Dosing for treatment with therapeutic Anti-tigit and Anti-PD-l1 antagonist antibodies

Abstract

To provide a medication method for treating a human patient having lung cancer such as non-small cell lung cancer (NSCLC).SOLUTION: Human patients having lung cancer, such as non-small cell lung cancer (NSCLC), are treated by administering a combination of an anti-TIGIT antagonist antibody (particularly tiragolumab) and a PD-1 axis binding antagonist (particularly ateozolizumab).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference. The ASCII copy created on September 23, 2020 is titled 50474-201WO4_Sequence_Listing_9.23.20_ST25 and is 30,100 bytes in size.

[0002] FIELD OF THE INVENTION The present invention relates to the treatment of cancer (e.g., lung cancer). More specifically, the present invention relates to the treatment of patients with cancer (e.g., lung cancer) by administering a combination of an anti-T cell immunoreceptor with Ig and ITIM domain (TIGIT) antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-programmed death-ligand-1 (PD-L1) antagonist antibody or an anti-programmed death-1 (PD-1) antagonist antibody). [Background technology]

[0003] Background of the Invention Cancer is characterized by the uncontrolled proliferation of cell subpopulations. It is the leading cause of death in developed countries and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. Therefore, cancer care represents a significant and growing societal burden.

[0004] Lung cancer, in particular, remains the leading cause of cancer death worldwide, accounting for approximately 13% of all new cancers in 2012. In the United States, an estimated 222,500 new cases of lung cancer and 155,870 lung cancer deaths were reported in 2017. Non-small cell lung cancer (NSCLC) is the predominant subtype, accounting for approximately 85% of all cases. The 5-year overall survival rate for advanced disease is 2% to 4%. Poor prognostic factors for survival in NSCLC patients include advanced stage of disease at initial diagnosis, poor performance status, and a history of unintentional weight loss. More than half of NSCLC patients are diagnosed with distant disease, which directly contributes to poor survival prospects.

[0005] Despite improvements in first-line treatment for patients with advanced NSCLC, which have resulted in longer survival and fewer disease-related symptoms, nearly all patients experience disease progression. Cancer immunotherapy, in particular, offers the potential for long-term disease control. In the setting of metastatic NSCLC, PD-L1 / PD-1-blocking antibodies (e.g., atezolizumab, nivolumab, and pembrolizumab) have provided clinically meaningful benefits in either unselected or PD-L1-selected patients with advanced NSCLC. However, a significant proportion of patients remain unresponsive or progress to anti-PD-L1 / PD-1 treatment, and the mechanisms of escape from such treatment are poorly understood.

[0006] Thus, there is an unmet need in the field to develop effective immunotherapies and methods of administering same for the treatment of cancer (e.g., lung cancer, e.g., NSCLC) that achieve a better benefit-risk profile. Summary of the Invention

[0007] Summary of the Invention The present invention relates to methods of treating a subject with cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) by administering a combination of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)).

[0008] In a first aspect, the present invention provides a method for treating a subject with lung cancer, comprising administering one or more administration cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of about 30 mg to about 1200 mg every three weeks, a fixed dose of about 300 mg to about 800 mg every two weeks, or a fixed dose of about 700 mg to about 1000 mg every four weeks) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) (e.g., a fixed dose of about 80 mg to about 1600 mg every three weeks, a fixed dose of about 200 mg to about 1200 mg every two weeks, or a fixed dose of about 1000 mg every four weeks). mg fixed dose, or a fixed dose of about 400 mg to about 2000 mg every 4 weeks) to a subject, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment results in (a) a complete response (CR) or partial response (PR), and / or (b) an increase in progression-free survival (PFS) compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0009] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 600 mg every three weeks. In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 400 mg to about 500 mg every two weeks. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg every two weeks. In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 800 mg to about 900 mg every two weeks. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg every two weeks.

[0010] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FR): FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7), FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8), FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9), and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FR: FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is Q or E), FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12), FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13), and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0011] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19, or (c) the VH domain described in (a) and the VL domain described in (b).

[0012] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

[0013] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0014] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is tiragolumab.

[0015] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0016] In some embodiments of the first aspect, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0017] In some embodiments of the first aspect, the method comprises administering to the subject a fixed dose of about 1200 mg of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antibody) every three weeks. In some embodiments of the first aspect, the method comprises administering to the subject a fixed dose of about 840 mg of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antibody) every two weeks. In some embodiments of the first aspect, the method comprises administering to the subject a fixed dose of about 1680 mg of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antibody) every four weeks.

[0018] In some embodiments of the first aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti-PD-L1 antagonist antibody is atezolizumab.

[0019] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain described in (a) and the VL domain described in (b).

[0020] In some embodiments of the first aspect, the anti-PD-L1 antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:26 and a VL domain comprising the amino acid sequence of SEQ ID NO:27.

[0021] In some embodiments of the first aspect, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a monoclonal antibody. In some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a humanized antibody (e.g., a monoclonal humanized antibody).

[0022] In some embodiments of the first aspect, the PD-1 axis binding antagonist (eg, an anti-PD-L1 antagonist antibody) is a full-length antibody.

[0023] In some embodiments of the first aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragments.

[0024] In some embodiments of the first aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0025] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 600 mg every three weeks and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) at a fixed dose of about 1200 mg every three weeks.

[0026] In some embodiments of the first aspect, each of the one or more administration cycles is 21 days in length.

[0027] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) on about day 1 of each of one or more administration cycles.

[0028] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 420 mg every two weeks and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) at a fixed dose of about 820 mg every two weeks. In some embodiments of the first aspect, the length of each of the one or more administration cycles is 28 days. In some embodiments of the first aspect, the method comprises administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) on about days 1 and 15 of each of the one or more administration cycles.

[0029] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 840 mg every four weeks and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) at a fixed dose of about 1680 mg every four weeks. In some embodiments of the first aspect, the length of each of the one or more administration cycles is 28 days. In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) on about day 1 of each of the one or more administration cycles.

[0030] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody before a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the method comprises a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0031] In some embodiments of the first aspect, the method comprises administering to the subject a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) prior to the anti-TIGIT antagonist antibody. In some embodiments, the method comprises a first observation period following administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and a second observation period following administration of the anti-TIGIT antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0032] In some embodiments of the first aspect, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) simultaneously.

[0033] In some embodiments of the first aspect, the method comprises intravenously administering to a subject an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the method comprises administering to a subject the anti-TIGIT antagonist antibody by intravenous infusion over 60±10 minutes. In some embodiments, the method comprises administering to a subject the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) by intravenous infusion over 60±15 minutes.

[0034] In some embodiments of the first aspect, the PD-L1-positive tumor cell fraction is determined by immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some embodiments, the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody (e.g., SP263, 22C3, SP142, or 28-8). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater when determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., the PD-L1-positive tumor cell fraction is calculated using a Ventana SP263 IHC assay). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater when determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., the PD-L1-positive tumor cell fraction is calculated using a pharmDx 22C3 IHC assay). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142 (e.g., the PD-L1 positive tumor cell fraction is calculated using a Ventana SP142 IHC assay). In some embodiments, the PD-L1 positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody 28-8.

[0035] In some embodiments of the first aspect, a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1, hi some embodiments, 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 technology, ISH, or a combination thereof.

[0036] In some embodiments of the first aspect, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not been previously treated for stage IV NSCLC.

[0037] In some embodiments of the first aspect, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0038] In some embodiments of the first aspect, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0039] In some embodiments of the first aspect, the subject does not have an active Epstein-Barr virus (EBV) infection or does not have or is not suspected of having a known chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or is negative by EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative by EBV PCR. In some embodiments, the subject is positive for EBV IgG or is positive for Epstein-Barr nuclear antigen (EBNA). In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0040] In some embodiments of the first aspect, the subject is EBV IgG negative or EBNA negative, hi some embodiments, the subject is EBV IgG negative and EBNA negative.

[0041] In some embodiments, the subject is likely to have an increased PFS in the subject compared to a baseline PFS time, which in some embodiments is the median PFS time in a population of subjects who have received treatment comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without an anti-TIGIT antagonist antibody.

[0042] In a second aspect, the present invention provides a method for treating a subject with NSCLC, comprising administering one or more administration cycles of an anti-TIGIT antagonist antibody (e.g., at a fixed dose of about 600 mg every three weeks, at a fixed dose of about 420 mg every two weeks, or at a fixed dose of about 840 mg every four weeks) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) (e.g., at a fixed dose of about 1200 mg every three weeks, at a fixed dose of about 840 mg every two weeks, or at a fixed dose of about 1680 mg every four weeks). the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0043] In a third aspect, the present invention provides a method for treating a subject with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by staining tumor cells from the tumor sample with the anti-PD-L1 antibody SP263, and determining the PD-L1-positive tumor cell fraction therefrom, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 50% or more; (c) administering one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every three weeks). the method comprises administering to a subject a therapy comprising atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0044] In a fourth aspect, the present invention provides a method for treating a subject with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by staining tumor cells from the tumor sample with anti-PD-L1 antibody 22C3, and determining the PD-L1-positive tumor cell fraction therefrom, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 50% or greater; and (c) administering one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every three weeks). and atezolizumab (e.g., at a fixed dose of 1200 mg every three weeks, at a fixed dose of 840 mg every two weeks, or at a fixed dose of 1680 mg every four weeks) to a subject, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0045] In a fifth aspect, the invention features a method for treating a subject with NSCLC, the method including administering one or more dosing cycles of tiragolumab (e.g., a fixed dose of 600 mg every 3 weeks, a fixed dose of 420 mg every 2 weeks, or a fixed dose of 840 mg every 4 weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every 3 weeks, a fixed dose of 840 mg every 2 weeks, or a fixed dose of 1680 mg every 4 weeks) to the subject, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

[0046] In a sixth aspect, the present invention provides a method for treating a subject with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using anti-PD-L1 antibody SP263, and determining the PD-L1-positive tumor cell fraction therefrom, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 50% or greater; and (c) administering one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every 3 weeks, 2 the method includes administering to a subject a therapy comprising atezolizumab (e.g., a fixed dose of 420 mg every week, or a fixed dose of 840 mg every four weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0047] In a seventh aspect, the present invention provides a method for treating a subject with NSCLC, comprising: (a) obtaining a tumor sample from the subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by IHC assay using anti-PD-L1 antibody 22C3, and determining the PD-L1-positive tumor cell fraction therefrom, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 50% or greater; and (c) administering one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every 3 weeks, the method includes administering to a subject a therapy comprising atezolizumab (e.g., a fixed dose of 420 mg every week, or a fixed dose of 840 mg every four weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0048] In an eighth aspect, the present invention provides an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) for use in a method of treating a subject with lung cancer, the method comprising administering one or more administration cycles of an anti-TIGIT antagonist antibody (e.g., a fixed dose of about 30 mg to about 1200 mg every three weeks, a fixed dose of about 300 mg to about 800 mg every two weeks, or a fixed dose of about 700 mg to about 1000 mg every four weeks) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) (e.g., a fixed dose of about 80 mg to about 1600 mg every three weeks). a fixed dose of about 200 mg to about 1200 mg every two weeks, a fixed dose of about 200 mg to about 1200 mg every two weeks, or a fixed dose of about 400 mg to about 2000 mg every four weeks) to a subject determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater), wherein the treatment features an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist for use that (a) results in a CR or PR, and / or (b) results in an increased PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0049] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 400 mg to about 500 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every two weeks.

[0050] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following light chain variable regions FR: FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7), FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8), FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9), and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FR: FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is Q or E), FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12), FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13), and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0051] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19, or (c) the VH domain described in (a) and the VL domain described in (b).

[0052] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

[0053] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0054] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is tiragolumab.

[0055] In some embodiments of the eighth aspect, the anti-TIGIT antagonist fragment is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragments.

[0056] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0057] In some embodiments of the eighth aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1200 mg every three weeks. In other embodiments, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 840 mg every two weeks. In other embodiments, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1680 mg every four weeks.

[0058] In some embodiments of the eighth aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody (e.g., atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736). In some embodiments, the PD-L1 antagonist is atezolizumab. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antagonist antibody (e.g., nivolumab (MDX-1106) or pembrolizumab (formerly lambrolizumab (MK-3475))). In some embodiments, the PD-1 binding antagonist is AMP-224. In some embodiments of the eighth aspect, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) the VH domain described in (a) and the VL domain described in (b).

[0059] In some embodiments of the eighth aspect, the anti-PD-L1 antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:26 and a VL domain comprising the amino acid sequence of SEQ ID NO:27.

[0060] In some embodiments of the eighth aspect, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a monoclonal antibody. In some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a humanized antibody (e.g., a monoclonal humanized antibody).

[0061] In some embodiments of the eighth aspect, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a full-length antibody.

[0062] In some embodiments of the eighth aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an antibody fragment that binds to PD-L1 or PD-1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0063] In some embodiments of the eighth aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0064] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1200 mg every three weeks.

[0065] In some embodiments of the eighth aspect, each of the one or more administration cycles is 21 days in length.

[0066] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) are administered to the subject on about day 1 of each of one or more administration cycles.

[0067] In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks, and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered at a fixed dose of about 820 mg every two weeks. In some embodiments, the length of each of the one or more administration cycles is 28 days. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) are administered on about days 1 and 15 of each of the one or more administration cycles.

[0068] In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks, and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered at a fixed dose of about 1680 mg every four weeks. In some embodiments, the length of each of the one or more administration cycles is 28 days. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) are administered on about day 1 of each of the one or more administration cycles.

[0069] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is administered to the subject before the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the first observation period follows administration of the anti-TIGIT antagonist antibody, and the second observation period follows administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0070] In some embodiments of the eighth aspect, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject before the anti-TIGIT antagonist antibody. In some embodiments, the first observation period follows administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), and the second observation period follows administration of the anti-TIGIT antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0071] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody).

[0072] In some embodiments of the eighth aspect, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) are administered intravenously to the subject. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over 60±10 minutes. In some embodiments, the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered to the subject by intravenous infusion over 60±15 minutes.

[0073] In some embodiments of the eighth aspect, the PD-L1-positive tumor cell fraction is determined by immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some embodiments, the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody (e.g., SP263, 22C3, SP142, or 28-8). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater when determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., the PD-L1-positive tumor cell fraction is calculated using a Ventana SP263 IHC assay). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater when determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., the PD-L1-positive tumor cell fraction is calculated using a pharmDx 22C3 IHC assay). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142 (e.g., the PD-L1 positive tumor cell fraction is calculated using a Ventana SP142 IHC assay). In some embodiments, the PD-L1 positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody 28-8.

[0074] In some embodiments of the eighth aspect, the IHC assay uses the anti-PD-L1 antibody SP263. In some embodiments, the IHC assay uses the anti-PD-L1 antibody 22C3.

[0075] In some embodiments of the eighth aspect, a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1. In some embodiments, 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 technology, ISH, or a combination thereof.

[0076] In some embodiments of the eighth aspect, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not been previously treated for stage IV NSCLC.

[0077] In some embodiments of the eighth aspect, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0078] In some embodiments of the eighth aspect, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0079] In some embodiments of the eighth aspect, the subject does not have an active EBV infection or does not have or is not suspected of having a known chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or is negative by EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative by EBV PCR. In some embodiments, the subject is positive for EBV IgG or is positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0080] In some embodiments of the eighth aspect, the subject is EBV IgG negative or EBNA negative, hi some embodiments, the subject is EBV IgG negative and EBNA negative.

[0081] In some embodiments of the eighth aspect, the subject's PFS is increased compared to a baseline PFS time, which in some embodiments is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0082] In a ninth aspect, the present invention provides an anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with NSCLC, the method comprising administering to the subject one or more dosing cycles of the anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every 3 weeks, a fixed dose of 420 mg every 2 weeks, or a fixed dose of 840 mg every 4 weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every 3 weeks, a fixed dose of 840 mg every 2 weeks, or a fixed dose of 1680 mg every 4 weeks). the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or more (e.g., 50% or more), and the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0083] In a tenth aspect, the invention features tiragolumab and atezolizumab for use in a method of treating a subject with NSCLC, the method comprising administering one or more dosing cycles of tiragolumab (e.g., a fixed dose of 600 mg every 3 weeks, a fixed dose of 420 mg every 2 weeks, or a fixed dose of 840 mg every 4 weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every 3 weeks, a fixed dose of 840 mg every 2 weeks, or a fixed dose of 1680 mg every 4 weeks) to the subject, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

[0084] In an eleventh aspect, the present invention provides use of an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) in the manufacture of a medicament for use in a method of treating a subject with lung cancer, the method comprising administering one or more dosing cycles of the medicament to the subject, the medicament comprising an anti-TIGIT antagonist antibody (e.g., a fixed dose of about 30 mg to about 1200 mg every three weeks, a fixed dose of about 300 mg to about 800 mg every two weeks, or a fixed dose of about 700 mg to about 1000 mg every four weeks) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 and (b) a fixed dose of about 80 mg to about 1600 mg every three weeks, about 200 mg to about 1200 mg every two weeks, or about 400 mg to about 2000 mg every four weeks), wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) an increase in PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0085] In a twelfth aspect, the present invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject with lung cancer, the method comprising administering to the subject one or more dosing cycles of a medicament and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), wherein the medicament comprises an anti-TIGIT antagonist antibody (e.g., a fixed dose of about 30 mg to about 1200 mg every three weeks, a fixed dose of about 300 mg to about 800 mg every two weeks, or a fixed dose of about 700 mg to about 1000 mg every four weeks) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 and (b) a fixed dose of about 80 mg to about 1600 mg every three weeks, about 200 mg to about 1200 mg every two weeks, or about 400 mg to about 2000 mg every four weeks), wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) an increase in PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0086] In a thirteenth aspect, the present invention provides use of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) in the manufacture of a medicament for use in a method of treating a subject with lung cancer, the method comprising administering to the subject one or more dosing cycles of a medicament and an anti-TIGIT antibody, the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) (e.g., a fixed dose of about 80 mg to about 1600 mg every three weeks, a fixed dose of about 200 mg to about 1200 mg every two weeks, or a fixed dose of about 400 mg to about 2000 mg every four weeks) and an anti-TIG The present invention relates to a method for treating a patient with a PD-L1 axis-binding agonist (e.g., an anti-TIGIT antagonist antibody) comprising administering an anti-TIGIT antibody (e.g., a fixed dose of about 30 mg to about 1200 mg every 3 weeks, a fixed dose of about 300 mg to about 800 mg every 2 weeks, or a fixed dose of about 700 mg to about 1000 mg every 4 weeks) to a patient in whom a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater) is determined, and the treatment (a) results in a complete response or response (CR) or a partial response (PR), and / or (b) results in increased PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0087] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 400 mg to about 500 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every two weeks.

[0088] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FR): FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7), FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8), FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9), and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FR: FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is Q or E), FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12), FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13), and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In some embodiments, X1 is E.

[0089] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19, or (c) the VH domain described in (a) and the VL domain described in (b).

[0090] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody (e.g., a monoclonal human antibody).

[0091] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments of any of the twenty-first, twenty-second, and twenty-third aspects, the anti-TIGIT antagonist antibody is tiragolumab.

[0092] In some embodiments of any of the 11th, 12th, and 13th aspects, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0093] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0094] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1200 mg every three weeks. In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 840 mg every two weeks. In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1680 mg every four weeks.

[0095] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody (e.g., atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736). In some embodiments, the PD-L1 antagonist is atezolizumab. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antagonist antibody (e.g., nivolumab (MDX-1106) or pembrolizumab (formerly lambrolizumab (MK-3475))). In some embodiments, the PD-1 binding antagonist is AMP-224.

[0096] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27, or (c) a VH domain described in (a) and a VL domain described in (b). In some embodiments, the anti-PD-L1 antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 26 and a VL domain comprising the amino acid sequence of SEQ ID NO: 27.

[0097] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some embodiments, the PD-1 axis-binding antagonist (e.g., the anti-PD-L1 antagonist antibody) is a humanized antibody (e.g., a monoclonal humanized antibody).

[0098] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is a full-length antibody.

[0099] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an antibody fragment that binds to PD-L1 or PD-1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragments.

[0100] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0101] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1200 mg every three weeks. In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 420 mg every two weeks, and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 840 mg every two weeks. In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 840 mg every two weeks, and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject at a fixed dose of about 1680 mg every three weeks.

[0102] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, each of the one or more administration cycles is 21 days in length.

[0103] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., the anti-PD-L1 antagonist antibody) are administered to the subject on about day 1 of each of one or more administration cycles.

[0104] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody is administered to the subject before the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the first observation period follows administration of the anti-TIGIT antagonist antibody, and the second observation period follows administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0105] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) is administered to the subject before the anti-TIGIT antagonist antibody. In some embodiments, the first observation period follows administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), and the second observation period follows administration of the anti-TIGIT antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0106] In some embodiments of the eleventh aspect, the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody).

[0107] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) are administered intravenously to the subject. In some embodiments, the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over 60±10 minutes. In some embodiments, the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered to the subject by intravenous infusion over 60±15 minutes.

[0108] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist (e.g., the anti-PD-L1 antagonist antibody) are administered subcutaneously to the subject.

[0109] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the PD-L1-positive tumor cell fraction is determined by immunohistochemistry (IHC) assay. In some embodiments, the IHC assay uses the anti-PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some embodiments, the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody (e.g., SP263, 22C3, SP142, or 28-8). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater, as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., the PD-L1-positive tumor cell fraction is calculated using a Ventana SP263 IHC assay). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., the PD-L1-positive tumor cell fraction is calculated using a pharmDx 22C3 IHC assay). In some embodiments, the PD-L1-positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142 (e.g., the PD-L1-positive tumor cell fraction is calculated using a Ventana SP142 IHC assay). In some embodiments, the PD-L1-positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody 28-8.

[0110] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the IHC assay uses the anti-PD-L1 antibody SP263. In some embodiments, the IHC assay uses the anti-PD-L1 antibody 22C3.

[0111] In some aspects of any of the eleventh, twelfth, and thirteenth embodiments, a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1. In some embodiments, 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 technology, ISH, or a combination thereof.

[0112] In some aspects of any of the eleventh, twelfth, and thirteenth embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0113] In some embodiments of any of the ninth, tenth, eleventh, twelfth, and thirteenth aspects, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC. In some embodiments, the NSCLC is stage IIIB NSCLC. In some embodiments, the NSCLC is recurrent or metastatic NSCLC. In some embodiments, the NSCLC is stage IV NSCLC. In some embodiments, the subject has not previously been treated for stage IV NSCLC.

[0114] In some embodiments of any of the ninth, tenth, eleventh, twelfth, and thirteenth aspects, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0115] In some embodiments of any of the ninth, tenth, eleventh, twelfth, and thirteenth aspects, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0116] In some embodiments of any of the ninth, tenth, eleventh, twelfth, and thirteenth aspects, the subject does not have an active EBV infection or does not have or is not suspected of having a known chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or is negative by EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative by EBV PCR. In some embodiments, the subject is positive for EBV IgG or is positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0117] In some embodiments of any of the ninth, tenth, eleventh, twelfth, and thirteenth aspects, the subject is EBV IgG negative or EBNA negative, hi some embodiments, the subject is EBV IgG negative and EBNA negative.

[0118] In some embodiments of any of the eleventh, twelfth, and thirteenth aspects, the subject's PFS is increased compared to a baseline PFS time, in some embodiments, the baseline PFS time is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody.

[0119] In a fourteenth aspect, the present invention provides a method for treating a subject with NSCLC, comprising administering to the subject one or more dosing cycles of a medicament comprising an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every three weeks, a fixed dose of 420 mg every two weeks, or a fixed dose of 840 mg every four weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1200 mg every two weeks). and (b) a fixed dose of 1680 mg every 4 weeks (or a fixed dose of 1680 mg every 4 weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0120] In a fifteenth aspect, the present invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering to the subject one or more dosing cycles of a medicament and atezolizumab, the medicament comprising an anti-TIGIT antagonist antibody (e.g., at a fixed dose of 600 mg every three weeks, at a fixed dose of 420 mg every two weeks, or at a fixed dose of 840 mg every four weeks) and atezolizumab (e.g., at a fixed dose of 1200 mg every three weeks, at a fixed dose of 840 mg every two weeks, or at a fixed dose of 1200 mg every three weeks, at a fixed dose of 840 mg every two weeks). and (b) a fixed dose of 1680 mg every 4 weeks (or a fixed dose of 1680 mg every 4 weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0121] In a sixteenth aspect, the present invention provides a method for treating a subject with NSCLC, comprising administering to the subject one or more dosing cycles of a medicament and an anti-TIGIT antagonist antibody, the medicament comprising atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks) and an anti-TIGIT antagonist antibody (e.g., a fixed dose of 600 mg every three weeks, a fixed dose of 420 mg every two weeks, or a fixed dose of 1680 mg every four weeks). and (b) a fixed dose of 840 mg every 4 weeks (or a fixed dose of 840 mg every 4 weeks), wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

[0122] In a seventeenth aspect, the invention features the use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject having NSCLC, the method comprising administering one or more dosing cycles of the medicament to the subject, the medicament being formulated for administration of tiragolumab (e.g., a fixed dose of 600 mg every three weeks, a fixed dose of 420 mg every two weeks, or a fixed dose of 840 mg every four weeks) and atezolizumab (e.g., a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks), the subject being determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

[0123] In an eighteenth aspect, the invention features the use of tiragolumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering one or more dosing cycles of the medicament and atezolizumab to the subject, wherein the medicament is formulated for administration of tiragolumab (e.g., at a fixed dose of 600 mg every three weeks, a fixed dose of 420 mg every two weeks, or a fixed dose of 840 mg every four weeks), and atezolizumab is administered (e.g., at a fixed dose of 1200 mg every three weeks, a fixed dose of 840 mg every two weeks, or a fixed dose of 1680 mg every four weeks), the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

[0124] In a nineteenth aspect, the invention features the use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering one or more dosing cycles of the medicament and tiragolumab to the subject, wherein the medicament is formulated for administration of atezolizumab (e.g., at a fixed dose of 1200 mg every three weeks, at a fixed dose of 840 mg every two weeks, or at a fixed dose of 1680 mg every four weeks), and tiragolumab (e.g., at a fixed dose of 600 mg every three weeks, at a fixed dose of 420 mg every two weeks, or at a fixed dose of 840 mg every four weeks), wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater), and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

[0125] In some embodiments of any of the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth aspects, the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

[0126] In some embodiments of any of the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth aspects, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

[0127] In some embodiments of any of the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth aspects, the subject does not have an active EBV infection or does not have or is not suspected of having a known chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or is negative by EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative by EBV PCR. In some embodiments, the subject is positive for EBV IgG or is positive for EBNA. In some embodiments, the subject is positive for EBV IgG and positive for EBNA.

[0128] In some embodiments of any of the fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, and nineteenth aspects, the subject is EBV IgG negative or EBNA negative. In some embodiments, the subject is EBV IgG negative and EBNA negative.

[0129] In some embodiments of any of the aforementioned aspects, the treatment results in an increase in PFS of at least about 3.1 months (e.g., at least about 4.9 months) compared to treatment with atezolizumab without tiragolumab.

[0130] In some embodiments of any of the aforementioned aspects, treatment results in an increase in OS of at least about 5.7 months (e.g., at least about 9 months) compared to treatment with atezolizumab without tiragolumab.

[0131] In a twentieth aspect, the invention features a method for treating a subject with lung cancer, comprising administering to the subject one or more administration cycles of an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist, wherein the subject has previously received combined chemoradiotherapy (cCRT) for the lung cancer, and the subject has not had disease progression after the cCRT (e.g., the subject has not had radiological disease progression after the cCRT). In some embodiments, the subject has previously received at least two cycles of cCRT (e.g., at least three cycles of cCRT, at least four cycles of cCRT, at least five cycles of cCRT, at least six cycles of cCRT, or more). In some embodiments, the cCRT comprises platinum-based chemotherapy (e.g., the cCRT comprises combination platinum-based CRT, e.g., combination CRT comprising administration of cisplatin (e.g., cisplatin-etoposide or cisplatin-vinorelbine) or combination CRT comprising administration of carboplatin (e.g., carboplatin-paclitaxel)). In some embodiments, the cCRT comprises thoracic radiation therapy. In some embodiments, radiation therapy is administered to the subject at 60-66 Gy in 30-33 fractions. In some embodiments, the cCRT is administered with curative intent. In some embodiments, the cCRT is administered as consolidation therapy.

[0132] In some embodiments, the anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following light chain variable region framework regions (FR): FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7), FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8), FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9), and FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some embodiments, the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FR: FR-H1 comprising the amino acid sequence of X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11) (wherein X1 is Q or E), FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12), FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13), and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, X1 is Q. In other embodiments, X1 is E. In some embodiments, the anti-TIGIT antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19, or (c) the VH domain described in (a) and the VL domain described in (b).In some embodiments, the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

[0133] In some embodiments, the anti-TIGIT antagonist antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antagonist antibody is a human antibody. In some embodiments, the anti-TIGIT antagonist antibody is a full-length antibody. In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab.

[0134] In some embodiments, the anti-TIGIT antagonist antibody is an antibody fragment that binds to TIGIT selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment.

[0135] In some embodiments, the anti-TIGIT antagonist antibody is an IgG class antibody (eg, an IgG1 subclass antibody).

[0136] In some embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist. In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody and is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736. In some embodiments, the anti-PD-L1 antagonist antibody is atezolizumab. In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antagonist antibody. In some embodiments, the anti-PD-1 antagonist antibody is nivolumab (MDX-1106) or pembrolizumab (MK-3475). In some embodiments, the PD-1 binding antagonist is AMP-224.

[0137] In some embodiments, the anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence of RASQDVSTAVA (SEQ ID NO: 23); an HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25). In some embodiments, the anti-PD-L1 antagonist antibody comprises: (a) a heavy chain variable (VH) domain having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27, or (c) a VH domain described in (a) and a VL domain described in (b). In some embodiments, the anti-PD-L1 antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 26; and a VL domain comprising the amino acid sequence of SEQ ID NO: 27.

[0138] In some embodiments, the PD-1 axis binding antagonist is a monoclonal antibody. In some embodiments, the PD-1 axis binding antagonist is a humanized antibody. In some embodiments, the PD-1 axis binding antagonist is a full-length antibody.

[0139] In some embodiments, the PD-1 antagonist is an antibody fragment that binds to PD-L1 selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain variable fragment (scFv), and (Fab')2 fragment. In some embodiments, the PD-1 axis-binding antagonist is an IgG class antibody. In some embodiments, the IgG class antibody is an IgG1 subclass antibody.

[0140] In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, e.g., a fixed dose of about 30 mg to about 600 mg every three weeks, e.g., a fixed dose of about 600 mg every three weeks. In some embodiments, the method comprises administering to the subject a PD-1 axis-binding antagonist at a fixed dose of about 80 mg to about 1600 mg every three weeks, e.g., a fixed dose of about 1200 mg every three weeks. In some embodiments, the method comprises administering to the subject a fixed dose of about 600 mg of the anti-TIGIT antagonist antibody every three weeks and a fixed dose of about 1200 mg of the PD-1 axis-binding antagonist every three weeks. In some embodiments, each of the one or more administration cycles is 21 days long. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist on about day 1 of each of one or more administration cycles.

[0141] In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 300 mg to about 800 mg every two weeks, e.g., a fixed dose of about 400 mg to about 500 mg every two weeks, e.g., a fixed dose of about 420 mg every two weeks. In some embodiments, the method comprises administering to the subject a PD-1 axis-binding antagonist at a fixed dose of about 200 mg to about 1200 mg every two weeks, e.g., a fixed dose of about 840 mg every two weeks. In some embodiments, the method comprises administering to the subject a fixed dose of about 420 mg of the anti-TIGIT antagonist antibody every two weeks and a fixed dose of about 840 mg of the PD-1 axis-binding antagonist every two weeks. In some embodiments, each of the one or more administration cycles is 28 days long. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist on about days 1 and 15 of each of one or more administration cycles.

[0142] In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody at a fixed dose of about 700 mg to about 1000 mg every 4 weeks, e.g., a fixed dose of about 800 mg to about 900 mg every 4 weeks, e.g., a fixed dose of about 840 mg every 4 weeks. In some embodiments, the method comprises administering to the subject a PD-1 axis-binding antagonist at a fixed dose of about 400 mg to about 2000 mg every 4 weeks, e.g., a fixed dose of about 1680 mg every 4 weeks. In some embodiments, the method comprises administering to the subject a fixed dose of about 840 mg of the anti-TIGIT antagonist antibody every 4 weeks and a fixed dose of about 1680 mg of the PD-1 axis-binding antagonist every 4 weeks. In some embodiments, each of the one or more administration cycles is 28 days long. In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist on about day 1 of each of one or more administration cycles.

[0143] In some embodiments, the method includes administering a PD-1 axis-binding antagonist to the subject prior to administering the anti-TIGIT antagonist antibody. In some embodiments, the method includes a first observation period after administration of the PD-1 axis-binding antagonist and a second observation period after administration of the anti-TIGIT antagonist antibody. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0144] In some embodiments, the method includes administering an anti-TIGIT antagonist antibody to a subject before administering a PD-1 axis-binding antagonist. In some embodiments, the method includes a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis-binding antagonist. In some embodiments, the first observation period and the second observation period are each about 30 minutes to about 60 minutes in length.

[0145] In some embodiments, the methods comprise administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist simultaneously.

[0146] In some embodiments, the method comprises administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist intravenously, e.g., by intravenous infusion over 60±10 minutes. In some embodiments, the method comprises administering to the subject a PD-1 axis-binding antagonist by intravenous infusion over 60±15 minutes.

[0147] In some embodiments, the methods comprise subcutaneously administering to the subject an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist.

[0148] In some embodiments, the subject's PD-L1-positive tumor cell fraction is determined. In some embodiments, the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, where the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8. In some embodiments, the staining is part of an IHC assay. In some embodiments, the PD-L1-positive tumor cell fraction is 1% or greater tumor cells (TC), as determined by positive staining with the anti-PD-L1 antibody SP263 or 22C3. In some embodiments, the PD-L1-positive tumor cell fraction is less than 1% TC (e.g., 0%-1% TC, e.g., PD-L1 negative), as determined by positive staining with the anti-PD-L1 antibody SP263 or 22C3. In some embodiments, PD-L1 expression is calculated using a Ventana SP263 IHC assay. In some embodiments, PD-L1 expression is calculated using a pharmDx 22C3 IHC assay.

[0149] In some embodiments, the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

[0150] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is squamous NSCLC. In other embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the NSCLC is locally advanced unresectable NSCLC (e.g., locally advanced unresectable NSCLC with a PD-L1 positive tumor cell fraction of <1% of TC or locally advanced unresectable NSCLC with a PD-L1 positive tumor cell fraction of ≥1% of TC). In some embodiments, the NSCLC is stage III NSCLC (e.g., stage IIIA NSCLC, stage IIIB NSCLC, or stage IIIC NSCLC), e.g., stage III NSCLC with a PD-L1-positive tumor cell fraction of less than 1% (e.g., stage IIIA NSCLC with a PD-L1-positive tumor cell fraction of less than 1% of the TC, stage IIIB NSCLC with a PD-L1-positive tumor cell fraction of less than 1% of the TC, or stage IIIC NSCLC with a PD-L1-positive tumor cell fraction of less than 1% of the TC), or stage III NSCLC with a PD-L1-positive tumor cell fraction of 1% or more of the TC (e.g., stage IIIA NSCLC with a PD-L1-positive tumor cell fraction of 1% or more of the TC, stage IIIB NSCLC with a PD-L1-positive tumor cell fraction of 1% or more of the TC, or stage IIIC NSCLC with a PD-L1-positive tumor cell fraction of 1% or more of the TC). In some embodiments, the NSCLC (eg, squamous NSCLC, non-squamous NSCLC, or locally advanced unresectable NSCLC) is not stage IV NSCLC.

[0151] In some embodiments, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. In some embodiments, the subject does not have an active Epstein-Barr virus (EBV) infection or does not have or is not suspected of having a known chronic active EBV infection. In some embodiments, the subject is negative for EBV IgM or is negative by EBV PCR. In some embodiments, the subject is negative for EBV IgM and negative by EBV PCR. In some embodiments, the subject is positive for EBV IgG or is positive for Epstein-Barr nuclear antigen (EBNA). In some embodiments, the subject is positive for EBV IgG and positive for EBNA. In some embodiments, the subject is negative for EBV IgG or is negative for EBNA. In some embodiments, the subject is negative for EBV IgG and negative for EBNA.

[0152] In some embodiments, the PFS is increased compared to a reference PFS time, e.g., the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist (e.g., durvalumab) without the anti-TIGIT antagonist antibody.

[0153] In a twenty-first aspect, provided herein is a method for treating a subject with NSCLC, comprising administering to the subject one or more administration cycles of an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, the subject has previously received cCRT for lung cancer, the subject has not experienced disease progression after cCRT, and the treatment (a) results in CR or PR and / or (b) results in increased PFS compared to treatment with durvalumab without the anti-TIGIT antagonist antibody. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every 3 weeks, and atezolizumab is administered at a fixed dose of 1200 mg every 3 weeks. In another embodiment, the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks. In another embodiment, the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

[0154] In some embodiments, the subject has previously received at least two cycles of cCRT. In some embodiments, the cCRT comprises platinum-based chemotherapy. In some embodiments, the cCRT comprises thoracic radiation therapy, e.g., 60-66 Gy administered to the subject in 30-33 fractions. In some embodiments, the cCRT is administered with curative intent. In some embodiments, the cCRT is administered as consolidation therapy.

[0155] In a twenty-second aspect, the invention features a method for treating a subject with NSCLC, comprising administering one or more dosing cycles of tiragolumab and atezolizumab to the subject, wherein the subject has previously received cCRT for lung cancer, the subject has not had disease progression after cCRT, and the treatment (a) results in a CR or PR and / or (b) results in increased PFS compared to treatment with durvalumab without tiragolumab. In some embodiments, tiragolumab is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks. In other embodiments, tiragolumab is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks. In other embodiments, tiragolumab is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

[0156] In some embodiments, the subject has previously received at least two cycles of cCRT. In some embodiments, the cCRT comprises platinum-based chemotherapy. In some embodiments, the cCRT comprises thoracic radiation therapy, e.g., 60-66 Gy administered to the subject in 30-33 fractions. In some embodiments, the cCRT is administered with curative intent. In some embodiments, the cCRT is administered as consolidation therapy.

[0157] In a twenty-third aspect, there is provided herein an anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method of treating a subject with lung cancer, wherein the method is according to any one of the preceding aspects.

[0158] In a twenty-fourth aspect, the invention features the use of an anti-TIGIT antagonist antibody in combination with an anti-PD-L1 antagonist antibody in the manufacture of a medicament for treating a subject with lung cancer, wherein the treatment is by the method of any one of the preceding aspects. In some embodiments, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated separately. In other embodiments, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated together.

[0159] In a twenty-fifth aspect, the invention features the use of an anti-PD-L1 antagonist antibody in combination with an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject with lung cancer, wherein the treatment is by the method of any one of the preceding aspects. In some embodiments, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated separately. In other embodiments, the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated together.

[0160] In some embodiments of any of the aforementioned aspects, the subject is a human (e.g., an adult patient). [Brief explanation of the drawings]

[0161] [Figure 1] FIG. 1 is a schematic diagram of the study design showing subject selection, randomization to treatment groups, and treatment endpoint parameters. [Figure 2] Table showing slight imbalances in gender, race, and ECOG in baseline patient demographics divided by TPS (TPS ≥ 50% and TPS 1-49%) at the time of the interim analysis. [Figure 3] Table showing differences in treatment outcomes and study discontinuations across the PD-L1 TPS > 50% and PD-L1 TPS 1-49% populations and monotherapy and combination therapy groups at the time of the interim analysis. [Figure 4]This table shows the differences in best response (BOR) observed in the primary population (PD-L1 TPS ≥ 1%), PD-L1 TPS ≥ 50% population, and PD-L1 TPS 1-49% population receiving either atezolizumab monotherapy or tiragolumab and atezolizumab combination therapy at the time of the interim analysis. [Figure 5] 1 is a series of tables showing improved BOR for squamous cell carcinoma patients in the intent-to-treat (ITT) population at the time of interim analysis. [Figure 6]

[0023] Figure 1 is a table and accompanying graph showing the relative frequency and types of adverse events recorded for patients receiving either atezolizumab monotherapy or the combination of tiragolumab and atezolizumab at the time of the interim analysis. Adverse events marked with an asterisk were observed more frequently in the combination therapy group than in the monotherapy group. [Figure 7] 1 is a table showing that at the time of the interim analysis, observed treatment-related and immune-related adverse events (AEs) were imbalanced between treatment groups due to rash and IRR. [Figure 8] Figures 8A and 8B are a pair of tables showing subgroup analyses of objective response rate (ORR) at the time of analysis of the primary endpoint. [Figure 9A] Table showing the difference in ORR observed in the primary population (PD-L1 TPS ≥ 1%) receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of analysis of the primary endpoint. [Figure 9B] A pair of tables showing the difference in ORR observed in the PD-L1 TPS ≥ 50% and PD-L1 TPS 1-49% populations receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of analysis of the primary endpoint. [Figure 10] Figures 10A and 10B are a pair of tables showing subgroup analyses of progression-free survival (PFS) at the time of analysis of the primary endpoint. [Figure 11A]Graph and accompanying table showing the difference in PFS observed in the primary population (PD-L1 TPS ≥ 1%) receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 11B] Figure 1 is a graph and accompanying table showing the difference in PFS observed in the PD-L1 TPS ≥ 50% population receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 11C] Graph and accompanying table showing the difference in PFS observed in the PD-L1 TPS 1–49% population receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 12] Figures 12A and 12B are a pair of tables showing subgroup analyses of overall survival (OS) at the time of analysis of the primary endpoint. [Figure 13A] Graph and accompanying table showing the difference in OS observed in the primary population (PD-L1 TPS ≥ 1%) receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 13B] Figure 1 is a graph and accompanying table showing the difference in OS observed in the PD-L1 TPS ≥ 50% population receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 13C] Graph and accompanying table showing the difference in OS observed in the PD-L1 TPS 1–49% population receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of the primary endpoint analysis. [Figure 14] Figures 14A-14D are a series of waterfall plots showing the best percent change from baseline for the PD-L1 TPS ≥ 50% and PD-L1 TPS 1-49% populations receiving either atezolizumab monotherapy or the combination of tiragolumab and atezolizumab at the time of the primary endpoint analysis. [Figure 15] Figures 15A-15D are a series of graphs showing the percent change in the sum of the longest diameters of target lesions (SLD) for the PD-L1 TPS > 50% and PD-L1 TPS 1-49% populations receiving either atezolizumab monotherapy or tiragolumab in combination with atezolizumab at the time of analysis of the primary endpoint. [Figure 16] Figure 1 is a schematic diagram of the study design showing parameters for subject selection, randomization to treatment groups, and treatment endpoints. 1L = first-line; ALK = anaplastic lymphoma kinase; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; PS = Performance Status; Q3W = every 3 weeks; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; TPS = tumor proportion score. [Figure 17] Schematic diagram of the Phase III study design showing subject selection, randomization to treatment arms, and treatment endpoint parameters. ALK = anaplastic lymphoma kinase; atezo = atezolizumab; durva = durvalumab; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; iDMC = Independent Data Monitoring Committee; NSCLC = non-small cell lung cancer; OS = overall survival; PD-L1 = programmed death-ligand 1; PFS = progression-free survival; pos = positive; PS = performance status; R = randomized; tira = tiragolumab. [Figure 18] 1 is a schematic diagram of the dosing schedule for the experimental and comparative groups of the Phase III study. D = day; Q2W = every 2 weeks; Q4W = every 4 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0162] Detailed Description of the Invention I. General techniques The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, for example, widely used methodologies such as those described in: Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (F.M.A.usubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988); Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (JECellis, ed., 1998) Academic Press; Animal Cell Culture (RIFreshney), ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998) Plenum Press; DG Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells(JMMiller and MPCalos,eds.,1987);PCR: The Polymerase Chain Reaction,(Mullis et al.,eds.,1994);Current Protocols in Immunology(JEColigan et al.,eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Press,2000);Using Antibodies:A Laboratory Manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and JDCapra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VTDeVita et al., eds., JBLippincott Company, 1993). .

[0163] II. Definition It is understood that aspects and embodiments of the invention described herein include aspects and embodiments "comprising," "consisting of," and "consisting essentially of." As used herein, the singular forms "a," "an," and "the" include plural unless otherwise indicated.

[0164] The term "about," as used herein, refers to a normal error range for the respective value, which is readily understood by one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself. For example, a statement referring to "about X" includes a statement of "X."

[0165] As used interchangeably herein, the "amount," "level," or "expression level" of a biomarker refers to a detectable level in a biological sample. "Expression" generally refers to the process by which information (e.g., genetic coding information and / or epigenetic information) is converted into structures present and functioning in a cell. Thus, as used herein, "expression" can refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide). Fragments of a transcribed polynucleotide, a translated polypeptide, or a polynucleotide and / or polypeptide modification (e.g., post-translational modification of a polypeptide) should also be considered expressed, regardless of whether they are derived from a transcript generated by alternative splicing or a degraded transcript, or from post-translational processing of a polypeptide, for example, by proteolysis. "Expressed genes" include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (e.g., transfer and ribosomal RNA). The expression level can be measured by methods known to those skilled in the art and also disclosed herein. The expression level or amount of a biomarker (e.g., PD-L1) can be used to identify / characterize subjects with cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) who are likely to respond to or benefit from a particular treatment (e.g., a treatment comprising one or more administration cycles of an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist, e.g., an anti-PD-L1 antagonist antibody).

[0166] The presence and / or expression levels / amounts of the various biomarkers described herein in a sample can be analyzed by several methodologies, many of which are known in the art and understood by those of skill in the art, including immunohistochemistry ("IHC"), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting ("FACS"), MassARRAY, proteomics, quantitative blood-based assays (e.g., serum ELISA), biochemical enzyme activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), and smearing. These include, but are not limited to, any one of a wide variety of assays that can be performed by Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real-time PCR (qRT-PCR) and other amplification-based detection methods such as branched DNA, SISBA, TMA, RNA-Seq, microarray analysis, gene expression profiling, and / or serial analysis of gene expression ("SAGE"), as well as protein, gene, and / or tissue array analysis. Exemplary protocols for assessing the status of genes and gene products can be found, for example, in Parts 2 (Northern blotting), 4 (Southern blotting), 15 (immunoblotting), and 18 (PCR analysis) of Ausubel et al., eds., 1995, Current Protocols in Molecular Biology. Multiplexed immunoassays, such as those available from Rules Based Medicine or Meso Scale Discovery ("MSD"), can also be used.

[0167] As used herein, "TIGIT" or "T-cell immunoreceptor with Ig and ITIM domains" refers to any naturally occurring 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 resulting from processing within a 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, such as splice variants or allelic variants. An exemplary amino acid sequence of human TIGIT can be found, for example, at UniProt Accession No. Q495A1.

[0168] The term "PD-L1" or "programmed death-ligand 1," as used herein, unless otherwise indicated, refers to any native PD-L1 from any vertebrate source, including mammals, e.g., primates (e.g., humans), and rodents (e.g., mice and rats). PD-L1 is also known in the art as the CD274 molecule, CD274 antigen, B7 homolog 1, PDCD1 ligand 1, PDCD1LG1, PDCD1L1, B7H1, PDL1, programmed death-ligand 1, B7-H1, and B7-H. The term also encompasses naturally occurring variants of PD-L1, such as splice variants or allelic variants. An exemplary amino acid sequence of human PD-L1 can be found under UniProt Accession No. Q9NZQ7 (SEQ ID NO: 32).

[0169] The term "antagonist" is used in the broadest sense and includes any molecule that partially or completely blocks, inhibits, or neutralizes the biological activity of a native polypeptide disclosed herein. Suitable antagonist molecules specifically include antagonist antibodies or antibody fragments (e.g., antigen-binding fragments), fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, and the like. Methods for identifying antagonists of a polypeptide may include contacting the polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.

[0170] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with any one or more of its binding partners to eliminate T cell dysfunction resulting from signaling on the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

[0171] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with any one or more of its binding partners (e.g., PD-1 or B7-1). In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1 or B7-1). In one embodiment, the PD-L1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediated signaling through PD-L1, alleviating the dysfunctional state of dysfunctional T cells (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody. The term "anti-PD-L1 antagonist antibody" refers to an antibody, or antigen-binding fragment or variant thereof, that can bind to PD-L1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-L1 (e.g., prevent or interfere with signaling resulting from the interaction of PD-L1 with any one or more of its binding partners (e.g., PD-1, B7-1)). For example, an anti-PD-L1 antagonist antibody may reduce the negative costimulatory signal mediated by or through cell surface proteins expressed upon T lymphocyte-mediated signaling through PD-L1, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, an anti-PD-L1 antagonist antibody is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to PD-1 and / or B7-1.In one embodiment, the extent of binding of the anti-PD-L1 antagonist antibody to an unrelated, non-PD-L1 protein is less than about 10% of the binding of the antibody to PD-L1 as measured, for example, by radioimmunoassay (RIA). In certain embodiments, PD-L1 binding to the anti-PD-L1 antagonist antibody is ≦1 μM, ≦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. 10 -8 M~10 -13 M, e.g. 10 -9 M~10- -13 Dissociation constant (K D ). In certain embodiments, the anti-PD-L1 antagonist antibody binds to an epitope of PD-L1 that is conserved among PD-L1 from different species. In some embodiments, the anti-PD-L1 antagonist antibody is MPDL3280A (atezolizumab), MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In a particular aspect, the anti-PD-L1 antagonist antibody is atezolizumab, which is sold as TECENTRIQ™ in the WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN:List 74, Vol. 29, No. 3, 2015 (see page 387). In another aspect, the anti-PD-L1 antagonist antibody is MDX-1105. In another specific embodiment, the anti-PD-L1 antagonist antibody is MSB0015718C. In yet another specific embodiment, the anti-PD-L1 antagonist antibody is MEDI4736.

[0172] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1, PD-L2. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In particular aspects, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that mediated signaling through PD-1, rendering dysfunctional T cells less dysfunctional (e.g., enhancing the effector response to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

[0173] The term "anti-PD-1 antagonist antibody" refers to an antibody or antigen-binding fragment or variant thereof that can bind to PD-1 with sufficient affinity to substantially or completely inhibit the biological activity of PD-1 (e.g., abrogate or interfere with signaling resulting from the interaction of PD-1 with any one or more of its binding partners, such as PD-L1). For example, an anti-PD-1 antagonist antibody may reduce negative costimulatory signals mediated by or through cell surface proteins expressed upon T lymphocyte-mediated signaling through PD-1, rendering dysfunctional T cells less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, an anti-PD-1 antagonist antibody is a molecule that inhibits the binding of PD-1 to its binding partners. In a specific aspect, an anti-PD-1 antagonist antibody inhibits the binding of PD-1 to PD-L1. In one embodiment, the extent of binding of the anti-PD-1 antagonist antibody to an unrelated, non-PD-1 protein is less than about 10% of the binding of the antibody to PD-1, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, PD-1 binding to the anti-PD-1 antagonist antibody is ≦1 μM, ≦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. 10 -8 M~10 -13 M, e.g. 10 -9 M~10- -13 Dissociation constant (K D). In certain embodiments, the anti-PD-1 antagonist antibody binds to an epitope of PD-1 that is conserved among PD-1 of different species. In some embodiments, the anti-PD-1 antagonist antibody is nivolumab (MDX-1106) or pembrolizumab (formerly lambrolizumab (MK-3475). In some embodiments, the anti-PD-1 antagonist antibody is MDX-1106 (nivolumab). In some embodiments, the anti-PD-1 antagonist antibody is MK-3475 (pembrolizumab). In some embodiments, the anti-PD-1 antagonist antibody is ME In some cases, the anti-PD-1 antagonist antibody is D1-0680. In some cases, the anti-PD-1 antagonist antibody is PDR001 (spartalizumab). In some cases, the anti-PD-1 antagonist antibody is REGN2810 (cemiplimab). In some cases, the anti-PD-1 antagonist antibody is BGB-108. In other cases, the anti-PD-1 antagonist antibody is prorugolimab, camrelizumab, sintilimab, tislelizumab, or toripalimab.

[0174] Further examples of PD-1 axis binding antagonists include cemiplimab, prorugolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarimab, retifanlimab, spartalizumab, southernlimab, penprimimab, CS1003, HLX10, SCT-I10A, SHR-1316, CS1001, embafolimab, TQB2450, ZKAB001, LP-002, gimvelelimab, balstilimab, genolimuzumab, BI754091, cetrelimab, YBL-006, BAT1306, HX008, CX-072, IMC-001, KL-A167, budicalimab, and AMG. 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, APL-502, cosibelimab, lodapolimab, GS-4224, INCB086550, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, MAX-10181, RC98, BION-004, AM0001, CB201, ENUM 244C8, ENUM 388D4, AUNP-012, STI-1110, ADG104, AK-103, LBL-006, hAb21, AVA-004, PDL-GEX, INCB090244, KD036, KY1003, LYN192, MT-6035, VXM10, YBL-007, ABSK041, GB7003, JS-003, and HS-636.

[0175] The term "anti-TIGIT antagonist antibody" refers to an antibody or antigen-binding fragment or variant thereof that can bind to TIGIT with sufficient affinity to substantially or completely inhibit the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody may block signaling via PVR, PVRL2, and / or PVRL3 to restore a functional response to antigen stimulation by T cells from a dysfunctional state (e.g., proliferation, cytokine production, target cell killing). It will be understood by those skilled in the art that in some cases, an anti-TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain 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, without affecting or minimally affecting any of the other TIGIT interactions. In one embodiment, 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, for example, by radioimmunoassay (RIA). In certain embodiments, TIGIT binding to the anti-TIGIT antagonist antibody is ≦1 μM, ≦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. 10 -8 M~10 -13 M, e.g. 10 -9 M~10- -13 Dissociation constant (K D In certain embodiments, the anti-TIGIT antagonist antibody binds to an epitope on TIGIT that is conserved among TIGITs from different species, or an epitope on TIGIT that allows cross-species reactivity. In one embodiment, the anti-TIGIT antagonist antibody is tiragolumab.

[0176] As used herein, "administering" refers to a method of providing a subject with a dosage of a compound (e.g., an anti-TIGIT antagonist antibody or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody)) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-TIGIT antibody and / or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody)). The compounds and / or compositions used in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, transcutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intraperitoneally, subconjunctivally, intravesicularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, injection, infusion, continuous infusion, localized perfusion directly into target cells, by catheter, lavage, cream, or in a lipid composition. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0177] A "fixed" or "flat" dose of a therapeutic agent (e.g., an anti-TIGIT antagonist antibody and / or a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody)) herein refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed or flat dose may be expressed as a mg / kg dose or a mg / m 2 It is not provided as a dose, but as an absolute amount (eg, mg) of therapeutic agent.

[0178] As used herein, the terms "treatment" or "treating" refer to a clinical intervention designed to alter the natural history of the individual or cell being treated during the course of a clinical lesion. Desirable effects of treatment include slowing or reducing the rate of disease progression, ameliorating or alleviating the disease state, and ameliorating or improving prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are reduced or eliminated, including, but not limited to, a reduction in the proliferation (or destruction) of cancerous cells, a decrease in symptoms resulting from the disease, an improvement in the quality of life of those suffering from the disease, a reduction in the dose of other medications required to treat the disease, a delay in the progression of the disease, and / or an increase in the individual's survival time.

[0179] As used herein, "disease progression" refers to worsening of the disease. If the disease remains stable or improved, "a subject does not have disease progression." In some cases, disease progression is radiological disease progression, as defined, for example, by growth of existing lesions, new lesions, or recurrence of previously resolved lesions. Disease progression (e.g., radiological disease progression) can be determined by RECIST v1.1. In some embodiments, disease progression (or lack of disease progression) is confirmed by confirmatory scans and / or pathology.

[0180] As used herein, "in conjunction with" refers to the administration of one treatment modality in addition to another treatment modality. Thus, "in conjunction with" refers to the administration of one treatment modality to an individual before, during, or after the administration of another treatment modality.

[0181] A "disorder" or "disease" is any condition that would benefit from treatment, including, but not limited to, a disorder associated with some degree of abnormal cell proliferation, e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC).

[0182] The term "dysfunction" in the context of immune dysfunction refers to a state of decreased immune responsiveness to antigenic stimulation.

[0183] As used herein, the term "dysfunctional" also includes refractoriness or unresponsiveness to antigen recognition, particularly an impaired ability to translate antigen recognition into downstream T cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon), and / or target cell killing.

[0184] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies.More specific examples of such cancers include, but are not limited to, lung cancer, such as non-small cell lung cancer (NSCLC), including squamous or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC), adenocarcinoma of the lung, or squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); esophageal cancer; peritoneal cancer; hepatocellular carcinoma; gastric or peritoneal cancer, including gastrointestinal cancer and gastrointestinal stromal cancer. Neck cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer (e.g., urothelial bladder cancer (UBC), muscle-invasive bladder cancer (MIBC), and BCG-resistant non-muscle-invasive bladder cancer (NMIBC)); cancer of the urinary tract; liver cancer; breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC) that are estrogen receptor (ER-), progesterone receptor (PR-), and HER2 (HER2-) negative); colon cancer; rectal cancer; colorectal cancer; endometrial or uterine carcinoma; salivary gland carcinoma; kidney Cancer of the liver or kidney (e.g., renal cell carcinoma (RCC)); prostate cancer; vulvar cancer; thyroid cancer; liver carcinoma; anal carcinoma; penile carcinoma; melanoma (including superficial spreading melanoma, lentigo maligna melanoma, acral lentigo melanoma, and nodular melanoma); multiple myeloma and B-cell lymphoma (including low-grade / follicular non-Hodgkin's lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-resectable cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myoblastic leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as lipomatosis, edema (such as that associated with brain tumors), Meigs syndrome, abnormal blood vessel growth associated with brain tumors, head and neck cancer, and related metastases.

[0185] The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0186] "Tumor immunity" refers to the process by which tumors evade immune recognition and elimination. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor regression, and tumor clearance.

[0187] As used herein, "metastasis" refers to the spread of cancer from its primary site to other locations within the body. Cancer cells may break away from the primary tumor, infiltrate lymphatic and blood vessels, circulate through the bloodstream, and grow (metastasize) at distant foci within normal tissue elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process in which tumor cells break away from the primary tumor, travel through the bloodstream, and arrest at a distant site. At the new site, the cells establish a blood supply and may grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within tumor cells control this behavior, and interactions between tumor cells and host cells at distant sites are also important.

[0188] The term "anti-cancer therapy" refers to a therapy useful for treating cancer (e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). Examples of anti-cancer therapeutic agents include, but are not limited to, immunomodulators (e.g., agents that reduce or inhibit one or more immune co-inhibitory receptors (e.g., one or more immune co-inhibitory receptors selected from TIGIT, PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, and / or VISTA)), CTLA-4 antagonists, and the like, such as an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®)), an anti-TIGIT antagonist antibody, or a PD-1 These include axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies), or agents that upregulate or activate one or more immune co-stimulatory receptors (e.g., one or more immune co-stimulatory receptors selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and / or GITR), OX-40 agonists, such as OX-40 agonist antibodies), chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, and other agents for treating cancer. Combinations of these are also encompassed by the present invention.

[0189] The term "cytotoxic agent," as used herein, refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, e.g., nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof); and various anti-tumor or anti-cancer agents disclosed below.

[0190] A "chemotherapeutic agent" includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech / OSI Pharm), bortezomib (VELCADE®, Millennium), and erythropoietin (ERT). Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), Radicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer / Sugen)), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasteride (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib (TYKERB®, GSK572016, GlaxoSmithKline), Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, thiotepa, and CYTOXAN® cyclophosphamide; alkylating agents such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocuron, metoledopa, and uredopa; ethylenimines such as altretamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trimethylmelamine; and methylmelamines; acetogenins (especially bullatacin and bullatacinone); camptothecins (topotecan and irinotecan); bryostatin; kallystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase inhibitors, including finasteride and dutasteride;vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatins; aldesleukin, talc duocarmycin (including synthetic analogs, KW-2189 and CB1-TM1); eletarobin; pancratistatin; sarcodictine; spongistatin, chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorestamine, mechlorestamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trophosfamide, nitrogen mustards such as uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as endene antibiotics (e.g., calicheamicins, particularly calicheamicin γ1I and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphonates such as clodronate; espermycin; as well as neocarzinostatin chromophores and related enediyne antibiotic chromophores), aclacinomycins, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin), morpholinodoxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, and mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiosteine, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilosteine; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; and bestravsil ;Bisantrene;Edatraxate;Defofamine;Demecolcine;Diaziquione;Elfomitin;Elliptinium acetate;Epothilone;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Lonidynin;Maytansinoids such as maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidanmol;Nitraerin;Pentostatin;Fenameth;Pirarubicin;Losoxantrone;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK(R) polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquione; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veraculin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE® (cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (paclitaxel; Sanofi-Aventis): chlorambucil, GEMZAR® (gemcitabine), 6-thioguanine, mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16);Ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); nobandrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, and pharmaceutically acceptable salts, acids, and derivatives of any of the above;

[0191] Chemotherapeutic agents also include: (i) antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX®, tamoxifen citrate), raloxifene, droxifene, iodoxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) agents that inhibit estrogen secretion in the adrenal glands; (iii) aromatase inhibitors, which inhibit the enzyme aromatase, which regulates aromatase production, such as 4(5)-imidazole, aminoglutethimide, MEGASE® (megstrol acetate), AROMASIN® (exemestane; Pfizer), formestany, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) flutamide, nilutamide, bicalutamide, ribavirin ... antiandrogens such as euprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retionic acid, fenretinide, and troxacitabine (1,3-dioxolane nucleoside cytosine analogs); (iv) protein kinase inhibitors (e.g., anaplastic lymphoma kinase (Alk) inhibitors such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides Nucleotides, particularly agents that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, VAXID®; PROLEUKIN®, rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN®;ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0192] Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech / Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, celizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, nat ... tuzumab, nimotuzumab, norobizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pexelizumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, reslizumab, reslivizumab, rovelizumab, lupizumab, sibrotuzumab, siplizumab, sontuzumab, tacatatuzumab tetraxetan, tadoxizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab selmoreukin, tuxituuzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and interleukin-12 and anti-interleukin-12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), a human-sequence only, full-length IgG1λ antibody genetically engineered to recognize the p40 protein.

[0193] Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and inhibit or reduce the signaling activity of EGFR, alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Pat. No. 4,943,533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or cetuximab; ERBUTIX®) and reshaped human 225 (H225) (see WO 96 / 40210, Imclone Systems, Inc.). Inc.); the fully human EGFR-targeting antibody IMC-11F8 (Imclone); antibodies that bind type II mutant EGFR (U.S. Pat. No. 5,212,290); humanized and chimeric antibodies that bind EGFR, such as those described in U.S. Pat. No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (WO 98 / 50433, Abgenix / Amgen); EMD 55900 (Stragliotto et al., Eur. J. Cancer 32A:636-640 (1996); EMD7200 (matuzumab), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for EGFR binding (EMD / Merck); the human EGFR antibody, HuMax-EGFR (GenMab); the fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, and E7.6.3 and described in U.S. Pat. No. 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al., J. Biol. Chem. 279(29):30375-30384 (2004)).Anti-EGFR antibodies can be conjugated to cytotoxic agents to generate immunoconjugates (see, e.g., European Patent Application Publication No. 659,439A2, Merck Patent GmbH). EGFR antagonists can be conjugated to cytotoxic agents, such as those described in U.S. 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, and 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, and the following PCT publications: WO 98 / 14451, WO 98 / 50038, WO 99 / 09016, and WO 99 / 24037.Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA®, Genentech / OSI Pharmaceuticals), PD183805 (CI1033, 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), ZM105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca), BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim), Ingelheim), PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol), (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine), CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide), EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano- 7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butynamide) (Wyeth), AG1478 (Pfizer), AG1571 (SU5271, Pfizer), and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

[0194] Chemotherapeutic agents include "tyrosine kinase inhibitors," such as the EGFR-targeted drugs described in the preceding paragraph; inhibitors of insulin receptor tyrosine kinase, such as anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; oral selectivity inhibitors of ErbB2 receptor tyrosine kinase, such as HER2 inhibitors ... dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR overexpressing cells; lapatinib (GSK572016, available from Glaxo-SmithKline); oral HER2 and EGFR tyrosine kinase inhibitors; PKI-166 (available from Novartis); pan-HER inhibitors, such as canertinib (CI-1033, Pharmacia); Raf-1 inhibitors, such as ISIS, which inhibits Raf-1 signaling antisense drug ISIS-5132 available from Pharmaceuticals; non-HER-targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from GlaxoSmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, available from Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261, and CGP 62706;Pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine;Curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide);Tyrphostins containing a nitrothiophene moiety; PD-0183805 (Warner-Lambert); antisense molecules (e.g., those that bind to HER-encoding nucleic acids); quinoxalines (U.S. Pat. No. 5,804,396); tryphostin (U.S. Pat. No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors, e.g., CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis / Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo) SmithKline; CI-1033 (Pfizer); EKB-569 (Wyeth); semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or the following patent publications: U.S. Pat. No. 5,804,396, WO 1999 / 09016 (American Cyanamid), WO 1998 / 43960 (American Cyanamid), WO 1997 / 38983 (Warner Lambert), WO 1999 / 06378 (Warner Lambert), WO 1999 / 06396 (Warner Lambert), 1996 / 30347 (Pfizer, Inc.), 1996 / 33978 (Zeneca), 1996 / 3397 (Zeneca), and 1996 / 33980 (Zeneca).

[0195] Chemotherapeutic agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG (raw), bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, and interferon alfa. Also included are benzodiazepine-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate, and zoledronic acid, and pharmaceutically acceptable salts thereof.

[0196] Chemotherapeutic agents 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, and hydrocortisone-17. -butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; phenylalanine-glutamine-glycine (FEG) and its D-form (feG) (IMULAN) Immunoselective anti-inflammatory peptides (ImSAIDs) such as those from BioTherapeutics, LLC; antirheumatic drugs such as azathioprine, cyclosporine (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, minocycline, and sulfasalazine; etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), cetolithumab pegol (Cimzia), and golimumab (Sympo); tumor necrosis factor alpha (TNFα) blockers such as lebrikizumab (Lyskin), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T-cell costimulation blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; rhuMAb beta7 integrin blockers such as Beta7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane-bound heterotrimeric LTa1 / β2 blockers such as anti-lymphotoxin alpha (LTa); radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioactive isotopes of Lu);Various investigational drugs, such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, and farnesyltransferase inhibitors (L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, betulinic acid and its derivatives; autophagy inhibitors, such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin; podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTA®) Bisphosphonates such as bisphosphonates such as benzodiazepine (BQ-1), benzodiazepine (BQ-2), benzodiazepine (BQ-3), benzodiazepine (BQ-4), benzodiazepine (BQ-5), benzodiazepine (BQ-6), benzodiazepine (BQ-7), benzodiazepine (BQ-8), benzodiazepine (BQ-9), benzodiazepine (BQ-10), benzodiazepine (BQ-11), benzodiazepine (BQ-12), benzodiazepine (BQ-13), benzodiazepine (BQ-14), benzodiazepine (BQ-15), benzodiazepine (BQ-16), benzodiazepine (BQ-17), benzodiazepine (BQ-18), benzodiazepine (BQ-19), benzodiazepine (BQ-20), benzodiazepine (BQ-21), benzodiazepine (BQ-22), benzodiazepine (BQ-23), benzodiazepine (BQ-24), benzodiazepine (BQ-25), benzodiazepine (BQ-26), benzodiazepine (BQ-27), benzodiazepine (BQ-28), benzodiazepine (BQ-29), benzodiazepine (BQ-29), benzodiazepine (BQ-29), benzodiazepine (BQ-21), benzodiazepine (BQ-22), benzodiazepine (BQ-23), benzodiazepine (BQ-24), benzodiazepine (BQ-25), benzodiazepine (BQ-25), benzodiazepine (BQ-26), benzodiazepine (BQ-27), benzodiazepine (BQ-28), benzodiazepine (BQ-29), benzodiazepine (BQ-29), benzo 6636, SARASARTM); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of CHOP, which is an abbreviation for combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, which is an abbreviation for a treatment regimen using oxaliplatin in combination with 5-FU and leucovorin (ELOXATIN™);

[0197] Chemotherapeutic agents may also include nonsteroidal anti-inflammatory drugs with analgesic, antipyretic, and anti-inflammatory effects.NSAIDs include nonselective 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, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs may be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathy, ankylosing spondylosis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue injury, fever, intestinal obstruction, and renal colic.

[0198] As used herein, the terms "chemoradiotherapy," "chemoradiation therapy," and "CRT" are used interchangeably to refer to therapy that involves the administration of a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent) in combination with radiation therapy (RT). CRT can be combination CRT or sequential CRT.

[0199] The term "concomitant chemoradiotherapy" or "cCRT" is used herein to refer to the administration of chemotherapy and radiation therapy, where at least a portion of the administration of chemotherapy overlaps in time with at least a portion of the administration of radiation therapy. Thus, concomitant chemoradiotherapy (cCRT) includes a chemotherapy dosing regimen in which the administration of one or more chemotherapeutic agents continues after the administration of radiation therapy has ceased. Alternatively, cCRT includes radiation therapy in which the administration of radiation therapy continues after the administration of chemotherapy has ceased. Concomitant chemoradiotherapy differs from sequential chemoradiotherapy, which refers to the administration of chemotherapy beginning after the administration of radiation therapy has ceased, or the administration of radiation therapy beginning after the administration of chemotherapy has ceased. An "effective amount" of a compound, e.g., an anti-TIGIT antagonist antibody or a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), or a composition (e.g., a pharmaceutical composition) thereof, is at least the minimum amount necessary to achieve a desired therapeutic outcome, e.g., a measurable increase in overall survival or progression-free survival of a particular disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). An effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the antibody to elicit a desired response in the subject. An effective amount is also one in which the beneficial effects of the treatment outweigh any toxic or adverse effects of the treatment. Beneficial or desired results for prophylactic use include results such as elimination or reduction of the risk of, reduction in severity of, or delay in the onset of disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifest during the development of the disease.For therapeutic use, the beneficial or desired result may include a reduction in one or more symptoms resulting from the disease (e.g., cancer-related pain, reduction or delay of symptomatic skeletal-related events (SSEs), a reduction in or delay of symptoms resulting from the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC)). Clinical outcomes such as a reduction in symptoms according to the QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea, or general level of physical, emotional, cognitive, or social functioning; a reduction in pain as measured by, e.g., a 10-point Numerical Rating Scale (NRS) of Pain Severity (measured at worst); and / or a reduction in symptoms related to lung cancer according to the Health-Related Quality of Life (HRQoL) Questionnaire as assessed by the Symptoms in Lung Cancer (SILC) scale (e.g., time to deterioration (TTD) in cough, dyspnea, and chest pain); an increase in the quality of life of a person with the disease; a reduction in the dose of another drug needed to treat the disease; an enhancement of the effect of another drug, such as by targeting; a delay in disease progression (e.g., progression-free survival or radiological progression-free survival (rPFS)); definite clinical progression (e.g., progression of cancer-related pain, symptomatic skeletal-related events, Eastern Cooperative Oncology Group (ECOG) Performance Indicators). These include delaying a decline in the patient's performance status (PS) (e.g., how the disease affects the patient's ability to perform daily activities, and / or the initiation of subsequent systemic anti-cancer therapy), and / or delaying the time to lung-specific antigen progression), and / or extending survival. In the case of cancer or tumors, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing to some extent, or preferably stopping) cancer cell invasion into peripheral organs, inhibiting (i.e., slowing to some extent, or preferably stopping) tumor metastasis, inhibiting tumor growth to some extent, and / or alleviating to some extent one or more symptoms associated with the disorder. An effective amount may be administered once or multiple times. In the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment.As is understood in the clinical field, 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. Thus, an "effective amount" can be considered in the context of administration of one or more therapeutic agents, and a single agent can be viewed as being given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0200] "Immunogenicity" refers to the ability of a particular substance to induce an immune response. Tumors are immunogenic, and enhancing tumor immunogenicity helps the immune response eliminate tumor cells. Examples of enhancing tumor immunogenicity include, but are not limited to, treatment with TIGIT and / or PD-L1 antagonists (e.g., anti-TIGIT antagonist antibodies and / or anti-PDL-1 antagonist antibodies).

[0201] An "individual response" or "response" includes, but is not limited to, (1) some inhibition (including slowing and complete halting) of disease progression (e.g., progression of cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)); (2) reduction in tumor size; (3) suppression (i.e., reduction, slowing, or complete halt) of cancer cell invasion into adjacent peripheral organs and / or tissues; (4) inhibition (i.e., reduction, slowing, or complete halt) of metastasis. , slowing, or complete cessation); (5) some alleviation of one or more symptoms associated with a disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)); (6) increased or prolonged survival, including overall survival and progression-free survival; and / or (9) reduced mortality at a given time point after treatment.

[0202] As used herein, "complete response" or "CR" refers to the disappearance of all target lesions.

[0203] As used herein, "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of target lesions, referenced to the baseline SLD.

[0204] As used herein, "objective response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0205] As used herein, "duration of objective response" (DOR) is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause within 30 days of the last dose of treatment, whichever occurs first.

[0206] A "durable response" refers to a sustained effect on reducing tumor growth after cessation of treatment. For example, the tumor size may remain the same or may be smaller compared to the size at the beginning of the administration period. In some embodiments, the durable response has a duration at least equal to the treatment period, at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0207] As used herein, the term "survival" refers to the patient being alive, and includes overall survival and progression-free survival.

[0208] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are alive after a particular period of time, such as 1 year or 5 years from the time of diagnosis or treatment.

[0209] As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete or partial remission, as well as the amount of time a patient experiences stable disease.

[0210] As used herein, "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify as PR nor sufficient increase to qualify as PD, based on the smallest SLD since treatment initiation.

[0211] As used herein, "progressive disease" or "PD" refers to at least a 20% increase in the SLD of a target lesion, relative to the smallest SLD recorded, since the start of treatment or the presence of one or more new lesions.

[0212] As used herein, "delaying the progression" of a disorder or disease means postponing, impeding, delaying, preventing, stabilizing, and / or postponing the onset of the disease or disorder (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). The delay can be of varying duration depending on the disease history and / or the subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease. For example, in late-stage cancer, the development of central nervous system (CNS) metastases can be delayed.

[0213] As used herein, the term "reducing or inhibiting cancer recurrence" means reducing or inhibiting the recurrence of a tumor or cancer, or the progression of a tumor or cancer.

[0214] "Reduce or inhibit" refers to the ability to result in an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more. Reduction or inhibition can refer to the symptoms of the disorder being treated (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the presence or size of metastases, or the size of the primary tumor.

[0215] By "prolonged survival" is meant an increase in overall survival or progression-free survival in treated patients relative to untreated patients (e.g., relative to patients not treated with the drug), or relative to patients who do not express the biomarker at the specified level, and / or relative to patients treated with an approved anti-tumor agent. Objective response refers to a measurable response, including a complete response (CR) or partial response (PR).

[0216] The terms "detect" and "detection" are used herein in the broadest sense to include both qualitative and quantitative measurements of a target molecule. Detection includes simply identifying the presence of a target molecule in a sample, as well as determining whether the target molecule is present in a sample at detectable levels. Detection can be direct or indirect.

[0217] As used herein, "PD-L1-positive tumor cell fraction" refers to the percentage of viable tumor cells that exhibit partial or complete membrane staining (excluding cytoplasmic staining) of any intensity relative to all viable tumor cells present in a sample following staining of the sample in the context of an immunohistochemistry (IHC) assay, e.g., an IHC assay to stain PD-L1 using antibodies SP263, 22C3, SP142, or 28-8. Thus, the PD-L1-positive tumor cell fraction can be calculated using the PD-L1 IHC SP263 (Ventana) assay, for example, by the formula: PD-L1-positive tumor cell fraction = (number of PD-L1-positive tumor cells) / (total number of PD-L1-positive and PD-L1-negative tumor cells), where PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) is excluded from evaluation and scoring. It will be understood that any given diagnostic PD-L1 antibody may correspond to a particular IHC assay protocol and / or scoring terminology that can be used to obtain the PD-L1-positive tumor cell fraction. For example, the PD-L1-positive tumor cell fraction can be obtained from tumor cell samples stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW® detection on a Benchmark ULTRA, EnVision Flex on an AutostainerLink 48, OPTIVIEW® detection and amplification on a Benchmark ULTRA, or EnVision Flex on an AutostainerLink 48, respectively. In another example, the PD-L1 IHC 22C3 pharmDx assay (Dako) can be used according to the formula above to calculate the PD-L1-positive tumor cell fraction. Those skilled in the art will understand that sensitivity can vary between different PD-L1 antibodies used in IHC assays. For example, only about 64% of samples meeting the 1% TC or 25% TC threshold defined by staining with 28-8 or 22C3 and SP263, respectively, meet the threshold when stained using SP142.Hirsch et al., Journal of Thoracic Oncology 2016, 12(2):208-222. As used herein, the terms PD-L1 positive tumor cell fraction and "tumor proportion score" (TPS) are used interchangeably.

[0218] As used herein, a "Ventana SP263 IHC assay" is performed in accordance with the Ventana PD-L1 (SP263) Assay Package Insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0219] As used herein, a "Ventana SP142 IHC assay" is performed in accordance with the Ventana PD-L1 (SP142) Assay Package Insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

[0220] As used herein, a "pharmDx 22C3 IHC assay" is performed in accordance with the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

[0221] As used herein, "tumor-infiltrating immune cells" refers to any immune cells present in a tumor or a sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stromal cells (e.g., fibroblasts), or any combination thereof. Such tumor-infiltrating immune cells may be, for example, T lymphocytes (such as CD8+ T lymphocytes and / or CD4+ T lymphocytes), B lymphocytes, or other myeloid cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.

[0222] The term "biomarker," as used herein, refers to an indicator, e.g., a predictive, diagnostic, and / or prognostic indicator, that can be detected in a sample. A biomarker can serve as an indicator of a particular subtype of a disease or disorder characterized by specific molecular, pathological, histological, and / or clinical features (e.g., cancer, e.g., lung cancer, e.g., NSCLC, e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)). In some embodiments, the biomarker is a gene. Biomarkers include, but are not limited to, polypeptide, polynucleotide (e.g., DNA, and / or RNA), polynucleotide copy number changes (e.g., DNA copy number), polypeptide and polynucleotide modifications (e.g., post-translational modifications), carbohydrate, and / or glycolipid-based molecular markers. In some embodiments, the biomarker is PD-L1.

[0223] The term "antibody" includes monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), and antibody fragments, including antigen-binding fragments such as Fab, F(ab'), and Fv. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein.

[0224] The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies consist of five basic heterotetrameric units, together with an additional polypeptide called a J chain, and contain ten antigen-binding sites, whereas IgA antibodies consist of two to five basic four-chain units, which can polymerize to form multivalent aggregates with the J chain. In the case of IgG, the four-chain unit is generally approximately 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, whereas the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain contains a variable domain (V) at its N-terminus. H ), followed by three constant domains (C H ), and four C for μ and ε isotypes H Each L chain has a variable domain (V L ) followed by a constant domain at the opposite end. L is V H It is aligned with C L is the first constant domain of the heavy chain (C H 1). Particular amino acid residues are thought to form an interface between the light-chain variable domain and the heavy-chain variable domain. V H and V Land pair together to form a single antigen-binding site. For the structure and properties of various classes of antibodies, see, for example, page 71 and chapter 6 of Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994. Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of the constant domain (CH) of their heavy chains, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each with a heavy chain designated α, δ, ε, γ, and μ. The gamma and alpha classes are further divided into subclasses based on relatively minor differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1, and IgA2.

[0225] The term "hypervariable region" or "HVR" refers to the region of an antibody variable domain that is hypervariable in sequence and / or forms structurally defined loops. Antibodies typically contain six HVRs: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In natural antibodies, H3 and L3 exhibit the highest diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring superior specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0226] Several HVR delineations are used and encompassed herein. Kabat complementarity-determining regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia instead refers to the location of structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent a compromise between Kabat HVRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35 H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H53-H55 H47-H58 H3 H95-H102 H95-H102 H96-H101 H93-H101

[0227] HVRs may include the following "extended HVRs": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al. (see above) for each of these definitions.

[0228] The phrases "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering scheme used for the heavy or light chain variable domains in the antibody organization 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, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat, etc.). The Kabat numbering of residues can be determined for a given antibody by alignment of the antibody's sequence with the "standard" Kabat-numbered sequence at the regions of homology.

[0229] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed throughout the variable domains. Rather, it is concentrated in three segments called hypervariable regions (HVRs) in both the light- and heavy-chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Natural heavy- and light-chain variable domains each contain four FR regions that largely adopt a beta-sheet configuration, connected by three HVRs that form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs within each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0230] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains may be referred to as "VH" and "VL," respectively. These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding site. "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0231] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically, a whole antibody includes one having heavy and light chains, including an Fc region. The constant domains may be native-sequence constant domains (e.g., human native-sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions. An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see Example 2 of U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10):1057-1062

[1995] ).

[0232] (See, e.g., ); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies yields two identical antigen-binding fragments called "Fab" fragments and a residual "Fc" fragment, a designation reflecting the ability to readily crystallize. The Fab fragment contains the variable region domain of the heavy chain (V H ), and the first constant domain of one heavy chain (C H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment, which roughly corresponds to two disulfide-linked Fab fragments with different antigen-binding activities and is still capable of cross-linking antigen. Fab' fragments contain one or more cysteines from the antibody hinge region, and the C HF(ab')2 antibody fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residues of the constant domains bear free thiol groups. F(ab')2 antibody fragments are produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0233] The Fc fragment contains the carboxy termini of both heavy chains held together by disulfides. The effector functions of the antibody are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain cell types.

[0234] "Functional fragments" of antibodies of the present invention include portions of intact antibodies, generally including the antigen-binding or variable region of the intact antibody, or the Fc region of the antibody that retains or has modified FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0235] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable domain in tight, non-covalent association. The folding of these two domains generates six hypervariable loops (three loops each from the H and L chains) that contribute antigen-binding amino acid residues and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind to antigen, albeit with lower affinity than the entire binding site.

[0236] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is a Fv consisting of V fragments joined together into a single polypeptide chain. H and V LPreferably, the sFv polypeptide is an antibody fragment containing the V H Domains and V L The sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-Verlag, New York, pp. 269-315 (1994).

[0237] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain and includes native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition can include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system (also referred to as 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.

[0238] The term "diabody" refers to a diabody that combines V domains to achieve inter-chain but not intra-chain V domain pairing, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domains and V L This refers to small antibody fragments prepared by constructing sFv fragments (see previous paragraph) with a short linker (approximately 5-10 residues) between the domains. Bispecific diabodies are small antibody fragments prepared by constructing sFv fragments (see previous paragraph) with a short linker (approximately 5-10 residues) between the domains. H Domain and V L Diabodies are heterodimers of two "crossover" sFv fragments in which the domains are present on different polypeptide chains. Diabodies are described in more detail in, for example, EP 404,097, WO 93 / 11161, and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993).

[0239] As used herein, monoclonal antibodies specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies, in which the antigen-binding region of the antibody is derived from an antibody produced, for example, by immunizing macaque monkeys with the antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0240] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0241] "Affinity" refers to the strength of the total non-covalent interactions between a single binding site of a molecule (e.g., an antibody, e.g., TIGIT or PD-L1) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0242] "Fc receptor" or "FcR" refers to a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors), including receptors of the FcγRI, FcγRII, and FcγRIII subclasses (including allelic variants and alternatively spliced ​​forms of these receptors). FcγRII receptors include FcγRIIA (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those identified in the future, are encompassed by the term "FcR" herein.

[0243] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by a human and / or an antibody produced using any of the techniques for producing human antibodies disclosed herein. This definition of a human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, that have been engineered to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via human B cell hybridoma technology.

[0244] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from an HVR (defined below) of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in either the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence and all or substantially all of the FR regions correspond to those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions which improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FRs will typically be no more than six in the H chain and no more than three in the L chain. The humanized antibody also optionally comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0245] The term "isolated antibody," as used to describe various antibodies disclosed herein, refers to an antibody that has been identified, separated, and / or recovered from the cell or cell culture in which it is expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). In preferred embodiments, antibodies are purified (1) sufficiently to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibodies include antibodies in situ within recombinant cells, since at least one component of the polypeptide's natural environment will not be present. Ordinarily, however, isolated polypeptides will be prepared by at least one purification step.

[0246] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies within the population are identical except for naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation), which may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they are synthesized by a hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be produced by, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2002) nded. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567), phage display technology (see, e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004)), and techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893, WO 1996 / 34096, WO 1996 / 33735, WO 1991 / 10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent No. 5,545,807; U.S. Patent No. 5,545,806; U.S. Patent No. 5,569,825; U.S. Patent No. 5,625,126; U.S. Patent No. 5,633,425; 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813(1994);Fishwild et al.,Nature Biotechnol.14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0247] As used herein, the terms "bind," "specifically bind to," or "specific for" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody that specifically binds to a target (which may be an epitope) is one that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than it binds to other targets. In one embodiment, the extent to which an antibody binds to an unrelated target is less than about 10% of the binding of the antibody to the target, as measured by radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (K) of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, or ≦0.1 nM. D In certain embodiments, the antibody specifically binds to an epitope on a protein that is conserved among proteins from different species. In another embodiment, specific binding can include, but is not required to include, exclusive binding. As used herein, the term "specific binding" refers to, for example, binding to an epitope on a protein that is conserved among proteins from different species. -4 M or less, or 10 -5 M or less, or 10 -6 M or less, or 10 -7 M or less, or 10 -8 M or less, or 10 -9 M or less, or 10 -10 M or less, or 10 -11 M or less, or 10 -12 K against targets less than or equal to M D , or 10 -4 M~10 -6 M or 10 -6 M~10 -10 M or 10 -7 M~10 -9 K in the M rangeD As will be appreciated by those skilled in the art, affinity and K D The values ​​are inversely correlated: a high affinity for the antigen corresponds to a low K D In one embodiment, the term "specific binding" refers to binding when a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptides or polypeptide epitopes.

[0248] The terms "substantially reduced" or "substantially different," as used herein, refer to a sufficiently high difference between two numerical values ​​(typically one associated with a molecule and the other associated with a reference / comparator molecule) such that one of skill in the art can easily determine that the difference between these two values ​​is sufficient to determine the degree of specificity of such values ​​(e.g., K D A difference between two such values ​​will be considered statistically significant with respect to a biological characteristic measured by a reference / comparator molecule (value). The difference between such two values ​​can be, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50% as a function of the value of the reference / comparator molecule.

[0249] The terms "substantially similar" or "substantially the same," as used herein, refer to a sufficiently high similarity between two numerical values ​​(typically one associated with a molecule and the other associated with a reference / comparison molecule) such that one of ordinary skill in the art would recognize the difference between these two values ​​as a significant difference between such values ​​(e.g., K D In some cases, a difference between two such values ​​may be considered to have little or no biological and / or statistical significance with respect to a biological characteristic measured by a reference / comparator value (e.g., a difference of less than about 50%, less than about 40%, less than about 30%, less than about 20%, and / or less than about 10%).

[0250] "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 to those in the reference polypeptide, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, 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 sequence alignment, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 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 can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (alternatively, it may be written as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y where X is the number of amino acid residues scored as identical by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A differs from the length of amino acid sequence B, the % amino acid sequence identity of A to B will differ from the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values ​​used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0251] As used herein, "subject" or "individual" means a mammal, including, but not limited to, a human or non-human mammal, such as a cow, horse, dog, sheep, or cat. In some embodiments, the subject is a human. A patient is also a subject herein.

[0252] As used herein, the term "sample" refers to a composition obtained from or derived from a subject and / or individual of interest that contains cellular and / or other molecular entities to be characterized and / or identified, e.g., based on physical, biochemical, chemical, and / or physiological properties. For example, the phrases "tumor sample," "disease sample," and variations thereof refer to any sample obtained from a subject of interest that is expected to contain or known to contain the cellular and / or molecular entities to be characterized. In some embodiments, the sample is a tumor tissue sample (e.g., a lung cancer tumor tissue sample, e.g., an NSCLC tumor tissue sample, e.g., a squamous or non-squamous NSCLC tumor tissue sample, e.g., a locally advanced unresectable NSCLC tumor tissue sample (e.g., a stage IIIB NSCLC tumor tissue sample) or a recurrent or metastatic NSCLC tumor tissue sample (e.g., a stage IV NSCLC tumor tissue sample). Other samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymphatic fluid, synovial fluid, follicular fluid, semen, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebrospinal fluid, saliva, sputum, tears, sweat, mucus, stool, tumor lysates, and tissue culture media, tissue extracts, e.g., homogenized tissue, cell extracts, and combinations thereof.

[0253] As used herein, a "reference sample," "reference cell," "reference tissue," "control sample," "control cell," or "control tissue" refers to a sample, cell, tissue, standard, or level used for comparison purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or unaffected part of the body (e.g., tissue or cells) of the same subject. For example, a healthy and / or unaffected cell or tissue adjacent to a diseased cell or tissue (e.g., a cell or tissue adjacent to a tumor). In another embodiment, the reference sample is obtained from untreated tissue and / or cells of the same subject's body. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or unaffected part of the body (e.g., tissue or cells) of a subject that is not the subject. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from untreated tissue and / or cells of the body of an individual that is not the subject.

[0254] Unless otherwise indicated, the term "protein," as used herein, refers to any naturally occurring protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice, rats), unless otherwise specified. The term encompasses "full-length," unprocessed proteins, and any form of a protein that results from processing within a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0255] As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA containing single- and double-stranded regions, single- and double-stranded RNA, and RNA containing single- and double-stranded regions, and hybrid molecules containing DNA and RNA that may contain single or, more typically, double strands, or may contain single and double-stranded regions. Additionally, as used herein, the term "polynucleotide" refers to triple-stranded regions containing RNA or DNA, or both RNA and DNA. The strands within such regions may be from the same molecule or from different molecules. These regions may include all of one or more of these molecules, but more typically include only some regions of these molecules. One of the molecules in the triple helix region is often an oligonucleotide. The terms "polynucleotide" and "nucleic acid" specifically include mRNA and cDNA.

[0256] A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label. Other types of modifications include, for example, "caps," substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those containing intercalating agents (e.g., acridine, psoralens, etc.), those containing chelating agents (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylating agents, those with modified linkages (e.g., alpha anomeric nucleic acids, etc.), and unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present in the sugar may be replaced with, for example, a phosphonate group, a phosphate group, protected with a standard protecting group, or activated to provide for additional linkage to an additional nucleotide, or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH may be phosphorylated or substituted with an amine or an organic capping group moiety of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups. Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such as arabinose, xylose, or lyxose, pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and abasic nucleoside analogs, such as methyl riboside.One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), "(O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C) (optionally containing an ether (-O-) linkage), aryl, alkenyl, cycloalkyl, cycloalkenyl, or araldyl. Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.

[0257] As used herein, the term "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid; 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 as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0258] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith.

[0259] The term "pharmaceutical formulation" refers to a preparation in which the biological activity of the active ingredient contained in the preparation is in a form such that it is effective, and which does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0260] III. Treatment Methods and Uses Provided herein are methods and uses for treating cancer in a subject (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)), the methods and uses comprising administering to the subject one or more administration cycles effective amounts of an anti-TIGIT antagonist antibody and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody).

[0261] Dosage Regimen and Administration The therapeutic methods and uses of the invention described herein, in one aspect, involve administering one or more administration cycles of PD-L1 therapy to a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 tumor cell fraction of 30% or greater (e.g., 50% or greater). The present invention relates to a method for treating a subject with PD-1 axis-binding antagonists, comprising administering an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), wherein the treatment results in a complete response (CR) or partial response (PR) compared to treatment with the PD-1 axis-binding antagonist without the anti-TIGIT antagonist antibody, thereby treating the subject. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered every 2 weeks (e.g., on days 1 and 15 of each 28-day administration cycle), every 3 weeks (e.g., on day 1 of each 21-day administration cycle), or every 4 weeks (e.g., on day 1 of each 28-day administration cycle).

[0262] In some aspects, the therapeutic methods and uses of the invention described herein comprise administering to a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., stage III NSCLC) who has previously received combined chemoradiotherapy (cCRT) for lung cancer and has not had disease progression after cCRT, one or more administration cycles of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), thereby treating the subject. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered every 2 weeks (e.g., on days 1 and 15 of each 28-day administration cycle), every 3 weeks (e.g., on day 1 of each 21-day administration cycle), or every 4 weeks (e.g., on day 1 of each 28-day administration cycle).

[0263] In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg, e.g., about For example, a fixed dose of about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some cases, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) administered in combination therapy (e.g., combination treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab)) may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as monotherapy.

[0264] In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 10 mg to about 1000 mg (e.g., about 20 mg to about 1000 mg, e.g., about 50 mg to about 900 mg, e.g., about 100 mg to about 850 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 600 mg, e.g., about 400 mg to about 500 mg, e.g., about 405 mg to about 450 mg, e.g., about 410 mg to about 430 mg, e.g., about 420 mg) every two weeks (Q2W). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) 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).

[0265] In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 200 mg to about 2000 mg (e.g., about 200 mg to about 1600 mg, e.g., about 250 mg to about 1600 mg, e.g., about 300 mg to about 1600 mg, e.g., about 400 mg to about 1 500 mg, for example, about 500 mg to about 1400 mg, for example, about 600 mg to about 1200 mg, for example, about 700 mg to about 1100 mg, for example, about 800 mg to about 1000 mg, for example, about 800 mg to about 900 mg, for example, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890 or about 900 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 840 mg every 4 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 4 weeks).

[0266] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, e.g., about 200 mg to about 1600 mg, e.g., about 300 mg to about 1600 mg, e.g., about 400 mg to about 1600 mg, e.g., about 500 mg to about 1600 mg, e.g., about 600 mg to about 1600 mg, e.g., about 700 mg to about 1600 mg, e.g., about 800 mg) every three weeks. In some cases, the effective dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some cases, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1200 mg every three weeks.

[0267] In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks (e.g., about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks). In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every three weeks, and the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks.

[0268] In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks.

[0269] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 20 mg to about 1600 mg (e.g., about 40 mg to about 1500 mg, e.g., about 200 mg to about 1400 mg, e.g., about 300 mg to about 1400 mg, e.g., about 400 mg to about 1400 mg, For example, about 500 mg to about 1300 mg, for example, about 600 mg to about 1200 mg, for example, about 700 mg to about 1100 mg, for example, about 800 mg to about 1000 mg, for example, about 800 mg to about 900 mg, for example, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg. In some cases, the effective amount of the PD-1 axis binding antagonist is a fixed dose of atezolizumab of about 840 mg / 2 weeks (e.g., 840 mg ± 10 mg, for example, 840 mg ± 6 mg, for example, 840 mg ± 5 mg, for example, 840 mg ± 3 mg, for example, 840 mg ± 1 mg, for example, 840 mg ± 0.5 mg, for example, 840 mg every 2 weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 800 mg avelumab every two weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 240 mg nivolumab every two weeks.

[0270] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 500 mg to about 3000 mg (e.g., about 500 mg to about 2800 mg, e.g., about 600 mg to about 2700 mg, e.g., about 650 mg to about 2600 mg, e.g., about 700 mg to about 2500 mg, e.g., about 1000 mg to about 2400 mg, e.g., about 1100 mg to about 2300 mg, e.g., about 1200 mg to about 2200 mg, e.g., about 1300 mg to about 2400 mg) every 4 weeks (Q4W). A fixed dose of about 2100 mg, for example, about 1400 mg to about 2000 mg, for example, about 1500 mg to about 1900 mg, for example, about 1600 mg to about 1800 mg, for example, about 1620 mg to about 1700 mg, for example, about 1640 mg to about 1690 mg, for example, about 1660 mg to about 1680 mg, about 1680 mg, for example, about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks (e.g., 1680 mg ± 10 mg, e.g., 1680 ± 6 mg, e.g., 1680 ± 5 mg, e.g., 1680 ± 3 mg, e.g., 1680 ± 1 mg, e.g., 1680 ± 0.5 mg, e.g., 1680 mg every four weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 480 mg of nivolumab every four weeks.

[0271] In some cases, the fixed dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the PD-1 axis-binding antagonist administered as monotherapy.

[0272] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 50 mg / kg of subject body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2. The dose is 5 mg / kg to about 30 mg / kg, for example, about 5 mg / kg to about 25 mg / kg, for example, about 10 mg / kg to about 20 mg / kg, for example, about 12.5 mg / kg to about 15 mg / kg, for example, about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, for example, about 15 mg / kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 15 mg / kg of subject body weight (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg) every two weeks, every three weeks, or every four weeks. For example, about 5 mg / kg to about 15 mg / kg, for example, about 7.5 mg / kg to about 15 mg / kg, for example, about 10 mg / kg to about 15 mg / kg, for example, about 12.5 mg / kg to about 15 mg / kg, for example, about 14 mg / kg to about 15 mg / kg, for example, about 15±1 mg / kg, for example, about 15±0.5 mg / kg, for example, about 15±0.2 mg / kg, for example, about 15±0.1 mg / kg, for example, about 15 mg / kg. In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 15 mg / kg administered every three weeks. In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 10 mg / kg administered every two weeks.In some cases, an effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a dose of about 20 mg / kg administered every two weeks. In some cases, the dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) can be reduced compared to the standard dose of the PD-1 axis-binding antagonist administered as monotherapy.

[0273] In any of the methods and uses of the present invention, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) may be administered in one or more administration cycles (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, or 50 or more administration cycles). In some cases, administration cycles of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) continue until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost. In some cases, the length of each administration cycle is about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days).

[0274] In some cases, the length of the dosing cycle is about 21 days. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab) is intravenously administered at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., a fixed dose of about 600 mg every 3 weeks). Similarly, in some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, in some instances, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., a fixed dose of about 1200 mg every 3 weeks). In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (e.g., days 1±3) of each administration cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 600 mg), and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 1200 mg).

[0275] In some cases, the length of the dosing cycle is about 28 days. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 420 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 420 mg every two weeks). Similarly, in some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about days 1 and 15 (e.g., days 1±3 and 15±3) of each dosing cycle. For example, in some instances, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 840 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 840 mg every two weeks). In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about days 1 and 15 of each administration cycle (e.g., days 1±3 and 15±3). For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 420 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 420 mg every two weeks), and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 840 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 840 mg every two weeks).

[0276] In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1±3) of each 28-day administration cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 840 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 420 mg every 4 weeks). Similarly, in some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about day 1 (e.g., day 1±3) of each administration cycle. For example, in some instances, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1680 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 840 mg every 4 weeks). In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (e.g., days 1±3) of each administration cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 840 mg on day 1 of each 28-day cycle (i.e., every 4 weeks at a fixed dose of about 820 mg), and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1680 mg on day 1 of each 28-day cycle (i.e., every 4 weeks at a fixed dose of about 1680 mg).

[0277] In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0278] In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to the subject before the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)). In some cases, for example, the method includes an intervening first observation period after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis-binding antagonist. In some cases, the method further includes a second observation period after administration of the PD-1 axis-binding antagonist. In some cases, the method includes both a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis-binding antagonist. In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30±10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15±10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist during the first and second observation periods, respectively.

[0279] In other cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some cases, for example, the method includes an intervening first observation period after administration of the PD-1 axis-binding antagonist and before administration of the anti-TIGIT antagonist antibody. In some cases, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period after administration of the PD-1 axis-binding antagonist and a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30±10 minutes after administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15±10 minutes after administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0280] In other cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 (atezolizumab) antagonist antibody) are administered simultaneously to the subject. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), the method includes an observation period. In some cases, the observation period is about 30 minutes to about 60 minutes in length. When the observation period is about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) during the observation period, about 30±10 minutes after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody. Where the observation period is about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) during the observation period, approximately 15±10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody.

[0281] In another aspect, the present invention provides a method of treating a subject with NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater) by administering to the subject a fixed dose of 600 mg every three weeks and a fixed dose of 1200 mg every three weeks of an anti-TIGIT antagonist antibody for one or more administration cycles, wherein the anti-TIGIT antagonist antibody has a VH domain having the amino acid sequence of SEQ ID NO: 17 or 18 and a VL domain having the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR and / or (b) results in increased PFS, as described in further detail below, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0282] In another aspect, the invention provides a method of treating a subject with NSCLC (e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater) by administering to the subject a fixed dose of 600 mg tiragolumab every 3 weeks and a fixed dose of 1200 mg atezolizumab every 3 weeks for one or more dosing cycles, wherein the treatment (a) results in a CR or PR and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0283] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis-binding antagonist (e.g., tiragolumab) for use in a method of treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) that has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater (e.g., 50% or greater). For example, an anti-PD-L1 antagonist antibody (e.g., atezolizumab), the method comprises administering to a subject one or more administration cycles of an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), wherein the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist antibody. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0284] In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg, e.g., about For example, a fixed dose of about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some cases, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered in combination therapy (e.g., combination treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab)) and may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

[0285] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, e.g., about 200 mg to about 1600 mg, e.g., about 300 mg to about 1600 mg, e.g., about 400 mg to about 1600 mg, e.g., about 500 mg to about 1600 mg, e.g., about 600 mg to about 1600 mg, e.g., about 700 mg to about 1600 mg, e.g., about 800 mg) every three weeks. In some cases, the effective dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some cases, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1200 mg every three weeks.

[0286] In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks (e.g., about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks). In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every three weeks, and the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks.

[0287] In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks.

[0288] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 20 mg to about 1600 mg (e.g., about 40 mg to about 1500 mg, e.g., about 200 mg to about 1400 mg, e.g., about 300 mg to about 1400 mg, e.g., about 400 mg to about 1400 mg, For example, about 500 mg to about 1300 mg, for example, about 600 mg to about 1200 mg, for example, about 700 mg to about 1100 mg, for example, about 800 mg to about 1000 mg, for example, about 800 mg to about 900 mg, for example, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg. In some cases, the effective amount of the PD-1 axis binding antagonist is a fixed dose of atezolizumab of about 840 mg / 2 weeks (e.g., 840 mg ± 10 mg, for example, 840 mg ± 6 mg, for example, 840 mg ± 5 mg, for example, 840 mg ± 3 mg, for example, 840 mg ± 1 mg, for example, 840 mg ± 0.5 mg, for example, 840 mg every 2 weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 800 mg avelumab every two weeks. In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 240 mg nivolumab every two weeks.

[0289] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 500 mg to about 3000 mg (e.g., about 500 mg to about 2800 mg, e.g., about 600 mg to about 2700 mg, e.g., about 650 mg to about 2600 mg, e.g., about 700 mg to about 2500 mg, e.g., about 1000 mg to about 2400 mg, e.g., about 1100 mg to about 2300 mg, e.g., about 1200 mg to about 2200 mg, e.g., about 1300 mg to about 2400 mg) every 4 weeks (Q4W). A fixed dose of about 2100 mg, for example, about 1400 mg to about 2000 mg, for example, about 1500 mg to about 1900 mg, for example, about 1600 mg to about 1800 mg, for example, about 1620 mg to about 1700 mg, for example, about 1640 mg to about 1690 mg, for example, about 1660 mg to about 1680 mg, about 1680 mg, for example, about 1600 mg, about 1610 mg, about 1620 mg, about 1630 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, or about 1700 mg. In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks (e.g., 1680 mg ± 10 mg, e.g., 1680 ± 6 mg, e.g., 1680 ± 5 mg, e.g., 1680 ± 3 mg, e.g., 1680 ± 1 mg, e.g., 1680 ± 0.5 mg, e.g., 1680 mg every four weeks). In some embodiments, the effective amount of the PD-1 axis binding antagonist is a fixed dose of about 480 mg of nivolumab every four weeks.

[0290] In some cases, the fixed dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) administered as monotherapy.

[0291] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 50 mg / kg of subject body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2. The dose is 5 mg / kg to about 30 mg / kg, for example, about 5 mg / kg to about 25 mg / kg, for example, about 10 mg / kg to about 20 mg / kg, for example, about 12.5 mg / kg to about 15 mg / kg, for example, about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, for example, about 15 mg / kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 15 mg / kg of subject body weight (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg, e.g., about ... In some cases, the effective dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 15 mg / kg administered every three weeks.In some cases, the dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) administered as monotherapy.

[0292] The anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) can be administered in one or more administration cycles (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, or 50 or more administration cycles). In some cases, the administration cycle of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost. In some cases, the length of each administration cycle is about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days). In some cases, the length of a dosing cycle is about 21 days. In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1±3) of each administration cycle. For example, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., a fixed dose of about 600 mg every 3 weeks). Similarly, in some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about day 1 (e.g., day 1±3) of each administration cycle.For example, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 1200 mg). In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (e.g., days 1±3) of each administration cycle. For example, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 600 mg), and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 1200 mg).

[0293] In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some cases, the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0294] In some cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to the subject before the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)). In some cases, the method includes an intervening first observation period, e.g., after administration of the anti-TIGIT antagonist antibody and before administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the method further includes a second observation period after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the method includes both a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) at about 30±10 minutes after administration of the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) at about 15±10 minutes after administration of the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody during the first and second observation periods, respectively.

[0295] In other cases, the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some cases, the method includes an intervening first observation period, e.g., after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and before administration of the anti-TIGIT antagonist antibody. In some cases, the method includes a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and a second observation period after administration of the anti-TIGIT antagonist antibody. In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30±10 minutes after administration of the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15±10 minutes after administration of the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0296] In other cases, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 (atezolizumab) antagonist antibody) are administered simultaneously to the subject. In some cases, for example, after administration of the anti-TIGIT antagonist antibody and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), the method includes an observation period. In some cases, the observation period is about 30 minutes to about 60 minutes in length. When the observation period is about 60 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) during the observation period, about 30±10 minutes after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody. Where the observation period is about 30 minutes in length, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) during the observation period, approximately 15±10 minutes after administration of the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the anti-TIGIT antagonist antibody.

[0297] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) for use in a method of treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater). ), the method comprising administering to a subject a fixed dose of 600 mg of an anti-TIGIT antagonist antibody every three weeks and a fixed dose of 1200 mg of atezolizumab every three weeks for one or more dosing cycles, wherein the anti-TIGIT antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in CR or PR and / or (b) results in increased PFS compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody, as described in further detail below. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0298] In another aspect, the present invention provides an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., Tigit) for use in a method of treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) that has been determined to have a PD-L1 tumor cell positive fraction of 30% or greater (e.g., 50% or greater). and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), the method comprising administering to a subject a fixed dose of 600 mg tiragolumab every three weeks and a fixed dose of 1200 mg atezolizumab every three weeks for one or more dosing cycles, wherein the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS compared to treatment with atezolizumab without tiragolumab. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0299] In another aspect, the present invention provides a method for treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more). Provided is a use of an axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)), the method comprising administering one or more dosing cycles of a medicament to a subject, wherein the medicament is formulated for administration of an effective amount of an anti-TIGIT antagonist antibody and an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), and the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0300] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) that has been determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering one or more doses of the use of a PD-L1-positive tumor cell fraction is greater than or equal to 50% (e.g., as determined by positive staining with anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), positive staining with anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or positive staining with anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is greater than or equal to 30% as determined by positive staining with the anti-PD-L1 antibody SP142.

[0301] In another aspect, the invention is directed to the use of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) in the manufacture of a medicament for use in a method of treating a subject having a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) that has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater). the method comprises administering to a subject one or more dosing cycles of a medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated for administration such that an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and an effective amount of the anti-TIGIT antagonist antibody are administered, and the treatment (a) results in a CR or PR and / or (b) results in increased PFS compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist. In some cases, the PD-L1-positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is greater than or equal to 30% as determined by positive staining with the anti-PD-L1 antibody SP142.

[0302] In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 30 mg to about 1200 mg every 2, 3, or 4 weeks (e.g., about 30 mg to about 600 mg every 2, 3, or 4 weeks (e.g., about 30 mg to about 600 mg every 3 weeks), e.g., about 600 mg every 3 weeks). In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks.

[0303] In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is about 30 mg to about 1200 mg (e.g., about 30 mg to about 1100 mg, e.g., about 60 mg to about 1000 mg, e.g., about 100 mg to about 900 mg, e.g., about 200 mg to about 800 mg, e.g., about 300 mg to about 800 mg, e.g., about For example, a fixed dose of about 400 mg to about 800 mg, for example, about 400 mg to about 750 mg, for example, about 450 mg to about 750 mg, for example, about 500 mg to about 700 mg, for example, about 550 mg to about 650 mg, for example, 600 mg ± 10 mg, for example, 600 ± 6 mg, for example, 600 ± 5 mg, for example, 600 ± 3 mg, for example, 600 ± 1 mg, for example, 600 ± 0.5 mg, for example, 600 mg). In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 30 mg to about 600 mg (e.g., about 50 mg to 600 mg, e.g., about 60 mg to about 600 mg, e.g., about 100 mg to about 600 mg, e.g., about 200 mg to about 600 mg, e.g., about 200 mg to about 550 mg, e.g., about 250 mg to about 500 mg, e.g., about 300 mg to about 450 mg, e.g., about 350 mg to about 400 mg, e.g., about 375 mg) every three weeks. In some cases, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks. In some cases, the effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is a fixed dose of 600 mg every 3 weeks. In some cases, the fixed dose of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered in combination therapy (e.g., combination treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab)) and may be reduced compared to the standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

[0304] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 80 mg to about 1600 mg (e.g., about 100 mg to about 1600 mg, e.g., about 200 mg to about 1600 mg, e.g., about 300 mg to about 1600 mg, e.g., about 400 mg to about 1600 mg, e.g., about 500 mg to about 1600 mg, e.g., about 600 mg to about 1600 mg, e.g., about 700 mg to about 1600 mg, e.g., about 800 mg) every three weeks. In some cases, the effective dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some cases, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1200 mg every three weeks.

[0305] In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 80 mg to about 2000 mg every 2 weeks, every 3 weeks, or every 4 weeks (e.g., about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks). In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1680 mg every 4 weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every 3 weeks, and the PD-1 axis binding antagonist is administered at a dose of about 1200 mg every 3 weeks. In some embodiments, the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a dose of about 600 mg every three weeks, and the PD-1 axis-binding antagonist is administered at a dose of about 840 mg every two weeks.

[0306] In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 840 mg every two weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks. In some instances, the effective amount of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of 1680 mg every four weeks.

[0307] In some cases, the fixed dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) administered as monotherapy.

[0308] In some cases, an effective amount of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 50 mg / kg of subject body weight (e.g., about 0.01 mg / kg to about 45 mg / kg, e.g., about 0.1 mg / kg to about 40 mg / kg, e.g., about 1 mg / kg to about 35 mg / kg, e.g., about 2. The dose is 5 mg / kg to about 30 mg / kg, for example, about 5 mg / kg to about 25 mg / kg, for example, about 10 mg / kg to about 20 mg / kg, for example, about 12.5 mg / kg to about 15 mg / kg, for example, about 15±2 mg / kg, about 15±1 mg / kg, about 15±0.5 mg / kg, about 15±0.2 mg / kg, or about 15±0.1 mg / kg, for example, about 15 mg / kg). In some cases, an effective amount of a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 0.01 mg / kg to about 15 mg / kg of subject body weight (e.g., about 0.1 mg / kg to about 15 mg / kg, e.g., about 0.5 mg / kg to about 15 mg / kg, e.g., about 1 mg / kg to about 15 mg / kg, e.g., about 2.5 mg / kg to about 15 mg / kg, e.g., about ... In some cases, the effective dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is about 15 mg / kg administered every three weeks.In some cases, the dose of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in combination therapy (e.g., combination treatment with an anti-TIGIT antagonist antibody, e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) may be reduced compared to the standard dose of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) administered as monotherapy.

[0309] In any use of the present invention, the medicament comprising the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) may be administered in one or more administration cycles (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, or 50 or more administration cycles). In some cases, the administration cycle of the medicament comprising the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) continues until clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity) is lost. In some cases, the length of each administration cycle is about 14 to 28 days (e.g., 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, or 28 days).

[0310] In some cases, the length of the dosing cycle is about 21 days. In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, such as tiragolumab) is intravenously administered at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., a fixed dose of about 600 mg every 3 weeks). Similarly, in some cases, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 1200 mg). In some cases, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (e.g., day 1±3) of each administration cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 600 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 600 mg), and a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1200 mg on day 1 of each 21-day cycle (i.e., every 3 weeks at a fixed dose of about 1200 mg).

[0311] In some cases, the length of the dosing cycle is about 28 days. In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1±3) of each dosing cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is intravenously administered at a fixed dose of about 420 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 420 mg every two weeks). Similarly, in some cases, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about days 1 and 15 (e.g., days 1±3 and 15±3) of each dosing cycle. For example, in some instances, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 840 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 840 mg every two weeks). In some instances, both a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about days 1 and 15 of each administration cycle (e.g., days 1±3 and 15±3). For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 420 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 420 mg every two weeks), and a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 840 mg on days 1 and 15 of each 28-day cycle (i.e., a fixed dose of about 840 mg every two weeks).

[0312] In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered on about day 1 (e.g., day 1±3) of each 28-day administration cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is intravenously administered at a fixed dose of about 840 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 420 mg every 4 weeks). Similarly, in some cases, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered on about day 1 (e.g., day 1±3) of each administration cycle. For example, in some instances, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1680 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 840 mg every 4 weeks). In some instances, both the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) are administered on about day 1 (e.g., day 1±3) of each administration cycle. For example, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered intravenously at a fixed dose of about 840 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 820 mg every 4 weeks), and a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously at a fixed dose of about 1680 mg on day 1 of each 28-day cycle (i.e., a fixed dose of about 1680 mg every 4 weeks).In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject by intravenous infusion over about 60±10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes). In some cases, a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to a subject by intravenous infusion over about 60±15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).

[0313] In some cases, a medicament comprising an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) is administered to a subject before a medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)). In some cases, the method includes an intervening first observation period, e.g., after administration of the medicament comprising the anti-TIGIT antagonist antibody and before administration of the medicament comprising the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the method further includes a second observation period after administration of the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the method includes both a first observation period after administration of the medicament comprising an anti-TIGIT antagonist antibody and a second observation period after administration of the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody). In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30±10 minutes after administration of the medicament comprising the anti-TIGIT antagonist antibody and the medicament comprising the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) at about 15±10 minutes after administration of the medication comprising the anti-TIGIT antagonist antibody and the medication comprising the PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) during the first and second observation periods, respectively.

[0314] In other cases, the medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered to the subject before the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab). In some cases, the method includes an intervening first observation period, e.g., after administration of the medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and before administration of the medicament comprising the anti-TIGIT antagonist antibody. In some cases, the method includes a second observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody. In some cases, the method includes both a first observation period after administration of the medicament comprising a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and a second observation period after administration of the medicament comprising the anti-TIGIT antagonist antibody. In some cases, the first and second observation periods are each about 30 minutes to about 60 minutes in length. In cases where the first and second observation periods are each about 60 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 30±10 minutes after administration of the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the medicament comprising an anti-TIGIT antagonist antibody during the first and second observation periods, respectively. In cases where the first and second observation periods are each about 30 minutes, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) about 15±10 minutes after administration of the medicament comprising a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) and the medicament comprising an anti-TIGIT antagonist antibody during the first and second observation periods, respectively.

[0315] In other cases, the medicament comprising the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and the medicament comprising the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 (atezolizumab) antagonist antibody) are administered simultaneously to the subject. In some cases, for example, after administration of the medicament comprising the anti-TIGIT antagonist antibody and the medicament comprising the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody), the method includes an observation period. In some cases, the observation period is about 30 minutes to about 60 minutes in length. When the observation period is about 60 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) during the observation period, about 30±10 minutes after administration of the medicament comprising the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and the medicament comprising the anti-TIGIT antagonist antibody.When the observation period is about 30 minutes long, the method may include recording the subject's vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) during the observation period, about 15±10 minutes after administration of the medicament comprising the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody) and the medicament comprising the anti-TIGIT antagonist antibody.

[0316] In another aspect, the present invention provides a method for treating a subject with a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1-positive tumor cell fraction of 30% or greater (e.g., 50% or greater) using an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 The present invention provides a use of a PD-1 axis-binding antagonist (e.g., atezolizumab) to a subject, the method comprising administering one or more dosing cycles of a medicament to the subject, wherein the medicament is formulated for administration of a fixed dose of about 30 mg to about 1200 mg of the anti-TIGIT antagonist antibody and a fixed dose of about 80 mg to about 1600 mg of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) every three weeks, wherein the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with the PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist.

[0317] In another aspect, the invention provides use of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) in the manufacture of a medicament for use in a method of treating a subject having a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., Stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC)) that has been determined to have a PD-L1 axis-binding tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering one or more dosing cycles of The present invention provides a use comprising administering to a subject a medicament and an anti-TIGIT antagonist antibody, wherein the medicament is formulated so that the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) is administered at a fixed dose of about 80 mg to about 1600 mg every three weeks, and the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 1200 mg every three weeks, wherein the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with the PD-1 axis-binding antagonist (e.g., anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0318] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject having a cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) that has been determined to have a PD-L1-positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering one or more dosing cycles of the medicament and a PD-1 axis-binding antagonist. the medicament is formulated for administration of a fixed dose of about 30 mg to about 1200 mg of an anti-TIGIT antagonist antibody and a fixed dose of about 80 mg to about 1600 mg of a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) every three weeks to a subject, wherein the treatment (a) results in CR or PR, and / or (b) results in increased PFS, compared to treatment with a PD-1 axis-binding antagonist (e.g., an anti-PD-L1 antagonist antibody) without the anti-TIGIT antagonist. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0319] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), wherein the method comprises administering one or more dosing cycles of the medicament to a subject. and a VL domain comprising the amino acid sequence of SEQ ID NO: 19; and (a) resulting in CR or PR and / or (b) increased PFS, as compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody, as described in further detail below. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0320] In another aspect, the invention provides use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering one or more dosing cycles of the medicament and atezolizumab to the subject. and administering to a patient a fixed dose of 600 mg of an anti-TIGIT antagonist antibody every three weeks and a fixed dose of 1200 mg of atezolizumab every three weeks, wherein the medicament is formulated for administration of an anti-TIGIT antagonist antibody comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment results in (a) CR or PR and / or (b) increased PFS compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody, as described in further detail below. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0321] In another aspect, the invention provides use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering to the subject one or more dosing cycles of a medicament and an anti-TIGIT antibody. and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the treatment (a) results in a CR or PR and / or (b) results in increased PFS compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody, as described in more detail below. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is greater than or equal to 30% as determined by positive staining with the anti-PD-L1 antibody SP142.

[0322] In another aspect, the invention provides use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1-positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering to the subject one or more dosing cycles of the medicament, the medicament formulated for administration of a fixed dose of 600 mg tiragolumab every three weeks and a fixed dose of 1200 mg atezolizumab every three weeks, wherein the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0323] In another aspect, the invention provides use of tiragolumab in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering to the subject one or more dosing cycles of the medicament and atezolizumab, wherein the medicament is formulated for administration of tiragolumab at a fixed dose of 600 mg every three weeks and atezolizumab administered at a fixed dose of 1200 mg every three weeks, and wherein the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab. In some cases, the PD-L1 positive tumor cell fraction is 50% or greater (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using a Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using a pharmDx assay), or as determined by positive staining with the anti-PD-L1 antibody 28-8). In some embodiments, the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

[0324] In another aspect, the invention provides use of atezolizumab in the manufacture of a medicament for use in a method of treating a subject with cancer (e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), e.g., squamous or non-squamous NSCLC, e.g., locally advanced unresectable NSCLC (e.g., stage IIIB NSCLC) or recurrent or metastatic NSCLC (e.g., stage IV NSCLC)) determined to have a PD-L1 positive tumor cell fraction of 30% or more (e.g., 50% or more), the method comprising administering to the subject one...

Claims

1. 1. A method for treating a subject having lung cancer, comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and wherein the treatment results in (a) a complete response (CR) or partial response (PR), and / or (b) an increase in progression-free survival (PFS), compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

2. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and 2. The method of claim 1, comprising an HVR-L3 sequence comprising the amino acid sequence QQYYSTPFT (SEQ ID NO: 6).

3. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework region (FR): FR-L1 comprising the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and 3. The method of claim 2, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

4. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FR: X １ FR-H1 (wherein X １ is Q or E); FR-H2 comprising the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and 3. The method of claim 2, further comprising FR-H4 comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14).

5. X １ The method of claim 4 , wherein

6. X １ The method of claim 4 , wherein

7. The anti-TIGIT antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) The method according to any one of claims 2 to 6, comprising a VH domain according to (a) and a VL domain according to (b).

8. The anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and The method of any one of claims 1 to 7, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

19.

9. The method of any one of claims 1 to 8, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

10. The method of claim 9 , wherein the anti-TIGIT antagonist antibody is a human antibody.

11. The method of any one of claims 1 to 10, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

12. The method of any one of claims 1 to 4 and 6 to 11, wherein the anti-TIGIT antagonist antibody is tiragolumab.

13. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The method according to any one of claims 1 to 10, wherein the antibody fragment is an antibody fragment that binds to TIGIT selected from the group consisting of antibody fragments.

14. The method according to any one of claims 1 to 13, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

15. The method according to claim 14, wherein the IgG class antibody is an IgG1 subclass antibody.

16. The method of any one of claims 1 to 15, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

17. 17. The method of claim 16, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

18. 18. The method of claim 17, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736.

19. 19. The method of claim 18, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

20. 17. The method of claim 16, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

21. 21. The method of claim 20, wherein the anti-PD-1 antagonist antibody is nivolumab (MDX-1106), pembrolizumab (MK-3475), MED1-0680, spartalizumab (PDR001), cemiplimab (REGN2810), BGB-108, prorugolimab, camrelizumab, sintilimab, tislelizumab, or toripalimab.

22. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and 18. The method of claim 17, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

23. The anti-PD-L1 antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) The method of claim 22, comprising a VH domain according to (a) and a VL domain according to (b).

24. The anti-PD-L1 antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 26; and 24. The method of claim 23, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

27.

25. The method of any one of claims 1 to 24, wherein the PD-1 axis binding antagonist is a monoclonal antibody.

26. The method of any one of claims 1 to 25, wherein the PD-1 axis binding antagonist is a humanized antibody.

27. The method of any one of claims 1 to 26, wherein the PD-1 axis binding antagonist is a full-length antibody.

28. The PD-1 axis binding antagonist is selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The method of any one of claims 1 to 26, wherein the antibody fragment that binds to PD-L1 is selected from the group consisting of antibody fragments.

29. The method of any one of claims 1 to 27, wherein the PD-1 axis binding antagonist is an IgG class antibody.

30. The method of claim 29, wherein the IgG class antibody is an IgG1 subclass antibody.

31. 31. The method of any one of claims 1 to 30, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 30 mg to about 1200 mg every three weeks.

32. 32. The method of claim 31, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 600 mg every three weeks.

33. 33. The method of any one of claims 1-32, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 80 mg to about 1600 mg every three weeks.

34. 34. The method of claim 33, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1200 mg every three weeks.

35. 35. The method of any one of claims 1-34, comprising administering to the subject a fixed dose of about 600 mg of the anti-TIGIT antagonist antibody every three weeks and a fixed dose of about 1200 mg of the PD-1 axis binding antagonist every three weeks.

36. 36. The method of any one of claims 1 to 35, wherein each of the one or more administration cycles is 21 days in length.

37. 37. The method of any one of claims 1-36, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about day 1 of each of the one or more administration cycles.

38. 31. The method of any one of claims 1 to 30, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 300 mg to about 800 mg every two weeks.

39. 39. The method of claim 38, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 400 mg to about 500 mg every two weeks.

40. 40. The method of claim 39, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 420 mg every two weeks.

41. 41. The method of any one of claims 1-30 and 38-40, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 200 mg to about 1200 mg every two weeks.

42. 42. The method of claim 41, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 840 mg every two weeks.

43. 43. The method of claim 42, comprising administering to the subject a fixed dose of about 420 mg of the anti-TIGIT antagonist antibody every two weeks and a fixed dose of about 840 mg of the PD-1 axis binding antagonist every two weeks.

44. 44. The method of claim 43, wherein each of the one or more administration cycles is 28 days in length.

45. 45. The method of claim 44, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about days 1 and 15 of each of the one or more administration cycles.

46. 31. The method of any one of claims 1 to 30, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 700 mg to about 1000 mg every four weeks.

47. 47. The method of claim 46, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 800 mg to about 900 mg every four weeks.

48. 48. The method of claim 47, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 840 mg every four weeks.

49. 49. The method of any one of claims 1-30 and 46-48, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 400 mg to about 2000 mg every four weeks.

50. 50. The method of claim 49, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1680 mg every four weeks.

51. 51. The method of claim 50, comprising administering to the subject a fixed dose of about 840 mg of the anti-TIGIT antagonist antibody every four weeks and a fixed dose of about 1680 mg of the PD-1 axis binding antagonist every four weeks.

52. 52. The method of any one of claims 1-30 and 46-51, wherein each of the one or more administration cycles is 28 days in length.

53. 53. The method of claim 52, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about day 1 of each of the one or more administration cycles.

54. 54. The method of any one of claims 1 to 53, comprising administering to the subject the PD-1 axis binding antagonist prior to the anti-TIGIT antagonist antibody.

55. 55. The method of claim 54, comprising a first observation period after administration of the PD-1 axis binding antagonist and a second observation period after administration of the anti-TIGIT antagonist antibody.

56. 56. The method of claim 55, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

57. 54. The method of any one of claims 1 to 53, comprising administering to the subject the anti-TIGIT antagonist antibody prior to the PD-1 axis binding antagonist.

58. 58. The method of claim 57, comprising a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis binding antagonist.

59. 59. The method of claim 58, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

60. 54. The method of any one of claims 1 to 53, comprising administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist simultaneously to the subject.

61. 61. The method of any one of claims 1 to 60, comprising intravenously administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject.

62. 62. The method of claim 61, comprising administering the anti-TIGIT antagonist antibody to the subject by intravenous infusion over 60±10 minutes.

63. 63. The method of claim 61 or 62, comprising administering the PD-1 axis binding antagonist to the subject by intravenous infusion over a period of 60±15 minutes.

64. 61. The method of any one of claims 1 to 60, comprising subcutaneously administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject.

65. The method of any one of claims 1 to 64, wherein the PD-L1 positive tumor cell fraction is determined by immunohistochemistry (IHC) assay.

66. 66. The method of any one of claims 1 to 65, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

67. 67. The method of claim 66, wherein 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 SP263.

68. 68. The method of claim 67, wherein the PD-L1 positive tumor cell fraction is calculated using a Ventana SP263 IHC assay.

69. 67. The method of claim 66, wherein 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.

70. 70. The method of claim 69, wherein the PD-L1 positive tumor cell fraction is calculated using a pharmDx 22C3 IHC assay.

71. 67. The method of claim 66, wherein the PD-L1 positive tumor cell fraction is 30% or greater as determined by positive staining with the anti-PD-L1 antibody SP142.

72. 67. The method of claim 66, wherein the PD-L1 positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody 28-8.

73. The method of any one of claims 1 to 72, wherein a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1.

74. 74. The method of claim 73, wherein the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

75. 75. The method of any one of claims 1 to 74, wherein the lung cancer is non-small cell lung cancer (NSCLC).

76. 76. The method of claim 75, wherein the NSCLC is squamous NSCLC.

77. 77. The method of claim 76, wherein the NSCLC is non-squamous NSCLC.

78. 78. The method of any one of claims 75 to 77, wherein the NSCLC is locally advanced unresectable NSCLC.

79. 79. The method of claim 78, wherein the NSCLC is stage IIIB NSCLC.

80. 78. The method of any one of claims 75 to 77, wherein the NSCLC is recurrent or metastatic NSCLC.

81. 81. The method of claim 80, wherein the NSCLC is stage IV NSCLC.

82. 82. The method of claim 80 or 81, wherein the subject has not been previously treated for stage IV NSCLC.

83. 83. The method of any one of claims 1 to 82, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

84. 84. The method of any one of claims 1 to 83, wherein the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

85. 85. The method of any one of claims 1 to 84, wherein the subject does not have an active Epstein-Barr virus (EBV) infection or does not have or is not suspected of having a known chronic active EBV infection.

86. 86. The method of any one of claims 1 to 85, wherein the subject is negative for EBV IgM or negative by EBV PCR.

87. 87. The method of claim 86, wherein the subject is negative for EBV IgM and negative by EBV PCR.

88. 88. The method of claim 86 or 87, wherein the subject is positive for EBV IgG or positive for Epstein-Barr Nuclear Antigen (EBNA).

89. 89. The method of claim 88, wherein the subject is positive for EBV IgG and positive for EBNA.

90. 90. The method of any one of claims 1 to 89, wherein the subject is EBV IgG negative or EBNA negative.

91. 91. The method of claim 90, wherein the subject is negative for EBV IgG and negative for EBNA.

92. 92. The method of any one of claims 1 to 91, wherein the PFS is increased compared to a baseline PFS time.

93. 93. The method of claim 92, wherein the reference PFS time is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

94. 1. A method for treating a subject with NSCLC, comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and The method comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

95. 95. The method of claim 94, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

96. 95. The method of claim 94, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

97. 95. The method of claim 94, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

98. 1. A method of treating a subject having NSCLC, comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by staining tumor cells from the tumor sample with the anti-PD-L1 antibody SP263, and determining the proportion of PD-L1-positive tumor cells therefrom, wherein 50% or more of the tumor cells stained with the anti-PD-L1 antibody SP263 are PD-L1-positive tumor cells; and (c) administering to the subject one or more dosing cycles of a treatment comprising an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the following: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19; The method, wherein the treatment (a) results in a CR or PR, and / or (b) results in increased PFS compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

99. 99. The method of claim 98, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

100. 99. The method of claim 98, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

101. 99. The method of claim 98, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

102. 1. A method for treating a subject with NSCLC, comprising administering one or more dosing cycles of tiragolumab and atezolizumab to the subject, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and wherein the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

103. 103. The method of claim 102, wherein tiragolumab is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

104. 103. The method of claim 102, wherein tiragolumab is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

105. 103. The method of claim 102, wherein tiragolumab is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

106. 1. A method of treating a subject having NSCLC, comprising: (a) obtaining a tumor sample from said subject; (b) detecting the protein expression level of PD-L1 in the tumor sample by an IHC assay using the anti-PD-L1 antibody SP263, and determining the PD-L1-positive tumor cell fraction therefrom, wherein the PD-L1-positive tumor cell fraction is determined to be 50% or more; and (c) administering to the subject one or more dosing cycles of a treatment comprising an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the following: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19; The method, wherein the treatment (a) results in a CR or PR, and / or (b) results in increased PFS compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

107. 107. The method of claim 106, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

108. 107. The method of claim 106, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

109. 107. The method of claim 106, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

110. 1. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having lung cancer, the method comprising administering one or more dosing cycles of the anti-TIGIT antagonist to the subject, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in an increased PFS, compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

111. The anti-TIGIT antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 110, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

112. The anti-TIGIT antagonist antibody comprises the following light chain variable region FR: FR-L1 comprising the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 111, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

113. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FR: X １ FR-H1 (wherein X １ is Q or E); FR-H2 comprising the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 111, further comprising FR-H4 comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14).

114. X １ The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 113, wherein is Q.

115. X １ The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of claim 113, wherein is E.

116. The anti-TIGIT antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 111 to 115, comprising the VH domain of (a) and the VL domain of (b).

117. The anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and 117. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 116, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

19.

118. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 117, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

119. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 118, wherein the anti-TIGIT antagonist antibody is a human antibody.

120. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 119, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

121. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 113 and 115 to 120, wherein the anti-TIGIT antagonist antibody is tiragolumab.

122. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 119, which is an antibody fragment that binds to TIGIT selected from the group consisting of:

123. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 122, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

124. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 123, wherein the IgG class antibody is an IgG1 subclass antibody.

125. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 124, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

126. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of claim 125, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

127. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of claim 126, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736.

128. The anti-TIGIT antagonist antibody and anti-PD-L1 antagonist antibody for use according to claim 127, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

129. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of claim 125, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

130. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist of claim 129, wherein the anti-PD-1 antagonist antibody is nivolumab (MDX-1106), pembrolizumab (MK-3475), MED1-0680, spartalizumab (PDR001), cemiplimab (REGN2810), BGB-108, prorugolimab, camrelizumab, sintilimab, tislelizumab, or toripalimab.

131. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 126, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

132. The anti-PD-L1 antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) An anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 131, comprising the VH domain of (a) and the VL domain of (b).

133. The anti-PD-L1 antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 26; and The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 132, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

27.

134. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 133, wherein the PD-1 axis binding antagonist is a monoclonal antibody.

135. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 134, wherein the PD-1 axis binding antagonist is a humanized antibody.

136. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 134 or 135, wherein the PD-1 axis binding antagonist is a full-length antibody.

137. The PD-1 axis binding antagonist is selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 135, which is an antibody fragment that binds to PD-L1 selected from the group consisting of:

138. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 136, wherein the PD-1 axis binding antagonist is an IgG class antibody.

139. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 138, wherein the IgG class antibody is an IgG1 subclass antibody.

140. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 30 mg to about 1200 mg every three weeks.

141. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 140, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks.

142. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 141, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 600 mg every three weeks.

143. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 142, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 80 mg to about 1600 mg every three weeks.

144. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 143, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1200 mg every three weeks.

145. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 144, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the PD-1 axis binding antagonist is administered to the subject at a fixed dose of about 1200 mg every three weeks.

146. 146. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 145, wherein each of said one or more administration cycles is 21 days in length.

147. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 146, wherein the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist are administered to the subject on about day 1 of each of the one or more administration cycles.

148. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 300 mg to about 800 mg every two weeks.

149. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 148, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 400 mg to 500 mg every two weeks.

150. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 149, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 420 mg every two weeks.

151. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139 and 148 to 150, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 200 mg to about 1200 mg every two weeks.

152. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 151, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 840 mg every two weeks.

153. 153. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for the method of claim 152, wherein the method comprises administering to the subject a fixed dose of about 420 mg of the anti-TIGIT antagonist antibody every two weeks and a fixed dose of about 840 mg of the PD-1 axis binding antagonist every two weeks.

154. 154. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 153, wherein each of said one or more administration cycles is 28 days in length.

155. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 154, wherein the method comprises administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject on about days 1 and 15 of each of the one or more administration cycles.

156. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 700 mg to about 1000 mg every four weeks.

157. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 156, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 800 mg to 900 mg every four weeks.

158. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 157, wherein the method comprises administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 840 mg every four weeks.

159. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139 and 156 to 158, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 400 mg to about 2000 mg every four weeks.

160. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 159, wherein the method comprises administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1680 mg every four weeks.

161. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 160, wherein the method comprises administering to the subject a fixed dose of about 840 mg of the anti-TIGIT antagonist antibody every four weeks and a fixed dose of about 1680 mg of the PD-1 axis binding antagonist every four weeks.

162. 162. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 139 and 156 to 161, wherein each of said one or more administration cycles is 28 days in length.

163. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 162, wherein the method comprises administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject on about day 1 of each of the one or more administration cycles.

164. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 163, wherein the PD-1 axis binding antagonist is administered to the subject before the anti-TIGIT antagonist antibody.

165. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 164, wherein a first observation period is after administration of the PD-1 axis binding antagonist and a second observation period is after administration of the anti-TIGIT antagonist antibody.

166. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 165, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

167. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 163, wherein the anti-TIGIT antagonist antibody is administered to the subject before the PD-1 axis binding antagonist.

168. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 167, wherein a first observation period is after administration of the anti-TIGIT antagonist antibody and a second observation period is after administration of the PD-1 axis binding antagonist.

169. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 168, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

170. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 163, wherein the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the PD-1 axis binding antagonist.

171. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 170, which are administered intravenously to the subject.

172. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 171, wherein the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over 60±10 minutes.

173. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 171 or 172, wherein the PD-1 axis binding antagonist is administered to the subject by intravenous infusion over 60±15 minutes.

174. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 170, which are administered subcutaneously to the subject.

175. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 174, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

176. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 175, wherein the staining is part of an immunohistochemistry (IHC) assay.

177. 177. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 175 or 176, wherein the PD-L1 positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody SP263, 22C3, or 28-8.

178. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 177, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with the anti-PD-L1 antibody SP263 using the Ventana SP263 IHC assay.

179. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 177, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with the anti-PD-L1 antibody 22C3 using the pharmDx 22C3 IHC assay.

180. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 179, wherein a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1.

181. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 180, wherein the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

182. 182. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 181, wherein the subject has been determined to have a PD-L1 positive tumor cell fraction of 50% or greater, as determined by positive staining with the anti-PD-L1 antibody SP263, 22C3, or 28-8.

183. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 182, wherein the lung cancer is non-small cell lung cancer (NSCLC).

184. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 183, wherein the NSCLC is squamous NSCLC.

185. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 184, wherein the NSCLC is non-squamous NSCLC.

186. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 183 to 185, wherein the NSCLC is locally advanced unresectable NSCLC.

187. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 186, wherein the NSCLC is stage IIIB NSCLC.

188. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 183 to 185, wherein the NSCLC is recurrent or metastatic NSCLC.

189. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 188, wherein the NSCLC is stage IV NSCLC.

190. 190. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 188 or 189, wherein the subject has not been previously treated for stage IV NSCLC.

191. 191. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 190, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

192. 192. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 191, wherein the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

193. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 192, wherein the subject does not have an active EBV infection or does not have or is not suspected of having a known chronic active EBV infection.

194. 194. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 193, wherein the subject is negative for EBV IgM or negative by EBV PCR.

195. 195. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 194, wherein the subject is negative for EBV IgM and negative by EBV PCR.

196. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 194 or 195, wherein the subject is positive for EBV IgG or positive for EBNA.

197. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 196, wherein the subject is positive for EBV IgG and positive for EBNA.

198. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 195, wherein the subject is negative for EBV IgG or negative for EBNA.

199. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 198, wherein the subject is negative for EBV IgG and negative for EBNA.

200. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to any one of claims 110 to 199, wherein the PFS is increased compared to a baseline PFS time.

201. The anti-TIGIT antagonist antibody and PD-1 axis binding antagonist for use according to claim 200, wherein the reference PFS time is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

202. 1. An anti-TIGIT antagonist antibody and atezolizumab for use in a method of treating a subject with NSCLC, the method comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and An anti-TIGIT antagonist antibody and atezolizumab for use, comprising a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the subject has been determined to have a PD-L1-positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS, compared to treatment with atezolizumab without the anti-TIGIT antagonist antibody.

203. 203. The anti-TIGIT antagonist antibody and atezolizumab for use according to claim 202, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

204. 203. The anti-TIGIT antagonist antibody and atezolizumab for use according to claim 202, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

205. 203. The anti-TIGIT antagonist antibody and atezolizumab for use according to claim 202, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

206. 1. Tiragolumab and atezolizumab for use in a method of treating a subject having NSCLC, said method comprising administering one or more dosing cycles of tiragolumab and atezolizumab to said subject, wherein said subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and wherein said treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

207. Tiragolumab and atezolizumab for use according to claim 206, wherein tiragolumab is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

208. Tiragolumab and atezolizumab for use according to claim 206, wherein tiragolumab is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

209. Tiragolumab and atezolizumab for use according to claim 206, wherein tiragolumab is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

210. 1. Use of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist in the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering one or more dosing cycles of the medicament to the subject, the medicament being formulated for administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the subject being determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS, compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

211. 1. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of the medicament and a PD-1 axis binding antagonist, the medicament being formulated for administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the subject being determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in an increased PFS, compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

212. 1. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for use in a method of treating a subject having lung cancer, the method comprising administering to the subject one or more dosing cycles of the medicament and an anti-TIGIT antagonist antibody, the medicament being formulated for administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody, the subject being determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in an increase in PFS, compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody.

213. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and 213. The use according to any one of claims 210 to 212, comprising an HVR-L3 sequence comprising the amino acid sequence QQYYSTPFT (SEQ ID NO: 6).

214. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework region (FR): FR-L1 comprising the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and The use of claim 213, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

215. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FR: X １ FR-H1 (wherein X １ is Q or E); FR-H2 comprising the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and The use of claim 213, further comprising FR-H4 comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14).

216. X １ The use described in claim 215, wherein is Q.

217. X １ The use described in claim 215, wherein is E.

218. The anti-TIGIT antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) The use according to any one of claims 215 to 217, comprising a VH domain according to (a) and a VL domain according to (b).

219. The anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and 219. The use according to any one of claims 210 to 218, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

19.

220. The use according to any one of claims 210 to 219, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody and / or a human antibody.

221. The use of any one of claims 210 to 220, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

222. The use according to any one of claims 210 to 215 and 217 to 221, wherein the anti-TIGIT antagonist antibody is tiragolumab.

223. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The use according to any one of claims 210 to 220, which is an antibody fragment that binds to TIGIT selected from the group consisting of fragments thereof.

224. The use according to any one of claims 210 to 223, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

225. The use described in claim 224, wherein the IgG class antibody is an IgG1 subclass antibody.

226. The use of any one of claims 223 to 225, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

227. The use of claim 226, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

228. The use of claim 227, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736.

229. The use of claim 228, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

230. 227. The use of claim 226, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

231. The use of claim 230, wherein the anti-PD-1 antagonist antibody is nivolumab (MDX-1106), pembrolizumab (MK-3475), MED1-0680, spartalizumab (PDR001), cemiplimab (REGN2810), BGB-108, prorugolimab, camrelizumab, sintilimab, tislelizumab, or toripalimab.

232. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and The use of claim 227, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

233. The anti-PD-L1 antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) The use of claim 232, comprising a VH domain according to (a) and a VL domain according to (b).

234. The anti-PD-L1 antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 26; and The use of claim 233, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

27.

235. The use of any one of claims 210 to 234, wherein the PD-1 axis binding antagonist is a monoclonal antibody.

236. The use of any one of claims 210 to 235, wherein the PD-1 axis binding antagonist is a humanized antibody.

237. The use of any one of claims 210 to 236, wherein the PD-1 axis binding antagonist is a full-length antibody.

238. The PD-1 axis binding antagonist is selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The use according to any one of claims 210 to 236, which is an antibody fragment that binds to PD-L1 selected from the group consisting of:

239. The use of claim 237, wherein the PD-1 axis binding antagonist is an IgG class antibody.

240. The use described in claim 239, wherein the IgG class antibody is an IgG1 subclass antibody.

241. 241. The use of any one of claims 210 to 240, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 1200 mg every three weeks.

242. The use of claim 241, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 600 mg every three weeks.

243. The use of claim 242, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks.

244. 244. The use of any one of claims 210-243, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 80 mg to about 1600 mg every three weeks.

245. 245. The use of claim 244, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks.

246. The use of any one of claims 210-245, wherein the anti-TIGIT antagonist antibody is administered to the subject at a fixed dose of about 600 mg every three weeks, and the PD-1 axis binding antagonist is administered to the subject at a fixed dose of about 1200 mg every three weeks.

247. 247. The use of any one of claims 210 to 246, wherein each of the one or more administration cycles is 21 days in length.

248. The use of any one of claims 210-247, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered to the subject on about day 1 of each of the one or more administration cycles.

249. 241. The use of any one of claims 210 to 240, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 300 mg to about 800 mg every two weeks.

250. 250. The use of claim 249, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 400 mg to about 500 mg every two weeks.

251. The use of claim 250, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks.

252. 252. The use of any one of claims 210-240 and claims 249-251, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 200 mg to about 1200 mg every two weeks.

253. 253. The use of claim 252, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks.

254. The use of claim 253, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks.

255. The use of any one of claims 210 to 240 and claims 249 to 254, wherein each of the one or more administration cycles is 28 days in length.

256. The use of claim 255, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on about days 1 and 15, respectively, of each of the one or more administration cycles.

257. 241. The use of any one of claims 210 to 240, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 700 mg to about 1000 mg every four weeks.

258. The use of claim 257, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every four weeks.

259. The use of claim 258, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks.

260. The use of any one of claims 210 to 240 and claims 257 to 259, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 400 mg to about 2000 mg every four weeks.

261. The use of claim 260, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks.

262. The use of claim 261, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks.

263. The use of any one of claims 210 to 240 and claims 257 to 262, wherein each of the one or more administration cycles is 28 days in length.

264. The use of claim 263, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are each administered on about day 1 of each of the one or more administration cycles.

265. The use of any one of claims 210 to 264, wherein the anti-TIGIT antagonist antibody is administered to the subject prior to the PD-1 axis binding antagonist.

266. The use of claim 265, wherein a first observation period is after administration of the PD-1 axis binding antagonist and a second observation period is after administration of the anti-TIGIT antagonist antibody.

267. 267. The use of claim 266, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

268. The use of any one of claims 210 to 264, wherein the anti-TIGIT antagonist antibody is administered to the subject prior to the PD-1 axis binding antagonist.

269. The use of claim 268, wherein a first observation period is after administration of the anti-TIGIT antagonist antibody and a second observation period is after administration of the PD-1 axis binding antagonist.

270. 270. The use of claim 269, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

271. The use of any one of claims 210 to 264, wherein the anti-TIGIT antagonist antibody is administered to the subject simultaneously with the PD-1 axis binding antagonist.

272. The use of any one of claims 210 to 271, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously to the subject.

273. 273. The use of claim 272, wherein the anti-TIGIT antagonist antibody is administered to the subject by intravenous infusion over 60±10 minutes.

274. 274. The use of claim 270 or 273, wherein the PD-1 axis binding antagonist is administered to the subject by intravenous infusion over 60±15 minutes.

275. The use of any one of claims 210 to 271, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered subcutaneously to the subject.

276. The use of any one of claims 210 to 275, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

277. The use of claim 276, wherein the staining is part of an immunohistochemistry (IHC) assay.

278. 278. The use of claim 276 or 277, wherein the PD-L1 positive tumor cell fraction is 50% or greater as determined by positive staining with the anti-PD-L1 antibody SP263, 22C3, or 28-8.

279. 279. The use of claim 278, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with the anti-PD-L1 antibody SP263 using a Ventana SP 263 IHC assay.

280. The use of claim 278, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with the anti-PD-L1 antibody 22C3 using a pharmDx 22C3 IHC assay.

281. The use of any one of claims 210 to 280, wherein a tumor sample obtained from the subject has been determined to have a detectable nucleic acid expression level of PD-L1.

282. The use of claim 281, wherein the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

283. The use of any one of claims 210 to 282, wherein the lung cancer is non-small cell lung cancer.

284. The use of claim 283, wherein the NSCLC is squamous NSCLC.

285. The use of claim 284, wherein the NSCLC is non-squamous NSCLC.

286. The use of any one of claims 283 to 285, wherein the NSCLC is locally advanced unresectable NSCLC.

287. The use of claim 286, wherein the NSCLC is stage IIIB NSCLC.

288. The use of any one of claims 283 to 286, wherein the NSCLC is recurrent or metastatic NSCLC.

289. The use of claim 288, wherein the NSCLC is stage IV NSCLC.

290. 290. The use of claim 288 or 289, wherein the subject has not been previously treated for stage IV NSCLC.

291. 291. The use of any one of claims 210 to 290, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

292. 292. The use of any one of claims 210 to 291, wherein the subject does not have the pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

293. 293. The use of any one of claims 210 to 292, wherein the subject does not have an active EBV infection or does not have or is not suspected of having a known chronic active EBV infection.

294. 294. The use of any one of claims 210 to 293, wherein the subject is negative for EBV IgM or negative by EBV PCR.

295. 295. The use of claim 294, wherein the subject is negative for EBV IgM and negative by EBV PCR.

296. 296. The use of claim 294 or 295, wherein the subject is positive for EBV IgG or positive for EBNA.

297. The use of claim 296, wherein the subject is positive for EBV IgG and positive for EBNA.

298. The use of any one of claims 210 to 297, wherein the subject is EBV IgG negative or EBNA negative.

299. The use of claim 298, wherein the subject is negative for EBV IgG and negative for EBNA.

300. 300. The use of any one of claims 210 to 299, wherein the PFS is increased compared to baseline PFS time.

301. The use of claim 300, wherein the reference PFS time is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

302. 1. Use of an anti-TIGIT antagonist antibody and atezolizumab in the manufacture of a medicament for use in a method of treating a subject with NSCLC, the method comprising administering one or more dosing cycles of the medicament to the subject, the medicament formulated for administration of an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and The subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without an anti-TIGIT antagonist antibody.

303. The use of claim 302, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

304. The use of claim 302, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

305. The use of claim 302, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

306. 1. Use of tiragolumab and atezolizumab in the manufacture of a medicament for use in a method of treating a subject having NSCLC, the method comprising administering one or more dosing cycles of the medicament to the subject, wherein the medicament is formulated for administration of tiragolumab and atezolizumab, the subject has been determined to have a PD-L1 positive tumor cell fraction of 30% or greater, and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS, compared to treatment with atezolizumab without tiragolumab.

307. 307. The use of claim 306, wherein tiragolumab is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

308. 307. The use of claim 306, wherein tiragolumab is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

309. The use of claim 306, wherein tiragolumab is administered at a fixed dose of 840 mg every 4 weeks and atezolizumab is administered at a fixed dose of 1680 mg every 4 weeks.

310. The method of any one of claims 1 to 109, the anti-TIGIT antagonist antibody of any one of claims 110 to 209, or the use of any one of claims 210 to 309, wherein the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab, and wherein the treatment results in an increase in PFS of atezolizumab of at least about 3.1 months compared to treatment with atezolizumab without tiragolumab.

311. The method of any one of claims 102 to 105, the tiragolumab and atezolizumab of any one of claims 206 to 209, or the use of any one of claims 306 to 309, wherein the treatment results in an increase in PFS of at least about 3.1 months compared to treatment with atezolizumab without tiragolumab.

312. The method of any one of claims 1 to 109, the anti-TIGIT antagonist antibody of any one of claims 110 to 209, or the use of any one of claims 210 to 309, wherein the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab, and wherein the treatment results in an increase in PFS of atezolizumab of at least about 4.9 months compared to treatment with atezolizumab without tiragolumab.

313. 309. The method of any one of claims 102 to 105, the tiragolumab and atezolizumab of any one of claims 206 to 209, or the use of any one of claims 306 to 309, wherein said treatment results in an increase in PFS of at least about 4.9 months compared to treatment with atezolizumab without tiragolumab.

314. The method of any one of claims 1 to 109, the anti-TIGIT antagonist antibody of any one of claims 110 to 209, or the use of any one of claims 210 to 309, wherein the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab, and the treatment results in an increase in OS of at least about 5.7 months compared to treatment with atezolizumab without tiragolumab.

315. 309. The method of any one of claims 102 to 105, the tiragolumab and atezolizumab of any one of claims 206 to 209, or the use of any one of claims 306 to 309, wherein said treatment results in an increase in OS of at least about 5.7 months compared to treatment with atezolizumab without tiragolumab.

316. The method of any one of claims 1 to 109, the anti-TIGIT antagonist antibody of any one of claims 110 to 209, or the use of any one of claims 210 to 309, wherein the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab, and the treatment results in an increase in OS of at least about 9 months compared to treatment with atezolizumab without tiragolumab.

317. 309. The method of any one of claims 102 to 105, the tiragolumab and atezolizumab of any one of claims 206 to 209, or the use of any one of claims 306 to 309, wherein said treatment results in an increase in OS of at least about 9 months compared to treatment with atezolizumab without tiragolumab.

318. 1. A method for treating a subject having lung cancer, comprising administering to the subject one or more administration cycles of an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist, wherein the subject has previously received concurrent chemoradiotherapy (cCRT) for lung cancer, and the subject has not had disease progression after the cCRT.

319. The method of claim 318, wherein the subject has previously received at least two cycles of the cCRT.

320. 320. The method of claim 318 or 319, wherein the cCRT comprises platinum-based chemotherapy.

321. 321. The method of any one of claims 318-320, wherein the cCRT comprises thoracic radiotherapy.

322. 322. The method of claim 321, wherein the thoracic radiation therapy is 60-66 Gy administered to the subject in 30-33 fractions.

323. 323. The method of any one of claims 318-322, wherein the cCRT is administered for therapeutic purposes.

324. The method of any one of claims 318 to 323, wherein the cCRT is administered as consolidation therapy.

325. The anti-TIGIT antagonist antibody comprises the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); an HVR-H2 sequence comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); an HVR-H3 sequence comprising the amino acid sequence ESTTYDLLAGPFDY (SEQ ID NO: 3); an HVR-L1 sequence comprising the amino acid sequence KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); an HVR-L2 sequence comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and 325. The method of any one of claims 318 to 324, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).

326. The anti-TIGIT antagonist antibody comprises the following light chain variable region framework region (FR): FR-L1 comprising the amino acid sequence DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and 326. The method of claim 325, further comprising FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

327. The anti-TIGIT antagonist antibody comprises the following heavy chain variable region FR: X １ FR-H1 (wherein X １ is Q or E); FR-H2 comprising the amino acid sequence WIRQSPSRGLEWLG (SEQ ID NO: 12); FR-H3 comprising the amino acid sequence RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and The method of claim 325, further comprising FR-H4 comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 14).

328. X １ The method of claim 327, wherein is Q.

329. X １ The method of claim 327, wherein is E.

330. The anti-TIGIT antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 17 or 18; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or (c) the method of any one of claims 325 to 329, comprising a VH domain according to (a) and a VL domain according to (b).

331. The anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and 331. The method of any one of claims 318 to 330, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

19.

332. The method of any one of claims 318 to 331, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

333. The method of claim 332, wherein the anti-TIGIT antagonist antibody is a human antibody.

334. The method of any one of claims 318 to 333, wherein the anti-TIGIT antagonist antibody is a full-length antibody.

335. The method of any one of claims 318 to 327 and 329 to 334, wherein the anti-TIGIT antagonist antibody is tiragolumab.

336. The anti-TIGIT antagonist antibody may be in the form of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The method of any one of claims 318 to 333, wherein the antibody fragment is an antibody fragment that binds to TIGIT selected from the group consisting of:

337. The method of any one of claims 318 to 335, wherein the anti-TIGIT antagonist antibody is an IgG class antibody.

338. The method of claim 337, wherein the IgG class antibody is an IgG1 subclass antibody.

339. The method of any one of claims 318 to 338, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

340. 340. The method of claim 339, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

341. The method of claim 340, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736.

342. The method of claim 341, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

343. 343. The method of claim 342, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

344. The method of claim 343, wherein the anti-PD-1 antagonist antibody is nivolumab (MDX-1106), pembrolizumab (MK-3475), MED1-0680, spartalizumab (PDR001), cemiplimab (REGN2810), BGB-108, prorugolimab, camrelizumab, sintilimab, tislelizumab, or toripalimab.

345. The anti-PD-L1 antagonist antibody comprises the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of GFTFSDSWIH (SEQ ID NO: 20); an HVR-H2 sequence comprising the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO: 21); an HVR-H3 sequence comprising the amino acid sequence of RHWPGGFDY (SEQ ID NO: 22); an HVR-L1 sequence comprising the amino acid sequence RASQDVSTAVA (SEQ ID NO: 23); An HVR-L2 sequence comprising the amino acid sequence of SASFLYS (SEQ ID NO: 24); and The method of claim 340, comprising an HVR-L3 sequence comprising the amino acid sequence of QQYLYHPAT (SEQ ID NO: 25).

346. The anti-PD-L1 antagonist antibody is selected from the group consisting of: (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 26; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 27; or (c) The method of claim 345, comprising a VH domain described in (a) and a VL domain described in (b).

347. The anti-PD-L1 antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 26; and The method of claim 346, comprising a VL domain comprising the amino acid sequence of SEQ ID NO:

27.

348. The method of any one of claims 318 to 347, wherein the PD-1 axis binding antagonist is a monoclonal antibody.

349. The method of any one of claims 1 to 348, wherein the PD-1 axis binding antagonist is a humanized antibody.

350. The method of any one of claims 1 to 349, wherein the PD-1 axis binding antagonist is a full-length antibody.

351. The PD-1 axis binding antagonist is selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single chain variable fragment (scFv), and (Fab'). ２ The method of any one of claims 1 to 349, wherein the antibody fragment that binds to PD-L1 is selected from the group consisting of:

352. The method of claim 350, wherein the PD-1 axis binding antagonist is an IgG class antibody.

353. The method of claim 352, wherein the IgG class antibody is an IgG1 subclass antibody.

354. 354. The method of any one of claims 318-353, comprising administering to the subject a fixed dose of about 30 mg to about 1200 mg of the anti-TIGIT antagonist antibody every three weeks.

355. 355. The method of claim 354, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 30 mg to about 600 mg every three weeks.

356. The method of claim 355, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 600 mg every three weeks.

357. 357. The method of any one of claims 318-356, comprising administering to the subject a fixed dose of about 80 mg to about 1600 mg of the PD-1 axis binding antagonist every three weeks.

358. 358. The method of claim 357, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1200 mg every three weeks.

359. 359. The method of any one of claims 318-358, comprising administering to the subject a fixed dose of about 600 mg of the anti-TIGIT antagonist antibody every three weeks and a fixed dose of about 1200 mg of the PD-1 axis binding antagonist every three weeks.

360. 360. The method of any one of claims 318-359, wherein each of the one or more administration cycles is 21 days in length.

361. The method of claim 360, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about day 1 of each of the one or more administration cycles.

362. The method of any one of claims 318-353, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 300 mg to about 800 mg every two weeks.

363. 363. The method of claim 362, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 400 mg to about 500 mg every two weeks.

364. The method of claim 363, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 420 mg every two weeks.

365. 365. The method of any one of claims 318-353 and 362-364, comprising administering to the subject a fixed dose of about 200 mg to about 1200 mg of the PD-1 axis binding antagonist every two weeks.

366. 366. The method of claim 365, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 840 mg every two weeks.

367. 367. The method of claim 366, comprising administering to the subject a fixed dose of about 420 mg of the anti-TIGIT antagonist antibody every two weeks and a fixed dose of about 840 mg of the PD-1 axis binding antagonist every two weeks.

368. 368. The method of any one of claims 318-353 and 362-367, wherein each of the one or more administration cycles is 28 days in length.

369. The method of claim 368, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about days 1 and 15 of each of the one or more administration cycles.

370. The method of any one of claims 318-353, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 700 mg to about 1000 mg every four weeks.

371. 371. The method of claim 370, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 800 mg to about 900 mg every four weeks.

372. The method of claim 371, comprising administering the anti-TIGIT antagonist antibody to the subject at a fixed dose of about 840 mg every four weeks.

373. 373. The method of any one of claims 318-353 and 370-372, comprising administering to the subject a fixed dose of about 400 mg to about 2000 mg of the PD-1 axis binding antagonist every four weeks.

374. 374. The method of claim 373, comprising administering the PD-1 axis binding antagonist to the subject at a fixed dose of about 1680 mg every four weeks.

375. 375. The method of claim 374, comprising administering to the subject a fixed dose of about 840 mg of the anti-TIGIT antagonist antibody every four weeks and a fixed dose of about 1680 mg of the PD-1 axis binding antagonist every four weeks.

376. 376. The method of any one of claims 318-353 and 370-375, wherein each of the one or more administration cycles is 28 days in length.

377. The method of claim 376, comprising administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist on about day 1 of each of the one or more administration cycles.

378. The method of any one of claims 318 to 377, comprising administering to the subject the PD-1 axis binding antagonist prior to the anti-TIGIT antagonist antibody.

379. The method of claim 378, comprising a first observation period after administration of the PD-1 axis binding antagonist and a second observation period after administration of the anti-TIGIT antagonist antibody.

380. 380. The method of claim 379, wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

381. The method of any one of claims 318 to 377, comprising administering to the subject the anti-TIGIT antagonist antibody prior to the PD-1 axis binding antagonist.

382. The method of claim 381, comprising a first observation period after administration of the anti-TIGIT antagonist antibody and a second observation period after administration of the PD-1 axis binding antagonist.

383. 383. The method of claim 382, ​​wherein the first observation period and the second observation period are each from about 30 minutes to about 60 minutes in length.

384. The method of any one of claims 318 to 377, comprising administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist simultaneously to the subject.

385. The method of any one of claims 318 to 384, comprising intravenously administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject.

386. 386. The method of claim 385, comprising administering the anti-TIGIT antagonist antibody to the subject by intravenous infusion over 60±10 minutes.

387. 387. The method of claim 385 or 386, comprising administering the PD-1 axis binding antagonist to the subject by intravenous infusion over a period of 60±15 minutes.

388. The method of any one of claims 318 to 384, comprising subcutaneously administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist to the subject.

389. The method of any one of claims 318 to 388, wherein the PD-L1 positive tumor cell fraction of the subject is determined.

390. The method of claim 389, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

391. The method of claim 389 or 390, wherein the staining is part of an IHC assay.

392. 392. The method of claim 391, wherein the PD-L1 positive tumor cell fraction is greater than or equal to 1% tumor cells (TC) as determined by positive staining with anti-PD-L1 antibody SP263 or 22C3.

393. 393. The method of claim 392, wherein the PD-L1 positive tumor cell fraction is less than 1% TC as determined by positive staining with anti-PD-L1 antibody SP263 or 22C3.

394. 394. The method of claim 393, wherein said PD-L1 expression is calculated using a Ventana SP263 IHC assay.

395. 394. The method of claim 393, wherein the PD-L1 expression is calculated using the pharmDx 22C3 IHC assay.

396. 396. The method of any one of claims 318-395, wherein the detectable nucleic acid expression level of PD-L1 is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH, or a combination thereof.

397. 397. The method of any one of claims 318 to 396, wherein the lung cancer is non-small cell lung cancer (NSCLC).

398. 398. The method of claim 397, wherein the NSCLC is squamous NSCLC.

399. 398. The method of claim 397, wherein the NSCLC is non-squamous NSCLC.

400. The method of any one of claims 394 to 396, wherein the NSCLC is locally advanced unresectable NSCLC.

401. The method of any one of claims 397 to 400, wherein the NSCLC is stage III NSCLC.

402. The method of any one of claims 397 to 401, wherein the NSCLC is not stage IV NSCLC.

403. 403. The method of any one of claims 318-402, wherein the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement.

404. 404. The method of any one of claims 318 to 403, wherein the subject does not have an active Epstein-Barr virus (EBV) infection or does not have or is not suspected of having a known chronic active EBV infection.

405. The method of any one of claims 318-404, wherein the subject is negative for EBV IgM or negative by EBV PCR.

406. The method of claim 405, wherein the subject is negative for EBV IgM and negative by EBV PCR.

407. The method of claim 405 or 406, wherein the subject is positive for EBV IgG or positive for Epstein-Barr Nuclear Antigen (EBNA).

408. The method of claim 407, wherein the subject is positive for EBV IgG and positive for EBNA.

409. The method of any one of claims 318 to 408, wherein the subject is negative for EBV IgG or negative for EBNA.

410. The method of claim 409, wherein the subject is negative for EBV IgG and negative for EBNA.

411. The method of any one of claims 318 to 410, wherein the PFS is increased compared to a baseline PFS time.

412. The method of claim 411, wherein the reference PFS time is the median PFS time of a population of subjects who have received treatment comprising a PD-1 axis binding antagonist without an anti-TIGIT antagonist antibody.

413. 1. A method for treating a subject with NSCLC, comprising administering to the subject one or more dosing cycles of an anti-TIGIT antagonist antibody and atezolizumab, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of: A VH domain comprising the amino acid sequence of SEQ ID NO: 17 or 18; and a VL domain comprising the amino acid sequence of SEQ ID NO: 19, wherein the subject has previously received cCRT for lung cancer, the subject has not had disease progression after the cCRT, and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS compared to treatment with durvalumab without an anti-TIGIT antagonist antibody.

414. The method of claim 413, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

415. 414. The method of claim 413, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

416. 414. The method of claim 413, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of 840 mg every four weeks and atezolizumab is administered at a fixed dose of 1680 mg every four weeks.

417. 1. A method for treating a subject with NSCLC, comprising administering one or more dosing cycles of tiragolumab and atezolizumab to the subject, wherein the subject has previously received cCRT for lung cancer, the subject has not had disease progression after the cCRT, and the treatment (a) results in a CR or PR, and / or (b) results in increased PFS compared to treatment with durvalumab without tiragolumab.

418. 418. The method of claim 417, wherein tiragolumab is administered at a fixed dose of 600 mg every three weeks and atezolizumab is administered at a fixed dose of 1200 mg every three weeks.

419. 418. The method of claim 417, wherein tiragolumab is administered at a fixed dose of 420 mg every two weeks and atezolizumab is administered at a fixed dose of 840 mg every two weeks.

420. 418. The method of claim 417, wherein tiragolumab is administered at a fixed dose of 840 mg every 4 weeks and atezolizumab is administered at a fixed dose of 1680 mg every 4 weeks.

421. The method of any one of claims 413 to 420, wherein the subject has previously received at least two cycles of said cCRT.

422. 422. The method of any one of claims 413-421, wherein said cCRT comprises platinum-based chemotherapy.

423. 423. The method of any one of claims 413-422, wherein the cCRT comprises chest radiotherapy.

424. 424. The method of claim 423, wherein said thoracic radiation therapy is 60-66 Gy administered to said subject in 30-33 fractions.

425. 425. The method of any one of claims 413 to 424, wherein the cCRT is administered for therapeutic purposes.

426. The method of any one of claims 413 to 425, wherein the cCRT is administered as consolidation therapy.

427. The method of any one of claims 1 to 109 and 318 to 426, wherein the subject is a human.

428. An anti-TIGIT antagonist antibody and an anti-PD-L1 antagonist antibody for use in a method for treating a subject with lung cancer, wherein the method is the method of any one of claims 318 to 427.

429. 428. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject with lung cancer in combination with an anti-PD-L1 antagonist antibody, wherein said treatment is by the method of any one of claims 318 to 427.

430. 428. Use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for treating a subject with lung cancer in combination with an anti-TIGIT antagonist antibody, wherein said treatment is by the method of any one of claims 318 to 427.

431. The use of claim 429 or 430, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated separately.

432. The use of claim 429 or 430, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated together.

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