WO2021194481A1

WO2021194481A1 - Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies

Info

Publication number: WO2021194481A1
Application number: PCT/US2020/024526
Authority: WO
Inventors: Janet LAU; Diana Mendus; Raymond D. Meng; Heather Blythe STEVENS; Benjamin Wu; Xiaosong Zhang; Hila BARAK; Edward Namserk CHA; Hui Min Phyllis CHAN; Tien HOANG
Original assignee: Genentech, Inc.
Priority date: 2020-03-24
Filing date: 2020-03-24
Publication date: 2021-09-30

Abstract

The invention provides methods of dosing for the treatment of cancers. In particular, provided are methods, compositions, uses, and kits for treating subjects having cancer by administering an anti-TIG IT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)).

Description

DOSING FOR TREATMENT WITH ANTI-TIG IT AND ANTI-PD-L1 ANTAGONIST ANTIBODIES

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 24, 2020, is named 50474-221 W01_Sequence_Listing_3.24.20_ST25 and is 29,971 bytes in size.

FIELD OF THE INVENTION

The present invention relates to the treatment of cancer. More specifically, the invention concerns the treatment of patients having cancer by administering a combination of an anti-T-cell immunoreceptor with Ig and ITIM domains (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 OF THE INVENTION

Cancers are characterized by the uncontrolled growth of cell subpopulations. Cancers are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over eight million cancer deaths occurring each year. Cancer care thus represents a significant and ever-increasing societal burden.

There is a particularly pressing need for therapeutic approaches for treatment of locally advanced and metastatic cancers, which are common and difficult to treat. Locally advanced and metastatic lung cancers and pancreatic cancers, for example, represent a substantial challenge. More than half of patients with non-small cell lung cancer (NSCLC) are diagnosed with distant disease, which directly contributes to poor survival prospects. Despite improvements in the first-line treatment of patients with advanced NSCLC that have resulted in longer survival times and reduced disease-related symptoms, nearly all patients experience disease progression. Among pancreatic cancer patients, 80% present with advanced disease at initial diagnosis. Even patients who receive curative surgery will have disease relapses, resulting in 5-year survival rates of 25%-30% and 10% in patients with node-negative and node positive disease at pancreaticoduodenectomy, respectively. Patients who have locally advanced and unresectable disease often receive radiochemotherapy, resulting in a median overall survival of 9-13 months, but rarely offering long-term survival.

Therefore, there is a high unmet need for improved medical intervention.

SUMMARY OF THE INVENTION

The present invention includes methods of treating a subject having cancer by administering a combination of an anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)). Methods of the invention include dosing regimens characterized by frequency of administration and, in some embodiments, combination with one or more chemotherapeutic agents. Compositions, uses, and kits involving such combinations and/or dosing regimens are also provided herein. In one aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 700 mg to about 1000 mg (e.g., about 700 mg to about 800 mg, about 800 mg to about 900 mg, or about 900 mg to about 1000 mg, e.g., about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1000 mg, e.g., about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, or about 890) every four weeks and a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 1400 mg to 2000 mg (e.g., about 1500 mg to about 1900 mg, about 1600 mg to about 1800 mg, or about 1600 mg to about 1750 mg, e.g., about 1400 mg to about 1450 mg, about 1450 mg to about 1500 mg, about 1500 mg to about 1550 mg, about 1550 mg to about 1600 mg, about 1600 mg to about 1650 mg, about 1650 mg to about 1700 mg, about 1700 mg to about 1750 mg, about 1750 mg to about 1800 mg, about 1800 mg to about 1850 mg, about 1850 mg to about 1900 mg, about 1900 mg to about 1950 mg, or about 1950 mg to about 2000 mg, e.g., about 1600 mg, about 1620 mg, about 1640 mg, about 1650 mg, about 1660 mg, about 1670 mg, about 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1740 mg, or about 1750 mg) every four weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every four weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1600 mg to 1800 mg every four weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks. 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 is administered at a fixed dose of about 1680 mg every four weeks. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously.

In some embodiments, the one or more dosing cycles are each 28-day dosing cycles. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 of each 28-day dosing cycle.

In another aspect, provided herein are methods of treating a subject having a cancer by administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 300 mg to about 600 mg (e.g., about 350 mg to about 550 mg, about 400 mg to about 500 mg, or about 410 mg to about 450 mg, e.g., about 300 mg to about 320 mg, about 320 mg to about 340 mg, about 340 mg to about 360 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 400 mg to about 420 mg, about 420 mg to about 440 mg, about 440 mg to about 460 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 500 mg to about 520 mg, about 520 mg to about 540 mg, about 540 mg to about 560 mg, about 560 mg to about 580 mg, about 580 mg to about 600 mg, e.g., about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, or about 480 mg) every two weeks and a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 600 mg to about 1200 mg (e.g., about 700 mg to about 1100 mg, about 800 mg to about 1000 mg, or about 820 mg to about 900 mg, e.g., about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 1000 mg, about 1000 mg to about 1100 mg, or about 1100 mg to about 1200 mg, e.g., about 700 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, or about 950 mg) every two weeks. In some embodiments, the anti-TIG IT 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 PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to 1000 mg every two weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 840 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 and the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously.

In some embodiments, the one or more dosing cycles are each 28-day dosing cycles. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 and Day 15 of each 28-day dosing cycle.

In some embodiments of either of the previous aspects, the method does not comprise further administering to the subject one or more chemotherapeutic agents.

In some embodiments, the method comprises further administering to the subject one or more chemotherapeutic agents. In some embodiments, the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent. In some embodiments, the first chemotherapeutic agent is a platinum agent (e.g., carboplatin or cisplatin) and/or the second chemotherapeutic agent is a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed), a topoisomerase II inhibitor (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), or a taxane (e.g., paclitaxel or nab- paclitaxel)).

In some embodiments, the platinum agent is carboplatin or cisplatin and the non-platinum agent is pemetrexed. In some embodiments, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min. In some embodiments, the cisplatin is administered at a dose of about 75 mg/m². In some embodiments, the pemetrexed is administered at a dose of about 500 mg/m².

In some embodiments, the platinum agent is carboplatin or cisplatin and the non-platinum agent is paclitaxel. In some embodiments, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min. In some embodiments, the cisplatin is administered at a dose of about 75 mg/m². In some embodiments, the paclitaxel is administered at a dose of about 175-200 mg/m² (e.g., about 175 mg/m² or about 200 mg/m²).

In some embodiments, the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel. In some embodiments, the gemcitabine is administered at a dose of about 1000 mg/m². In some embodiments, the nab-paclitaxel is administered at a dose of about 125 mg/m².

In some of the preceding embodiments in which one or more chemotherapeutic agents are administered, the method comprises further administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents. In some embodiments, the one or more subsequent doses is equal to or lower than the preceding dose of the one or more chemotherapeutic agents (e.g., the one or more subsequent doses is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the preceding dose). In some embodiments, the one or more chemotherapeutic agents are each administered once per week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

In some embodiments, the method comprises further administering to the subject gemcitabine at a cumulative dose of about 1000 mg/m² to about 6000 mg/m² (e.g., about 2000 mg/m² to about 5000 mg/m², e.g., about 2500 mg/m² to about 3500 mg/m²) over the course of each 28-day dosing cycle (e.g., at a cumulative dose of about 3000 mg/m² over the course of each 28-day dosing cycle). In some embodiments, the gemcitabine is administered three times over the course of each 28-day dosing cycle.

In some embodiments, the gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, each dose of the gemcitabine is about 500 mg/m² to about 2000 mg/m² (e.g., about 1000 mg/m²). In some embodiments, the method comprises further administering to the subject nab-paclitaxel at a cumulative dose of about 200 mg/m² to about 600 mg/m² (e.g., about 250 mg/m² to about 500 mg/m², e.g., about 300 mg/m² to about 450 mg/m²) over the course of each 28-day dosing cycle (e.g., at a cumulative dose of about 375 mg/m² over the course of each 28-day dosing cycle). In some embodiments, the nab-paclitaxel is administered three times over the course of each 28-day dosing cycle. In some embodiments, the nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28- day dosing cycle. In some embodiments, each dose of the nab-paclitaxel is about 50 mg/m² to about 200 mg/m² (e.g., about 125 mg/m²).

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28-day dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 300 mg to about 600 mg (e.g., about 350 mg to about 550 mg, about 400 mg to about 500 mg, or about 410 mg to about 450 mg, e.g., about 300 mg to about 320 mg, about 320 mg to about 340 mg, about 340 mg to about 360 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 400 mg to about 420 mg, about 420 mg to about 440 mg, about 440 mg to about 460 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 500 mg to about 520 mg, about 520 mg to about 540 mg, about 540 mg to about 560 mg, about 560 mg to about 580 mg, about 580 mg to about 600 mg, e.g., about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, or about 480 mg) on Days 1 and 15 of each 28-day dosing cycle, a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 600 mg and 1200 mg (e.g., about 700 mg to about 1100 mg, about 800 mg to about 1000 mg, or about 820 mg to about 900 mg, e.g., about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 1000 mg, about 1000 mg to about 1100 mg, or about 1100 mg to about 1200 mg, e.g., about 700 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, or about 950 mg) on Days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 500 mg/m² to about 2000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle, and nab-paclitaxel at a dose of about 50 mg/m² to about 200 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle. In some embodiments, the gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, the nab-paclitaxel is administered at a dose of about 125 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, on Days 1 and 15 of each 28-day dosing cycle, the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the nab-paclitaxel is administered after the anti-TIGIT antagonist antibody, and the gemcitabine is administered after the nab- paclitaxel. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered intravenously. In some embodiments, the gemcitabine and the nab-paclitaxel are administered intravenously.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tiragolumab) at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist (e.g., atezolizumab) at a fixed dose of about 80 and 1600 mg every three weeks, a platinum agent every three weeks, and a non-platinum agent every three weeks. In some embodiments, the platinum agent is carboplatin or cisplatin and/or the non-platinum agent is an antimetabolite or a taxane. In some embodiments, the platinum agent is carboplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed). In some embodiments, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min. In other embodiments, the platinum agent is cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed). In some embodiments, the cisplatin is administered at a dose of 75 mg/m². In some embodiments, the antimetabolite is pemetrexed, and the pemetrexed is administered at a dose of about 500 mg/m². In some embodiments, the dosing regimen comprises an induction phase comprising four to six initial 21- day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the antimetabolite are administered on Day 1 of each 21 -day dosing cycle of the induction phase. In some embodiments, the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the platinum agent is administered after the anti-TIGIT antagonist antibody, and the antimetabolite is administered after the platinum agent. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg, the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min or the cisplatin is administered at a dose of 75 mg/m², and the pemetrexed is administered at a dose of about 500 mg/m², each on Day 1 of each 21 -day dosing cycle of the induction phase.

In some embodiments, the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more additional 21 -day dosing cycles, and wherein the anti-TIG IT antagonist antibody (e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., atezolizumab), and the antimetabolite (e.g., pemetrexed) are administered on Day 1 of each 21 -day dosing cycle of the maintenance phase. In some embodiments, the one or more additional 21 -day dosing cycles of the maintenance phase do not comprise administration of the platinum agent. In some embodiments, the platinum agent is carboplatin and the non-platinum agent is a taxane (e.g., paclitaxel).

In some embodiments, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min. In some embodiments, the taxane (e.g., paclitaxel) is administered at a dose of about 175-200 mg/m² (e.g., about 175 mg/m² or about 200 mg/m²).

In some embodiments, the dosing regimen comprises an induction phase comprising four to six initial 21 -day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the taxane are administered on Day 1 of each 21 -day cycle of the induction phase. In some embodiments, the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the platinum agent is administered after the anti-TIGIT antagonist antibody, and the taxane is administered after the platinum agent.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist at a fixed dose of about 80 and 1600 mg every three weeks, gemcitabine, and nab-paclitaxel. In some embodiments, the anti-TIGIT antagonist antibody is administered 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 at a fixed dose of about 600 mg every three weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to about 1400 mg every three weeks. In some embodiments, the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks. In some embodiments, the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks.

In some embodiments of any of the preceding methods, a tumor sample (e.g., a solid tumor sample, e.g., a lung tumor) from the subject has been determined to have a PD-L1 -positive tumor cell fraction. In some embodiments, the tumor sample from the subject has been determined to have a PD- L1 -positive tumor cell fraction of greater than, or equal to, 30% (e.g., greater than, or equal to, 50%). In some embodiments, the PD-L1 -positive tumor cell fraction has been determined by an immunohistochemical (IHC) assay. In some embodiments, the PD-L1 -positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody suitable for staining, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8. In some embodiments, 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.

In some embodiments, the PD-L1 -positive tumor cell fraction is calculated using the Ventana SP263 IHC assay. In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50%, as determined by positive staining with the anti-PD-L1 antibody 22C3. In some embodiments, the PD-L1 - positive tumor cell fraction is calculated using the pharmDx 22C3 IHC assay. In some embodiments, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 30% (e.g., greater than, or equal to, 50%), as determined by positive staining with the anti-PD-L1 antibody SP142. In some embodiments, the PD- L1 -positive tumor cell fraction is greater than, or equal to, 50%, as determined by positive staining with the anti-PD-L1 antibody 28-8.

In some embodiments, a tumor sample from the subject has been determined to have a detectable nucleic acid expression level of PD-L1 , e.g., as determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

In some embodiments, the cancer is a lung cancer, e.g., a non-small cell lung cancer (NSCLC), e.g., a squamous NSCLC or a non-squamous NSCLC. In some embodiments, the NSCLC is a locally advanced unresectable NSCLC. In some embodiments, the NSCLC is a Stage NIB NSCLC. In some embodiments, the NSCLC is a recurrent or metastatic NSCLC (e.g., a Stage IV NSCLC). In some embodiments, the subject has not been previously treated for Stage IV NSCLC.

In some embodiments, the subject does not have a sensitizing epidermal growth factor receptor ( EGFR ) gene mutation or anaplastic lymphoma kinase ( ALK) gene rearrangement. In some embodiments, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

In some embodiments, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection and/or the subject is negative for EBV IgM or negative by EBV PCR (e.g., the subject is negative for EBV IgM and negative by EBV PCR).

In some embodiments, the subject is positive for EBV IgG or positive for Epstein-Barr nuclear antigen (EBNA). In some embodiments, the subject is positive for EBV IgG and positive for EBNA. In other embodiments, the subject is negative for EBV IgG or negative for EBNA.

In some embodiments of any of the preceding methods, the anti-TIG IT 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 (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an 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 FRs: an FR-H1 comprising the amino acid sequence of Xi VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11 ), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of ITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). In some embodiments, Xi is E. In other embodiments, Xi is Q.

In some embodiments, the anti-TIG IT antagonist antibody comprises: (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) a VH domain as in (a) and a VL domain as 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. In some embodiments, the anti-TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 17 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti- TIGIT antagonist antibody comprises: a VH domain comprising the amino acid sequence of SEQ ID NO: 18 and a VL domain comprising the amino acid sequence of SEQ ID NO: 19.

In some embodiments of any of the preceding methods, 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.

In some embodiments, the anti-TIGIT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments. In some embodiments, the anti-TIGIT antagonist antibody is an IgG class antibody (e.g., an lgG1 subclass antibody).

In some embodiments of any of the preceding methods, 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. In some embodiments, the anti-PD-L1 antagonist antibody 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, e.g., nivolumab (MDX-1106), pembrolizumab (MK-3475), or AMP-224.

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 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) a VH domain as in (a) and a VL domain as 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.

In some embodiments of any of the preceding methods, 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. In some embodiments, the PD-1 axis binding antagonist is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments. In some embodiments, the PD-1 axis binding antagonist is an antibody fragment that binds PD-1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments. In some embodiments, the PD-1 axis binding antagonist is an IgG class antibody (e.g., an IgG 1 subclass antibody).

In some embodiments of any of the preceding methods, the method comprises administering to the subject the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody. In some embodiments, the method comprises a first observation period following administration of the PD-1 axis binding antagonist and 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 between about 30 minutes to about 60 minutes in length.

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

In some embodiments, the method comprises administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist simultaneously.

In some embodiments, the method comprises administering to the subject the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously. In some embodiments, the method comprises administering to the subject the anti-TIGIT antagonist antibody by intravenous infusion over 60 ± 10 minutes and/or administering to the subject the PD-1 axis binding antagonist by intravenous infusion over 60 ± 15 minutes.

In some embodiments, the method comprises administering to the subject the one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) intravenously (e.g., by intravenous infusion).

In some embodiments of the any of the preceding methods, the cancer is a solid tumor. In some embodiments, the cancer is locally advanced or metastatic. In some embodiments, the cancer is a lung cancer (e.g., a small cell lung cancer (SCLC), a non-small cell lung cancer (NSCLC)), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative). In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the pancreatic cancer is a pancreatic duct adenocarcinoma (PDAC). In some embodiments, the PDAC is a metastatic PDAC.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 840 mg every four weeks and atezolizumab at a fixed dose of about 1680 mg every four weeks.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 420 mg every two weeks and atezolizumab at a fixed dose of about 840 mg every two weeks.

In some embodiments, the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent. In some embodiments, the first chemotherapeutic agent is a platinum agent and the second chemotherapeutic agent is a non-platinum chemotherapeutic agent. In some embodiments, the platinum agent is carboplatin or cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed), a topoisomerase II inhibitor (e.g., etoposide), or a taxane (e.g., paclitaxel).

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks or cisplatin at a dose of 75 mg/m² every three weeks, and pemetrexed at a dose of about 500 mg/m² every three weeks. In some embodiments, the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks, and paclitaxel at a dose of about 200 mg/m² every three weeks. In some embodiments, the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.

In another aspect, the invention features a method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks, and paclitaxel at a dose of about 175 mg/m² every three weeks. In some embodiments, the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.

In some embodiments, the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent, wherein the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel. In some embodiments, the cancer is a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC).

In another aspect, the invention features a method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28- day dosing cycles of tiragolumab at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle, atezolizumab at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle, and nab-paclitaxel at a dose of about 125 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle. In some embodiments, the cancer is a pancreatic cancer (e.g., PDAC, e.g., metastatic PDAC).

In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle).

In some embodiments, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).

In some embodiments of any of the preceding aspects, the treatment results in a complete response or a partial response. In some embodiments, the treatment results in an increase in progression-free survival of the subject as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

In some embodiments of any of the preceding aspects, the subject is a human.

In another aspect, the invention features a kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to any of the preceding methods. In some embodiments, the kit further comprises the PD-1 axis binding antagonist. In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab.

In another aspect, the invention features a kit comprising a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody for treating a subject having a cancer according to any of the preceding methods. In some embodiments, the kit further comprises the anti-TIGIT antagonist antibody. In some embodiments, the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab. In another aspect, the invention provides an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in the method of any of the preceding aspects for treating a subject having a cancer.

In another aspect, provided herein is a use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of the preceding aspects.

In another aspect, provided herein is a use of a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having a cancer in combination with an anti-TIGIT antagonist antibody, wherein the treatment is according to the method of any one of the preceding aspects. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated separately. In some embodiments, the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated together.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase lb Q4W dosing expansion).

DETAILED DESCRIPTION

The present invention is based, at least in part, on the discovery that immunotherapies including an anti-TIGIT antibody (e.g., an anti-TIGIT antagonist antibody, such as tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., an anti-programmed death ligand-1 (PD-L1 ) antibody (e.g., atezolizumab) or an anti-programmed death-1 (PD-1) antibody) can be useful in the treatment of cancer (e.g., a solid tumor or a locally advanced or metastatic cancer (e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)))). In certain aspects, the invention features combinations of an anti-TIGIT antibody (e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., atezolizumab), and one or more chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))). Compositions, uses, and kits involving such combinations and/or dosing regimens are also provided herein. 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, such as, for example, the widely utilized methodologies described in Sambrook et al. , Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, 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.l. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.l. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology ( D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V T . DeVita et al., eds.,

J.B. Lippincott Company, 1993).

II. DEFINITIONS

It is to be understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments. As used herein, the singular form “a,” “an,” and “the” includes plural references unless indicated otherwise.

The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

The “amount,” “level,” or “expression level,” used herein interchangeably, of a biomarker is a detectable level in a biological sample. “Expression” generally refers to the process by which information (e.g., gene-encoded and/or epigenetic) is converted into the structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., 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 (for example, transfer and ribosomal RNAs). Expression levels can be measured by methods known to one skilled in the art and also disclosed herein.

The presence and/or expression level/amount of various biomarkers described herein in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, 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 enzymatic activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), Southern analysis, 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 type detection methods, such as, for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray analysis, gene expression profiling, and/or serial analysis of gene expression (“SAGE”), as well as any one of the wide variety of assays that can be performed by protein, gene, and/or tissue array analysis. Typical protocols for evaluating the status of genes and gene products are found, for example in Ausubel et al., eds., 1995, Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4 (Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Multiplexed immunoassays such as those available from Rules Based Medicine or Meso Scale Discovery (“MSD”) may also be used.

The term “TIGIT” or “T -cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM. The term encompasses “full-length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 30), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 31). The term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1 .

The term “PD-L1” or “Programmed Cell Death Ligand 1 ” refers herein to any native PD-L1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. PD-L1 is also known in the art as CD274 molecule, CD274 antigen, B7 homolog 1 , PDCD1 Ligand 1 , PDCD1 LG1 , PDCD1 L1 , B7H1 , PDL1 , programmed death ligand 1 , B7-H1 , and B7-H. The term also encompasses naturally occurring variants of PD-L1 , e.g., splice variants, or allelic variants. The amino acid sequence of an exemplary human PD-L1 may be found under UniProt Accession Number Q9NZQ7 (SEQ ID NO: 32).

The term “antagonist” is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a 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, etc. Methods for identifying antagonists of a polypeptide may comprise contacting a polypeptide with a candidate antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.

The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist.

The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 , PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the 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 decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD- 1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist is MDX- 1106 (nivolumab) described herein. In another specific aspect, a PD-1 binding antagonist is pembrolizumab (formerly lambrolizumab (MK-3475)) described herein. In another specific aspect, a PD-1 binding antagonist is AMP-224 described herein.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 , 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, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 . In some embodiments, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD- 1 , B7-1 . In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific aspect, an anti-PD-L1 antibody is atezolizumab described herein (e.g., MPDL3280A). In another specific aspect, an anti-PD-L1 antibody is MDX-1105 described herein. In still another specific aspect, an anti- PD-L1 antibody is MEDI4736 described herein. The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 . In some embodiments, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD- L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin.

The term “anti-TIG IT antagonist antibody” refers to an antibody or an antigen-binding fragment or variant thereof that is capable of binding TIGIT with sufficient affinity such that it substantially or completely inhibits the biological activity of TIGIT. For example, an anti-TIG IT antagonist antibody may block signaling through PVR, PVRL2, and/or PVRL3 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation. For example, an anti-TIGIT antagonist antibody may block signaling through PVR without impacting PVR- CD226 interaction. It will be understood by one of ordinary skill in the art that in some instances, 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 of the methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions. 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, e.g., by a radioimmunoassay (RIA). In certain embodiments, an anti-TIGIT antagonist antibody that binds to TIGIT has a dissociation constant (KD) of < 1 mM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10⁸ M or less, e.g. from 10⁸ M to 10¹³ M, e.g., from 10⁹ M to 10¹³ M). In certain embodiments, an anti-TIGIT antagonist antibody binds to an epitope of TIGIT that is conserved among TIGIT from different species or an epitope on TIGIT that allows for cross-species reactivity. In one embodiment, the anti-TIGIT antagonist antibody is tiragolumab.

As used herein, “administering” is meant a method of giving a dosage of a compound (e.g., an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), or a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an anti-TIGIT antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), and/or a chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) to a subject. The compounds and/or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. 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).

A “fixed” or “flat” dose of a therapeutic agent (e.g., an anti-TIG IT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody)) herein refers to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose is therefore not provided as a mg/kg dose or a mg/m² dose, but rather as an absolute amount of the therapeutic agent (e.g., mg).

As used herein, the term “treatment” or “treating” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.

As used herein, “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.

A “disorder” or “disease” is any condition that would benefit from treatment including, but not limited to, disorders that are associated with some degree of abnormal cell proliferation, e.g., cancer, e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)), kidney or renal cancer (e.g., renal cell carcinoma (RCC)), melanoma, head and neck cancer (e.g., head and neck squamous cell cancer (HNSCC)), ovarian cancer (OC), gastric cancer (GC) (e.g., gastroesophageal junction (GEJ) cancer), bladder cancer (e.g., urothelial bladder cancer (UBC)), colorectal cancer (CRC), or breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative). The term “dysfunction,” in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation.

The term “dysfunctional,” as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into downstream T-cell effector functions, such as proliferation, cytokine production (e.g., gamma interferon) and/or target cell killing.

The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Cancers include locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors). Particular examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include, but are not limited to, lung cancer, such as small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung, or squamous cell cancer (e.g., epithelial squamous cell cancer); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)); head and neck cancer (e.g., head and neck squamous cell cancer (HNSCC)), ovarian cancer (OC), esophageal cancer; cancer of the peritoneum; hepatocellular cancer; gastric cancer (GC) (e.g., gastroesophageal junction (GEJ) cancer) or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; glioblastoma; cervical cancer; liver cancer; bladder cancer (e.g., urothelial bladder cancer (UBC), muscle invasive bladder cancer (MIBC), and BCG-refractory non-muscle invasive bladder cancer (NMIBC)); cancer of the urinary tract; hepatoma; breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative); colon cancer; rectal cancer; colorectal cancer (CRC); endometrial or uterine carcinoma; salivary gland carcinoma; kidney or renal cancer (e.g., renal cell carcinoma (RCC)); prostate cancer; vulval cancer; thyroid cancer; hepatic carcinoma; anal carcinoma; penile carcinoma; melanoma, including superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, and nodular melanomas; 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- cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom’s Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myologenous leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs’ syndrome, brain cancer, and associated metastases.

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 as referred to herein.

“Tumor immunity” refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

As used herein, “metastasis” is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.

The term “anti-cancer therapy” refers to a therapy useful in treating cancer (e.g., lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)), kidney or renal cancer (e.g., renal cell carcinoma (RCC)), melanoma, head and neck cancer (e.g., head and neck squamous cell cancer (HNSCC)), ovarian cancer (OC), gastric cancer (GC) (e.g., gastroesophageal junction (GEJ) cancer), bladder cancer (e.g., urothelial bladder cancer (UBC)), colorectal cancer (CRC), or breast cancer). Examples of anti-cancer therapeutic agents include, but are limited to, e.g., immunomodulatory agents (e.g., an immunomodulatory agent (e.g., an agent that decreases or inhibits 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), such as a CTLA-4 antagonist, e.g., an anti-CTLA-4 antagonist antibody (e.g., ipilimumab (YERVOY®)), an anti-TIG IT antagonist antibody, or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), or an agent that increases or activates 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), such as an OX-40 agonist, e.g., an OX-40 agonist antibody), chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, agents used in radiation therapy, anti-angiogenesis agents, apoptotic agents, anti-tubulin agents, and other agents to treat cancer. Combinations thereof are also included in the invention.

The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹, I¹³¹, 1¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; 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 the various antitumor or anti-cancer agents disclosed below. “Chemotherapeutic agent” includes chemical compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA®, Genentech/OSI Pharm.), bortezomib (VELCADE®, Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX®, AstraZeneca), sunitib (SUTENT®, Pfizer/Sugen), letrozole (FEMARA®, Novartis), imatinib mesylate (GLEEVEC®, Novartis), finasunate (VATALANIB®, Novartis), oxaliplatin (ELOXATIN®, Sanofi), 5-FU (5-fluorouracil), leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR®, Bayer Labs), gefitinib (IRESSA®, AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin g11 and calicheamicin w11 (Angew Chem. Inti. Ed. Engl. 199433:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T- 2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (e.g., nanoparticle albumin- engineered paclitaxel (nab-paclitaxel)) (American Pharmaceutical Partners, Schaumberg, III.), and TAXOTERE® (docetaxel, doxetaxel; Sanofi-Aventis); chloranmbucil; GEMZAR® (gemcitabine); 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene , 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all trans retionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors (e.g., an anaplastic lymphoma kinase (Aik) inhibitor, such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, 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®, and VAXID®; PROLEUKIN®, rlL-2; a topoisomerase 1 inhibitor such as LURTOTECAN®; ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Chemotherapeutic agent also includes antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), 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, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human-sequence, full-length IgG 1 l antibody genetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agent also includes “EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an “EGFR antagonist.” Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which 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, US Patent 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.); IMC-11 F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891 ,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); 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 US 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)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001 , 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521 ,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391 ,874, 6,344,455, 5,760,041 , 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451 , W098/50038, W099/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP- 358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4- d]pyrimidine-2, 8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1 H-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-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); 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).

Chemotherapeutic agents also include “tyrosine kinase inhibitors” including the EGFR-targeted drugs noted in the preceding paragraph; inhibitors of insulin receptor tyrosine kinases, including anaplastic lymphoma kinase (Aik) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib), ASP3026, X396, LDK378, AP26113, crizotinib (XALKORI®), and ceritinib (ZYKADIA®); small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR- overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKIine), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (Cl- 1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVEC®, available from Glaxo SmithKIine); 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; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521 ; Isis/Lilly); imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKIine); CI-1033 (Pfizer); EKB- 569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1 C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent 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); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

Chemotherapeutic agents also include dexamethasone, interferons, colchicine, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacuzimab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alfa-2a, interferon alfa-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed (e.g., 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.

Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Flumira), certolizumab pegol (Cimzia), golimumab (Simponi), 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; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTa1/p2 blockers such as Anti- lymphotoxin alpha (LTa); radioactive isotopes (e.g., At211 , 1131 , 1125, Y90, Re186, Re188, Sm153,

Bi212, P32, Pb212 and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341 , phenylbutyrate, ET-18- OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9- tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; acetylcamptothecin, scopolectin, and 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin.

Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

Chemotherapeutic agents also include “platinum-based” chemotherapeutic agents, also referred to herein as “platinum agents,” which comprise an organic compound which contains platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes called “platins” in the art. Examples of platinum-based chemotherapeutic agents include, but are not limited to, carboplatin, cisplatin, and oxaliplatin.

Chemotherapeutic agents also include “non-platinum agents,” which, as used herein, refer to chemotherapeutic agents that are not “platinum-based.” Exemplary non-platinum agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), taxanes (e.g., paclitaxel (e.g., albumin-engineered paclitaxel, also referred to as nanoparticle- albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).

A “taxane” as used herein is a diterpene which may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization. Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof. Examplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS # 33069-62-4), docetaxel (i.e., TAXOTERE®, CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel. In some embodiments, the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e., ABRAXANE® and/or nab-docetaxel, ABI-008). In some embodiments, the taxane is nab-paclitaxel (ABRAXANE®). In some embodiments, the taxane is formulated in CREMAPHOR® (e.g., TAXOL®) and/or in Tween such as polysorbate 80 (e.g., TAXOTERE®). In some embodiments, the taxane is liposome-encapsulated taxane. In some embodiments, the taxane is a prodrug form and/or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleyl carbonate-paclitaxel). In some embodiments, the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR and/or Tween-such as TOCOSOL® paclitaxel).

An “antimetabolite” as used herein is a chemotherapeutic agent that interferes with and inhibits (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.

An “effective amount” of a compound, for example, an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., anti-PD-L1 antibody), and/or a chemotherapeutic agent (e.g., a platinum agent, pemetrexed, a topoisomerase II inhibitor, paclitaxel (e.g., nab-paclitaxel), or gemcitabine) or a composition thereof (e.g., a pharmaceutical composition thereof, e.g., a pharmaceutical composition including an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antibody), and/or a chemotherapeutic agent (e.g., a platinum agent, pemetrexed, a topoisomerase II inhibitor, paclitaxel (e.g., nab-paclitaxel), or gemcitabine)) is at least the minimum amount required to achieve the desired therapeutic result, such as a measurable increase in overall survival or progression-free survival of a particular disease or disorder (e.g., cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative))). An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the subject.

An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSE), reduction in symptoms per the European Organization for Research and Treatment of Cancer Qual ity-of-Life Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or general level of physical emotional, cognitive, or social functioning), reduction in pain as measured by, e.g., the 10-point pain severity (measured at its worst) numerical rating scale (NRS), and/or reduction in symptoms associated with lung cancer per the health- related quality of life (HRQoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspenea and chest pain), increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease (e.g. progression-free survival or radiographic progression-free survival (rPFS); delay of unequivocal clinical progression (e.g., cancer-related pain progression, symptomatic skeletal-related event, deterioration in Eastern Cooperative Group Oncology Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily living abilities of the patient), and/or initiation of next systemic anti-cancer therapy), and/or delaying time to lung-specific antigen progression), and/or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations.

For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, 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” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

“Immunogenicity” refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response. Examples of enhancing tumor immunogenicity include but are not limited to treatment with a TIGIT and/or PD-L1 antagonist (e.g., anti-TIG IT antagonist antibodies and/or anti-PD-L1 antibodies).

“Individual response” or “response” can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., progression of cancer, e.g., e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative))), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e. reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer); (6) increase or extend in the length of survival, including overall survival and progression-free survival; and/or (9) decreased mortality at a given point of time following treatment.

As used herein, “complete response” or “CR” refers to disappearance of all target lesions.

As used herein, “partial response” or “PR” refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD.

As used herein, “objective response rate” (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate. 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 a treatment, whichever occurs first.

“Sustained response” refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1 .5x, 2. Ox, 2.5x, or 3. Ox length of the treatment duration.

An “effective response” of a subject or a subject’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a subject as risk for, or suffering from, a disease or disorder, such as cancer. In one embodiment, such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.

A subject who “does not have an effective response” to treatment refers to a subject who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.

As used herein, “survival” refers to the patient remaining alive, and includes overall survival as well as progression-free survival.

As used herein, “overall survival” (OS) refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., 1 year or 5 years from the time of diagnosis or treatment.

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., SCLC, e.g., ES- SCLC) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.

As used herein, “stable disease” or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.

As used herein, “progressive disease” or “PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.

As used herein, “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., cancer, e.g., lung cancer, e.g., SCLC, e.g., ES-SCLC). This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated. As is evident to one skilled 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 a late stage cancer, development of central nervous system (CNS) metastasis, may be delayed. As used herein, the term “reducing or inhibiting cancer relapse” means to reduce or inhibit tumor or cancer relapse, or tumor or cancer progression.

By “reduce or inhibit” is meant the ability to cause an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. Reduce or inhibit can refer to the symptoms of the disorder being treated (e.g., cancer, e.g., lung cancer, e.g., SCLC, e.g., ES-SCLC), the presence or size of metastases, or the size of the primary tumor.

By “extending survival” is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent. An objective response refers to a measurable response, including complete response (CR) or partial response (PR).

As used herein, the “Ventana SP263 IHC assay” is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

As used herein, the “Ventana SP142 IHC assay” is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

As used herein, the “pharmDx 22C3 IHC assay” is conducted according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

A “tumor-infiltrating immune cell,” as used herein, refers to any immune cell 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 stroma cells (e.g., fibroblasts), or any combination thereof. Such tumor-infiltrating immune cells can be, for example, T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.

The term “biomarker,” as used herein, refers to an indicator, e.g., predictive, diagnostic, and/or prognostic, which can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder (e.g., cancer, e.g., e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)))) characterized by certain, molecular, pathological, histological, and/or clinical features. In some embodiments, a biomarker is a gene. Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA, and/or RNA), polynucleotide copy number alterations (e.g.,

DNA copy numbers), polypeptide and polynucleotide modifications (e.g., posttranslational modifications), carbohydrates, and/or glycolipid-based molecular markers. In some embodiments, the biomarker is PD- L1 .

The term “antibody” includes monoclonal antibodies (including full-length antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies, and single-chain molecules, as well as antibody fragments, including antigen-binding fragments, such as Fab, F(ab’)2, and Fv. The term “immunoglobulin” (Ig) is used interchangeably with “antibody” herein.

The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4-chain units which can polymerize to form polyvalent assemblages in combination with the J chain. In the case of IgGs, the 4-chain unit is generally about 150,000 Daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while 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 has at the N-terminus, a variable domain (VH) followed by three constant domains (CH) for each of the a and g chains and four CH domains for m and e isotypes. Each L chain has at the N-terminus, a variable domain (VL) followed by a constant domain at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (CH1 ). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated a, d, e, g, and m, respectively. The g and a classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, e.g., humans express the following subclasses: lgG1 , lgG2A, lgG2B, lgG3, lgG4, lgA1 and lgA2.

The term “hypervariable region” or “HVFt” refers to the regions of an antibody variable domain which are hypervariable in sequence and/or form structurally defined loops. Generally, antibodies comprise six HVRs; three in the VH (H1 , H2, H3), and three in the VL (L1 , L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et at., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1 -25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman etal., Nature 363:446-448 (1993); Sheriff etal., Nature Struct. Biol. 3:733-736 (1996).

A number of HVR delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The AbM HVRs represent a compromise between the Kabat HVRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software. The “contact” HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted 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

HVRs may comprise “extended HVRs” as follows: 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 etal., supra, for each of these definitions.

The expression “variable-domain residue-numbering as in Kabat” or “amino-acid-position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat etal., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues ( e.g . residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

The term “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, the variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from 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 Institute of Health, Bethesda, MD (1991 )). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody- dependent cellular toxicity.

The “variable region” or “variable domain” of an antibody refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.

“Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1- H1 (L1 )-FR2-H2(L2)-FR3-H3(L3)-FR4.

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, whole antibodies include those with 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, the 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 the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab’, F(ab’)2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641 ,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produced two identical antigen-binding fragments, called “Fab” fragments, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1 ). 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 having different antigen-binding activity and is still capable of cross-linking antigen. Fab’ fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

The Fc fragment comprises the carboxy-terminal portions of both FI chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.

“Functional fragments” of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability. Examples of antibody fragments include linear antibody, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

“Fv” is the minimum antibody fragment which contains a complete antigen-recognition and - binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

“Single-chain Fv” also abbreviated as “sFv” or “scFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of the sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl- terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies of the invention include human IgG 1 , lgG2 (lgG2A, lgG2B), lgG3 and lgG4. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 .

“Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.

(see M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel etal., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein.

The term “diabodies” refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two “crossover” sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described in greater detail in, for example, EP 404,097; WO 93/11161 ; Hollinger etal., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).

The monoclonal antibodies herein specifically include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with 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(are) identical with 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. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED^® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest.

As used herein, “humanized antibody” is used a subset of “chimeric antibodies.”

The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, lgG3, lgG4, IgAi, and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, d, e, g, and m, respectively.

“Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen, e.g., TIGIT or PD- L1). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). 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 in the following.

A “human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising 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 etal., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are 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). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.

“Humanized” forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR (hereinafter defined) 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 the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. In general, 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 are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR are typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally will also comprise 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 also, for example, 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. Pat. Nos. 6,982,321 and 7,087,409.

The term an “isolated antibody” when used to describe the various antibodies disclosed herein, means an antibody that has been identified and separated and/or recovered from a cell or cell culture from which it was expressed. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS- PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). In preferred embodiments, the antibody will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of 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 antibody includes antibodies in situ within recombinant cells, because at least one component of the polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g., isomerizations, amidations) that 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, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (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, 2^nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T- Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), phage-display technologies (see, e.g., Clackson etal., Nature, 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Sidhu etal., J. Mol. Biol. 338(2): 299-310 (2004); Lee etal., 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 technologies for producing human or human-like antibodies in animals that have parts 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 etal., 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 Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661 ,016; Marks etal., Bio/Technology 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).

As used herein, the term “binds,” “specifically binds to,” or is “specific for” refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, for example, by a radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (KD) of < 1 mM, < 100 nM, < 10 nM, < 1 nM, or < 0.1 nM. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species. In another embodiment, specific binding can include, but does not require exclusive binding. The term as used herein can be exhibited, for example, by a molecule having a KD for the target of 10^_4 M or lower, alternatively 10^_5 M or lower, alternatively 10^-6 M or lower, alternatively 10^-7 M or lower, alternatively 10^-8 M or lower, alternatively 10^-9 M or lower, alternatively 10^_1° M or lower, alternatively 10^-11 M or lower, alternatively 10^-12 M or lower or a KD in the range of 10^-4 M to 10^-6 M or 10^-6 M to 10^-10 M or 10^-7 M to 10^-9 M. As will be appreciated by the skilled artisan, affinity and KD values are inversely related. A high affinity for an antigen is measured by a low KD value. In one embodiment, the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

“Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

As used herein, “subject” or “individual” is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human. Patients are also subjects herein.

The term “sample,” as used herein, refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics. For example, the phrase “tumor sample,” “disease sample,” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is 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., squamous or non-squamous NSCLC tumor tissue sample, e.g., locally advanced unresectable NSCLC tumor tissue sample (e.g., Stage NIB NSCLC tumor tissue sample), or recurrent or metastatic NSCLC tumor tissue sample (e.g., 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, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, stool, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, cellular extracts, and combinations thereof.

By “tissue sample” or “cell sample” is meant a collection of similar cells obtained from a tissue of a subject or individual. The source of the tissue or cell sample may be solid tissue as from a fresh, frozen, and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject. The tissue sample may also be primary or cultured cells or cell lines. Optionally, the tissue or cell sample is obtained from a diseased tissue/organ. The tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.

A “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject. For example, healthy and/or non-diseased cells or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of a subject who is not the subject. In even another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject.

The term “protein,” as used herein, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

“Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length, and include DNA and RNA. The nucleotides can 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 instance, polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA including single- and double-stranded regions, single- and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single- stranded or, more typically, double-stranded or include single- and double-stranded regions. In addition, the term “polynucleotide” as used herein refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules. The regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. The terms “polynucleotide” and “nucleic acid” specifically includes mRNA and cDNAs.

A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification 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, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, and the like) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the like), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, and the like), those with intercalators (e.g., acridine, psoralen, and the like), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, and the like), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids), as well as unmodified forms of the polynucleotide(s). Further, any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5’ and 3’ terminal OFI can be phosphorylated or substituted with amines or organic capping group moieties of from 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 that are generally known in the art, including, for example, 2’-0-methyl-, 2’-0-allyl-, 2’-fluoro-, or 2’-azido-ribose, carbocyclic sugar analogs, a-anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, 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 wherein phosphate is replaced by P(0)S (“thioate”), P(S)S (“dithioate”), “(0)NR2 (“amidate”), P(0)R, P(0)OR’, CO or CH2 (“formacetal”), in which each R or R’ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical. The preceding description applies to all polynucleotides referred to herein, including RNA and DNA.

“Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; 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 dextrins; 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™.

The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

III. THERAPEUTIC METHODS AND USES

Provided herein are methods and uses for treating cancer (e.g., a solid tumor and/or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)) in a subject comprising administering to the subject one or more dosing cycles of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab).

The present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, administration of the effective amount of 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, such as atezolizumab) results in a complete response (CR) or a partial response (PR). In some instances, administration of the effective amount of 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, such as atezolizumab) results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

In some instances, the effective amount of 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, such as atezolizumab) extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

The present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every four weeks (e.g., on Day 1 of each 28-day dosing cycle).

In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in progression-free survival of the subject compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends overall survival of the subject.

The present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab) to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, administration of the effective amount of 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, such as atezolizumab) results in a complete response or a partial response. In some instances, administration of the effective amount of 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, such as atezolizumab) results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In some instances, administration of the effective amount of 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, such as atezolizumab) extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

In certain instances, the present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) to a subject in need thereof every two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle). In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) results in an increase in progression-free survival of the subject compared to a reference. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) extends overall survival of the subject.

In certain instances, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered without a chemotherapeutic agent (e.g., without any chemotherapeutic agent, e.g., the entire dosing regimen is devoid of administration of a chemotherapeutic agent to the subject). In some instances, the subject has not received chemotherapy within the month prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (e.g., within the two months prior, three months prior, four months prior, six months prior, one year prior, two years prior, three years prior, four years prior, five years prior, or ten years prior to the administration with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody). In some instances, the subject is chemotherapy naive.

In other embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered in conjunction with a chemotherapy. For example, a once-every-two-weeks (Q2W), once-every-three-weeks (Q3W), or once-every-four-weeks (Q4W) dosing regimen of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody can be administered in conjunction with one or more chemotherapeutic agents. The one or more chemotherapeutic agents can be administered at the same frequency as the frequency of administration of the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody (Q2W, Q3W, or Q4W) or at a different frequency. For example, in some embodiments, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every two weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody are administered every three weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks. Alternatively, the PD-1 axis binding antagonist and the anti-TIG IT antagonist antibody are administered every four weeks and the one or more chemotherapeutic agents is administered every two weeks, every three weeks, or every four weeks. In certain instances, a chemotherapeutic agent is administered multiple times per week (e.g., 2,

3, 4, 5, 6 or 7 times per week (e.g., at Days 1 , 2, and 3 of a dosing cycle).

In some embodiments, the dose of a chemotherapeutic agent is reduced after one or more initial doses (e.g., after one, two, three, four, or more initial doses). For example, a subsequent dose of the chemotherapeutic agent (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) can be administered at about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial dose. For example, an initial dose of nab-paclitaxel of 125 mg/m² can be reduced for a subsequent dose, e.g., to 100 mg/m² or 75 mg/m²; an initial dose of paclitaxel of about 175 mg/m² can be reduced for a subsequent dose, e.g., to 150 mg/m², 125 mg/m², 100 mg/m², or 75 mg/m²; an initial dose of paclitaxel of about 200 mg/m² can be reduced for a subsequent dose, e.g., to 175 mg/m², 150 mg/m²,

125 mg/m², 100 mg/m², or 75 mg/m²; an initial dose of gemcitabine of about 1000 mg/m² can be reduced for a subsequent dose, e.g., to 900 mg/m², 800 mg/m², 750 mg/m², 700 mg/m², 600 mg/m², or 500 mg/m²; an initial dose of cisplatin of about 75 mg/m² can be reduced for a subsequent dose, e.g., to 70 mg/m², 65 mg/m², 60 mg/m², 55 mg/m², 50 mg/m², or 45 mg/m²; an initial dose of pemetrexed of about 500 mg/m² can be reduced for a subsequent dose, e.g., to 450 mg/m², 400 mg/m², 350 mg/m², 300 mg/m², 250 mg/m², or 200 mg/m²; and/or an initial dose of carboplatin of a dose sufficient to achieve AUC = 6 mg/ml/min can be reduced for a subsequent dose, e.g., to a dose sufficient to achieve AUC = 5.5. mg/ml/min, 5.0 mg/ml/min, 4.5 mg/ml/min, or 4.0 mg/ml/min.

The present invention includes methods and uses involving administration of an effective amount of an anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof. In some embodiments, the anti-TIGIT antagonist antibody (e.g., 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the chemotherapy combination includes an effective amount of a first non-platinum agent and an effective amount of a second non-platinum agent. In some instances, the first non-platinum agent is an antimetabolite and the second non-platinum agent is a taxane. In some embodiments, the chemotherapy combination (e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)) is administered weekly, biweekly, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), gemcitabine, and paclitaxel to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle) and the chemotherapy combination (e.g., the antimetabolite and the taxane (e.g., gemcitabine and paclitaxel)) is administered more frequently (e.g., three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).

In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) results in an increase in progression-free survival of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) extends overall survival of the subject.

In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the antimetabolite (e.g., gemcitabine), and the taxane (e.g., paclitaxel) is being treated for a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)).

The present invention includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent. In some instances, the anti-TIGIT antagonist antibody (e.g., 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some instances, the platinum agent is carboplatin or cisplatin and the non-platinum agent is an antimetabolite (e.g., pemetrexed). In some embodiments, the chemotherapy combination (e.g., the platinum agent and the antimetabolite (e.g., pemetrexed)) are administered weekly, every two weeks, every four weeks, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and an antimetabolite (e.g., pemetrexed) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., anti-TIG IT 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 three weeks (e.g., on Day 1 of each 21 -day dosing cycle) and the chemotherapy combination (e.g., the platinum agent (e.g., carboplatin or cisplatin) and the antimetabolite (e.g., pemetrexed) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21 -day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles).

After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum agent.

In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) results in an increase in progression- free survival of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) extends overall survival of the subject.

In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the antimetabolite (e.g., pemetrexed) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)). The present invention also includes methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent, wherein the non-platinum agent is a taxane (e.g., paclitaxel or nab-paclitaxel). In some instances, the anti-TIGIT antagonist antibody (e.g., 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some embodiments, the chemotherapy combination (e.g., the platinum agent and the taxane (e.g., paclitaxel or nab-paclitaxel)) are administered weekly, every two weeks, every four weeks, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle).

In particular embodiments, the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and a taxane (e.g., paclitaxel or nab-paclitaxel) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., 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 three weeks (e.g., on Day 1 of each 21 -day dosing cycle) and the chemotherapy combination (e.g., the platinum agent (e.g., carboplatin or cisplatin) and the taxane (e.g., paclitaxel or nab-paclitaxel) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21 -day dosing cycle). In some instances, the dosing continues for four-to-six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum agent.

In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) results in a complete response or a partial response. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) results in an increase in progression-free survival of the subject. In some instances, administration of the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab- paclitaxel) extends overall survival of the subject. In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the taxane (e.g., paclitaxel or nab-paclitaxel) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)).

Also provided herein are methods and uses involving administration of an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, such as atezolizumab), and a chemotherapy combination to a subject in need thereof, wherein the chemotherapy combination includes an effective amount of a platinum agent and an effective amount of a non-platinum agent, wherein the non-platinum agent is a topoisomerase II inhibitor (e.g., etoposide). In some instances, the anti-TIGIT antagonist antibody (e.g., 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 two weeks (e.g., on Days 1 and 15 of each 28-day dosing cycle), every three weeks (e.g., on Day 1 of each 21 -day dosing cycle), or every four weeks (e.g., on Day 1 of each 28-day dosing cycle). In some embodiments, the chemotherapy combination (e.g., the platinum agent and the topoisomerase II inhibitor (e.g., etoposide)) are administered weekly, every two weeks, every four weeks, or three times every four weeks (e.g., on Days 1 , 8, and 15 of each 28-day dosing cycle). In some embodiments, the topoisomerase II inhibitor (e.g., etoposide) is administered more frequently than the platinum agent (e.g., three times per week, e.g., on Days 1 , 2, and 3 of each dosing cycle).

In particular embodiments, the method involves administration of an effective amount of an anti- TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody, e.g., atezolizumab), a platinum agent (e.g., carboplatin or cisplatin), and a topoisomerase II inhibitor (e.g., etoposide) to a subject in need thereof, wherein the anti-TIGIT antagonist antibody (e.g., 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 three weeks (e.g., on Day 1 of each 21 -day dosing cycle) and the chemotherapy combination (e.g., the platinum agent (e.g., carboplatin or cisplatin) and the topoisomerase II inhibitor (e.g., etoposide) are administered at the same frequency (e.g., every three weeks, e.g., on Day 1 of each 21 -day dosing cycle). In some instances, the dosing continues for four-to- six induction dosing cycles (e.g., four induction dosing cycles, five induction dosing cycles, or six induction dosing cycles). After the induction dosing cycles, maintenance therapy can be administered in one or more subsequent (maintenance) dosing cycles. In certain embodiments, the one or more maintenance dosing cycles does not include the platinum agent or the topoisomerase II inhibitor (e.g., etoposide).

In some instances, the effective amount of the anti-TIG IT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) results in (a) a complete response or a partial response (PR). In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) results in an increase in progression-free survival of the subject. In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) extends overall survival of the subject.

In some instances, the subject receiving the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab), the PD-1 axis binding antagonist (e.g., anti- PD-L1 antagonist antibody, such as atezolizumab), the platinum agent (e.g., carboplatin or cisplatin), and the topoisomerase II inhibitor (e.g., etoposide) is being treated for a solid tumor or a locally advanced or metastatic cancer. Additionally or alternatively, the cancer may be a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma (RCC)), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer (HNSCC)), an ovarian cancer (OC), a gastric cancer (GC) (e.g., a gastroesophageal junction (GEJ) cancer), a bladder cancer (e.g., a urothelial bladder cancer (UBC)), a colorectal cancer (CRC), or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)).

Dosing of anti-TIGIT antagonist antibodies

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

In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ± 10 mg, e.g., 600 ± 6 mg, e.g., 600 ± 5 mg, e.g., 600 ± 3 mg, e.g., 600 ± 1 mg, e.g., 600 ± 0.5 mg, e.g., 600 mg) every three weeks (Q3W). In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 600 mg every three weeks.

In some instances, the effective amount of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 1600 mg, e.g., between about 250 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1500 mg, e.g., between about 500 mg to about 1400 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every four weeks (Q4W). In some instances, the effective amount of anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g.,

840 mg every four weeks).

In some instances, the fixed dose of the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) administered in a combination therapy (e.g., a combination treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)), with or without one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel or nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))), may be reduced as compared to a standard dose of the anti-TIGIT antagonist antibody administered as a monotherapy.

In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered intravenously. Alternatively, in some embodiments, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) is administered subcutaneously. Dosing of PD-1 axis binding antagonists

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 20 mg to about 1600 mg (e.g., between about 40 mg to about 1500 mg, e.g., between about 200 mg to about 1400 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1400 mg, e.g., between about 500 mg to about 1300 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every two weeks (Q2W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 840 mg every two 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 two weeks).

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., 1200 mg ± 5 mg, e.g., 1200 ± 2.5 mg, e.g., 1200 ± 1 .0 mg, e.g., 1200 ± 0.5 mg, e.g., 1200 mg) every three weeks (Q3W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of about 1200 mg every three weeks (e.g., 1200 mg ± 10 mg, e.g., 1200 ± 6 mg, e.g., 1200 ± 5 mg, e.g., 1200 ± 3 mg, e.g., 1200 ± 1 mg, e.g., 1200 ± 0.5 mg, e.g., 1200 mg every three weeks).

In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is a fixed dose of between about 500 mg to about 3000 mg (e.g., between about 500 mg to about 2800 mg, e.g., between about 600 mg to about 2700 mg, e.g., between about 650 mg to about 2600 mg, e.g., between about 700 mg to about 2500 mg, e.g., between about 1000 mg to about 2400 mg, e.g., between about 1100 mg to about 2300 mg, e.g., between about 1200 mg to about 2200 mg, e.g., between about 1300 mg to about 2100 mg, e.g., between about 1400 mg to about 2000 mg, e.g., between about 1500 mg to about 1900 mg, e.g., between about 1600 mg to about 1800 mg, e.g., between about 1620 mg to about 1700 mg, e.g., between about 1640 mg to about 1690 mg, e.g., between about 1660 mg to about 1680 mg, about 1680 mg, e.g., 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) every four weeks (Q4W). In some instances, the effective amount of the PD-1 axis binding antagonist (e.g., 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 instances, the fixed dose of the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) administered in a combination therapy (e.g., a combination treatment with an anti-TIGIT antagonist antibody, such as an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab), with or without one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or a non-platinum agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) may be reduced as compared to a standard dose of the PD-1 axis binding antagonist administered as a monotherapy.

In some instances, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered intravenously. Alternatively, in some embodiments, the PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) is administered subcutaneously.

Dosing of chemotherapeutic agents

Therapeutically effective amounts of various chemotherapeutic agents are known in the art and contemplated in the present invention. In particular instances, one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) are administered according to the doses recited herein.

Platinum agents

In some instances, the effective amount of a platinum agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve an AUC from 1 -50 mg/ml/min (e.g., 2-25 mg/ml/min, 3-15 mg/ml/min, 4-10 mg/ml/min, or 5 mg/ml/min, e.g., 2 mg/ml/min, 3 mg/ml/min, 4 mg/ml/min, 5 mg/ml/min, 6 mg/ml/min, 7 mg/ml/min, 8 mg/ml/min, 9 mg/ml/min, 10 mg/ml/min, 11 mg/ml/min, 12 mg/ml/min, 13 mg/ml/min, 14 mg/ml/min, 15 mg/ml/min, 20 mg/ml/min, 25 mg/ml/min, 30 mg/ml/min, 35 mg/ml/min, 40 mg/ml/min, 45 mg/ml/min, 50 mg/ml/min). In some instances, the effective amount of the platinum agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve an AUC = 6 mg/ml/min. In some instances, the effective amount of the platinum agent (e.g., carboplatin or cisplatin) is a dose sufficient to achieve an AUC = 5 mg/ml/min.

AUC can be calculated using the Calvert formula (Calvert et al., J. Clin. Oncol. 1989, 7:1748-56):

Total dose (mg) = (target AUC) x (glomerular filtration rate [GFR] + 25)

In some instances, the effective amount of the platinum agent (e.g., carboplatin or cisplatin) is 200 mg-1500 mg (e.g., 300 mg-1200 mg, 400 mg-1100 mg, or 500 mg-1000 mg, e.g., 300 mg-400 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-750 mg, 750 mg-800 mg, 800 mg-900 mg,

900 mg-1000 mg, 1000 mg-1100 mg, or 1100 mg-1200 mg, e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg). In some instances, the effective amount of the platinum agent (e.g., carboplatin or cisplatin) is about 500 mg-1000 mg (e.g., about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg).

In some instances, the platinum agent (e.g., carboplatin or cisplatin) is administered to the subject intravenously (e.g., over a 30-120-minute infusion). In some instances, carboplatin is administered intravenously over a 30-60-minute infusion. In some instances, cisplatin is administered intravenously over a 60-120-minute infusion.

Topoisomerase II inhibitors

In some instances, the effective amount of a topoisomerase II inhibitor (e.g., etoposide) is from 10-1000 mg/m² (e.g., from 20-800 mg/m², from 30-700 mg/m², from 40-500 mg/m², from 50-300 mg/m², from 75-200 mg/m², or from 80-150 mg/m², e.g., about 20 mg/m², about 30 mg/m², about 40 mg/m², about 50 mg/m², about 60 mg/m², about 70 mg/m², about 80 mg/m², about 90 mg/m², about 100 mg/m², about 110 mg/m², about 120 mg/m², about 130 mg/m², about 140 mg/m², about 150 mg/m², about 160 mg/m², about 170 mg/m², about 180 mg/m², about 190 mg/m², about 200 mg/m², about 250 mg/m², about 300 mg/m², about 400 mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m², about 800 mg/m², about 900 mg/m², or about 1000 mg/m²). In some instances, the effective amount of the topoisomerase II inhibitor (e.g., etoposide) is about 100 mg/m².

In some embodiments, the topoisomerase II inhibitor (e.g., etoposide) is administered to the subject intravenously (e.g., over a 60-minute infusion).

Taxanes

A therapeutically effective amount of a taxane (e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel) administered to a human will be in the range of about 25 to about 300 mg/m² (e.g., about 25 mg/m², about 50 mg/m², about 75 mg/m², about 100 mg/m², about 125 mg/m², about 150 mg/m², about 175 mg/m², about 200 mg/m², about 225 mg/m², about 250 mg/m², about 275 mg/m², or about 300 mg/m²) whether by one or more administrations. For example, in some embodiments, about 100 mg/m² of nab-paclitaxel (ABRAXANE®) is administered. In some embodiments, nab-paclitaxel (ABRAXANE®) is administered at 100 mg/m² IV every week. In some embodiments, about 200 mg/m² of paclitaxel is administered. In some embodiments, about 175 mg/m² of paclitaxel is administered. In some embodiments, paclitaxel is administered at 200 mg/m² IV every 3 weeks. In some embodiments, the taxane (e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel) may be administered weekly, every 2 weeks, every 3 weeks, every 4 weeks, on days 1 , 8 and 15 of each 21 -day cycle, or on days 1 , 8, and 15 of each 28-day cycle.

In some embodiments, the taxane (e.g., nab-paclitaxel (ABRAXANE®) or paclitaxel) is administered to the subject intravenously (e.g., over a 3-hour infusion).

Antimetabolites

In some instances, the effective amount of an antimetabolite (e.g., pemetrexed or gemcitabine) administered as part of the methods described herein is from 10-10000 mg/m² (e.g., from 20-8000 mg/m², from 30-5000 mg/m², from 40-2500 mg/m², from 50-2000 mg/m², from 100-1500 mg/m², or from 400-1200 mg/m², e.g., about 20 mg/m², about 30 mg/m², about 40 mg/m², about 50 mg/m², about 60 mg/m², about 70 mg/m², about 80 mg/m², about 90 mg/m², about 100 mg/m², about 110 mg/m², about 120 mg/m², about 130 mg/m², about 140 mg/m², about 150 mg/m², about 160 mg/m², about 170 mg/m², about 180 mg/m², about 190 mg/m², about 200 mg/m², about 250 mg/m², about 300 mg/m², about 400 mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m², about 800 mg/m², about 900 mg/m², about 1000 mg/m², about 1500 mg/m², about 2000 mg/m², about 3000 mg/m², about 4000 mg/m², about 5000 mg/m², about 6000 mg/m², about 7000 mg/m², about 8000 mg/m², about 9000 mg/m², or about 10000 mg/m²). In some instances, the effective amount of the antimetabolite (e.g., pemetrexed or gemcitabine) is about 500 mg/m² or about 1000 mg/m².

In some instances, the effective amount of pemetrexed administered as part of the methods described herein is from 10-1000 mg/m² (e.g., from 20-900 mg/m², from 30-800 mg/m², from 40-700 mg/m², from 50-650 mg/m², from 100-600 mg/m², or from 200-550 mg/m², e.g., about 20 mg/m², about 30 mg/m², about 40 mg/m², about 50 mg/m², about 60 mg/m², about 70 mg/m², about 80 mg/m², about 90 mg/m², about 100 mg/m², about 110 mg/m², about 120 mg/m², about 130 mg/m², about 140 mg/m², about 150 mg/m², about 160 mg/m², about 170 mg/m², about 180 mg/m², about 190 mg/m², about 200 mg/m², about 250 mg/m², about 300 mg/m², about 400 mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m², about 800 mg/m², about 900 mg/m², or about 1000 mg/m²). In some instances, the effective amount of pemetrexed is about 500 mg/m².

In some embodiments, the pemetrexed is administered to the subject intravenously (e.g., over a 10-minute infusion).

In some instances, the effective amount of gemcitabine administered as part of the methods described herein is from 10-10000 mg/m² (e.g., from 20-8000 mg/m², from 30-5000 mg/m², from 40-2500 mg/m², from 50-2000 mg/m², from 100-1500 mg/m², or from 400-1200 mg/m², e.g., about 20 mg/m², about 30 mg/m², about 40 mg/m², about 50 mg/m², about 60 mg/m², about 70 mg/m², about 80 mg/m², about 90 mg/m², about 100 mg/m², about 110 mg/m², about 120 mg/m², about 130 mg/m², about 140 mg/m², about 150 mg/m², about 160 mg/m², about 170 mg/m², about 180 mg/m², about 190 mg/m², about 200 mg/m², about 250 mg/m², about 300 mg/m², about 400 mg/m², about 500 mg/m², about 600 mg/m², about 700 mg/m², about 800 mg/m², about 900 mg/m², about 1000 mg/m², about 1500 mg/m², about 2000 mg/m², about 3000 mg/m², about 4000 mg/m², about 5000 mg/m², about 6000 mg/m², about 7000 mg/m², about 8000 mg/m², about 9000 mg/m², or about 10000 mg/m²). In some instances, the effective amount of gemcitabine is about 500 mg/m² or about 1000 mg/m².

In some embodiments, the gemcitabine is administered to the subject intravenously (e.g., over a 30-minute infusion).

Cancer characterization and selection

In any of the methods, uses, or compositions for use described herein, the cancer may be solid tumor or a locally advanced or metastatic cancer. In some instances, the cancer is a lung cancer, such as NSCLC. The cancer may be at an early or late stage. In some instances, the NSCLC is a squamous NSCLC. In some instances, the NSCLC is a non-squamous NSCLC. In some instances, the NSCLC is a locally advanced unresectable NSCLC. In some instances, the NSCLC is a Stage NIB NSCLC. In some instances, the NSCLC is a recurrent or metastatic NSCLC. In some instances, the NSCLC is a Stage IV NSCLC. In some instances, the subject has not been previously treated for Stage IV NSCLC.

In some instances, in any of the methods, uses, or compositions for use described herein, the subject has no EGFR or ALK genomic tumor aberrations. In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a sensitizing epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase ( ALK) gene rearrangement. In some instances, the subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 .

Methods for detecting the mutational status EGFR and ALK are well known in the art, and include, but are not limited to, sequencing DNA from clinical samples (e.g., tumor biopsies or blood samples (e.g., circulating tumor DNA in blood)) using a next-generation sequencing method, such as the targeted gene pulldown and sequencing method described in Frampton et al. ( Nature Biotechnology. 31 (11): 1023-1033, 2013), which is incorporated by reference herein in its entirety. Such a next- generation sequencing method can be used with any of the methods disclosed herein to detect various mutations (e.g., insertions, deletions, base substitutions, focal gene amplifications, and/or homozygous gene deletions), while enabling the use of small samples (e.g., from small-core needle biopsies, fine- needle aspirations, and/or cell blocks) or fixed samples (e.g., formalin-fixed and paraffin-embedded (FFPE) samples). Other methods for the detection of the mutational status of EGFR and ALK include fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) methods. Exemplary methods for the detection of the mutational status of ALK are disclosed in U.S. Patent No: 9,651 ,555, which is herein incorporated by reference in its entirety. In some instances, the VENTANA® anti -ALK (D5F3) IHC assay is used to determine the mutational status of the ALK gene.

In some instances of any of the methods described herein, the mutation is a sensitizing EGFR mutation. Sensitizing EGFR mutations are well known in the art and include those described in U.S. Publication No: US 2018/0235968 and in Juan et al. (Therapeutic Advances in Medical Oncology. 9(3): 201-216, 2017), which are incorporated by reference herein in their entireties. In some instances, the sensitizing EGFR mutation is a mutation in any one of exons 18-21 (e.g., a mutation in exon 18, exon 19, exon 20, and/or exon 21). In some instances, the sensitizing EGFR mutation is a deletion of exon 19 (dell 9). In other instances, sensitizing EGFR mutation is a L858R point mutation in exon 21 . In some instances, the sensitizing EGFR mutation is a G719X point mutation in exon 18, wherein “X” is most commonly C, A, or S. In some instances, the sensitizing EGFR mutation is a G719S point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a G719A point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a S720F point mutation in exon 18. In some instances, the sensitizing EGFR mutation is a L861 Q point mutation in exon 21 . In some instances, the sensitizing EGFR mutation is a L861 R point mutation in exon 21 . In other instances, the sensitizing EGFR mutation is a T790M point mutation. In some instances, the sensitizing EGFR mutation is an E709X point mutation, where “X” is most commonly K, A, or H. In some instances, the sensitizing EGFR mutation is a S768I point mutation.

In some instances of any of the methods described herein, the mutation is an ALK gene rearrangement. ALK gene rearrangements are well known in the art and include those described in U.S. Patent No: 9,651 ,555 and in Du et al. ( Thoracic Cancer. 9: 423-430, 2018), which are incorporated herein by reference in their entireties. In some instances, the ALK gene rearrangement results in the creation of an oncogenic ALK tyrosine kinase that activates downstream signaling pathways resulting in increased cell proliferation and survival. In some instances, the A K- gene rearrangement is an A K^" rearrangement with a gene selected from the group consisting of EML4, KIF5B, KLC1, TFG, TPR, HIP1, STRN, DCTN1, SQSTM1, NPM1, BCL11A, BIRC6, RANBP2, ATIC, CLTC, TMP4, and MSN resulting in the formation of a fusion oncogene. In some instances, the ALK gene rearrangement is an EML4 rearrangement with ALK resulting in the formation of the fusion oncogene EML4-ALK.

In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC. Methods for detecting the subtype of NSCLC are well known in the art, and include, but are not limited to, methods of determination by histopathological criteria, or by molecular features (e.g., a subtype characterized by expression of one or a combination of biomarkers (e.g., particular genes or proteins encoded by said genes)). In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample.

In some instances, in any of the methods, uses, or compositions for use described herein, the subject does not have an active Epstein-Barr virus (EBV) infection or a known or suspected chronic active EBV infection. Indicators of active or chronic active EBV infections for use in the methods described herein can include, but are not limited to, EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles detected in a sample from the subject (e.g., a blood or serum sample).

Methods for detecting the presence of one or more indicators of active or chronic active EBV infection, including EBV IgM, EBV IgG, Epstein-Barr nuclear antigen (EBNA), and Epstein-Barr viral particles in a sample from a subject are well known in the art, and include, but are not limited to, methods involving serological diagnosis (e.g., the detection of EBV DNA (e.g., by PCR analysis of a blood sample for the detection of EBV viral particles) or EBV antigens or anti-EBV antibodies (e.g., detection of EBNA, EBV IgM, or EBV IgG using heterophilic antibodies). In some instances, the sample is selected from the group consisting of a whole blood sample, a serum sample, and a plasma sample. In some instances, the subject is negative for EBV IgM and/or negative by EBV PCR. In some instances, the subject is negative for EBV IgM and/or negative by EBV PCR and is positive for EBV IgG and/or positive for Epstein-Barr nuclear antigen (EBNA). In other instances, the subject is negative for EBV IgG and/or negative for EBNA.

In some instances, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., a tumor PD-L1 expression with a minimum PD-L1 -positive tumor cell fraction or TPS > 30% (e.g., > 50%) as determined by an IHC with the SP263 or 22C3 antibody). In some instances, the PD-L1 selected tumor is a tumor that has been determined to have a PD-L1 -positive tumor cell fraction or PD-L1 TPS of greater than, or equal to, 30% (e.g., greater than, or equal to, 50%) by an immunohistochemical (IHC) assay. In some instances, the IHC assay uses the anti- PD-L1 antibody SP263, 22C3, SP142, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the tumor sample has been determined to have a TPS of greater than, or equal to, 50%. In some instances, the PD-L1 -positive tumor cell fraction is greater than, or equal to, 50% (e.g., as determined by positive staining with the anti-PD-L1 antibody SP263 (e.g., using the Ventana assay), as determined by positive staining with the anti-PD-L1 antibody 22C3 (e.g., using the 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 greater than, or equal to, 30%, as determined by positive staining with the anti-PD-L1 antibody SP142.

In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1 . In some instances, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5% and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.

In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1 . In some instances, the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof. In some instances, the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample. In some instances, the tissue sample is a tumor sample. In some instances, the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof.

Responses to Treatment

In some embodiments of any of the methods described herein, a subject’s response to the therapy can be characterized by one or more measures. In some embodiments, the treatment results in a complete response or a partial response. In some instances, the treatment results in an increase in progression-free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIG IT antagonist antibody or as compared to treatment with the anti-TIG IT antagonist antibody without the PD-1 axis binding antagonist. For example, in embodiments in which no chemotherapeutic agent is administered (e.g., only an anti-TIG IT antagonist antibody (e.g., tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., atezolizumab) is administered), the treatment may result in an increase in progression- free survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIG IT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))), the treatment may result in an increase in progression-free survival of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without the PD-1 axis binding antagonist; and/or (iii) as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without the one or more chemotherapeutic agents.

In some instances, the treatment extends overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. For example, in embodiments in which no chemotherapeutic agent is administered (e.g., only an anti- TIGIT antagonist antibody (e.g., tiragolumab) in combination with a PD-1 axis binding antagonist (e.g., atezolizumab) is administered), the treatment may result in an increase in overall survival of the subject, e.g., as compared to treatment with the PD-1 axis binding antagonist without the anti-TIGIT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist. In embodiments in which an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered in combination with one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))), the treatment may result in an increase in overall survival of the subject, e.g., as compared to (i) treatment with the PD-1 axis binding antagonist and the one or more chemotherapeutic agents without the anti-TIGIT antagonist antibody; (ii) as compared to treatment with the anti-TIGIT antagonist antibody and the one or more chemotherapeutic agents without the PD-1 axis binding antagonist; and/or (iii) as compared to treatment with the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody without the one or more chemotherapeutic agents.

Progression-free survival of the subject can be measured according to RECIST v1 .1 criteria, as described in Eisenhauer et al., Eur. J. Cancer. 2009, 45:228-47. In some embodiments, PFS is measured as the period of time from the start of treatment to the first occurrence of disease progression as determined by RECIST v1 .1 criteria. In some embodiments, PFS is measured as the time from the start of treatment to the time of death.

In some embodiments, a treatment described herein extends the PFS of the subject by at least about 2.4 months (e.g., by 2.4-120 months, by 2.5-100 months, by 3.0-80 months, by 4.0-60 months, by 5.0-48 months, by 6.0-36 months, by 8.0-24 months, or by 10-12 months, e.g., by at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the PFS of the subject by at least about 4 months (e.g., by 4-120 months, by 5-100 months, by 6-80 months, by 7-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months,

28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some embodiments, the treatment extends the PFS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-100 months, by 4-80 months, by 6-60 months, by 8-48 months, by 9-36 months, or by 10-24 months, e.g., by at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

In some embodiments, overall survival is measured as the period of time from the start of treatment to death. In some instances, the treatment extends the OS of the subject by at least about 2 months (e.g., by 2-120 months, by 3-110 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the overall survival of the subject by at least about 3.3 months (e.g., by 3.3-120 months, by 4-100 months, by 5-80 months, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment extends the overall survival of the subject by at least about 5.3 months (e.g., by 5.3-120, by 6-60 months, by 7-48 months, by 8-36 months, or by 10-24 months, e.g., by at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11 .5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

IV. EXEMPLARY ANTI-TIGIT ANTAGONIST ANTIBODIES, PD-1 AXIS BINDING ANTAGONISTS,

AND CHEMOTHERAPEUTIC AGENTS

Exemplary anti-TIG IT antagonist antibodies and PD-1 axis binding antagonists (e.g., anti-PD-L1 antibodies) useful for treating a subject (e.g., a human) having cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)) in accordance with the methods, uses, and compositions for use of the invention are described herein. A. Anti-TIGIT Antagonist Antibodies

The invention provides anti-TIG IT antagonist antibodies useful for treating cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)) in a subject (e.g., a human).

In some instances, the anti-TIGIT antagonist antibody is tiragolumab (CAS Registry Number: 1918185-84-8). Tiragolumab (Genentech) is also known as MTIG7192A.

In certain instances, the anti-TIGIT antagonist antibody includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and/or (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g.,

90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 1-6.

In some instances, anti-TIGIT antagonist antibodies may include (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4); (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). In some instances, the anti-TIGIT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of,

EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 17) or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of,

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 18); and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 19). In some instances, the anti-TIG IT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 17 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19. In some instances, the anti-TIG IT antagonist antibody has a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 18 and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 19.

In some instances, the anti-TIGIT antagonist antibody includes a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence:

EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVK GRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33); and (b) the light chain comprises the amino acid sequence:

DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFS GSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSS PVTKSFNRGEC (SEQ ID NO: 34).

In some instances, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and/or an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 7-10. In some instances, for example, the antibody further comprises an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10). In some instances, the anti-TIGIT antagonist antibody further comprises at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR- H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 11- 14. The anti-TIGIT antagonist antibody may further include, for example, at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12-15. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14. In another instance, for example, the anti-TIGIT antagonist antibody may further include at least one, two, three, or four of the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of

QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and/or an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14), or a combination of one or more of the above FRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%,

93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) to any one of SEQ ID NOs: 12-14 and 16. In some instances, the anti-TIGIT antagonist antibody includes an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16); an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

In another aspect, an anti-TIGIT antagonist antibody is provided, wherein the antibody comprises a VH as in any of the instances provided above, and a VL as in any of the instances provided above, wherein one or both of the variable domain sequences include post-translational modifications.

In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to rabbit TIGIT, in addition to human TIGIT. In some instances, any one of the anti-TIGIT antagonist antibodies described above is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any one of the anti-TIG IT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any one of the anti-TIG IT antagonist antibodies described above is capable of binding to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not murine TIGIT.

In some instances, the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or lower and cyno TIGIT with a KD of about 10 nM or lower (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and cyno TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or lower and cyno TIGIT with a KD of about 0.5 nM or lower).

In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR). In some instances, the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an IC50 value of 10 nM or lower (e.g., 1 nM to about 10 nM). In some instances, the anti-TIGIT antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with PVR, without impacting PVR-CD226 interaction. In some instances, the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or lower (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM). In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 with TIGIT. In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

In some instances, the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with any of the anti-TIGIT antagonist antibodies described above. For example, the method may include administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1); (b) an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2); (c) an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3); (d) an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4), (e) an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and (f) an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6). The methods described herein may also include administering an isolated anti-TIGIT antagonist antibody that binds to the same epitope as an anti-TIGIT antagonist antibody described above.

An anti-TIGIT antagonist antibody according to any of the above instances may be a monoclonal antibody, comprising a chimeric, humanized, or human antibody. In some instances, the anti-TIGIT antagonist antibody is tiragolumab. In one instance, an anti-TIGIT antagonist antibody is an antibody fragment, for example, a Fv, Fab, Fab’, scFv, diabody, or F(ab’)2 fragment. In another instance, the antibody is a full-length antibody, e.g., an intact IgG antibody (e.g., an intact lgG1 antibody) or other antibody class or isotype as defined herein.

In a further aspect, an anti-TIGIT antagonist antibody according to any of the above instances may incorporate any of the features, singly or in combination, as described in Section C below. B. PD- 1 Axis Binding Antagonists

Provided herein are methods for treating cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, (e.g., a lung cancer, e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non- squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage NIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)) in a subject (e.g., a human) comprising administering to the subject an effective amount of a PD-1 axis binding antagonist. PD-1 axis binding antagonists include PD-L1 binding antagonists (e.g., PD-L1 antagonist antibodies), PD-1 binding antagonists (e.g., PD-1 antagonist antibodies), and PD-2 binding antagonists (e.g., PD-L2 antagonist antibodies).

In some instances, the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, PD-L1 binding partners are PD-1 and/or B7-1 . In some instances, the anti-PD-L1 antagonist antibody is capable of inhibiting binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1.

In some instances, the PD-1 axis binding antagonist is an anti-PD-L1 antibody.

In some instances, the anti-PD-L1 antibody is atezolizumab (CAS Registry Number: 1422185-06- 5). Atezolizumab (Genentech) is also known as MPDL3280A.

In some instances, the anti-PD-L1 antibody (e.g., atezolizumab) includes at least one, two, three, four, five, or six HVRs selected from: (a) an HVR-H1 sequence is GFTFSDSWIH (SEQ ID NO: 20); (b) an HVR-H2 sequence is AWISPYGGSTYYADSVKG (SEQ ID NO: 21); (c) an HVR-H3 sequence is RHWPGGFDY (SEQ ID NO: 22), (d) an HVR-L1 sequence is RASQDVSTAVA (SEQ ID NO: 23); (e) an HVR-L2 sequence is SASFLYS (SEQ ID NO: 24); and (f) an HVR-L3 sequence is QQYLYHPAT (SEQ ID NO: 25).

In some instances, the anti-PD-L1 antibody (e.g., atezolizumab) comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain variable (VH) region sequence comprises the amino acid sequence:

EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 26); and (b) the light chain variable (VL) region sequence comprises the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 27).

In some instances, the anti-PD-L1 antibody (e.g., atezolizumab) comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRF TISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKP SNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPRE PQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 28); and (b) the light chain comprises the amino acid sequence:

DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC (SEQ ID NO: 29).

In some instances, the anti-PD-L1 antibody comprises (a) a VH domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of (SEQ ID NO: 26); (b) a VL domain comprising an amino acid sequence comprising having at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of (SEQ ID NO: 27); or (c) a VH domain as in (a) and a VL domain as in (b). In other instances, the anti-PD-L1 antagonist antibody is selected from YW243.55.S70, MDX- 1105, and MEDI4736 (durvalumab), and MSB0010718C (avelumab). Antibody YW243.55. S70 is an anti- PD-L1 described in PCT Pub. No. WO 2010/077634. MDX-1105, also known as BMS-936559, is an anti- PD-L1 antibody described in PCT Pub. No. WO 2007/005874. MEDI4736 (durvalumab) is an anti-PD-L1 monoclonal antibody described in PCT Pub. No. WO 2011/066389 and U.S. Pub. No. 2013/034559. Examples of anti-PD-L1 antibodies useful for the methods of this invention, and methods for making thereof are described in PCT Pub. Nos. WO 2010/077634, WO 2007/005874, and WO 2011/066389, and also in U.S. Pat. No. 8,217,149, and U.S. Pub. No. 2013/034559, which are incorporated herein by reference. The anti-PD-L1 antagonist antibodies (e.g., atezolizumab) useful in this invention, including compositions containing such antibodies, may be used in combination with an anti-TIGIT antagonist antibody, a topoisomerase II inhibitor, and/or a platinum agent to treat lung cancer, e.g., SCLC, e.g., ES- SCLC.

In some instances, the anti-PD-L1 antagonist antibody is a monoclonal antibody. In some instances, the anti-PD-L1 antagonist antibody is an antibody fragment selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some instances, the anti-PD-L1 antagonist antibody is a humanized antibody. In some instances, the anti-PD-L1 antagonist antibody is a human antibody. In some instances, the anti-PD-L1 antagonist antibody described herein binds to human PD-L1 .

In some instances, the PD-1 axis binding antagonist is an anti-PD-1 antagonist antibody that inhibits the binding of PD-1 to its binding partner (e.g., PD-L1). In some instances, the anti-PD-1 antagonist antibody is capable of inhibiting binding between PD-L1 and PD-1 .

In some instances, the PD-1 axis binding antagonist is an anti-PD-1 antibody. In some instances, the anti-PD-1 antibody is nivolumab (MDX-1106), pembrolizumab (formerly lambrolizumab (MK-3475)), or AMP-224. In a further aspect, a PD-1 axis binding antagonist is a PD-1 axis binding antagonist antibody according to any of the above instances may incorporate any of the features, singly or in combination, as described in Section C below.

C. Antibody Formats and Properties 1. Antibody Affinity

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) provided herein has a dissociation constant (KD) of < 1 mM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10^-8 M or less, e.g., from 10^-8 M to 10¹³ M, e.g., from 10⁹ M to 10¹³ M).

In one instance, KD is measured by a radiolabeled antigen binding assay (RIA). In one instance, an RIA is performed with the Fab version of an antibody of interest and its antigen. For example, solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of (¹²⁵l)- labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al. , J. Mol. Biol. 293:865-881 (1999)). To establish conditions for the assay, MICROTITER^® multi-well plates (Thermo Scientific) are coated overnight with 5 pg/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23°C). In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [¹²⁵l]- antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti- VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20^®) in PBS. When the plates have dried, 150 mI/well of scintillant (MICROSCINT-20™; Packard) is added, and the plates are counted on a TOPCOUNT™ gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.

According to another instance, KD is measured using a BIACORE^® surface plasmon resonance assay. For example, an assay using a BIACORE^®-2000 or a BIACORE ^®-3000 (BIAcore, Inc.,

Piscataway, NJ) is performed at 25°C with immobilized antigen CM5 chips at -10 response units (RU). In one instance, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N- ethyl-N’- (3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier’s instructions. Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml (-0.2 pM) before injection at a flow rate of 5 pl/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25°C at a flow rate of approximately 25 pl/min. Association rates (k_on) and dissociation rates (k_0ft) are calculated using a simple one-to-one Langmuir binding model (BIACORE^® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams. The equilibrium dissociation constant (KD) is calculated as the ratio koff/kon. See, for example, Chen et al ., J. Mol. Biol. 293:865-881 (1999). If the on-rate exceeds 10⁶M-¹s-¹ by the surface plasmon resonance assay above, then the on-rate can be determined by using a fluorescent quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm band-pass) at 25°C of a 20 nM anti-antigen antibody (Fab form) in PBS, pH 7.2, in the presence of increasing concentrations of antigen as measured in a spectrometer, such as a stop-flow equipped spectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

2. Antibody Fragments

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) provided herein is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g., PluckthOn, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab’)2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).

Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain instances, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1 ).

Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g. E. coli or phage), as described herein.

3. Chimeric and Humanized Antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81 :6851 -6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. In certain instances, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some instances, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Natl Acad. Set. USA 86:10029-10033 (1989); US Patent Nos. 5, 821 ,337, 7,527,791 , 6,982,321 , and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61 -68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151 :2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271 :22611 -22618 (1996)).

4. Fluman Antibodies

In certain instances, an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) provided herein is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U.S. Patent No. 5,770,429 describing HUMAB® technology; U.S. Patent No. 7,041 ,870 describing K-M MOUSE® technology, and U.S. Patent Application Publication No. US 2007/0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al. , Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.

5. Library-Derived Antibodies

Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1 -37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001 ) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991 ); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); 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).

In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

6. Antibody Variants

In certain instances, amino acid sequence variants of the anti-TIG IT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention are contemplated. As described in detail herein, anti-TIG IT antagonist antibodies and PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) may be optimized based on desired structural and functional properties. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen-binding.

I. Substitution, Insertion, and Deletion Variants

In certain instances, anti-TIG IT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs and FRs. Conservative substitutions are shown in Table A under the heading of “preferred substitutions.” More substantial changes are provided in Table A under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

Table A. Exemplary and Preferred Amino Acid Substitutions

Amino acids may be grouped according to common side-chain properties:

(1) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody ( e.g . a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and/or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).

Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e. , residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179- 196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al. , ed., Human Press, Totowa, NJ, (2001).) In some instances of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

In certain instances, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may, for example, be outside of antigen contacting residues in the HVRs. In certain instances of the variant VH and VL sequences provided above, each HVR either is unaltered, or includes no more than one, two, or three amino acid substitutions.

A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244:1081 -1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen- antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody. II. Glycosylation variants

In certain instances, anti-TIG IT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies) of the invention can be altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to anti-TIG IT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) of the invention may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some instances, modifications of the oligosaccharide in an antibody of the invention are made in order to create antibody variants with certain improved properties.

In one instance, anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621 ; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; W02005/053742;

W02002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003/0157108 A1 , Presta, L; and WO 2004/056312 A1 , Adams etal., especially at Example 11), and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003/085107).

In view of the above, in some instances, the methods of the invention involve administering to the subject in the context of a fractionated, dose-escalation dosing regimen an anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) variant that comprises an aglycosylation site mutation. In some instances, the aglycosylation site mutation reduces effector function of the antibody. In some instances, the aglycosylation site mutation is a substitution mutation. In some instances, the antibody comprises a substitution mutation in the Fc region that reduces effector function.

In some instances, the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering). In some instances, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G. In some instances, the substitution mutation is at amino acid residue N297. In a preferred instance, the substitution mutation is N297A.

Anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody) variants are further provided with bisected oligosaccharides, for example, in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.) ; US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

III. Fc region variants

In certain instances, one or more amino acid modifications are introduced into the Fc region of an anti-TIGIT antagonist (e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) of the invention, thereby generating an Fc region variant (see e.g., US 2012/0251531 ).

The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG 1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.

In certain instances, the invention contemplates an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII, and Fc(RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Flellstrom, I. et al. Proc. Nat’l Acad. Sci. USA 83:7059-7063 (1986)) and Flellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821 ,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CYTOTOX 96^® non-radioactive cytotoxicity assay (Promega, Madison, Wl). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Nat’l Acad. Sci. USA 95:652-656 (1998). C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro etal. J. Immunol. Methods 202:163 (1996); Cragg, M.S. et al. Blood. 101 :1045-1052 (2003); and Cragg, M.S. and M.J. Glennie Blood. 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S.B. et al. Int’l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent Nos. 6,737,056 and 8,219,149). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 and 8,219,149).

In certain instances, the proline at position 329 of a wild-type human Fc region in the antibody is substituted with glycine or arginine or an amino acid residue large enough to destroy the proline sandwich within the Fc/Fc. gamma receptor interface that is formed between the proline 329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgFtlll (Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). In certain instances, the antibody comprises at least one further amino acid substitution. In one instance, the further amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and still in another instance the at least one further amino acid substitution is L234A and L235A of the human lgG1 Fc region or S228P and L235E of the human lgG4 Fc region (see e.g., US 2012/0251531), and still in another instance the at least one further amino acid substitution is L234A and L235A and P329G of the human lgG1 Fc region.

Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)

In certain instance, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

In some instances, alterations are made in the Fc region that result in altered ( i.e ., either improved or diminished) C1q binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in US Patent No. 6,194,551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US2005/0014934A1 (Hinton et al.)· Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcFtn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants.

In some aspects, the anti-TIGIT antagonist antibody (e.g., an anti-TIG IT antagonist antibody disclosed herein, e.g., tiragolumab) and/or anti-PD-L1 antagonist antibody (e.g., atezolizumab) comprises an Fc region comprising an N297G mutation (EU numbering).

In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 domain, a first CH2 (CH2j) domain, a first CH3 (CH3j) domain, a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain. In some instances, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some instances, the CH3j and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3j domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain. In some instances, the CH3j and CH3₂ domains meet at an interface between said protuberance and cavity. In some instances, the CH2j and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain. In other instances, the CH2j and CH2₂ domains meet at an interface between said protuberance and cavity. In some instances, the anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or anti-PD-L1 antagonist antibody (e.g., atezolizumab) is an lgG1 antibody.

IV. Cysteine engineered antibody variants

In certain instances, it is desirable to create cysteine engineered anti-TIGIT antagonist antibodies and/or PD-1 axis binding antagonist antibodies (e.g., anti-PD-L1 antagonist antibodies), e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular instances, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain instances, any one or more of the following residues are substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibodies may be generated as described, for example, in U.S. Patent No. 7,521 ,541 . V. Antibody derivatives

In certain instances, an anti-TIGIT antagonist antibody of the invention (e.g., an anti-TIG IT antagonist antibody (e.g., tiragolumab) or a variant thereof) and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody of the invention (e.g., atezolizumab or a variant thereof)) provided herein are further modified to contain additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1 ,3, 6-trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched.

The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

In another instance, conjugates of an antibody and nonproteinaceous moiety that may be selectively heated by exposure to radiation are provided. In one instance, the nonproteinaceous moiety is a carbon nanotube (Kam et al. , Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation may be of any wavelength, and includes, but is not limited to, wavelengths that do not harm ordinary cells, but which heat the nonproteinaceous moiety to a temperature at which cells proximal to the antibody- nonproteinaceous moiety are killed.

Recombinant Production Methods

Anti-TIGIT antagonist antibodies (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist antibodies (e.g.,anti-PD-L1 antagonist antibodies (e.g., atezolizumab)) of the invention may be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567, which is incorporated herein by reference in its entirety.

For recombinant production of an anti-TIGIT antagonist antibody and/or PD-1 axis binding antagonist antibody (e.g., anti-PD-L1 antagonist antibody), nucleic acid encoding an antibody, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al.,

Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1 ); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

Immu noconjugates

The invention also provides immunoconjugates comprising an anti-TIG IT antagonist (e.g., an anti- TIGIT antagonist antibody as disclosed herein, e.g., tiragolumab) and/or PD-1 axis binding antagonist (e.g., anti-PD-L1 antagonist antibody (e.g., atezolizumab)) of the invention conjugated to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

In some instances, an immunoconjugate is an antibody-drug conjugate (ADC) in which an antibody is conjugated to one or more drugs, including but not limited to a maytansinoid (see U.S. Patent Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1 ); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Patent Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicin or derivative thereof (see U.S. Patent Nos.

5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701 , 5,770,710, 5,773,001 , and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al. , Cancer Res. 58:2925-2928 (1998)); an anthracycline such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg.

& Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; a trichothecene; and CC1065.

In another instance, an immunoconjugate comprises an anti-TIG IT antagonist antibody as described herein (e.g., tiragolumab) or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody (e.g., atezolizumab)) conjugated to an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

In another instance, an immunoconjugate comprises an anti-TIG IT antagonist antibody as described herein (e.g., tiragolumab) and/or a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody) as described herein (e.g., atezolizumab) conjugated to a radioactive atom to form a radioconjugate. A variety of radioactive isotopes are available for the production of radioconjugates. Examples include At²¹¹ , I¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, for example tc99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131 , indium-111 , fluorine- 19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of an antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N- maleimidomethyl) cyclohexane-1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCI), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1 ,5-difluoro-2, 4-dinitrobenzene).

For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1 -isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026. The linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell. For example, an acid- labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker, or disulfide-containing linker (Chari et al. , Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020) may be used.

The immunuoconjugates or ADCs herein expressly contemplate, but are not limited to such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo- KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB (succinimidyl-(4- vinylsulfone)benzoate) which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL, U.S. A).

D. Platinum Agents

Platinum agents include an organic compound which contains platinum as an integral part of the molecule. Typically platinum-based chemotherapeutic agents are coordination complexes of platinum agents include, but are not limited to, carboplatin, cisplatin, and oxaliplatin.

Platinum agents (such as cisplatin, carboplatin, oxaliplatin, and staraplatin) are widely used antitumor drugs that cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Platinum agents typically act on the adjacent N-7 position of guanine, forming a 1 , 2 intrastrand crosslink (Poklar et al. (1996). Proc. Natl. Acad. Sci. U.S.A. 93 (15): 7606-11 ; Rudd et al. (1995). Cancer Chemother. Pharmacol. 35 (4): 323-6). The resultant crosslinking inhibits DNA repair and/or DNA synthesis in cancer cells.

Carboplatin is an exemplary platinum coordination compound used in the methods described herein. The chemical name for carboplatin is platinum, diammine[l, l-cyclobutanedicarboxylato(2-)- 0,0']-, (SP- 4-2), and carboplatin has the following structural formula:

Carboplatin is a crystalline powder with the molecular formula of C6H12N204Pt and a molecular weight of 371 .25. It is soluble in water at a rate of approximately 14 mg/mL, and the pH of a 1 % solution is 5 to 7. It is virtually insoluble in ethanol, acetone, and dimethylacetamide. Carboplatin produces predominantly interstrand DNA cross-links, and this effect is cell-cycle nonspecific. Carboplatin is commercially available as PARAPLATIN®, BIOCARN, BLASTOCARB, BLASTOPLATIN, CARBOKEM, CARBOMAX, CARBOPA, CARBOPLAN, CARBOTEEN, CARBOTINAL, CYTOCARB, DUCARB, KARPLAT, KEMOCARB, NAPROPLAT, NEOPLATIN, NISCARBO, ONCOCARBIN, TEVACARB, WOMASTIN, and others.

Another exemplary platinum agent useful in the methods of the present invention is cisplatin, which has the following structure:

E. Non-platinum Agents

Non-platinum agents are another class of chemotherapeutic agents useful as part of the methods, uses, and compositions described herein. Exemplary non-platinum agents include antimetabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331), and taxanes (e.g., paclitaxel (e.g., nanoparticle-albumin bound (nab)-paclitaxel), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel).

Antimetabolites

Antimetabolites interfere with and inhibit (wholly or partially) an endogenous (normal) metabolic process within a cell (e.g., a cancer cell). Antimetabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, mercaptopurine, and pralatrexate.

Gemcitabine is an exemplary antimetabolite used in the methods described herein and has the following structure:

In some instances, pemetrexed can be administered as part of the methods of the present invention. Pemetrexed has the following structure:

Topoisomerase II Inhibitors

Inhibitors of topoisomerase II (e.g., etoposide (VP-16), teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, and HU-331) are also widely used antitumor drugs that stabilize topoisomerase IEDNA covalent complexes (i.e., cleavage complexes) following the formation of enzyme-mediated DNA breaks. The accumulation of such cleavage complexes induces cell death pathways.

Etoposide is an exemplary topoisomerase II inhibitor used in the methods described herein. Etoposide is typically administered as the prodrug etoposide phosphate, the chemical name for which is: 4'-Demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene- -Dglucopyranoside], 4' (dihydrogen phosphate). Etoposide phosphate has the following structure:

Etoposide phosphate, a phosphate ester of etoposide, is a semi-synthetic derivative of podophyllotoxin and is converted to etoposide by dephosphorylation. Etoposide causes the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals, leading to cell cycle arrest (primarily at the G2 stage of the cell cycle) and cell death. Etoposide is commercially available as ETOPOPHOS®, TOPOSAR™, VP-16, VEPESID®, ACTITOP, ASIDE, BIOPOSIDE, CTOP, CYTOP, EPOSED, ESIDE, ETHOPUL, ETOLON, ETONIS, ETOPLAST, ETOSID, ETOVEL, FYTOP, FYTOSID, LASTET, NZYTOP, ONCOSIDE, PLACID, POSID, RETOPSON, TEV ASIDE, TOPOK, TOPOSIDE, and others.

Taxanes

Taxanes are chemotherapeutic agents that may bind to tubulin, promoting microtubule assembly and stabilization and/or prevent microtubule depolymerization. Taxanes included herein include taxoid 10-deacetylbaccatin III and/or derivatives thereof. Examplary taxanes include, but are not limited to, paclitaxel (i.e., TAXOL®, CAS # 33069-62-4), docetaxel (i.e., TAXOTERE®, CAS # 114977-28-5), larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel. In some embodiments, the taxane is an albumin-coated nanoparticle (e.g., nano-albumin bound (nab)-paclitaxel, i.e., ABRAXANE® and/or nab- docetaxel, ABI-008). In some embodiments, the taxane is nab-paclitaxel (ABRAXANE®). In some embodiments, the taxane is formulated in CREMAPHOR® (e.g., TAXOL®) and/or in Tween such as polysorbate 80 (e.g., TAXOTERE®). In some embodiments, the taxane is liposome-encapsulated taxane. In some embodiments, the taxane is a prodrug form and/or conjugated form of taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleyl carbonate-paclitaxel). In some embodiments, the paclitaxel is formulated with substantially no surfactant (e.g., in the absence of CREMAPHOR and/or Tween-such as TOCOSOL® paclitaxel).

In some instances, paclitaxel is administered as part of the methods of the present invention. Paclitaxel may have the following structure:

In some instances, the methods include administration of nano-albumin bound (nab)-paclitaxel.

A skilled artisan will appreciate that any of the aforementioned chemotherapeutic agents can be administered in various forms, such as salt forms, which are contemplated as part of the present invention.

V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, AND KITS

Any of the anti-TIG IT antagonist antibodies, PD-1 axis binding antagonists (e.g., anti-PD-L1 antagonist antibodies), and chemotherapeutic agents (e.g., platinum agents (e.g., carboplatin or cisplatin) and/or non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))) described herein can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of an anti-TIGIT antagonist antibody, a PD-1 axis binding antagonist (e.g., an anti-PD-L1 antagonist antibody), and/or one or more chemotherapeutic agents can be prepared by mixing one, two, three, or all four agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers ( Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX^®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958.

Aqueous antibody formulations include those described in US Patent No. 6,171 ,586 and WO 2006/044908, the latter formulations including a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredients as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above). Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

In another embodiment of the invention, a kit is provided comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist, a platinum agent, and a topoisomerase II inhibitor for treating a subject having a lung cancer according to any of the methods described herein. In some instances, the kit further comprises the PD-1 axis binding antagonist.

In another embodiment, a kit comprises tiragolumab for use in combination with atezolizumab, a platinum agent, and a topoisomerase II inhibitor for treating a subject having cancer according to a any of the methods described herein. In some embodiments, the kit further comprises atezolizumab.

Kits provided herein may include a PD-1 axis binding antagonist (e.g., atezolizumab) for use in combination with an anti-TIGIT antagonist antibody (e.g., tiragolumab), and/or one or more chemotherapeutic agents for treating a subject having a cancer (e.g., a solid tumor or a locally advanced or metastatic cancer, (e.g., a lung cancer (e.g., small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non- squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage 11 IB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung), a pancreatic cancer (e.g., a pancreatic ductal adenocarcinoma (PDAC), e.g., a metastatic PDAC)), a kidney or renal cancer (e.g., a renal cell carcinoma), a melanoma, a head and neck cancer (e.g., a head and neck squamous cell cancer), an ovarian cancer, a gastric cancer (e.g., a gastroesophageal junction cancer), a bladder cancer (e.g., a urothelial bladder cancer), a colorectal cancer, or a breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC), which are estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-) negative)) according to any of the methods described herein. In some embodiments, the kit further comprises tiragolumab. Any of the PD-1 axis binding antagonist and/or chemotherapeutic agents known in the art or described herein may be included in the article of manufacture or kits. In some embodiments, the kit comprises tiragolumab and atezolizumab. In some embodiments, the kit comprises tiragolumab, atezolizumab, and one or more chemotherapeutic agents (e.g., a platinum agent (e.g., carboplatin or cisplatin) and/or one or more non-platinum agents (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine), a taxane (e.g., paclitaxel, e.g., nab-paclitaxel), and/or a topoisomerase II inhibitor (e.g., etoposide))).

EXAMPLES

The following are examples of the methods of the invention. It is understood that various other embodiments may be practiced, given the general description provided above. Example 1. A Phase la/lb, open-label, dose-escalation study of the safety and pharmacokinetics of tiragolumab as a single agent and in combination with atezolizumab administered with and without chemotherapy in patients with locally advanced or metastatic tumors

This study evaluates the safety, PK, pharmacodynamics, and preliminary anti-tumor activity of tiragolumab (MTIG7192A) when administered as a single agent (Phase la) or in combination with atezolizumab with and without chemotherapy (Phase lb) in patients with locally advanced or metastatic tumors. Specific objectives and corresponding endpoints for the study are outlined in Table 1 .

Table 1. Objectives and Endpoints

Study Design

This is a first-in-human Phase I open-label, multicenter, global, dose-escalation study designed to evaluate the safety, tolerability, and PK of tiragolumab as a single agent inpatients with locally advanced, recurrent, or metastatic incurable tumors for whom standard therapy does not exist, has proven to be ineffective or intolerable, or is considered inappropriate, or for whom a clinical trial of an investigational agent is a recognized standard of care. This study is also designed to enable evaluation of the safety, tolerability, and PK of tiragolumab when administered with atezolizumab with and without chemotherapy in patients with locally advanced, recurrent, or metastatic incurable tumors for whom standard therapy does not exist, has proven to be ineffective or intolerable, or is considered inappropriate, or for whom a clinical trial of an investigational agent is a recognized standard of care, or for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option.

FIG. 1 is a flow chart showing the Phase lb chemotherapy expansion and Phase lb Q4W dosing expansion). During the dose-escalation stage, cohorts of approximately 3-6 patients each will be evaluated at escalating dose levels to determine the MTD or maximum administered dose (MAD) for tiragolumab as a single agent or in combination with atezolizumab.

In the dose-expansion stage, patients are enrolled and treated at or below the MTD or MAD of tiragolumab as a single agent (Phase la), or in combination with atezolizumab with or without chemotherapy (Phase lb). Tiragolumab as a single agent (Phase la) or the combination of tiragolumab and atezolizumab (Phase lb cohorts without chemotherapy) is administered by IV infusion on Day 1 of each 21 -day cycle or on Day 1 of each 28-day cycle (Phase lb Q4W dosing expansion), with tiragolumab being administered prior to atezolizumab in the Phase lb cohorts without chemotherapy. In the absence of unacceptable toxicity or clinically compelling evidence of disease progression, treatment with either tiragolumab (Phase la) or tiragolumab in combination with atezolizumab (Phase lb) is continued beyond Cycle 1 based on a favorable assessment of benefit and risk by the investigator.

In the Phase lb chemotherapy expansion cohorts and the Phase lb Q4W dosing expansion cohort (FIG. 1), a safety run-in of 3 patients is completed. All relevant safety data from the safety run-in is thoroughly reviewed by an IMC and with the investigators before enrollment is continued.

In the chemotherapy expansion cohort, tiragolumab and atezolizumab is combined with specific chemotherapy regimens in each of the three cohorts: carboplatin or cisplatin and pemetrexed in Cohort A, carboplatin and paclitaxel in Cohort B and carboplatin or cisplatin and etoposide in Cohort C (see FIG. 1). In each cohort, treatment includes of an induction phase and a maintenance phase. In the induction phase, the combination of tiragolumab and atezolizumab with chemotherapy is administered by IV infusion on a 21 -day cycle for 4 to 6 cycles for Cohorts A and B and for 4 cycles for Cohort C. The number of cycles of induction treatment for Cohort A and B is at the discretion of the investigator.

Following the induction phase, patients who have not experienced disease progression or unacceptable toxicity continue treatment with maintenance therapy. During the maintenance phase, patients in Cohorts B and C continue tiragolumab and atezolizumab only, while patients in Cohort A continue tiragolumab and atezolizumab with pemetrexed. In all the chemotherapy expansion cohorts, atezolizumab is administered prior to tiragolumab. When chemotherapy is given, it is administered after atezolizumab and tiragolumab.

All patients are closely monitored for adverse events throughout the study and for at least 90 days after the last dose of study treatment or until initiation of another systemic anti-cancer therapy, whichever occurs first. Adverse events will be graded according to the NCI CTCAE, Version 4.0.

To characterize the PK properties, immunogenic response, and pharmacodynamic effects of tiragolumab as a single agent (Phase la) or in combination with atezolizumab with and without chemotherapy (Phase lb), blood samples are taken at various timepoints before and after dosing. Depending on the results from the interim PK analyses, the frequency of PK sampling may be reduced later in the study.

Patients undergo tumor assessments at screening and during the study, which are measured by standard Response Evaluation Criteria in Solid Tumors (RECIST) v1 .1 criteria. Patients may be permitted to continue study treatment even if standard RECIST v1 .1 criteria for progression of disease are met in the Phase la or Phase lb portions of the study, provided that they meet the criteria for continued treatment. Patients who discontinue the Phase la portion of the study may be permitted to cross over into the Phase lb portion of the study and receive treatment with tiragolumab in combination with atezolizumab, provided that they meet the criteria for crossover and consent to a biopsy of an accessible lesion.

Approximately 60-320 patients with locally advanced, recurrent, or metastatic incurable malignancies that have progressed after available standard therapy; or for whom standard therapy has proven to be ineffective or intolerable, or is considered inappropriate; or for whom a clinical trial of an investigational agent is a recognized standard of care, are enrolled in the expansion cohorts of the study. For the Phase lb portion of the study, patients for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody with or without chemotherapy is considered an acceptable treatment option may be enrolled in the expansion cohorts.

This expansion stage includes defined cohorts of patients to better characterize the safety, tolerability, PK variability, pharmacodynamic activity, and preliminary anti-tumor activity of tiragolumab as a single agent (Phase la) or in combination with atezolizumab with or without chemotherapy (Phase lb) in specific cancer settings. Enrollment in the expansion cohorts will be initiated at a selected dose level at or below the MAD or MTD of tiragolumab as a single agent (Phase la) or tiragolumab in combination with atezolizumab with or without chemotherapy (Phase lb), as determined by the Sponsor in consultation with the study investigators, based on an assessment of accumulating safety, tolerability, PK, pharmacodynamic, and anti-tumor activity data.

In the Phase la portion of the study, up to approximately 40 patients are enrolled in a planned expansion cohort of multiple tumor indications that are PD-L1 -selected and/or TIGIT-selected, including NSCLC, RCC, TNBC, melanoma, HNSCC, OC, GC including GEJ cancer, UBC, and CRC, including CRC that is MSS or MSI-Low.

In the Phase lb portion of the study (without chemotherapy), approximately 20-40 patients are enrolled in each of the following planned indication-specific expansion cohorts: NSCLC: Cancer immunotherapy (CIT)-Naive (e.g., no prior treatment with anti-PD-L1/PD-1 ); NSCLC: CIT-Treated (e.g., including prior treatment with anti-PD-L1/PD-1 ); RCC; TNBC; Melanoma; HNSCC; OC; GC, including GEJ cancer; UBC; CRC, including CRC that is MSS or MSI-Low; Biopsy cohort of specific tumor indications, including melanoma, OC, RCC, and UBC.

In the Phase lb chemotherapy expansion portion of the study, approximately 20-40 patients are enrolled in each of the following planned chemotherapy expansion cohorts (See FIG. 1 ):

Cohort A:

- Induction phase - atezolizumab and tiragolumab in combination with cisplatin or carboplatin and pemetrexed

- Maintenance phase - atezolizumab and tiragolumab in combination with Pemetrexed

Cohort B:

- Induction phase - atezolizumab and tiragolumab in combination with carboplatin and paclitaxel

- Maintenance phase - atezolizumab and tiragolumab

Cohort C:

- Induction phase - atezolizumab and tiragolumab in combination with cisplatin or carboplatin and etoposide

- Maintenance phase - atezolizumab and tiragolumab

The treatment combinations in each cohort are shown in Table 2.

Table 2. Treatment Regimens in the Chemotherapy Expansion Cohorts

Phase lb Chemotherapy Expansion Cohorts: Dosing and Administration

In the induction phase, patients in the specific chemotherapy expansion cohorts receive the following:

Cohort A receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by the combination of cisplatin 75 mg/m² IV or carboplatin AUC of 6 mg/mL min IV and pemetrexed 500 mg/m² IV on Day 1 of an every 21 -day cycle. Four to six cycles of induction-phase treatment will be administered in the absence of disease progression or unacceptable toxicity.

Cohort B receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by the combination of carboplatin AUC of 6 mg/mL min IV and paclitaxel 200 mg/m² IV on Day 1 of an every 21 -day cycle. Four to six cycles of induction phase treatment will be administered in the absence of disease progression or unacceptable toxicity.

Cohort C receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV followed by cisplatin 75 mg/m2 IV or carboplatin AUC of 5 mg/mL min IV on Day 1 of an every 21 -day cycle and then etoposide 100 mg/m² IV on Days 1 - 3 of an every 21 -day cycle. Four cycles of induction phase treatment will be administered in the absence of disease progression or unacceptable toxicity.

Following the induction phase, treatment continues in the maintenance phase in the absence of unacceptable toxicity, clinically compelling disease progression, and/or loss of clinical benefit at the investigator’s discretion following a careful assessment and thorough discussion of the potential risks and benefits with the patient. In the maintenance phase, patients in the specific chemotherapy expansion cohorts receive the following:

Cohort A receives atezolizumab 1200 mg IV, then tiragolumab 600 mg IV, followed by pemetrexed 500 mg/m² IV on Day 1 of an every-21 -day cycle; Cohort B receives atezolizumab 1200 mg IV and then tiragolumab 600 mg IV on Day 1 of an every-21 -day cycle; Cohort C receives atezolizumab 1200 mg IV and then tiragolumab 600 mg IV on Day 1 of an every-21 -day cycle.

In the event of toxicity and the absence of disease progression, individual chemotherapy or immunotherapy agents are independently discontinued.

Phase lb Q4W Dosing Expansion Cohort

The objectives of the Phase lb Q4W dosing expansion cohort are to better characterize the safety, tolerability, PK, and preliminary efficacy data and to explore potential tumor biomarkers of pharmacodynamic activity in patients treated with tiragolumab 840 mg IV in combination with atezolizumab 1680 mg IV with an every 4 week (28 day) dosing schedule.

The Phase lb Q4W cohort includes approximately 20-40 patients with tumors that can be PD-L1 - selected and/or TIG IT-selected based on prospective testing of tumor tissue during screening or rescreening. A patient with insufficient or unavailable archival tissue may be eligible for enrollment in this cohort, if deemed so by the Medical Monitor based upon a discussion with the investigator. Patients with a tumor type for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option may be enrolled in these expansion cohorts.

Additional Inclusion Criteria for Patients in Each Indication-Specific Expansion Cohort of Phase lb

The NSCLC Cohort (CIT-naive) includes patients with histologically confirmed incurable, advanced NSCLC not previously treated with CIT (investigational or approved), including anti-PD-L1/PD-1 and/or anti-CTLA-4, for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents) is approved as treatment for NSCLC by local regulatory authorities. Patients whose tumors have a known sensitizing epidermal growth factor receptor (EGFR) mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with an EGFR tyrosine kinase inhibitor(s). Patients whose tumors have a known anaplastic lymphoma kinase (ALK) rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ALK tyrosine kinase inhibitor(s). Patients whose tumors have a known ROS1 rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ROS1 tyrosine kinase inhibitor(s). Patients whose tumors have a BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib.

The NSCLC cohort (CIT-treated) includes patients with histologically confirmed incurable, advanced NSCLC previously treated with CIT (investigational or approved) including anti-PD-L1/PD-1 . Patients whose tumors have a known sensitizing EGFR mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with EGFR tyrosine kinase inhibitor(s). Patients whose tumors have a known ALK rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ALK tyrosine kinase inhibitor(s). Patients whose tumors have a known ROS1 rearrangement must also have experienced disease progression (during or after treatment) or intolerance to treatment with an ROS1 tyrosine kinase inhibitor(s). Patients whose tumors have a BRAFV600E mutation must also have experienced disease progression (during or after treatment) or intolerance to treatment with dabrafenib in combination with trametinib. Patients must have experienced documented disease progression on CIT monotherapy and/or combination therapy (investigational or approved), which must have included a prior anti-PD- L1/PD-1 .

At least approximately 10 patients who experienced a documented best response of investigator- assessed confirmed PR or CR per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy or combination therapy may be enrolled. At least approximately 10 patients who experienced a documented best response of investigator-assessed SD per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may be enrolled. At least approximately 10 patients who experienced a documented best response of investigator-assessed progressive disease (PD) per RECIST v1 .1 at any time while receiving the prior anti-PD-L1/PD-1 as monotherapy and/or as combination therapy may be enrolled. The prior anti-PD- L1/PD-1 as monotherapy and/or as combination therapy must represent the most recent systemic anti cancer therapy administered prior to enrollment in this expansion cohort. Patients who discontinued the prior anti-PD-L1/PD-1 monotherapy and/or combination therapy primarily for toxicity or intolerability are not eligible for enrollment in this expansion cohort.

The TNBC cohort includes patients with histologically confirmed incurable, advanced estrogen receptor (ER)-negative, progesterone receptor-negative, and human EGFR 2 (HER2)-negative adenocarcinoma of the breast (triple-negative). Triple-negative status must be documented as defined by the American Society of Clinical Oncology College of American Pathologists (ASCO-CAP) guidelines:

< 1% of tumor cell nuclei are immunoreactive for ER and < 1% of tumor cell nuclei are immunoreactive for progesterone receptor and HER2 tests demonstrate IHC 1+, IHC 0, or in situ hybridization (ISH) negative The CRC cohort includes patients with histologically confirmed incurable, advanced adenocarcinoma of the colon or rectum. Patients with tumors of appendiceal origin are not eligible.

The GC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic or recurrent gastric or GEJ adenocarcinoma, not amenable to curative therapy. Patients with Type 1 GEJ tumor, defined by RQdiger Siewert et al. (2000) as adenocarcinoma of the distal esophagus with the tumor center located within 1 to 5 cm above the anatomic esophagogastric junction, are eligible for the study. Patients with esophageal cancers (squamous cell carcinoma or adenocarcinoma) may be eligible following a discussion with the Medical Monitor. Patients whose tumors are HER2-positive must also have experienced disease progression (during or after treatment) or intolerance to treatment with HER2-targeting antibody/HER2 inhibitor(s). HER2-positivity is defined as either IHC 3+ or IHC 2+/ISH+ (where ISH positivity is defined as a HER2:CEP17 ratio of > 2), as assessed by a local laboratory test on the primary tumor or on a metastatic lesion. Patients who have not had HER2 testing due to insufficient or unavailable tissue (e.g., archival and/or biopsy), and thus the HER2 status of the tumor is unknown, may still be eligible.

The HNSCC cohort includes patients with histologically confirmed inoperable, locally advanced or metastatic, recurrent, or persistent head and neck squamous cell carcinoma (oral cavity, oropharynx, hypopharnyx, or larynx), not amenable to curative therapy. Patients with HNSCC of any other primary anatomic location in the head and neck, patients with HNSCC of unknown primary, or patients with tumors of non-squamous histologies are not eligible. Patients with HNSCC of the nasopharynx may be eligible. HPV status for the HNSCC must be known.

The UBC cohort includes patients with histologically confirmed incurable advanced transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Patients with mixed histologies are required to have a dominant transitional cell pattern.

The melanoma cohort includes patients with histologically confirmed incurable, advanced metastatic melanoma. Patients with melanoma for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents and/or anti-CTLA-4 agents) is approved as treatment for melanoma by local regulatory authorities. Patients whose tumors have a known BRAFV600 mutation must also have experienced disease progression (during or after treatment) or intolerance with BRAF inhibitor (s) and/or MEK inhibitor(s). Enrollment will be managed so that no more than approximately 20% of patients in this cohort will be patients with ocular (uveal) melanoma.

The OC cohort includes patients with histologically confirmed incurable, advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Borderline ovarian epithelial neoplasms (e.g., tumors of low malignant potential, atypical proliferative tumors) are excluded.

The RCC cohort includes patients with histologically confirmed incurable, advanced RCC with component of clear cell histology and/or component of sarcomatoid histology. Patients with RCC for whom a clinical trial of an investigational agent in combination with an anti-PD-L1 antibody is considered an acceptable treatment option, if CIT (including anti-PD-L1/PD-1 agents) is approved as treatment for RCC by local regulatory authorities. Dosing and Administration

The dose of atezolizumab administered in combination with tiragolumab in the Phase lb portion of this study is 1200 mg IV every three weeks, except in the Phase lb Q4W dosing cohort where atezolizumab 1680 mg IV Q4W is administered. This dose is fixed and not dependent on body weight. In all Phase lb cohorts without chemotherapy, atezolizumab is administered after the tiragolumab infusion and subsequent observation period. In the Phase lb chemotherapy expansion cohorts, atezolizumab is administered before tiragolumab.

The initial dose of atezolizumab will be delivered over 60 (± 10) minutes. If the first infusion is tolerated without infusion-associated adverse events, the second infusion may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes. For Cycle 1 , dosing of atezolizumab will be followed by a 90-minute observation period.

All subsequent infusions of atezolizumab may be followed by a 30-minute observation period. Patients who have previously received atezolizumab on another clinical trial may receive the initial dose at the fastest rate that was previously tolerated.

Chemotherapy in the Phase lb Expansion Cohorts

Chemotherapy is administered after the atezolizumab and tiragolumab infusions and subsequent observation periods. During the induction phase, a chemotherapy cycle counts toward the prespecified number of induction chemotherapy cycles as long as at least one chemotherapy component has been administered at least once during a 21 -day cycle. Cycles in which no chemotherapy component is given do not count toward the total number of induction chemotherapy cycles.

Patients receive anti-emetics and IV hydration for chemotherapy agents according to the local standard-of-care and manufacturer’s instruction. However, because of the immunomodulatory effects of steroids, premedication with steroids should be minimized to the extent that is clinically feasible.

Cohort A - Atezolizumab plus tiragolumab plus Carboplatin/Cisplatin plus Pemetrexed

On Day 1 of each 21 day cycle, all eligible patients will receive drug infusions in the following order:

Induction: Atezolizumab > tiragolumab > pemetrexed > carboplatin or cisplatin

After 4 to 6 cycles in the induction phase, patients will begin maintenance therapy in the following order of administration:

Maintenance: Atezolizumab > tiragolumab > pemetrexed

Table 3. Treatment Regimen for Pemetrexed and Carboplatin or Cisplatin

AUC = area under the concentration-time curve; IV _^intravenous; Q3W = every 3 weeks.

Table 4 lists suggested infusion times for treatment administration for pemetrexed and carboplatin or cisplatin during the induction phase and for pemetrexed during the maintenance phase.

Table 4. Premedication for Paclitaxel

IV = intravenous; PO= orally

Cohort B Atezolizumab plus tiragolumab plus Carboplatin plus Paclitaxel On Day 1 of each 21 -day cycle, all eligible patients will receive drug infusions in the following order:

Induction: Atezolizumab > tiragolumab > paclitaxel > carboplatin

Table 4 lists the suggested premedication for induction treatment for patients in Cohort B. Table 5 lists the suggested infusion times for treatment administration for paclitaxel and carboplatin during the induction phase.

Table 5. Treatment Regimen for Paclitaxel and Carboplatin

AUC = area under the concentration-time curve; IV _^intravenous; Q3W = every 3 weeks. ^a See section 4.3.2.4.5 for more details.

Cohort C - Atezolizumab plus tiragolumab plus Carboplatin or Cisplatin plus Etoposide On Day 1 of each 21 -day cycle, all eligible patients will be administered study drug infusions in the following order:

Induction: Atezolizumab > tiragolumab > cisplatin or carboplatin > etoposide After the induction phase, patients begin maintenance therapy in the following order of administration:

Maintenance: Atezolizumab > tiragolumab

Table 6 lists the suggested infusion times for treatment administration for carboplatin or cisplatin and etoposide during the induction phase.

Table 6. Treatment Regimen for Carboplatin or Cisplatin and Etoposide

every 3 weeks.

Guidelines for the administration of cisplatin in different cohorts are shown in Table 7.

Table 7. Cisplatin Administration Timing and Guidelines

IV = intravenous

Note: Patients must receive adequate anti-emetic treatment and appropriate hydration prior to and after receiving cisplatin. Refer to local clinical practice guidelines for further details.

Carboplatin

Guidelines for the administration of cisplatin in different cohorts are shown in Table 8. Table 8. Carboplatin Administration Timing and Guidelines

AUC= area under time-concentration curve; IV = intravenous

Note: Standard antiemetics should be given with carboplatin administration per local practice guidelines, The carboplatin dose of AUC 5 or 6 will be calculated using Calvert formula (Calvert et al. 1989): For the purposes of this study, the GFR is considered to be equivalent to the calculated creatinine clearance (CrCI). The CrCI is calculated by institutional guidelines or by the method of Cockcroft and Gault (1976) using the following formula:

For patients with an abnormally low serum creatinine level, estimate the GFR through use of a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 125 mL/min.

If a patient’s GFR is estimated based on serum creatinine measurements by the isotope dilution mass spectroscopy method, the U.S. FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as follows:

Maximum carboplatin dose (mg) = target AUC (mg min/mL) (GFR + 25 mL/min).

The maximum dose is based on a GFR estimate that is capped at 150 mL/min for patients with normal renal function. No higher estimated GFR values should be used.

For a target AUC = 6, the maximum dose is 6 150 = 900 mg.

For a target AUC = 5, the maximum dose is 5 150 = 750 mg.

For a target AUC = 4, the maximum dose is 4 150 = 600 mg.

Pemetrexed

Guidelines for the administration of pemetrexed in Cohort A is shown in Table 9. Table 9. Pemetrexed Administration Timing and Guidelines

IV = intravenous

Premedication doses administered complies with the prescribing information. All patients eligible for pemetrexed therapy should avoid taking non-steroidal anti-inflammatory drugs with long elimination half-lives for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration.

Paclitaxel

Guidelines for the administration of paclitaxel in Cohort B is shown in Table 10.

Table 10. Paclitaxel Administration Timing and Guidelines

IV = intravenous

Patients of Asian race/ethnicity have a lower starting dose of paclitaxel at 175 mg/m2 IV over 3 hours. The lower starting dose of paclitaxel is based on a higher overall incidence of hematologic toxicities in patients from Asian countries compared with those from non-Asian countries, as observed during internal safety review of lung cancer clinical trials. As used in this study, Asian race/ethnicity refers to a panethnic/racial group that includes diverse populations who either live or have ancestral origins in East Asia, Southeast Asia, or South Asia. The applicability of such term in a particular patient will be at the discretion of the treating investigator and should be based on the patient’s clinical characteristics and country of origin.

Etoposide

Guidelines for the administration of etoposide in Cohort C is shown in Table 11 . Table 11. Etoposide Administration Timing and Guidelines

IV= intravenous Example 2. A Phase lb/11, open-label, randomized study of atezolizumab and chemotherapy in combination with tiragolumab

This study evaluates the efficacy, safety, and pharmacokinetics of atezolizumab and chemotherapy (nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine) in combination with tiragolumab in patients who have received no prior systemic therapy for metastatic pancreatic ductal adenocarcinoma (PDAC). This study evaluates the efficacy, safety, and pharmacokinetics of immunotherapy-based treatment combinations in patients with metastatic PDAC.

Study Design

Patients in Cohort 1 are randomly assigned to a control arm (chemotherapy) or an experimental arm consisting of atezolizumab and chemotherapy in combination with tiragolumab. Enrollment within the experimental arms will take place in two phases: a preliminary phase followed by an expansion phase. Approximately 20 patients are enrolled during the preliminary phase. Randomization issuspended to allow for a safety evaluation in a minimum of 6 patients. The safety evaluation is based on safety data from a minimum of 6 patients who have received at least one dose of treatment (i.e. , one dose of each agent for a given combination) and completed safety follow-up assessments during at least one full treatment cycle. If the combination is determined to be sufficiently safe, enrollment is resumed in that arm. If clinical activity is observed in an experimental arm during the preliminary phase, approximately 25 additional patients may be enrolled in that arm during the expansion phase. Additional patients may be enrolled to ensure balance among treatment arms with respect to demographic and baseline characteristics, including potential predictive biomarkers, to enable further subgroup analyses.

Patients are randomly assigned to treatment arms, and the randomization ratio will depend on the number of experimental arms that are open for enrollment (e.g., if an arm is added or enrollment in an arm is suspended pending analysis of results from the preliminary phase), with the stipulation that the likelihood of being allocated to the control arm is no more than 35%.

The end of this study is defined as the date when the last patient completes the last visit (LPLV), including survival follow-up visits conducted by telephone or in the clinic. The total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 3-5 years.

A schedule of the activities is outlined in Table 12.

Table 12: Schedule of Activities

ADA = anti-drug antibody; Atezo + Chemo + Tira = atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tiragolumab; CIT = cancer immunotherapy; CT = computed tomography; Discon. = discontinuation; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form; HBV = hepatitis B virus; nab-paclitaxel = nanoparticle albumin = bound paclitaxel; PK = pharmacokinetic; RBR = Research Biosample Repository; RECIST v1 .1 = Response Evaluation Criteria in Solid Tumors, Version 1 .1 ; T3 = triiodothyronine; T4 = thyroxine; Treat. = treatment; TSH = thyroid-stimulating hormone

On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. ^a If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window if Medical Monitor agreement has been obtained. b It is recommended that treatment be initiated no later than 7 days after randomization. c Patients will return to the clinic for a treatment discontinuation visit not more than 30 days after the last dose of study treatment. The visit at which disease progression is confirmed may be used as the treatment discontinuation visit. Patients will then undergo follow-up assessments. d Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, and temperature. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. For the first infusion of atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 (± 5) minutes during and 30 (± 10) minutes after the infusion. For subsequent infusions, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 30 (± 10) minutes after the infusion. For the first infusion of tiragolumab, vital signs should be measured within 60 minutes prior to the infusion and every 15 (± 5) minutes during and 30 (± 10) minutes after the infusion. For subsequent infusions of tiragolumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 15 (± 10) minutes after the infusion. e Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. f Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints. Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.

⁹ It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. h Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells).

' Laboratory tests must be performed within 96 hours prior to Day 1 of Cycle 1 and within 24 hours prior to specified subsequent visits during the treatment period. i If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1 , they do not have to be repeated. k Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST.

¹ TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed at screening and on Day 1 of Cycle 1 and every third cycle thereafter (i.e., Cycles 4, 7, 10, etc.). m Patients with a positive quantitative HBV DNA at screening (must be < 500 lU/mL per the eligibility criteria) will undergo additional HBV DNA tests on Day 1 of every third cycle (i.e., Cycles 3, 6, 9, etc.), at treatment discontinuation (± 7 days), and at 3, 6, 9, and 12 months (± 14 days at each timepoint) after treatment discontinuation. Study treatment and procedures may proceed while HBV DNA is being processed, but results should be reviewed by the investigator as soon as they are available. If HBV DNA increases to < 500 lU/mL, consultation with the Medical Monitor is required prior to continuation of study treatment and consultation with a hepatologist or gastroenterologist with specialty in hepatitis B is recommended. n All women of childbearing potential have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 6 months after the last dose of study treatment. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.

⁰ Includes pH, specific gravity, glucose, protein, ketones, and blood; dipstick permitted p Autoantibody analysis includes anti-nuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody.

P Autoantibody analysis should be repeated for patients who develop signs or symptoms suggestive of autoimmune disease (e.g., lupus erythematosus). r Not applicable for a site that has not been granted approval for RBR sampling. Performed only for patients at participating sites who have provided written informed consent to participate. s Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the investigator, if deemed clinically feasible by the investigator. Biopsies should be performed within 40 days after determination of unacceptable toxicity or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner. In addition, patients enrolled during the expansion phase will undergo tumor biopsy sample collection 4 weeks (± 7 days) after treatment initiation (if deemed clinically feasible), unless on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination.

* Patients who consent to optional biopsies will undergo tumor biopsy sample collection 4 weeks (± 7 days) after treatment initiation, if deemed clinically feasible (does not apply to patients enrolled during the expansion phase who are already undergoing an on-treatment biopsy) and may undergo additional on-treatment biopsies at any other time at the investigator's discretion. u Patients will undergo tumor assessments at baseline, every 6 weeks (± 1 week) for the first 48 weeks following treatment initiation, and every 12 weeks (± 2 weeks) thereafter, regardless of dose delays, until radiographic disease progression according to RECIST v1 .1 , except in the case of patients who continue treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks (± 1 week) until loss of clinical benefit as determined by the investigator. Thus, tumor assessments are to continue according to schedule in patients who discontinue treatment for reasons other than disease progression, even if they start new non-protocol-specified anti-cancer therapy. v All measurable and/or evaluable lesions identified at baseline should be re-assessed at each subsequent tumor evaluations according to the tumor assessment schedule described above (see footnote “t”). The same radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). w Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-mandated study treatment from 10 days prior to initiation of study treatment until the treatment discontinuation visit. ^x After initiation of study treatment, all adverse events will be reported until 30 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be reported until 135 days after the last dose of study treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first. After this period, all deaths, regardless of cause, should be reported. In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior exposure to study treatment. The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent. Every effort should be made to follow all serious adverse events considered to be related to study treatment or trial-related procedures until a final outcome can be reported. y Atezolizumab is administered by IV infusion at a fixed dose of 840 mg on Days 1 and 15 of each 28-day cycle. The initial dose of atezolizumab is delivered over 60 (± 15) minutes. Subsequent infusions are delivered over 30 (± 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 (± 15) minutes if the patient experienced an infusion-associated adverse event with the previous infusion. z Treatment continues until unacceptable toxicity or loss of clinical benefit as determined by the investigator. a^a Tiragolumab is administered by IV infusion at a fixed dose of 420 mg on Days 1 and 15 of each 28-day cycle. The initial dose of tiragolumab is delivered over 60 (± 10) minutes. Subsequent infusions will be delivered over 30 (± 10) minutes if the previous infusion was tolerated without infusion-associated adverse events, or 60 (± 10) minutes if the patient experienced an infusion-associated adverse event with the previous infusion. On Day 1 of Cycle 1 , tiragolumab will be administered 60 minutes after completion of the atezolizumab infusion. The interval between subsequent infusions is 30 minutes if the previous atezolizumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous atezolizumab infusion. b^b On Days 1 , 8, and 15, patients receive nab-paclitaxel 125 mg/m², administered by IV infusion over 30 (± 5) minutes, followed by gemcitabine 1000 mg/m², administered by IV infusion over 30 (± 5) minutes. On Day 1 of Cycle 1 , nab-paclitaxel will be administered 60 minutes after completion of the tiragolumab infusion to allow for observation after tiragolumab administration. The interval between subsequent infusions will be 30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous tiragolumab infusion. c^c After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) is collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death (unless the patient withdraws consent or the Sponsor terminates the study). If a patient requests to be withdrawn from follow-up, this request must be documented in the source documents and signed by the investigator. If the patient withdraws from the study, the study staff may use a public information source (e.g., county records) to obtain information about survival status only. Assessments and Monitoring

All patients are closely monitored for adverse events throughout the study, and adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Patients undergo tumor assessments every 6 weeks (from Day 1 of Cycle 1 ) during the first 48 weeks and then every 6 or 12 weeks thereafter. Response will be assessed by the investigator using RECIST v1 .1 . Response per modified RECIST v1 .1 for immune based therapeutics (iRECIST) will be determined programmatically by the Sponsor on the basis of investigator- assessed individual lesion data. If clinical activity is demonstrated in an experimental arm, the Sponsor may request that tumor assessment scans for that arm be submitted for evaluation by an independent review facility.

Baseline tumor tissue samples are collected from all patients, e.g., by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy. If deemed clinically feasible by the investigator, tumor tissue will also be collected for patients who discontinue Stage 1 because of unacceptable toxicity, disease progression per RECIST v1 .1 , or loss of clinical benefit as determined by the investigator. For patients enrolled in an experimental arm during the expansion phase, an on-treatment tumor tissue sample will be collected 4 weeks after initiation of Stage 1 treatment (if clinically feasible), unless on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination. These samples will be utilized for biomarker research (see rationale for biomarker assessments

To characterize the pharmacokinetic (PK) properties and/or immunogenicity of atezolizumab and the other therapeutic agents, blood samples are taken at various timepoints before and during study treatment administration (Table 13). On the basis of a review of real-time safety data and available PK data, treatment regimens may be modified.

Table 13: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples

ADA = anti-drug antibody; Atezo + Chemo + Tira = atezolizumab plus chemotherapy (nab-paclitaxel and gemcitabine) plus tiragolumab; nab-paclitaxel = nanoparticle albumin-bound paclitaxel; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetic. Note: On the basis of emerging safety or efficacy data, the number of PK and ADA samples may be reduced or sample collection may cease altogether. Additionally, collected samples may not be analyzed if not warranted. On the basis of emerging biomarker data, the number of biomarker samples may be reduced or sample collection may cease altogether. Laboratory, Biomarker, and Other Biological Samples

Exploratory biomarker research includes, but is not limited to, analysis of genes or gene signatures associated with tumor immunobiology, PD-L1 , cytokines associated with T-cell activation, T- cell receptor repertoire, carcinoembryonic antigen, or density, localization, and activation status of immune cells and their subsets, and may involve DNA or RNA extraction, analysis of somatic mutations, and use of NGS (including WES).

Samples for the following laboratory tests will be sent to the study site's local laboratory for analysis:

• Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells) · Chemistry panel (serum or plasma): CPK, bicarbonate or carbon dioxide (if considered standard of care for the region), sodium, potassium, magnesium, chloride, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin, ALP, ALT, and AST

• Coagulation: INR and aPTT • Thyroid function testing: thyroid-stimulating hormone, free triiodothyronine (T3) (or total T3 for sites where free T3 is not performed), and free thyroxine (also known as T4)

• Ferritin and y-glutamyl transferase

• HIV serology, unless not permitted per local regulations

• HAV serology: HAV IgM

• HBV serology: HBsAg, total HBcAb, and (if HBsAg test is negative and total HBcAb test is positive) HBV DNA

If a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test must also be performed to determine if the patient has an HBV infection.

• HCV serology: HCV antibody and (if HCV antibody test is positive) HCV RNA

If a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed to determine if the patient has an active HCV infection.

• HEV serology: HEV IgM

• C-reactive protein

• LDH

• CA19-9

• EBV serology:

- EBV VCA IgM

- EBV VCA IgG or EBNA IgG

- EBV PCR (only if clinically indicated)

• Pregnancy test

All women of childbearing potential will have a serum pregnancy test at Stage 1 screening. Urine or serum pregnancy tests will be performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.

A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (> 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).

• Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood)

Dipstick urinalysis is permitted. However, patients with > 2+ protein on dipstick urinalysis at screening must undergo a 24-hour urine collection for protein if a bevacizumab-containing arm is open for enrollment.

Samples for the following laboratory test will be sent to a central laboratory or to the study site's local laboratory for analysis:

• Soluble CD25

The following samples will be sent to one or several central laboratories or to the Sponsor or a designee for analysis:

• Serum sample for analysis of autoantibodies: anti-nuclear antibody, anti-double-stranded DNA, circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody

• Plasma or serum samples for PK analysis through use of validated assays • Plasma or serum samples for immunogenicity analysis through use of validated assays

• Plasma, serum, and peripheral blood mononuclear cell (PBMC) samples for exploratory research on biomarkers

• Tumor tissue sample collected at baseline for determination of PD-L1 expression and for exploratory research on biomarkers

Baseline tumor tissue samples from the primary lesion or a metastatic lesion will be collected from all patients, preferably by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy.

A representative FFPE tumor specimen in a paraffin block (preferred) or at least 16 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. If only 10-15 slides are available, the patient may still be eligible for the study, after Medical Monitor approval has been obtained.

Tumor tissue should be of good quality based on total and viable tumor content. Samples must contain a minimum of 50 viable tumor cells that preserve cellular context and tissue architecture regardless of needle gauge or retrieval method. Samples collected via resection, core-needle biopsy (at least three cores, 18-gauge needle or larger [16-gauge needle preferred], embedded in a single paraffin block), or excisional, incisional, punch, or forceps biopsy are acceptable. Fine- needle aspiration (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, cell pellets from pleural effusion, and lavage samples are not acceptable. Tumor tissue from bone metastases that have been decalcified is not acceptable. Remaining archival tumor tissue blocks will be returned to the site upon request or 18 months after final closure of the study database, whichever occurs first.

• Patients enrolled in an experimental arm during the expansion phase: tumor tissue sample collected 4 weeks (± 7 days) after initiation of treatment (if deemed clinically feasible by the investigator) for exploratory research on biomarkers

Samples will not be collected if on-treatment tissue samples have already been collected, and determined to be evaluable, from a minimum of 15 patients treated with the same CIT combination.

Samples collected via resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, punch, or forceps biopsy are preferred.

• Tumor tissue sample collected at the time of unacceptable toxicity, disease progression per RECIST v1 .1 , or loss of clinical benefit as determined by the investigator, if deemed clinically feasible by the investigator, for exploratory research on biomarkers

Biopsies should be performed within 40 days after determination of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is sooner. Samples collected via resection, core-needle biopsy (at least three cores preferred), or excisional, incisional, punch, or forceps biopsy are preferred. Atezolizumab dose and schedule

Atezolizumab is administered at a fixed dose of 840 mg every two weeks (Q2W) (840 mg on Days 1 and 15 of each 28-day cycle).

Tiragolumab dose and schedule

Tiragolumab is administered at a fixed dose of 420 mg Q2W (420 mg on Days 1 and 15 of each 28-day cycle). The average concentration following the 420 mg Q2W dose is expected to be equivalent to that of 600 mg every three weeks (Q3W). The fixed tiragolumab dose of 600 mg IV Q3W was selected on the basis of available pharmacokinetic (PK), efficacy, and safety data from Study G030103, in which patients received single-agent tiragolumab or tiragolumab plus atezolizumab. The MTD was not reached, and no DLTs were observed with tiragolumab monotherapy or with tiragolumab at doses of 2-1200 mg Q3W in combination with atezolizumab 1200 mg Q3W. In addition, development of anti-drug antibodies (ADAs) to tiragolumab was observed in 3 of 145 evaluable patients receiving tiragolumab (doses of 2-600 mg Q3W) in combination with atezolizumab. Complete occupancy of peripheral TIGIT receptors on CD4⁺, CD8⁺, and NK cells was observed beginning at the 30 mg Q3W dose of tiragolumab and remained sustained at all higher doses. Anti-tumor activity (radiographic partial response) was observed at tiragolumab doses of 30-600 mg Q3W when given in combination with atezolizumab 1200 mg Q3W.

Dosage and Administration

Patients receive treatment as outlined until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such as pain secondary to disease).

Participants receive atezolizumab 840 mg IV infusion on Days 1 and 15 of each 28 day cycle per the instructions outlined in Table 14.

Participants receive tiragolumab 420 mg IV infusion on Days 1 and 15 of each 28 day cycle per the instructions outlined in Table 15. On Day 1 of Cycle 1 , tiragolumab is administered 60 minutes after completion of the atezolizumab infusion. The interval between subsequent infusions is 30 minutes if the previous atezolizumab infusion was given without premedication and tolerated without an infusion-related reaction (IRR) or 60 minutes if the patient experienced an IRR with the previous atezolizumab infusion.

Participants receive nab-paclitaxel 125 mg/m² IV infusion on Days 1 , 8, and 15 of each 28 day cycle, administered by IV infusion over 30 (± 5) minutes, followed by gemcitabine 1000 mg/m², administered by IV infusion over 30 (± 10) minutes. On Day 1 of Cycle 1 , nab-paclitaxel will be administered 60 minutes after completion of the tiragolumab infusion. The interval between subsequent infusions is 30 minutes if the previous tiragolumab infusion was tolerated without an IRR or 60 minutes if the patient experienced an IRR with the previous tiragolumab infusion. Table 14: Administration of First and Subsequent Atezolizumab Infusions

Table 15: Administration of First and Subsequent Tiragolumab Infusions

Dose Modifications

There are no dose modifications for atezolizumab or tiragolumab in this study. For management of drug-related toxicities, the dose of nab-paclitaxel may be reduced by 25 mg/m² (one dose level) up to two times and the dose of gemcitabine may be reduced by 200 mg/m² (one dose level) up to two times, as outlined in Table 16.

If further dose reduction is indicated for nab-paclitaxel and/or gemcitabine after two dose reductions, that drug (or both drugs, if applicable) is discontinued, but the patient may continue other study treatments at the investigator’s discretion. After dose reduction, the dose may be escalated during subsequent administrations at the investigator's discretion.

Table 16: Recommended Dose Reductions for Nab-Paclitaxel and Gemcitabine

Concomitant Therapy

Concomitant therapy includes of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-mandated study treatment from 10 days prior to initiation of study treatment to the treatment discontinuation visit.

Patients are permitted to use the following therapies during the study:

• Colony-stimulating factors (CSFs), such as granulocyte colony-stimulating factors (G-CSFs), and erythropoiesis-stimulating agents (ESAs) per local practice/institutional guidelines or the American Society of Clinical Oncology guidelines for hematopoietic CSFs (Smith et al. 2006) and American Society of Hematology/American Society of Clinical Oncology guidelines for ESAs (Rizzo et al. 2010)

Evidence supporting the use of long-acting (PEGylated) forms of G-CSF in patients receiving weekly chemotherapy (i.e., nab-paclitaxel) is limited. Thus, investigators should consider giving preference to conventional formulations of G-CSF.

• Oral contraceptives

• Flormone-replacement therapy

• Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or low- molecular-weight heparin) Inactivated influenza vaccinations

Megestrol acetate administered as an appetite stimulant after initiation of study treatment Mineralocorticoids (e.g., fludrocortisone)

Inhaled corticosteroids administered for chronic obstructive pulmonary disease or asthma Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical insufficiency Hormonal therapy with gonadotropin-releasing hormone agonists or antagonists for prostate cancer Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief of pain) as outlined below:

Palliative radiotherapy is permitted, provided it does not interfere with the assessment of tumor target lesions (e.g., the lesion to be irradiated must not be the only site of measurable disease). Treatment with nab-paclitaxel and gemcitabine should be withheld during palliative radiotherapy. Treatment with atezolizumab and tiragolumab may be continued during palliative radiotherapy.

• Radiotherapy to the brain as outlined below:

Patients whose extracranial tumor burden is stable or responding to study treatment and who are subsequently found to have three or fewer brain metastases may receive radiotherapy to the brain (either stereotactic radiosurgery or whole-brain radiation therapy) provided that all of the following criteria are met:

- The patient has no evidence of progression or hemorrhage after completion of CNS-directed therapy.

- The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.

Patients who require corticosteroid therapy for more than 7 days after completion of radiotherapy must be discontinued from study treatment.

- Anti-convulsant therapy, if required, is administered at a stable dose.

Premedication with antihistamines, anti-pyretics, and/or analgesics may be administered for the second and subsequent atezolizumab and tiragolumab infusions only, at the discretion of the investigator. In general, investigators should manage a patient’s care with supportive therapies as clinically indicated, per local standard practice. Patients who experience infusion associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2-adrenergic agonists).

Inclusion Criteria

Patients meet the following criteria:

• Age > 18 years at the time of signing Informed Consent Form

• ECOG Performance Status of 0 or 1

• Histologically or cytologically confirmed metastatic PDAC

The definitive diagnosis of metastatic PDAC is made by evaluating the histopathologic data within the context of clinical and radiographic data. Patients with endocrine or acinar pancreatic carcinoma are not eligible for the study.

• No prior systemic treatment for PDAC

• Life expectancy > 3 months, as determined by the investigator

• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing

Baseline tumor tissue samples will be collected from all patients, preferably by means of a biopsy performed at study entry. If a biopsy is not deemed feasible by the investigator, archival tumor tissue may be submitted after Medical Monitor approval has been obtained, provided the tissue was obtained from a biopsy performed within 3 months prior to enrollment and the patient has not received any anti-cancer therapy since the time of the biopsy.

A formalin-fixed, paraffin-embedded tumor specimen in a paraffin block (preferred) or at least 16 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. If only 10-15 slides are available, the patient may still be eligible for the study, after Medical Monitor approval has been obtained.

• Signed Informed Consent Form

• Ability to comply with the study protocol, in the investigator’s judgment

• Measurable disease (at least one target lesion) according to RECIST v1 .1

Previously irradiated lesions can be considered as measurable disease only if progressive disease has been unequivocally documented at that site since radiation.

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:

- ANC > 1.5 x 10⁹/L (1500/pL) without granulocyte colony-stimulating factor support within 14 days prior to screening laboratory test

- WBC count > 2.5 x 10⁹/L (2500/pL)

- Lymphocyte count > 0.5 x 10⁹/L (500/pL)

- Platelet count > 100 x 10⁹/L (100,000/pL) without transfusion within 7 days prior to screening laboratory test

- Hemoglobin > 90 g/L (9.0 g/dL)

Patients may be transfused to meet this criterion after discussion with the Medical

Monitor.

- AST, ALT, and ALP < 2.5 x upper limit of normal (ULN), with the following exceptions:

Patients with documented liver metastases: AST and ALT < 5 x ULN Patients with documented liver or bone metastases: ALP < 5 x ULN

- Serum bilirubin < 1 .5 x ULN with the following exception:

Patients with known Gilbert disease: serum bilirubin level < 3 x ULN

- Creatinine clearance > 50 mL/min (calculated using the Cockcroft-Gault formula)

- Serum albumin > 25 g/L (2.5 g/dL)

- For patients not receiving anticoagulation: INR or aPTT < 1 .5 x ULN

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen

• Tumor accessible for biopsy • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Safety

Measures are taken to ensure the safety of patients participating in this study, including the use of stringent inclusion and exclusion criteria and close monitoring of patients during the study. Administration of study treatment will be performed in a monitored setting in which there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. Adverse events will be reported as described.

Verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory Activities thesaurus terms, and adverse event severity will be graded according to NCI CTCAE v4.0.

Safety will be assessed through summaries of adverse events, changes in laboratory test results, changes in vital signs and ECGs, and exposure to study drugs. Exposure to combination treatment and length of safety follow-up will be summarized by treatment arm within each stage.

Treatment-emergent adverse events occurring after initiation of treatment will be summarized. For each patient, the maximum reported severity of each adverse event will be used in the summaries by severity grade. All treatment-emergent adverse events, serious adverse events, adverse events leading to withdrawal of study treatment, Grade 3 adverse events, deaths, and causes of death will be listed and summarized by mapped term, appropriate thesaurus level, and NCI CTCAE severity grade. Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse oximetry, and temperature), and ECG data will be displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests will be used to summarize the baseline and maximum post-baseline severity grade. Changes in vital signs and ECGs will be summarized.

Atezolizumab has been associated with risks such as the following: IRRs and immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barre syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, myocarditis, nephritis, and myositis. Immune-mediated reactions may involve any organ system and may lead to hemophagocytic lymphohistiocytosis and macrophage activation syndrome (considered to be potential risks for atezolizumab).

The following are the most common adverse events observed with nab-paclitaxel in patients with PDAC: neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The following adverse events have also been observed: myelosuppression (primarily neutropenia, anemia, thrombocytopenia), cranial nerve palsies, hypersensitivity reactions, pneumonitis, myalgia, arthralgia, cardiotoxicity (myocardial disorders, cardiac failure, angina, tachycardia, ventricular arrhythmia), cystoid macular edema, Stevens-Johnson syndrome/toxic epidermal necrolysis, sepsis, infusion-site reactions/extravasation, hepatic toxicity (drug- induced liver injury), acute renal failure, hemolytic-uremic syndrome, and drug-induced lupus erythematous. The most common adverse events observed with gemcitabine are nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema.

IRR is an identified risk for tiragolumab. While clinical evaluation of tiragolumab is limited and not all risks are known, as an antagonist of TIGIT, tiragolumab is anticipated to enhance T-cell and NK-cell proliferation, survival, and function. Therefore, tiragolumab may increase the risk of autoimmune inflammation (also described as immune-mediated adverse events). In addition, due to the intact Fc effector function of tiragolumab, lymphopenia via antibody-dependent cellular cytotoxicity (ADCC) is a theoretical risk.

Because tiragolumab is a therapeutic monoclonal antibody and targets immune cells, IRRs associated with hypersensitivity reactions, target-mediated cytokine release, and/or emergent ADAs may occur. Clinical signs and symptoms of such reactions may include rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. IRRs have been reported in patients treated with tiragolumab alone or in combination atezolizumab. The majority of events were mild to moderate and manageable.

To minimize the risk and sequelae of IRRs, the initial dose of tiragolumab will be administered over 60 minutes followed by a 60-minute observation period. Subsequent infusions and observation times may be shortened if the preceding infusion was well tolerated. All infusions of tiragolumab will be administered in an appropriate medical setting.

Nonclinical models have suggested a role of TIGIT signaling interruption in autoimmunity. In a knockout model (TIGIT -/-), loss of TIGIT signaling resulted in hyperproliferative T-cell responses and exacerbation of experimental autoimmune encephalitis (EAE). TIGIT -/- and wild-type B6 mice were immunized with suboptimal doses of myelin oligodendrocyte glycoprotein peptide to induce EAE. In contrast to the wild-type B6 mice, the majority of the TIGIT -/- mice developed severe EAE (Joller et al. 2011 ).

Clinical experience with therapeutics intended to enhance anti-tumor T-cell responses has demonstrated that development of autoimmune inflammatory conditions is a general risk and may therefore be considered a potential risk of tiragolumab. Such immune-mediated adverse events have been described for virtually all organ systems and include, but are not limited to, colitis, hepatitis, pneumonitis, endocrinopathy, ocular toxicity, pancreatic toxicity, neurologic toxicity, myocarditis, nephritis, myositis, and rash.

Patients with a history of autoimmune disease will be excluded from this study. In addition, patients with a history of severe immune-mediated adverse events associated with prior immunotherapy or adverse events that did not resolve to baseline after discontinuation of prior immunotherapy will be excluded from this study.

In this study, specified immune-mediated adverse events will be considered adverse events of special interest and will be captured accordingly.

Given the IgG 1 backbone of tiragolumab with intact Fc-effector function, ADCC-mediated reduction in lymphocyte count is a potential risk. However, in a repeat-dose toxicity study in cynomolgus monkeys, there were no tiragolumab-related decreases in overall lymphocyte counts. Transient lymphocyte count decreases without clinical sequelae have been observed in patients treated with tiragolumab, alone or in combination with atezolizumab, in the Phase I study in solid tumors (Study GO30103). Because of this potential risk of tiragolumab to induce lymphopenia, patients with a lymphocyte count < 0.5 x 10⁹/L (500/mI_) will be excluded from the study. Complete blood counts will be monitored throughout the study.

The following adverse events are potential overlapping toxicities associated with combination use of atezolizumab, nab-paclitaxel, gemcitabine, and tiragolumab: immune-mediated toxicities, including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and others, gastrointestinal toxicities, hematologic toxicity, and dermatologic toxicities.

On Day 1 of each cycle, patients are required to have an ANC of > 1 .5c 10⁹/L (1500/pL) and a platelet count of > 100x 10⁹/L (100,000/pL) to receive treatment with nab-paclitaxel and gemcitabine.

Treatment Interruption for Toxicities

Atezolizumab and/or tiragolumab may be temporarily suspended in patients experiencing toxicity considered to be related to study treatment. If corticosteroids are initiated for treatment of the toxicity, they must be tapered over > 1 month to equivalent of < 10 mg/day oral prednisone or equivalent before drug can be resumed. If atezolizumab or tiragolumab is withheld for > 12 weeks, the patient will be discontinued from that drug. However, the drug may be withheld for > 12 weeks to allow for patients to taper off corticosteroids prior to resuming treatment. Atezolizumab or tiragolumab can be resumed after being withheld for > 12 weeks if the Medical Monitor agrees that the patient is likely to derive clinical benefit.

On the basis of the available characterization of mechanism of action, tiragolumab may cause adverse events similar to, but independent of, atezolizumab. Tiragolumab may also exacerbate the frequency or severity of atezolizumab-related adverse events or may have non-overlapping toxicities with atezolizumab. Because these scenarios may not be distinguishable from each other in the clinical setting, immune-mediated adverse events should generally be attributed to both agents, and dose interruptions or treatment discontinuation in response to immune-mediated adverse events should be applied to both tiragolumab and atezolizumab.

Nab-paclitaxel and/or gemcitabine treatment may be temporarily suspended in patients experiencing toxicity considered to be related to study treatment. If nab-paclitaxel or gemcitabine have been withheld for > 56 days because of toxicity, the patient should be discontinued from both chemotherapy agents. However, nab-paclitaxel or gemcitabine can be resumed after being withheld for > 56 days if the Medical Monitor agrees that the patient is likely to derive clinical benefit.

If atezolizumab is discontinued, tiragolumab should also be discontinued, but nab-paclitaxel and gemcitabine may be continued if the patient is likely to derive clinical benefit, as determined by the investigator. If nab-paclitaxel, gemcitabine, or tiragolumab is discontinued, the other drugs can be continued if the patient is likely to derive clinical benefit, as determined by the investigator.

Statistics The final study analysis will be based on patient data collected through study discontinuation. If not otherwise specified, efficacy analyses will be based on the efficacy-evaluable population, defined as all patients who receive at least one dose of each drug for their assigned treatment regimen, and safety analyses will be based on the safety-evaluable population, defined as all patients who receive any amount of study treatment.

Data will be described and summarized as warranted by sample size. Continuous variables will be summarized through use of means, standard deviations, medians, and ranges. Categorical variables will be summarized through use of counts and percentages. Listings will be used in place of tables in the event of small sample sizes. This study is not designed to make explicit power and Type I error considerations for a hypothesis test. Instead, this study is designed to obtain preliminary efficacy, safety, and PK data on immunotherapy-based treatment combinations when administered to patients with metastatic PDAC.

Table 17 shows estimated differences in ORR between an experimental arm and a control arm, along with 90% confidence intervals, with a sample size of 15 patients each in the preliminary phase, assuming asymptotic normality.

Table 17: Estimated Differences in Objective Response Rate between Experimental and Control Arms of 15 Patients Each (Preliminary Phase)

Table 18 shows estimated differences in ORR between an experimental arm and a control arm, along with 90% confidence intervals, with a sample size of 40 patients each in the preliminary and expansion phases combined, assuming asymptotic normality.

Table 18: Estimated Differences in Objective Response Rate between Experimental and Control Arms of 15 Patients Each (Preliminary Phase)

Objectives and Endpoints

A summary of objectives and corresponding endpoints for the study can be found in Table 19.

Table 19: Objectives and Corresponding Endpoints

ADA = anti-drug antibody; DOR = duration of response; iRECIST = modified RECIST v1 .1 for immune- based therapeutics; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors.

Overall response at a single timepoint will be assessed by the investigator using RECIST v1 .1 . Overall response per iRECIST will not be captured in the eCRF, but will instead be calculated programmatically on the basis of investigator-assessed individual lesion data recorded in the eCRF.

Efficacy Analysis

The primary efficacy endpoint is objective response. ORR, the proportion of patients with a complete or partial response, is calculated for each arm, along with 90% confidence intervals (Clopper- Pearson method). The difference in ORR between the experimental arms and the control arm is calculated, along with 90% confidence intervals. Confidence intervals are estimated by asymptotic normality methods, depending on the sample size.

The secondary efficacy endpoints are PFS, OS, OS at specific timepoints (e.g., 6 months), duration of response (DOR), and disease control PFS, DOR, and disease control are determined by the investigator according to RECIST v1 .1 . DOR is derived for efficacy-evaluable patients with a complete or partial response. For patients who do not have documented disease progression or death in a study stage, PFS and DOR will be censored at the day of the last tumor assessment. Patients who are still alive at the time of OS analysis will be censored at the last date they were known to be alive.

The Kaplan-Meier method is used to estimate the median for PFS, OS, and DOR, with 90% confidence intervals constructed through use of the Brookmeyer and Crowley method. OS rate at specific timepoints will also be estimated using the Kaplan-Meier method, with 90% confidence intervals calculated on the basis of Greenwood’s estimate for the variance. Disease control rate, the proportion of patients with stable disease for > 12 weeks, a partial response, or a complete response, will be calculated for each treatment arm, with 90% confidence intervals estimated through use of Clopper-Pearson’s exact method.

The exploratory efficacy endpoints are objective response, PFS, DOR, and disease control as determined by the investigator according to iRECIST ; and change from baseline in CA19-9 at subsequent timepoints during both stages. DOR will be derived for efficacy-evaluable patients with a complete or partial response. CA19-9 change from baseline over time will be summarized. In addition, the proportion of patients with a maximum decrease from baseline in CA19-9 of > 50% or other thresholds may be calculated for each treatment arm, with 90% confidence intervals estimated through use of Clopper- Pearson’s exact method.

Pharmacokinetic Analyses

Sparse samples can be collected for potential PK analyses of atezolizumab (patients who receive at least one dose of atezolizumab) and specified drugs given in combination with atezolizumab (patients who receive at least one dose of the drug). Serum or plasma concentrations of the various study drugs may be reported as individual values and summarized (mean, standard deviation, coefficient of variation, median, range, geometric mean, and geometric mean coefficient of variation) by treatment arm, and by cycle and day when appropriate and as data allow. Individual and median serum or plasma concentrations of the various study drugs may be plotted by treatment arm and cycle and day. PK data for combination drugs may be compared with available historical data from internal and published previous studies. Atezolizumab concentration data may be pooled with data from other studies using an established population PK model to derive PK parameters such as clearance, volume of distribution, and area under the curve.

Immunogenicity Analysis

Immunogenicity may be assessed for atezolizumab and other study treatments as appropriate (refer to arm-specific appendices for details). The immunogenicity analyses will include all patients with at least one anti-drug antibody (ADA) assessment. Patients will be grouped according to treatment received or, if no treatment is received prior to study discontinuation, according to treatment assigned.

For atezolizumab, the numbers and proportions of ADA-positive patients and ADA-negative patients at baseline (baseline prevalence) and after baseline (post-baseline incidence) will be summarized by treatment group. When determining post-baseline incidence, patients are considered to be ADA positive if they are ADA negative or are missing data at baseline but develop an ADA response following study drug exposure (treatment-induced ADA response), or if they are ADA positive at baseline and the titer of one or more post-baseline samples is at least 0.60 titer units greater than the titer of the baseline sample (treatment-enhanced ADA response). Patients are considered to be ADA negative if they are ADA negative or are missing data at baseline and all post-baseline samples are negative, or if they are ADA positive at baseline but do not have any post-baseline samples with a titer that is at least 0.60 titer units greater than the titer of the baseline sample (treatment unaffected).

For other study treatments for which ADAs are tested, ADA positivity will be determined according to standard methods established for previous studies of these drugs. The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints may be analyzed and reported via descriptive statistics.

Claims

WHAT IS CLAIMED IS:

1 . A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 700 mg to about 1000 mg every four weeks and a PD-1 axis binding antagonist at a fixed dose of about 1400 mg to 2000 mg every four weeks.

2. The method of claim 1 , wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 800 mg to about 900 mg every four weeks.

3. The method of claim 2, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 840 mg every four weeks.

4. The method of any one of claims 1 -3, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 1600 mg to about 1800 mg every four weeks.

5. The method of claim 4, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 1680 mg every four weeks.

6. The method of any one of claims 1 -5, 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.

7. The method of any one of claims 1 -6, wherein the one or more dosing cycles are each 28-day dosing cycles.

8. The method of claim 7, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 of each 28-day dosing cycle.

9. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 300 mg to about 600 mg every two weeks and a PD-1 axis binding antagonist at a fixed dose of about 600 mg to about 1200 mg every two weeks.

10. The method of claim 9, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 400 mg to about 500 mg every two weeks.

11 . The method of claim 10, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg every two weeks.

12. The method of any one of claims 9-11 , wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to 1000 mg every two weeks.

13. The method of claim 12, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg every two weeks.

14. The method of any one of claims 9-13, 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.

15. The method of any one of claims 9-14, wherein the one or more dosing cycles are each 28-day dosing cycles.

16. The method of claim 15, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are administered on Day 1 and Day 15 of each 28-day dosing cycle.

17. The method of any one of claims 1 -16, wherein the method does not comprise further administering to the subject one or more chemotherapeutic agents.

18. The method of any one of claims 1 -16, wherein the method comprises further administering to the subject one or more chemotherapeutic agents.

19. The method of claim 18, wherein the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent.

20. The method of claim 19, wherein the first chemotherapeutic agent is a platinum agent.

21 . The method of claim 20, wherein the platinum agent is carboplatin or cisplatin.

22. The method of claim 20 or 21 , wherein the second chemotherapeutic agent is a non-platinum agent.

23. The method of claim 22, wherein the non-platinum agent is an antimetabolite, a topoisomerase II inhibitor, or a taxane.

24. The method of claim 23, wherein the antimetabolite is pemetrexed.

25. The method of claim 23, wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331 .

26. The method of claim 23, wherein the taxane is paclitaxel.

27. The method of claim 23, wherein the taxane is nab-paclitaxel.

28. The method of any one of claims 20-24, wherein the platinum agent is carboplatin or cisplatin and the non-platinum agent is pemetrexed.

29. The method of claim 28, wherein the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min or the cisplatin is administered at a dose of about 75 mg/m².

30. The method of claim 24 or 28, wherein the pemetrexed is administered at a dose of about 500 mg/m²

31 . The method of claim 26, wherein the paclitaxel is administered at a dose of about 175-200 mg/m².

32. The method of claim 19, wherein the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel.

33. The method of claim 32, wherein the gemcitabine is administered at a dose of about 1000 mg/m².

34. The method of claim 32 or 33, wherein the nab-paclitaxel is administered at a dose of about 125 mg/m².

35. The method of any one of claims 18-34, wherein the method comprises further administering to the subject one or more subsequent doses of the one or more chemotherapeutic agents.

36. The method of claim 35, wherein the one or more subsequent doses is equal to or lower than the preceding dose of the one or more chemotherapeutic agents.

37. The method of any one of claims 18-36, wherein the one or more chemotherapeutic agents are each administered once per week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, twice every four weeks, or three times every four weeks.

38. The method of claim 15 or 16, wherein the method comprises further administering to the subject gemcitabine at a cumulative dose of about 1000 mg/m² to about 6000 mg/m² over the course of each 28- day dosing cycle.

39. The method of claim 38, wherein the gemcitabine is administered at a cumulative dose of about 3000 mg/m² over the course of each 28-day dosing cycle.

40. The method of claim 38 or 39, wherein the gemcitabine is administered three times over the course of each 28-day dosing cycle.

41 . The method of claim 40, wherein the gemcitabine is administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

42. The method of claim 40 or 41 , wherein each dose of the gemcitabine is about 500 mg/m² to about 2000 mg/m².

43. The method of claim 42, wherein each dose of the gemcitabine is about 1000 mg/m².

44. The method of any one of claims 38-43, wherein the method comprises further administering to the subject nab-paclitaxel at a cumulative dose of about 200 mg/m² to about 600 mg/m² over the course of each 28-day dosing cycle.

45. The method of claim 44, wherein the nab-paclitaxel is administered at a cumulative dose of about 375 mg/m² over the course of each 28-day dosing cycle.

46. The method of claim 44 or 45, wherein the nab-paclitaxel is administered three times over the course of each 28-day dosing cycle.

47. The method of claim 46, wherein the nab-paclitaxel is administered on Days 1 , 8, and 15 of each 28-day dosing cycle.

48. The method of claim 46 or 47, wherein each dose of the nab-paclitaxel is about 50 mg/m² to about 200 mg/m².

49. The method of claim 48, wherein each dose of the nab-paclitaxel is about 125 mg/m².

50. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28-day dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 300 mg to about 600 mg on Days 1 and 15 of each 28-day dosing cycle, a PD-1 axis binding antagonist at a fixed dose of about 600 mg and 1200 mg on Days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 500 mg/m² to about 2000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle, and nab-paclitaxel at a dose of about 50 mg/m² to about 200 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle.

51 . The method of claim 50, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle.

52. The method of claim 50 or 51 , wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle.

53. The method of any one of claims 50-52, wherein the gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle.

54. The method of any one of claims 50-53, wherein the nab-paclitaxel is administered at a dose of about 125 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle.

55. The method of claim 54, wherein, on Days 1 and 15 of each 28-day dosing cycle, anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the nab-paclitaxel is administered after the anti-TIGIT antagonist antibody, and the gemcitabine is administered after the nab- paclitaxel.

56. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist at a fixed dose of about 80 and 1600 mg every three weeks, a platinum agent every three weeks, and a non platinum agent every three weeks.

57. The method of claim 56, wherein the platinum agent is carboplatin or cisplatin.

58. The method of claim 56 or 57, wherein the non-platinum agent is an antimetabolite or a taxane.

59. The method of claim 57 or 58, wherein the platinum agent is carboplatin and the non-platinum agent is an antimetabolite.

60. The method of claim 59, wherein the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min.

61 . The method of claim 57 or 58, wherein the platinum agent is cisplatin and the non-platinum agent is an antimetabolite.

62. The method of claim 61 , wherein the cisplatin is administered at a dose of 75 mg/m².

63. The method of any one of claims 58-62, wherein the antimetabolite is pemetrexed.

64. The method of claim 63, wherein the pemetrexed is administered at a dose of about 500 mg/m².

65. The method of any one of claims 59-64, wherein the dosing regimen comprises an induction phase comprising between four to six initial 21 -day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the antimetabolite are administered on Day 1 of each 21 -day dosing cycle of the induction phase.

66. The method of any one of claims 59-65, wherein the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the platinum agent is administered after the anti- TIGIT antagonist antibody, and the antimetabolite is administered after the platinum agent.

67. The method of claim 65 or 66, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg, the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg, the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min or the cisplatin is administered at a dose of 75 mg/m², and the pemetrexed is administered at a dose of about 500 mg/m², each on Day 1 of each 21 -day dosing cycle of the induction phase.

68. The method of any one of claims 65-67, wherein the dosing regimen comprises a maintenance phase following the induction phase, wherein the maintenance phase comprises one or more additional 21 -day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, and the antimetabolite are administered on Day 1 of each 21 -day dosing cycle of the maintenance phase.

69. The method of claim 68, wherein the one or more additional 21 -day dosing cycles of the maintenance phase do not comprise administration of the platinum agent.

70. The method of claim 57 or 58, wherein the platinum agent is carboplatin and the non-platinum agent is a taxane.

71 . The method of claim 70, wherein the carboplatin is administered at a dose sufficient to achieve AUC = 6 mg/ml/min.

72. The method of claim 70 or 71 , wherein the taxane is paclitaxel.

73. The method of any one of claims 70-72, wherein the taxane is administered at a dose of about 175-200 mg/m².

74. The method of any one of claims 70-73, wherein the dosing regimen comprises an induction phase comprising between four to six initial 21 -day dosing cycles, and wherein the anti-TIGIT antagonist antibody, the PD-1 axis binding antagonist, the platinum agent, and the taxane are administered on Day 1 of each 21 -day cycle of the induction phase.

75. The method of any one of claims 70-74, wherein the anti-TIGIT antagonist antibody is administered after the PD-1 axis binding antagonist, the platinum agent is administered after the anti- TIGIT antagonist antibody, and the taxane is administered after the platinum agent.

76. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of an anti-TIGIT antagonist antibody at a fixed dose of about 30 mg to about 1200 mg every three weeks, a PD-1 axis binding antagonist at a fixed dose of about 80 and 1600 mg every three weeks, gemcitabine, and nab-paclitaxel.

77. The method of any one of claims 56-66 and 70-76, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 30 mg to about 600 mg every three weeks.

78. The method of claim 77, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks.

79. The method of any one of claims 56-66 and 70-78, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 800 mg to about 1400 mg every three weeks.

80. The method of claim 79, wherein the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks.

81 . The method of any one of claims 56-66 and 70-80, wherein the anti-TIGIT antagonist antibody is administered at a fixed dose of about 600 mg every three weeks and the PD-1 axis binding antagonist is administered at a fixed dose of about 1200 mg every three weeks.

82. The method of any one of claims 1 -81 , wherein a tumor sample from the subject has been determined to have a PD-L1 -positive tumor cell fraction.

83. The method of claim 82, wherein the tumor sample has been determined to have a PD-L1- positive tumor cell fraction of greater than, or equal to, 30%.

84. The method of claim 82 or 83, wherein the PD-L1 -positive tumor cell fraction has been determined by an immunohistochemical (IHC) assay.

85. The method of any one of claims 82-84, wherein the PD-L1 -positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody suitable for staining, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.

86. The method of claim 85, 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.

87. The method of claim 86, wherein the PD-L1 -positive tumor cell fraction is calculated using the Ventana SP263 IHC assay.

88. The method of claim 85, 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.

89. The method of claim 88, wherein the PD-L1 -positive tumor cell fraction is calculated using the pharmDx 22C3 IHC assay.

90. The method of claim 85, wherein 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.

91 . The method of claim 85, 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 28-8.

92. The method of any one of claims 82-91 , wherein a tumor sample from the subject has been determined to have a detectable nucleic acid expression level of PD-L1 .

93. The method of claim 92, wherein the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.

94. The method of any one of claims 82-93, wherein the cancer is a lung cancer.

95. The method of claim 94, wherein the lung cancer is a non-small cell lung cancer (NSCLC).

96. The method of claim 95, wherein the NSCLC is a squamous NSCLC.

97. The method of claim 95, wherein the NSCLC is a non-squamous NSCLC.

98. The method of any one of claims 95-97, wherein the NSCLC is a locally advanced unresectable NSCLC.

99. The method of claim 98, wherein the NSCLC is a Stage NIB NSCLC.

100. The method of any one of claims 95-99, wherein the NSCLC is a recurrent or metastatic NSCLC.

101 . The method of claim 100, wherein the NSCLC is a Stage IV NSCLC.

102. The method of claim 100 or 101 , wherein the subject has not been previously treated for Stage IV NSCLC.

103. The method of any one of claims 82-102, wherein the subject does not have a sensitizing epidermal growth factor receptor ( EGFR ) gene mutation or anaplastic lymphoma kinase ( ALK) gene rearrangement.

104. The method of any one of claims 82-103, wherein the subject does not have a pulmonary lymphoepithelioma-like carcinoma subtype of NSCLC.

105. The method of any one of claims 82-104, wherein the subject does not have an active Epstein- Barr virus (EBV) infection or a known or suspected chronic active EBV infection.

106. The method of any one of claims 82-105, wherein the subject is negative for EBV IgM or negative by EBV PCR.

107. The method of claim 106, wherein the subject is negative for EBV IgM and negative by EBV PCR.

108. The method of claim 106 or 107, wherein the subject is positive for EBV IgG or positive for Epstein-Barr nuclear antigen (EBNA).

109. The method of claim 108, wherein the subject is positive for EBV IgG and positive for EBNA.

110. The method of any one of claims 82-109, wherein the subject is negative for EBV IgG or negative for EBNA.

111. The method of claim 110, wherein the subject is negative for EBV IgG and negative for EBNA.

112. The method of any one of claims 1-111 , wherein the anti-TIG IT 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).

113. The method of claim 112, wherein the anti-TIG IT antagonist antibody further comprises the following light chain variable region framework regions (FRs): an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7); an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8); an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).

114. The method of claim 112 or 113, wherein the anti-TIGIT antagonist antibody further comprises the following heavy chain variable region FRs: an FR-H1 comprising the amino acid sequence of XiVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11 ), wherein Xi is E or Q; an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).

115. The method of claim 114, wherein Xi is E.

116. The method of claim 114, wherein Xi is Q.

117. The method of any one of claims 112-116, wherein the anti-TIGIT antagonist antibody comprises:

(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) a VH domain as in (a) and a VL domain as in (b).

118. The method of claim 117, 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.

119. The method of any one of claims 1-118, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody.

120. The method of claim 119, wherein the anti-TIGIT antagonist antibody is a human antibody.

121 . The method of any one of claims 1-120, wherein the anti-TIGIT antagonist antibody is a full- length antibody.

122. The method of any one of claims 1-115 and 117-121 , wherein the anti-TIG IT antagonist antibody is tiragolumab.

123. The method of any one of claims 1-122, wherein the anti-TIG IT antagonist antibody is an antibody fragment that binds TIGIT selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

124. The method of any one of claims 1-123, wherein the anti-TIG IT antagonist antibody is an IgG class antibody.

125. The method of claim 124, wherein the IgG class antibody is an lgG1 subclass antibody.

126. The method of any one of claims 1 -125, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist or a PD-1 binding antagonist.

127. The method of claim 126, wherein the PD-L1 binding antagonist is an anti-PD-L1 antagonist antibody.

128. The method of claim 127, wherein the anti-PD-L1 antagonist antibody is atezolizumab (MPDL3280A), MSB0010718C, MDX-1105, or MEDI4736.

129. The method of claim 128, wherein the anti-PD-L1 antagonist antibody is atezolizumab.

130. The method of claim 126, wherein the PD-1 binding antagonist is an anti-PD-1 antagonist antibody.

131 . The method of claim 130, wherein the anti-PD-1 antagonist antibody is nivolumab (MDX-1106), pembrolizumab (MK-3475), or AMP-224.

132. The method of claim 127, wherein 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).

133. The method of claim 132, wherein the anti-PD-L1 antagonist antibody comprises:

(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) a VH domain as in (a) and a VL domain as in (b).

134. The method of claim 133, wherein 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.

135. The method of any one of claims 1-134, wherein the PD-1 axis binding antagonist is a monoclonal antibody.

136. The method of any one of claims 1-135, wherein the PD-1 axis binding antagonist is a humanized antibody.

137. The method of any one of claims 1 -136, wherein the PD-1 axis binding antagonist is a full-length antibody.

138. The method of any one of claims 1-127 and 132-136, wherein the PD-1 axis binding antagonist is an antibody fragment that binds PD-L1 selected from the group consisting of Fab, Fab’, Fab’-SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

139. The method of any one of claims 1 -126, 130, 135, and 136, wherein the PD-1 axis binding antagonist is an antibody fragment that binds PD-1 selected from the group consisting of Fab, Fab’, Fab’- SH, Fv, single chain variable fragment (scFv), and (Fab’)2 fragments.

140. The method of any one of claims 1-139, wherein the PD-1 axis binding antagonist is an IgG class antibody.

141 . The method of any one of claims 1 -140, wherein the method comprises administering to the subject the PD-1 axis binding antagonist before the anti-TIGIT antagonist antibody.

142. The method of claim 141 , wherein the method comprises a first observation period following administration of the PD-1 axis binding antagonist and second observation period following administration of the anti-TIGIT antagonist antibody.

143. The method of claim 142, wherein the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.

144. The method of any one of claims 1-140, wherein the method comprises administering to the subject the anti-TIG IT antagonist antibody before the PD-1 axis binding antagonist.

145. The method of claim 144, wherein the method comprises a first observation period following administration of the anti-TIGIT antagonist antibody and second observation period following administration of the PD-1 axis binding antagonist.

146. The method of claim 145, wherein the first observation period and the second observation period are each between about 30 minutes to about 60 minutes in length.

147. The method of any one of claims 1-140, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist simultaneously.

148. The method of any one of claims 1-147, wherein the method comprises administering to the subject the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist intravenously.

149. The method of claim 148, wherein the method comprises administering to the subject the anti- TIGIT antagonist antibody by intravenous infusion over 60 ± 10 minutes.

150. The method of claim 148 or 149, wherein the method comprises administering to the subject the PD-1 axis binding antagonist by intravenous infusion over 60 ± 15 minutes.

151 . The method of any one of claims 21 , 23-26, 28-31 , 50-55, 57, 59-64, 67, 70-72, and 76, wherein the method comprises administering to the subject the gemcitabine, nab-paclitaxel, carboplatin, cisplatin, pemetrexed, paclitaxel, or topoisomerase II inhibitor intravenously.

152. The method of any one of claims 1-151 , wherein the cancer is a solid tumor.

153. The method of any one of claims 1 -152, wherein the cancer is locally advanced or metastatic.

154. The method of any one of claims 1 -93 and 103-153, wherein the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.

155. The method of claim 154, wherein the lung cancer is a non-small cell lung cancer.

156. The method of claim 154, wherein the pancreatic cancer is a pancreatic duct adenocarcinoma (PDAC).

157. The method of claim 156, wherein the PDAC is a metastatic PDAC.

158. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 840 mg every four weeks and atezolizumab at a fixed dose of about 1680 mg every four weeks.

159. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 420 mg every two weeks and atezolizumab at a fixed dose of about 840 mg every two weeks.

160. The method of claim 158 or 159, wherein the method comprises administering to the subject a first chemotherapeutic agent and a second chemotherapeutic agent.

161 . The method of claim 160, wherein the first chemotherapeutic agent is a platinum agent and the second chemotherapeutic agent is a non-platinum chemotherapeutic agent.

162. The method of claim 161 , wherein the platinum agent is carboplatin or cisplatin and the non platinum agent is an antimetabolite, a topoisomerase II inhibitor, or a taxane.

163. The method of claim 162, wherein the antimetabolite is pemetrexed.

164. The method of claim 162 or 163, wherein the topoisomerase II inhibitor is etoposide.

165. The method of any one of claims 162-164, wherein the taxane is paclitaxel.

166. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks or cisplatin at a dose of 75 mg/m² every three weeks, and pemetrexed at a dose of about 500 mg/m² every three weeks.

167. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks, and paclitaxel at a dose of about 200 mg/m² every three weeks.

168. A method of treating a subject having a cancer, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of tiragolumab at a fixed dose of about 600 mg every three weeks, atezolizumab at a fixed dose of about 1200 mg every three weeks, carboplatin at a dose sufficient to achieve AUC = 6 mg/ml/min every three weeks, and paclitaxel at a dose of about 175 mg/m² every three weeks.

169. The method of any one of claims 158-168, wherein the cancer is a lung cancer, a pancreatic cancer, a kidney or renal cancer, a melanoma, a head and neck cancer, an ovarian cancer, a gastric cancer, a bladder cancer, a colorectal cancer, or a breast cancer.

170. The method of claim 160, wherein the first chemotherapeutic agent is gemcitabine and the second chemotherapeutic agent is nab-paclitaxel.

171 . The method of claim 170, wherein the cancer is a pancreatic cancer.

172. A method of treating a subject having a pancreatic cancer, the method comprising administering to the subject a dosing regimen comprising one or more 28-day dosing cycles of tiragolumab at a fixed dose of about 420 mg on Days 1 and 15 of each 28-day dosing cycle, atezolizumab at a fixed dose of about 840 mg on Days 1 and 15 of each 28-day dosing cycle, gemcitabine at a dose of about 1000 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle, and nab-paclitaxel at a dose of about 125 mg/m² on Days 1 , 8, and 15 of each 28-day dosing cycle.

173. The method of claim 171 or 172, wherein the pancreatic cancer is a pancreatic duct adenocarcinoma (PDAC).

174. The method of claim 173, wherein the PDAC is a metastatic PDAC.

175. The method of any one of claims 1 -174, wherein the treatment results in a complete response or a partial response.

176. The method of any one of claims 1 -175, wherein the treatment results in an increase in progression-free survival (PFS) of the subject as compared to treatment with the PD-1 axis binding antagonist without the anti-TIG IT antagonist antibody or as compared to treatment with the anti-TIGIT antagonist antibody without the PD-1 axis binding antagonist.

177. The method of any one of claims 1 -176, wherein the subject is a human.

178. A kit comprising an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist for treating a subject having a cancer according to the method of any one of claims 1- 177.

179. The kit of claim 178, wherein the kit further comprises the PD-1 axis binding antagonist.

180. A kit comprising a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody for treating a subject having a cancer according to the method of any one of claims 1 - 177.

181 . The kit of claim 180, wherein the kit further comprises the anti-TIGIT antagonist antibody.

182. The kit of any one of claims 178-181 , wherein the anti-TIGIT antagonist antibody is tiragolumab and the PD-1 axis binding antagonist is atezolizumab.

183. An anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist for use in a method of treating a subject having a cancer, wherein the method is according to any one of claims 1-177.

184. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for treating a subject having a cancer in combination with a PD-1 axis binding antagonist, wherein the treatment is according to the method of any one of claims 1 -177.

185. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for treating a subject having a cancer in combination with an anti-TIGIT antagonist antibody, wherein the treatment is according to the method of any one of claims 1 -177.

186. The use of claim 184 or 185, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated separately.

187. The use of claim 184 or 185, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated together.