously on Day 1 of each 21 -day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m 2 on Day 1 of each 21 -day dosing cycle.
  • 4 cycles of cisplatin and pemetrexed are administered to the subject.
  • the subject has a squamous NSCLC
  • the platinum-based adjuvant chemotherapy comprises cisplatin and gemcitabine.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m 2 intravenously on Day 1 of each 21 -day dosing cycle, and gemcitabine is administered at a dose of about 1250 mg/m 2 on Days 1 and 8 of each 21 -day dosing cycle.
  • 4 cycles of cisplatin and gemcitabine are administered to the subject.
  • the subject has a squamous NSCLC
  • the platinum-based adjuvant chemotherapy comprises cisplatin and docetaxel.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75 mg/m 2 intravenously on Day 1 of each 21 -day dosing cycle, and docetaxel is administered at a dose of about 75 mg/m 2 on Day 1 of each 21 -day dosing cycle.
  • 4 cycles of cisplatin and docetaxel are administered to the subject.
  • the platinum-based adjuvant chemotherapy comprises cisplatin and vinorelbine.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, wherein cisplatin is administered at a dose of about 50 mg/m 2 intravenously on Days 1 and 8 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 25 mg/m 2 on Days 1 , 8, 15, and 22 of each 28-day dosing cycle.
  • cisplatin is administered at a dose of about 100 mg/m 2 intravenously on Day 1 of each 28-day dosing cycle
  • vinorelbine is administered at a dose of about 30 mg/m 2 on Days 1 , 8, 15, and 22 of each 28-day dosing cycle.
  • 4 cycles of cisplatin and vinorelbine are administered to the subject.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein cisplatin is administered at a dose of about 75-80 mg/m 2 intravenously on Days 1 and 8 of each 21 -day dosing cycle, and vinorelbine is administered at a dose of about 25-30 mg/m 2 on Days 1 and 8 of each 21 -day dosing cycle. In some aspects, 4 cycles of cisplatin and vinorelbine are administered to the subject.
  • the platinum-based adjuvant chemotherapy comprises cisplatin and etoposide.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 28 days, wherein cisplatin is administered at a dose of about 100 mg/m 2 intravenously on Day 1 of each 28- day dosing cycle, and etoposide is administered at a dose of about 100 mg/m 2 on Days 1 -3 of each 28- day dosing cycle.
  • 4 cycles of cisplatin and etoposide are administered to the subject.
  • the platinum-based adjuvant chemotherapy comprises carboplatin and paclitaxel.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 6 intravenously on Day 1 of each 21 -day dosing cycle, and paclitaxel is administered at a dose of about 200 mg/m 2 on Day 1 of each 21 - day dosing cycle.
  • 4 cycles of cisplatin and paclitaxel are administered to the subject.
  • the platinum-based adjuvant chemotherapy comprises carboplatin and gemcitabine.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle, and gemcitabine is administered at a dose of about 1000 mg/m 2 on Days 1 and 8 of each 21 -day dosing cycle.
  • 4 cycles of cisplatin and gemcitabine are administered to the subject.
  • the platinum-based adjuvant chemotherapy comprises carboplatin and pemetrexed.
  • the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered at AUC 5 intravenously on Day 1 of each 21 -day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m 2 on Day 1 of each 21 - day dosing cycle.
  • 4 cycles of cisplatin and pemetrexed are administered to the subject.
  • Adjuvant treatment comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist
  • an adjuvant therapy comprising administration of one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab).
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • a subject who is administered the adjuvant therapy comprising the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist has not experienced recurrence of the NSCLC (e.g., has not experienced recurrence of the NSCLC following the complete resection or during or following the adjuvant chemotherapy).
  • the subject begins adjuvant chemotherapy within 12 weeks of their surgery date (e.g., the one or more dosing cycles of the adjuvant chemotherapy are initiated within one week, two weeks, six weeks, seven weeks, or eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks (e.g., within 1 -2 weeks, 2-4 weeks, 4-6 weeks, or 6-8 weeks, 8-10 weeks, or 10-12 weeks) of the surgery date.
  • the one or more dosing cycles of the adjuvant chemotherapy are initiated within one week, two weeks, six weeks, seven weeks, or eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks (e.g., within 1 -2 weeks, 2-4 weeks, 4-6 weeks, or 6-8 weeks, 8-10 weeks, or 10-12 weeks) of the surgery date.
  • the subject has not received an anti-cancer therapy for the NSCLC other than the surgical resection and adjuvant chemotherapy. In some aspects, the subject has not had prior treatment with a CD137 agonist or an immune checkpoint blockade therapy.
  • the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist may be initiated at any appropriate time following the completion of the surgical resection and the adjuvant chemotherapy (e.g., at a time when the subject has recovered adequately from the surgery and adjuvant chemotherapy).
  • the one or more dosing cycles of the anti- TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated at least six weeks after the surgical resection (e.g., are initiated at least 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 weeks after the surgical resection (e.g., are initiated at least 6-8 weeks, 8-10 weeks, 10-12 weeks, 12-14 weeks, 14-16 weeks, 16-18 weeks, 18-20 weeks, 20-22 weeks, 22-24 weeks, 24-26 weeks, 26-28 weeks, or 28-30 weeks after the surgical resection) or are initiated more than 30 weeks after the surgical resection).
  • the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated less than six weeks after the surgical resection (e.g., are initiated within 1 , 2, 3, 4, 5, or 6 weeks of the surgical resection). In some aspects, the one or more dosing cycles are initiated within 26 weeks of the surgical resection.
  • the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD- 1 axis binding antagonist are initiated within 10 weeks (e.g., within 70 days) after the last administered dose of the adjuvant chemotherapy).
  • the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated within 1 day, 5 days, 1 week, two weeks, six weeks, seven weeks, eight weeks, nine weeks, or ten weeks (e.g., within 1 -2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, or 8-10 weeks) of the last administered dose of the adjuvant chemotherapy.
  • the one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are initiated more than 10 weeks after the last administered dose of the adjuvant chemotherapy.
  • the PD-1 axis binding antagonist e.g., atezolizumab
  • the PD-1 axis binding antagonist is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on about Day 1 (e.g., on Day 1 ⁇ 3 days, e.g., on Day 1 ) of each of one or more 28-day dosing cycles).
  • Exemplary PD-1 axis binding antagonists, and dosing regimens for the same, are provided in Section III, below.
  • the PD-1 axis binding antagonist is atezolizumab, and the atezolizumab is administered at a fixed dose of about 1680 mg (e.g., a fixed dose of 1680 mg) every four weeks.
  • the length of each of the one or more dosing cycles is 28 days, and the atezolizumab is administered on about Day 1 (e.g., on Day 1 ⁇ 3 days, e.g., on Day 1 ) of each 28-day dosing cycle.
  • the methods provided herein comprise administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.
  • the PD-1 axis binding antagonist e.g., atezolizumab
  • the PD-1 axis binding antagonist is administered intravenously.
  • the PD-1 axis binding antagonist e.g., atezolizumab
  • the anti-TIGIT antagonist antibody e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., atezolizumab
  • the anti-TIGIT antagonist antibody is administered every four weeks (e.g., is administered in 28-day dosing cycles, e.g., is administered on about Day 1 (e.g., on Day 1 ⁇ 3 days, e.g., on Day 1 ) of each of one or more 28-day dosing cycles).
  • Exemplary anti-TIGIT antagonist antibodies, and dosing regimens for the same, are provided in Section IV, below.
  • the treatment results in a 7-year DFS rate of the population of subjects of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 1 1 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%).
  • 10% e.g., about 10% to about 100% (
  • a treatment described herein increases the DFS rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) of a population of subjects treated according to the method compared to a reference DFS rate by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100%, e.g., increases DFS rate by 5%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-100% relative to a reference DFS rate.
  • DFS rate e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate
  • the reference DFS rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) is a DFS resection rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage I HA NSCLC, or a T3N2 Stage IIIB NSCLC) who have been treated according to a method comprising administering to the subject one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIG IT antagonist antibody (e.g., tiragolumab), and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has received an adjuvant chemotherapy (e.g., an adjuvant platinum-based chemotherapy).
  • an adjuvant chemotherapy e.g., an adjuvant platinum-based chemotherapy
  • the reference DFS rate is a DFS rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage I II A NSCLC, or a T3N2 Stage IIIB NSCLC) who have been treated according to a method comprising administering to the subject (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tiragolumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tiragolumab) and wherein, prior to the administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the subject has not received an adjuvant chemotherapy.
  • the reference DFS rate is a DFS rate in a population of subjects having an NSCLC (e.g., a Stage I IB NSCLC, a Stage III A NSCLC, or a T3N2 Stage IIIB NSCLC) in which the NSCLC has been completely resected and the subject has not received any adjuvant treatment for the NSCLC.
  • an NSCLC e.g., a Stage I IB NSCLC, a Stage III A NSCLC, or a T3N2 Stage IIIB NSCLC
  • the expression of PD-L1 may be assessed in a subject treated according to any of the methods, uses, and compositions for use described herein.
  • the methods, uses, and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample, e.g., an NSCLC sample) obtained from the subject.
  • a biological sample e.g., a tumor sample, e.g., an NSCLC sample
  • the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject has been determined prior to initiation of treatment or after initiation of treatment.
  • PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application Pub. Nos.
  • Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.
  • FFPE formalin-fixed and paraffin-embedded
  • PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 .
  • the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody).
  • an anti-PD-L1 antibody e.g., the SP142 antibody
  • Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28- 8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 .
  • the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD- L1 antibody is 28-8.
  • a tumor sample obtained from the subject has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.
  • a tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.
  • tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table 2 and/or Table 3, respectively.
  • the subject has a PD-L1 selected tumor (e.g., a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) is greater than or equal to 5% in the tumor sample as determined by an IHC with the SP142 antibody).
  • the PD-L1 selected tumor is a tumor that has been determined to have a proportion of tumor area occupied by PD-L1 expressing immune cells (ICs) greater than or equal to 5% by an immunohistochemical (IHC) assay.
  • the IHC assay uses the anti-PD-L1 antibody SP142, SP263, 22C3, or 28-8.
  • the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 28-8.
  • the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 5% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be 2 or 3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
  • the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 10% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% and less than 50% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
  • the proportion of tumor area occupied by PD-L1 -expressing ICs has been determined to be greater than, or equal to, 1% and less than 30% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
  • a tumor sample obtained from the individual has a detectable protein expression level of PD-L1 .
  • the detectable protein expression level of PD-L1 has been determined by an IHC assay.
  • the IHC assay uses anti-PD-L1 antibody SP142.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor- infiltrating immune cells that comprise greater than, or equal to, 5% and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1 % of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1 % and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample.
  • the subject has a PD-L1 selected tumor (e.g., a PD-L1 high (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody).
  • a PD-L1 selected tumor e.g., a PD-L1 high (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody).
  • TPS tumor proportion score
  • the PD-L1 selected tumor is a PD-L1 high selected tumor.
  • the PD-L1 selected tumor is a tumor that has been determined to have TPS greater than or equal to 50% by an immunohistochemical (IHC) assay.
  • IHC immunohistochemical
  • the TPS has been determined to be greater than, or equal to, 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1 % (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1 % and less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).
  • the IHC assay uses the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3.
  • a tumor sample obtained from the individual has a detectable protein expression level of PD-L1 .
  • the detectable protein expression level of PD-L1 has been determined by an IHC assay.
  • the IHC assay uses anti-PD-L1 antibody SP263.
  • the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction greater than, or equal to, 50% of the tumor sample.
  • the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction less than 50% of the tumor sample.
  • the tumor sample has been determined to have a PD-L1 -positive tumor cell fraction greater than, or equal to, 1 % and less than 50% of the tumor sample.
  • the IHC assay uses the anti-PD-L1 antibody 22C3. In some instances, the IHC assay is the pharmDx 22C3 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the tumor sample has been determined to have a combined positive score (CPS) of greater than, or equal to, 10 or a tumor proportion score (TPS) of greater than or equal to 1 % in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay.
  • CPS combined positive score
  • TPS tumor proportion score
  • the tumor sample has been determined to have a CPS of greater than, or equal to, 10 or a TPS of greater than or equal to 1 % and less than 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 20 or a TPS of greater than or equal to 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, tumor samples that have been determined to have a CPS of greater than, or equal to, 1 are comparable to tumor samples that have a TIC of greater than, or equal to, 5%.
  • the IHC assay uses the anti-PD-L1 antibody 28-8. In some instances, the IHC assay is the pharmDx 28-8 IHC assay. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 28-8.
  • a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1 .
  • the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.
  • the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.
  • the tissue sample is a tumor sample.
  • the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.
  • PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used for treating a subject having a cancer (e.g., an NSCLC, e.g., a Stage IIB NSCLC, a Stage II IA NSCLC, or a T3N2 Stage IIIB NSCLC).
  • a cancer e.g., an NSCLC, e.g., a Stage IIB NSCLC, a Stage II IA NSCLC, or a T3N2 Stage IIIB NSCLC.
  • the PD-L1 binding antagonist inhibits the binding of PD-L1 to one or more of its ligand binding partners. In other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 . In yet other instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1 . In some instances, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1 .
  • the PD-L1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 ).
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA.
  • the PD-L1 binding antagonist is CA-170 (also known as AUPM-170).
  • the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3.
  • the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.
  • the PD-L1 binding antagonist is an anti-PD-L1 antibody.
  • a variety of anti-PD- L1 antibodies are contemplated and described herein.
  • the isolated anti- PD-L1 antibody can bind to a human PD-L1 , for example a human PD-L1 as shown in UniProtKB/Swiss- Prot Accession No. Q9NZQ7-1 , or a variant thereof.
  • the anti-PD-L1 antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1 .
  • the anti-PD-L1 antibody is a monoclonal antibody.
  • the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.
  • the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody.
  • Exemplary anti-PD-L1 antibodies include atezolizumab, MDX- 1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636.
  • anti-PD-L1 antibodies useful in the methods of this invention and methods of making them are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.
  • the anti-PD-L1 antibody comprises:
  • HVR-H1 , HVR-H2, and HVR-H3 sequence of GFTFSDSWIH SEQ ID NO: 3
  • AWISPYGGSTYYADSVKG SEQ ID NO: 4
  • RHWPGGFDY SEQ ID NO: 5
  • the anti-PD-L1 antibody comprises:
  • VH heavy chain variable region
  • VL the light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10).
  • the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 9; (b) a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 10; or (c) a VH as in (a) and a VL as in (b).
  • a VH comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of SEQ ID NO: 9
  • a VL comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%,
  • the anti-PD-L1 antibody comprises atezolizumab, which comprises:
  • the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8).
  • Avelumab also known as MSB0010718C, is a human monoclonal lgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).
  • the anti-PD-L1 antibody is durvalumab (CAS Registry Number: 1428935-60- 7).
  • Durvalumab also known as MEDI4736, is an Fc-optimized human monoclonal IgG 1 kappa anti-PD- L1 antibody (Medlmmune, AstraZeneca) described in WO 2011/066389 and US 2013/034559.
  • the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb).
  • MDX-1105 also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.
  • the anti-PD-L1 antibody is LY3300054 (Eli Lilly).
  • the anti-PD-L1 antibody is STI-A1014 (Sorrento).
  • STI-A1014 is a human anti- PD-L1 antibody.
  • the anti-PD-L1 antibody is KN035 (Suzhou Alphamab).
  • KN035 is singledomain antibody (dAB) generated from a camel phage display library.
  • the anti-PD-L1 antibody comprises a cleavable moiety or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates an antibody antigen-binding domain to allow it to bind its antigen, e.g., by removing a non-binding steric moiety.
  • the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).
  • the anti-PD-L1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Pat. No. 9,205,148, WO 2013/181634, or WO 2016/061142.
  • the anti-PD-L1 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the effector-less Fc mutation is an N297A substitution in the constant region.
  • the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue.
  • the tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain.
  • O-linked glycosylation refers to the attachment of one of the sugars N- acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.
  • Removal of glycosylation sites from an antibody is conveniently accomplished by altering the amino acid sequence such that one of the abovedescribed tripeptide sequences (for N-linked glycosylation sites) is removed.
  • the alteration may be made by substitution of an asparagine, serine or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).
  • the PD-1 axis binding antagonist is a PD-1 binding antagonist.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to one or more of its ligand binding partners.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 .
  • the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.
  • the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2.
  • the PD-1 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
  • the PD-1 binding antagonist is an Fc-fusion protein.
  • the PD-1 binding antagonist is AMP-224.
  • AMP-224 also known as B7-DCIg, is a PD- L2-Fc fusion soluble receptor described in WO 2010/027827 and WO 2011/066342.
  • the PD-1 binding antagonist is a peptide or small molecule compound.
  • the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011 /161699.
  • the PD-1 binding antagonist is a small molecule that inhibits PD-1 .
  • the PD-1 binding antagonist is an anti-PD-1 antibody.
  • a variety of anti-PD-1 antibodies can be utilized in the methods and uses disclosed herein. In any of the instances herein, the PD-1 antibody can bind to a human PD-1 or a variant thereof.
  • the anti-PD-1 antibody is a monoclonal antibody. In some instances, the anti-PD-1 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-1 antibody is a humanized antibody. In other instances, the anti-PD-1 antibody is a human antibody.
  • anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI
  • the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4).
  • Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS- 936558, and OPDI VO®, is an anti-PD-1 antibody described in WO 2006/121168.
  • the anti-PD-1 antibody is pembrolizumab (CAS Registry Number: 1374853- 91 -4).
  • Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lambrolizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335.
  • the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca).
  • MEDI-0680 is a humanized lgG4 anti-PD-1 antibody.
  • the anti-PD-1 antibody is PDR001 (CAS Registry No. 1859072-53-9; Novartis).
  • PDR001 is a humanized lgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.
  • the anti-PD-1 antibody is REGN2810 (Regeneron).
  • REGN2810 is a human anti-PD-1 antibody.
  • the anti-PD-1 antibody is BGB-108 (BeiGene).
  • the anti-PD-1 antibody is BGB-A317 (BeiGene).
  • the anti-PD-1 antibody is JS-001 (Shanghai Junshi).
  • JS-001 is a humanized anti-PD-1 antibody.
  • the anti-PD-1 antibody is STI-A1110 (Sorrento).
  • STI-A1110 is a human anti- PD-1 antibody.
  • the anti-PD-1 antibody is INCSHR-1210 (Incyte).
  • INCSHR-1210 is a human lgG4 anti-PD-1 antibody.
  • the anti-PD-1 antibody is PF-06801591 (Pfizer).
  • the anti-PD-1 antibody is TSR-042 (also known as ANB011 ; Tesaro/AnaptysBio).
  • the anti-PD-1 antibody is AM0001 (ARMO Biosciences).
  • the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings).
  • ENUM 244C8 is an anti-PD-1 antibody that inhibits PD-1 function without blocking binding of PD-L1 to PD-1.
  • the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings).
  • ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits binding of PD-L1 to PD-1 .
  • the anti-PD-1 antibody comprises the six HVR sequences (e.g., the three heavy chain HVRs and the three light chain HVRs) and/or the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160, and WO 2014/194302.
  • the six HVR sequences e.g., the three heavy chain HVRs and the three light chain HVRs
  • the heavy chain variable domain and light chain variable domain from an anti-PD-1 antibody described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769 , WO2016/0898
  • the anti-PD-1 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the isolated anti-PD-1 antibody is aglycosylated.
  • the PD-1 axis binding antagonist is a PD-L2 binding antagonist.
  • the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partners.
  • the PD-L2 binding ligand partner is PD-1 .
  • the PD-L2 binding antagonist may be, without limitation, an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, or a small molecule.
  • the PD-L2 binding antagonist is an anti-PD-L2 antibody.
  • the anti-PD-L2 antibody can bind to a human PD-L2 or a variant thereof.
  • the anti-PD-L2 antibody is a monoclonal antibody.
  • the anti-PD-L2 antibody is an antibody fragment selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.
  • the anti-PD-L2 antibody is a humanized antibody.
  • the anti-PD-L2 antibody is a human antibody.
  • the anti-PD-L2 antibody has reduced or minimal effector function.
  • the minimal effector function results from an “effector-less Fc mutation” or aglycosylation mutation.
  • the effector-less Fc mutation is an N297A or D265A/N297A substitution in the constant region.
  • the isolated anti-PD-L2 antibody is aglycosylated.
  • the therapeutically effective amount of a PD-1 axis binding antagonist e.g., atezolizumab
  • a subject having a cancer e.g., a non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • PD-1 axis binding antagonists Exemplary doses and dosing regimens for PD-1 axis binding antagonists are provided, e.g., in PCT Application Pub. No. WO 2021/154761 , which is incorporated herein by reference in its entirety.
  • the PD-1 axis binding antagonist e.g., a PD-1 axis binding antagonist as disclosed herein, e.g., atezolizumab
  • Day 1 e.g., Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3 of a dosing cycle.
  • the PD-1 axis binding antagonist is atezolizumab, and atezolizumab is administered to the subject intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg of every 4 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 1680 mg every 4 weeks. For example, in some aspects, atezolizumab is administered to the subject intravenously at a dose of 1200 mg every 3 weeks. In some aspects, atezolizumab is administered to the subject intravenously at a dose of 840 mg every 2 weeks.
  • a subject is administered a total of 1 to 60 doses of a PD-1 axis binding antagonist (e.g., atezolizumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses,
  • the doses may be administered intravenously.
  • the PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered in any suitable manner known in the art.
  • the PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered sequentially (on different days) or concurrently (on the same day or during the same treatment cycle).
  • the PD-1 axis binding antagonist is administered prior to the additional therapeutic agent.
  • the PD-1 axis binding antagonist is administered after the additional therapeutic agent.
  • the PD-1 axis binding antagonist and/or any additional therapeutic agent(s) may be administered on the same day.
  • the PD-1 axis binding antagonist may be administered prior to an additional therapeutic agent that is administered on the same day.
  • the PD-1 axis binding antagonist may be administered prior to chemotherapy on the same day.
  • the PD-1 axis binding antagonist may be administered prior to both chemotherapy and another drug on the same day.
  • the PD-1 axis binding antagonist may be administered after an additional therapeutic agent that is administered on the same day.
  • the PD-1 axis binding antagonist is administered at the same time as the additional therapeutic agent.
  • the PD-1 axis binding antagonist is in a separate composition as the additional therapeutic agent.
  • the PD-1 axis binding antagonist is in the same composition as the additional therapeutic agent.
  • the PD-1 axis binding antagonist is administered through a separate intravenous line from any other therapeutic agent administered to the subject on the same day.
  • the PD-1 axis binding antagonist and any additional therapeutic agent(s) may be administered by the same route of administration or by different routes of administration.
  • the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the additional therapeutic agent is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • the anti-TIGIT antagonist antibody e.g., tiragolumab
  • the PD-1 axis binding antagonist e.g., atezolizumab
  • the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs), e.g., are combined in an IV bag prior to administration.
  • the coinfused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an IV-administered fixed dose combination (FDC).
  • the IV-administered co-infusion of tiragolumab and atezolizumab comprises atezolizumab at a dose of 1680 mg and tiragolumab at a dose of 840 mg.
  • tiragolumab and atezolizumab are co-infused intravenously every four weeks (Q4W) at a dose of 1680 mg of atezolizumab and a dose of 840 mg of tiragolumab.
  • the IV-administered co-infusion of tiragolumab and atezolizumab comprises atezolizumab at a dose of 1200 mg and tiragolumab at a dose of 600 mg.
  • tiragolumab and atezolizumab are co-infused intravenously every three weeks (Q3W) at a dose of 1200 mg of atezolizumab and a dose of 600 mg of tiragolumab.
  • tiragolumab and atezolizumab are co-infused simultaneously.
  • the co-infused tiragolumab and atezolizumab are mixed prior to infusion (e.g., are formulated separately and are mixed by the physician administering the drugs).
  • the co-infused tiragolumab and atezolizumab are formulated together (i.e., are not mixed by the physician administering the drugs) and are administered as an SC-administered FDC.
  • the SC-administered co-infusion of tiragolumab and atezolizumab comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 880 mg.
  • the SC-administered co-infusion of tiragolumab and atezolizumab comprises atezolizumab at a dose of 1875 mg or 2000 mg and tiragolumab at a dose of 1000 mg.
  • the method comprises both IV and SC administration of tiragolumab and/or atezolizumab, e.g., comprises one or more IV-administered doses and one or more SC-administered doses of tiragolumab and/or atezolizumab.
  • the method comprises administering at least one dose of tiragolumab and atezolizumab as an IV-administered FDC and comprises administering at least one dose of tiragolumab and atezolizumab as an SC-administered FDC.
  • Exemplary IV and SC FDC doses and formulations of tiragolumab and atezolizumab are provided in PCT Application Pub. No. WO 2023/1 2665 and in U.S. Provisional Patent Application Nos. 63/493,691 (filed March 31 , 2023) and 63/494,983 (filed April 7, 2023) (both titled “Methods of Treating Tumors with Anti-TIGIT Antibodies”), each of which is incorporated herein by reference in its entirety.
  • the invention provides anti-TIG IT antagonist antibodies useful for treating cancer in a subject (e.g., a human) having a cancer (e.g., an NSCLC, e.g., a resectable NSCLC).
  • a subject e.g., a human
  • a cancer e.g., an NSCLC, e.g., a resectable NSCLC.
  • the anti-TIG IT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8).
  • Tiragolumab (Genentech) is also known as MTIG7192A.
  • the anti-TIG IT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 16), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.
  • anti-TIG IT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 16).
  • the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 27) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAV
  • the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 27 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 29.
  • VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 29.
  • the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 27 and a VL domain comprising the amino acid sequence of SEQ ID NO: 29.
  • the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 28 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 29.
  • the anti-TIGIT antagonist antibody has a VH domain comprising the amino acid sequence of SEQ ID NO: 28 and a VL domain comprising the amino acid sequence of SEQ ID NO: 29.
  • the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPP
  • the anti-TIG IT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and/or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 17-20.
  • FRs light
  • the antibody further comprises an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20).
  • the anti-TIG IT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 21 ), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity
  • the anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs:
  • the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24).
  • the anti-TIG IT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NO:
  • the anti-TIG IT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24).
  • an anti-TIGIT antagonist antibody comprising a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications.
  • any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIG IT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.
  • the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).
  • the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR).
  • PVR poliovirus receptor
  • the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM).
  • the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction.
  • the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM).
  • the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT.
  • the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.
  • the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above.
  • the method may include administering an isolated anti-TIG IT antagonist antibody that competes for binding to TIGIT with an anti-TIG IT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 11 ); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) an HVR-H
  • the anti-TIGIT antagonist antibody exhibits Fc-mediated effector function, e.g., participates in antibody-dependent cellular cytotoxicity (ADCC).
  • the anti-TIGIT antagonist antibody is an antibody having intact Fc-mediated effector function (e.g., tiragolumab, vibostolimab, etigilimab, EQS084448, or TJ-T6) or enhanced effector function (e.g., SGN-TGT).
  • the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902).
  • Fc-mediated effector function e.g., domvanalimab, BMS-986207, ASP8374, or COM902.
  • the anti-TIGIT antagonist antibody is an IgG class antibody.
  • the anti-TIGIT antagonist antibody is an IgG 1 class antibody, e.g., tiragolumab, vibostolimab, domvanalimab, BMS-986207, etigilimab, BGB-A1217, SGN-TGT, EQS084448 (EOS-448), TJ-T6, or AB308.
  • the antibody is a human monoclonal full-length IgG 1 class antibody comprising an Fc region.
  • the anti-TIGIT antagonist antibody is a human, monoclonal full-length IgG 1 subclass antibody comprising a human IgG 1 Fc region, a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 29.
  • the anti-TIGIT antagonist antibody is an lgG4 class antibody, e.g., ASP8374 or COM902.
  • the anti-TIGIT antibody comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the six HVRs of any of the anti-TIGIT antibodies disclosed herein.
  • HVRs hypervariable regions
  • the anti-TIGIT antibody comprises the six HVRs of any one of the antibodies selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).
  • tiragolumab ASP8374
  • BGB-A1217 BMS-986207 (ONO-4686)
  • COM902 CGEN-15137
  • M6223 IBI939
  • EOS884448 EOS-448
  • domvanalimab AB154
  • vibostolimab MK-7684
  • SEA-TGT SGN-TGT
  • the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any one of the anti- TIGIT antibodies disclosed herein and the light chain comprises a light chain variable region (VL) of the same antibody.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-TIGIT antibody comprises the VH and VL of an anti- TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK-7684), and SEA-TGT (SGN-TGT).
  • the anti-TIGIT antibody comprises the heavy chain and the light chain of any of the anti-TIGIT antibodies disclosed herein.
  • the anti-TIGIT antibody comprises the heavy chain and the light chain of an anti-TIGIT antibody selected from the group consisting of tiragolumab, ASP8374 (PTZ-201 ), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibostolimab (MK- 7684), and SEA-TGT (SGN-TGT).
  • the therapeutically effective amount of an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a subject having a cancer e.g., an NSCLC
  • the therapeutically effective amount of an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • administered to a subject is in the range of 0.01 to 50 mg/kg of subject body weight, whether by one or more administrations.
  • the anti-TIG IT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • Day 1 e.g., Day -3, Day -2, Day -1 , Day 1 , Day 2, or Day 3 of a dosing cycle.
  • the effective amount of anti-TIGIT antagonist antibody is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ⁇ 10 mg, e.g., 840 ⁇ 6 mg, e.g., 840 ⁇ 5 mg, e.g., 840 ⁇ 3 mg, e.g., 840 ⁇ 1 mg, e.g., 840 ⁇ 0.5 mg, e.g., 840 mg every four weeks).
  • the effective amount of the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of about 600 mg every three weeks.
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of 600 mg every three weeks.
  • the effective amount of the anti-TIGIT antagonist antibody is a fixed dose of about 420 mg every two weeks (e.g., 420 mg ⁇ 10 mg, e.g., 420 ⁇ 6 mg, e.g., 420 ⁇ 5 mg, e.g., 420 ⁇ 3 mg, e.g., 420 ⁇ 1 mg, e.g., 420 ⁇ 0.5 mg, e.g., 420 mg every two weeks).
  • the anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • the anti-TIGIT antagonist antibody is administered subcutaneously.
  • tiragolumab is administered to the subject intravenously at a dose of about 420 mg every 2 weeks, about 600 mg every 3 weeks, or about 840 mg of every 4 weeks.
  • tiragolumab is administered to the subject intravenously at a dose of 420 mg every 2 weeks, 600 mg every 3 weeks, or 840 mg every 4 weeks.
  • a subject is administered a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, or 60 doses.
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • an anti-TIGIT antagonist antibody e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab
  • a subject is administered a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 2
  • the anti-TIGIT antagonist antibody may be administered in any suitable manner known in the art. In some instances, the anti-TIGIT antagonist antibody is administered on about Day 1 (e.g., Day -3, Day - 2, Day -1 , Day 1 , Day 2, or Day 3) of a dosing cycle. In some instances, the anti-TIGIT antagonist antibody may be administered on the same day. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously.
  • Day 1 e.g., Day -3, Day - 2, Day -1 , Day 1 , Day 2, or Day 3
  • the anti-TIGIT antagonist antibody may be administered on the same day.
  • the PD-1 axis binding antagonist is administered intravenously, intra
  • the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, there is a first observation period following administration of anti-TIGIT antagonist antibody. In some instances, the observation period is between about 30 minutes to about 60 minutes in length. In some instances, the anti-TIGIT antagonist antibody is administered intravenously or subcutaneously.
  • tiragolumab may be administered intravenously over 60 minutes; if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.
  • each dosing cycle may have any suitable length, e.g., about 7 days (about 5, 6, 7, 8, or 9 days), about 14 days (e.g., about 12, 13, 14, 15, or 16 days), about 21 days (e.g., about 18, 19, 20, 21 , 22, 23, or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30, or 31 days), or longer. In some instances, each dosing cycle is about 21 days.
  • any of the anti-cancer agents described herein e.g., a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tiragolumab) can be used in pharmaceutical compositions and formulations.
  • Pharmaceutical compositions and formulations of a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tiragolumab) can be prepared by mixing one or both agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers ⁇ Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed.
  • Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m- cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such
  • Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH- 20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.).
  • sHASEGP soluble neutral-active hyaluronidase glycoproteins
  • rHuPH20 HYLENEX®, Baxter International, Inc.
  • Certain exemplary sHASEGPs and methods of use, including rHuPH20 are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968.
  • a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.
  • Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958.
  • Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and PCT Application Pub. No. WO 2006/044908, the latter formulations including a histidine-acetate buffer.
  • An exemplary atezolizumab formulation comprises glacial acetic acid, L-histidine, polysorbate 20, and sucrose, with a pH of 5.8.
  • atezolizumab may be provided in a 20 mL vial containing 1200 mg of atezolizumab that is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821 .6 mg), with a pH of 5.8.
  • Atezolizumab may be provided in a 14 mL vial containing 840 mg of atezolizumab that is formulated in glacial acetic acid (11 .5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) with a pH of 5.8.
  • An exemplary tiragolumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine, and WFI.
  • Tiragolumab may be provided in a 15-mL vial containing 10 mL of tiragolumab drug product at an approximate concentration of tiragolumab antibody of 60 mg/mL.
  • the formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent. Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.
  • Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.
  • the formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
  • kits that include (a) a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIG IT antagonist antibody for use in combination with a PD-1 axis binding antagonist, or (c) a PD-1 axis binding antagonist and an anti- TIGIT antagonist antibody for treating a subject having a cancer (e.g., a non-small cell lung cancer (NSCLC)) according to any of the methods described herein.
  • a cancer e.g., a non-small cell lung cancer (NSCLC)
  • the article of manufacture or kit further comprises package insert comprising instructions for using (a) a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist or (c) a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody to treat or delay progression of a cancer (e.g., an NSCLC) in a patient.
  • a cancer e.g., an NSCLC
  • kits that include (a) atezolizumab for use in combination with tiragolumab, (b) tiragolumab for use in combination with atezolizumab, or (c) atezolizumab and tiragolumab for treating a subject having a cancer (e.g., an NSCLC) according to any of the methods described herein.
  • a cancer e.g., an NSCLC
  • the article of manufacture or kit further comprises package insert comprising instructions for using (a) atezolizumab in combination with tiragolumab, (b) tiragolumab in combination with atezolizumab, or (c) atezolizumab and tiragolumab to treat or delay progression of a cancer (e.g., an NSCLC) in a patient.
  • a cancer e.g., an NSCLC
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • an anti-TIGIT antagonist antibody e.g., tiragolumab
  • Suitable containers include, for example, bottles, vials, bags and syringes.
  • the container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy).
  • the container holds the formulation and the label on, or associated with, the container may indicate directions for use.
  • the article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • the article of manufacture further includes one or more of another agent (e.g., an additional chemotherapeutic agent or anti-neoplastic agent).
  • Suitable containers for the one or more agents include, for example, bottles, vials, bags and syringes.
  • Example 1 A Phase III, Randomized, Double-Blind Study of Tiragolumab Plus Atezolizumab Compared with Placebo Plus Atezolizumab in Participants With Completely Resected Stage IIB, IIIA, or Select IIIB, PD-L1 Positive, Non-Small Cell Lung Cancer Who Have Received Adjuvant Platinum-Based Chemotherapy
  • G045006 is a Phase III, randomized, double-blind, global, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of tiragolumab plus atezolizumab compared with placebo plus atezolizumab administered to participants with PD-L1 positive (percentage of tumor cells with any membrane staining above background > 1% (>1% TC) as determined using the investigational VENTANA PD-L1 (SP263) CDx assay) Stage IIB, IIIA, or select IIIB (T3N2 only) non-small cell lung cancer (NSCLC) following resection and adjuvant platinum-based chemotherapy.
  • PD-L1 positive percentage of tumor cells with any membrane staining above background > 1% (>1% TC) as determined using the investigational VENTANA PD-L1 (SP263) CDx assay
  • Stage IIB, IIIA, or select IIIB T3N2 only) non-small cell lung cancer (NSCLC) following resection and adjuvant
  • NSCLC staging is determined according to the American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) non-small cell lung cancer (NSCLC) Staging, 8th edition (AJCC 8 th edition (Detterbeck et al., Chest, 151 : 193-203, 2017); see, e.g., Table 4 herein).
  • AJCC American Joint Committee on Cancer
  • UICC Union Internationale Contre le Cancer
  • NSCLC non-small cell lung cancer Staging
  • T3N2 Stage 11 IB NSCLC is NSCLC in which the primary tumor is T3 (i.e., is > 5 cm but ⁇ 7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, and parietal pericardium) and the lymph node status is N2 (i.e., regional lymph node involvement is characterized as metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)).
  • T3 i.e., is > 5 cm but ⁇ 7 cm in greatest dimension or associated with separate tumor nodule(s) in the same lobe as the primary tumor or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumors), phrenic nerve, and parietal pericardium) and the lymph
  • PD-L1 positive subjects have > 1% TC as determined using the investigational VENTANA PD-L1 (SP263) CDx assay).
  • PD-L1 high subjects have > 50% TC as determined using the investigational VENTANA PD-L1 (SP263) CDx assay.
  • Table 5 presents the primary objectives for the study expressed using the estimand framework in accordance with the International Council for Harmonisation (ICH) E9(R1 ) statistical principles for clinical trials (ICH 2020) and select secondary objective and corresponding endpoints.
  • Table 6 presents further secondary and exploratory objectives and corresponding endpoints. Table 5.
  • FIG. 1 A study schema for the G045006 study is provided in Fig. 1 .
  • EGFR and/or ALK status may be assessed locally or at a central laboratory.
  • Randomization must be completed 70 days at the latest after the final dose of chemotherapy. Eligible participants are randomized in a 1 :1 ratio to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. Participants receive their first dose of study treatment on the day of randomization, if possible. If this is not possible, the first dose should occur within 5 days of randomization.
  • Eligible participants are stratified by tumor histology (squamous vs. non-squamous), disease stage (Stage I IB vs. Stage 11 IA + select II IB (T3N2 only)) and PD-L1 status (>1% and ⁇ 50% TC vs. > 50% TC). Enrollment into the PD-L1 >1% and ⁇ 50% TC sub-group is capped at approximately 450 participants (approximately 40% of participants), and enrollment into the PD-L1 > 50% TC sub-group is capped at approximately 700 participants (approximately 60% of participants).
  • tiragolumab at a dose of 840 mg plus atezolizumab at a dose of 1680 mg is administered by IV co-infusion (tiragolumab and atezolizumab are mixed and administered in one IV bag) on Day 1 of each 28-day cycle for a total of 13 cycles (approximately 1 year).
  • placebo plus atezolizumab at a dose of 1680 mg is administered by IV co-infusion on Day 1 of each 28-day cycle for a maximum of 13 cycles.
  • Treatment is continued for a maximum of 13 cycles (approximately 1 year) in the absence of disease recurrence or unacceptable toxicity.
  • serum samples are collected to monitor atezolizumab and tiragolumab pharmacokinetics and to detect the presence of antibodies to atezolizumab and tiragolumab.
  • Participant samples including archival and fresh tumor tissue, serum, plasma, and blood samples, are also collected for exploratory biomarker assessments.
  • Post-treatment follow-up consists of ongoing assessments as described above.
  • follow-up information is collected until death, loss to follow-up, or study termination, whichever occurs first.
  • the study enrolls participants with PD-L1 > 1% TC Stage I IB, 11 IA, or select I IIB (T3N2) NSCLC.
  • CIT cancer immunotherapy
  • targeted therapies becoming available for resectable NSCLC, treatment options for some patients have improved over chemotherapy-based regimens. Nevertheless, a significant proportion of patients will still experience disease recurrence and will die from their disease, highlighting the need to continue to build on the recent successes.
  • DFS the primary efficacy endpoint in this study
  • OS is the gold standard for establishing benefit in oncology clinical trials
  • the time necessary for an OS readout in the adjuvant NSCLC setting could lead to an unacceptable delay in making a new effective therapy available to participants.
  • DFS (the primary efficacy endpoint in this study) is a meaningful and reliable efficacy endpoint with earlier time to evaluation compared to OS. DFS appears strongly correlated with OS in the adjuvant NSCLC setting, as demonstrated in several metaanalyses with chemotherapy (Michiels et al., Journal of Clinical Oncology, 29(15): 7004, 2011 ; Mauguen et al., Lancet Oncol, 14: 619-626, 2013).
  • DFS is recommended by the FDA as a surrogate endpoint for both accelerated and traditional approval and has as such been used as the primary basis for approval for adjuvant therapy in several indications including for adjuvant CIT in NSCLC (FDA Guidance to Industry, 2018; and KEYTRUDA® U.S. Package Insert).
  • the end of the study occurs when the last patient, last visit has occurred or the date at which the last data point required for statistical analysis (i.e., final analysis for DFS) or safety follow-up is received from the last participant, whichever occurs later.
  • the total length of study, from randomization of the first participant to the end of study, is expected to be approximately 15 years.
  • ECOG Eastern Cooperative Oncology Group
  • NSCLC with histology of large cell neuroendocrine carcinoma, sarcomatoid carcinoma, or NSCLC not otherwise specified are not eligible.
  • Accepted types of resection include any of the following: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Participants who have had only segmentectomies or wedge resections are not eligible for this study.
  • MLND mediastinal lymph node dissection
  • diagnostic mediastinal lymph node sampling can be used to meet the minimum of 2 lymph node N2 stations.
  • FFPE formalin-fixed, paraffin-embedded
  • ANC Absolute neutrophil count
  • BEN benign ethnic neutropenia
  • BEN also known as constitutional neutropenia
  • constitutional neutropenia is an inherited cause of mild or moderate neutropenia that is not associated with any increased risk for infections or other clinical manifestations (Atallah-Yunes et al., Blood Rev, 37: 100586, 2019).
  • BEN is referred to as ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups.
  • Negative HIV test at screening with the following exception: participants with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count > 200/pL, and have an undetectable viral load.
  • HBV hepatitis B virus
  • HBsAb Positive hepatitis B surface antibody
  • HBcAb negative total hepatitis B core antibody
  • Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening.
  • the HCV RNA test must be performed for participants who have a positive HCV antibody test.
  • NSCLC known to have a mutation in the EGFR gene or an ALK fusion oncogene:
  • EGFR and/or ALK status may be assessed locally or at a central laboratory.
  • EGFR and or ALK status assessed locally must be performed on tissue using a validated health authority-approved or an appropriately validated next-generation sequencing (NGS) test performed in a Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified laboratory.
  • NGS next-generation sequencing
  • CLIA Clinical Laboratory Improvement Amendments
  • EGFR test must detect mutations in exons 18-21 . If samples are submitted for central EGFR and/or ALK testing, an additional five slides must be provided.
  • autoimmune disease or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjogren syndrome, Guillain Barre syndrome, or multiple sclerosis, with the following exceptions:
  • rash must cover ⁇ 10% of body surface area; disease is well controlled at baseline and requires only low-potency topical corticosteroids; there has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
  • EBV Epstein-Barr virus
  • Severe infection within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact participant safety.
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-a (TNF-a) agents
  • systemic immunosuppressive medication including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-a (TNF-a) agents
  • Table 7 provides a description of assigned study treatments for the G045006 study.
  • Study treatment refers to the combination of treatments assigned to participants as part of the study (e.g., atezolizumab plus tiragolumab). Administration of study treatment is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.
  • Tiragolumab/atezolizumab and placebo/atezolizumab co-infusions are administered per the instructions outlined in Table 8.
  • Tiragolumab or placebo is administered by IV infusion at a fixed dose of 840 mg together with 1680 mg of atezolizumab mixed in the same IV bag for co-infusion on Day 1 of each 28-day cycle.
  • the study is a randomized, double-blind study.
  • Randomization must be completed within 70 days (10 weeks) after the final dose of chemotherapy. Eligible participants are randomized in a 1 :1 ratio to receive either tiragolumab plus atezolizumab or placebo plus atezolizumab. Participants receive their first dose of study treatment on the day of randomization, if possible. If this is not possible, the first dose should occur within 5 days of randomization.
  • Eligible participants are stratified by tumor histology (squamous vs. non-squamous), disease stage (Stage II vs. Stage I HA + select II IB (T3N2)), and PD-L1 status ((>1 % and ⁇ 50% TC vs. > 50% TC) by the investigational VENTANA PD-L1 (SP263) CDx assay.
  • a permuted-block randomization is applied to ensure a balanced assignment to each treatment arm within levels of the stratification factors.
  • Prophylactic or therapeutic anticoagulation therapy such as warfarin at a stable dose or low-molecular- weight heparin.
  • Vaccinations such as influenza, COVID 19
  • Live, attenuated vaccines are not permitted.
  • Megestrol acetate administered as an appetite stimulant.
  • Mineralocorticoids e.g., fludrocortisone
  • Premedication with antihistamines, antipyretic medications, and/or analgesics may be administered for the second and subsequent infusions, at the discretion of the investigator.
  • participant's care including preexisting conditions
  • supportive therapies other than those defined below as cautionary or prohibited therapies as clinically indicated, per local standard practice.
  • Participants who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice.
  • H2 receptor antagonists e.g., famotidine, cimetidine
  • Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress are managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2-adrenergic agonists).
  • Systemic corticosteroids, immunosuppressive medications, and TNF-a inhibitors may attenuate potential beneficial immunologic effects of treatment with tiragolumab and/or atezolizumab. Therefore, in situations in which systemic corticosteroids, immunosuppressive medications, or TNF-a inhibitors would be routinely administered, alternatives, including antihistamines, should be considered. If the alternatives are not feasible, systemic corticosteroids, immunosuppressive medications and TNF-a inhibitors may be administered at the discretion of the investigator.
  • Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion of the investigator, for the treatment of specific adverse events when associated with tiragolumab and/or atezolizumab therapy.
  • Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety profiles, and potential drug-drug interactions are generally unknown.
  • herbal therapies not intended for the treatment of cancer may be used during the study at the discretion of the investigator.
  • Concomitant therapy intended for the treatment of cancer including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy (RT), and herbal therapy), whether health authority- approved or experimental, for various time periods prior to starting study treatment, depending on the agent, and during study treatment, until disease recurrence is documented and the participant has discontinued study treatment.
  • Systemic immunostimulatory agents including, but not limited to, IFNs and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with study treatment.
  • Participants are closely monitored for safety throughout the study. Participants should be assessed for toxicity prior to each dose; treatment will be administered only if the clinical assessment and local laboratory test values are acceptable.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • MRI scan preferred or contrast CT of the brain must be done at screening to evaluate CNS metastasis in all participants (MRI scan must be performed if CT scan is contraindicated).
  • An MRI scan of the brain is required to confirm or refute the diagnosis of CNS metastases at baseline in the event of an equivocal CT scan. Bone scans and CT scans of the neck should also be performed if clinically indicated.
  • PRO Patient-reported outcome
  • PRO data are collected through use of the following instruments: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, and PRO- CTCAE (selected items), and EQ-5D-5L.
  • EORTC European Organisation for Research and Treatment of Cancer
  • PRO- CTCAE selected items
  • the PROs are administered in the following order: EORTC QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, PRO-CTCAE (selected items), and EQ-5D-5L.
  • the QLQ-C30 is a validated, reliable self-reported measure (see Aaronson et al., J Natl Cancer Inst, 85: 365-376, 1993; Fitzsimmons et al., EurJ Cancer, 35: 939-941 , 1999).
  • the EORTC QLQ-LC13 is a self-reported PRO measure that is a lung cancer-specific module to the EORTC QLQ-C30 (Bergman et al., Eur J Cancer, 30A: 635-642, 1994).
  • the PRO-CTCAE is a validated item library that is used to characterize the presence, frequency of occurrence, severity, and/or degree of interference with daily function of 78 participant-reportable symptomatic treatment toxicities (Basch et al., J Natl Cancer Inst, 106: 1 -11 , 2014; Dueck et al., JAMA Oncol, 1 : 1051 -1059, 2015).
  • the EORTC IL46 is a validated single item from the EORTC Item Library which assesses the extent that participants have been troubled by the side effects from their treatment. It is rated on a 4-point scale, ranging from “not at all” to “very much.”
  • the EQ-5D-5L is a validated self-reported health status questionnaire that is used to calculate a health status utility score for use in health economic analyses (EuroQol Group, Health Policy, 16: 199- 208, 1990; Brooks, Health Policy, 37: 53-72, 1996; Herdman et al., Qual Life Res, 20: 1727-1736, 2011 ; Janssen et al., Qual Life Res, 22: 1717-1727, 2013)
  • the overall type I error rate for the study is 0.05 (two-sided).
  • the primary endpoints of investigator-assessed DFS in the PHAS and FAS are tested at a two-sided a level of 0.038 and 0.012, respectively.
  • the two-sided aof 0.012 is recycled to the PHAS to be tested at a two-sided a of 0.05 level.
  • participant analysis sets for the purposes of analyses are defined in Table 9.
  • ADA anti-drug antibody
  • FAS full analysis set
  • PHAS PD-L1 high analysis set
  • SAS safety analysis set
  • PKAS Phamacokinetic analysis set.
  • the primary objective for the study is to evaluate the efficacy of tiragolumab plus atezolizumab compared with placebo plus atezolizumab in participants with resected, Stage I IB, 111 A, or select 11 IB (T3N2 only) (AJCC 8th edition) PD-L1 > 50% TC and PD-L1 > 1% TC NSCLC who have received adjuvant platinum-based chemotherapy.
  • the primary endpoints are investigator-assessed DFS in the PHAS and FAS.
  • Investigator-assessed DFS is defined as the time from randomization to the occurrence of local/regional or distant recurrence of NSCLC, new primary NSCLC, or death from any cause (whichever occurs first), as determined by the investigator.
  • the stratified log-rank test is used to compare DFS between the two treatment arms.
  • the HR for DFS is estimated using a stratified Cox regression model, along with the 95% Cl.
  • Stratification factors for analysis in the FAS include histology (non squamous vs. squamous), stage of disease (Stage I IB vs. Stage IIIA + select IIIB (T3N2)) and PD-L1 status (>1% and ⁇ 50% TC vs. >50% TC).
  • Stratification factors for analysis in the PHAS include histology and stage of disease. Results of the unstratified analysis are also provided.
  • Kaplan-Meier methodology is used to estimate the median DFS for each treatment arm, and the Kaplan-Meier curve is constructed to provide a visual description of the difference among arms.
  • the Brookmeyer-Crowley methodology is used to construct the two-sided 95% Cl for the median DFS for each treatment arm.
  • the methodology for comparing OS between treatment arms in the PHAS and FAS is the same as the method used for treatment comparison for the primary endpoints of investigator-assessed DFS. Overall survival is analyzed at the time of the DFS analyses.
  • the investigator-assessed DFS rate at 3 years, 5 years, and 7 years is analyzed by treatment arm.
  • the DFS rates are estimated by the Kaplan-Meier methodology for each treatment arm, with two- sided 95% Cis calculated using Greenwood’s formula.
  • Safety analyses are conducted in the SAS, defined as participants who receive at least one dose of tiragolumab/placebo or atezolizumab. Safety is assessed through summaries of exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.
  • Study treatment exposure (such as treatment duration, total dose received, and number of cycles and dose modifications) is summarized with descriptive statistics.
  • vital sign pulse rate, respiratory rate, blood pressure, and temperature
  • ECG data are displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests is used to summarize the baseline and maximum post-baseline severity grade. Changes in vital signs and ECGs are summarized.
  • the analysis population for the EORTC QLQ-C30 and QLQ-LC13 is the FAS. Completion rates are summarized at each timepoint by treatment arm for the EORTC QLQ-C30, QLQ-LC13 and EQ-5D-5L using the FAS.
  • the analysis population for the PRO-CTCAE and EORTC IL46 is the SAS. Summaries of the data over time are based on the number of participants who provided data at each time point. Completion rates are summarized at each timepoint by treatment arm for the PRO-CTCAE and EORTC IL46 using the SAS population.
  • PRO-CTCAE analyses are primarily descriptive, with a focus on characterizing the pattern of symptomatic AE occurrence over the course of the study.
  • PRO-CTCAE data are analyzed at the item level in accordance with current NCI recommendations for data handling (Basch et al., J Natl Cancer Inst, 106: 1 -11 , 2014).
  • the number (percentage) of participants reporting symptoms by frequency, severity, and interference is reported at each visit by treatment arm.
  • the change in the frequency of responses from baseline for each symptom is also summarized at each visit by treatment arm.
  • Patient-reported bother with side effects, as measured by the EORTC IL46 item is summarized descriptively at each assessment timepoint.
  • the number (percentage) of participants reporting bother is reported at each visit by treatment arm.
  • the change in the frequency of responses from baseline is also summarized at each visit by treatment arm.
  • the DFS and OS rates (for example 3-year, 5-year, and 7-year rates) at various other timepoints in the PHAS and FAS are estimated by the Kaplan-Meier methodology for each treatment arm, with two-sided 95% Cis calculated using Greenwood’s formula for exploratory purposes.
  • the pharmacokinetic (PK) analysis population for atezolizumab consists of all participants who received any dose of atezolizumab with at least 1 post-baseline atezolizumab PK assessment available.
  • the PK analysis population for tiragolumab consists of all participants who received any dose of tiragolumab with at least 1 post-baseline tiragolumab PK assessment available.
  • Samples are collected for PK analyses, and serum concentrations of atezolizumab and tiragolumab are reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation) by treatment arm and cycle, when appropriate and as data allow. Individual and median serum atezolizumab and tiragolumab concentrations are plotted for PK-evaluable participants by day.
  • the immunogenicity analyses include participants with any ADA assessments, with participants grouped according to treatment received.
  • the numbers and proportions of treatment-emergent ADApositive participants and ADA-negative participants for both tiragolumab and atezolizumab are summarized.
  • the relationship between ADA status and safety, efficacy, and PK endpoints may be analyzed and reported via descriptive statistics.
  • DFS One interim analysis is planned for investigator-assessed DFS in the PHAS and FAS.
  • the planned interim analysis of DFS is conducted when approximately 249 DFS events have occurred in the PHAS (77% of the total planned DFS events) and approximately 539 DFS events have occurred in the FAS (83% of the total planned DFS events), whichever occurs later. This interim analysis is estimated to occur approximately 90 months after the first participant is enrolled in the study.
  • the final DFS analysis is conducted when approximately 322 DFS events have occurred in the PHAS and approximately 652 DFS events have occurred in the FAS, whichever occurs later. This is estimated to occur approximately 120 months after the first participant is enrolled in the study.
  • the stopping boundaries for the interim and final analyses of DFS are computed using the Generalized Haybittle-Peto boundaries (Haybittie, Brit J Radiology, 44: 793-797, 1971 ) with unequal two- sided p-values of 0.0260 and 0.0252 for the PHAS, and 0.0090 and 0.0071 for the FAS, in the order of analysis. If the PHAS achieves statistical significance, then a is recycled to the FAS, and the two-sided p- values for the FAS are 0.0250 and 0.0436. If the FAS achieves statistical significance, then a is recycled to the PHAS, and the two-sided p-values for the PHAS are 0.0350 and 0.0331 .

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Abstract

La présente divulgation concerne le traitement du cancer du poumon non à petites cellules (CPNPC). Plus particulièrement, la divulgation concerne le traitement de patients atteints d'un CPNPC par l'administration d'un régime de traitement qui comprend un anticorps antagoniste anti-TIGIT (p. ex., le tiragolumab) et un antagoniste se liant à l'axe PD-1 (p. ex., l'atezolizumab) après une résection chirurgicale et une chimiothérapie adjuvante ou par l'administration d'un régime de traitement qui comprend une chimiothérapie adjuvante, un anticorps antagoniste anti-TIGIT (p. ex., le tiragolumab), et un antagoniste se liant à l'axe PD-1 (p. ex., l'atezolizumab) après une résection chirurgicale.
PCT/US2024/043565 2023-08-25 2024-08-23 Méthodes et compositions pour le traitement du cancer du poumon non à petites cellules comprenant un anticorps antagoniste anti-tigit et un antagoniste de liaison de l'axe pd-1 Pending WO2025049277A1 (fr)

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