Combination Therapy for Lung Cancer

Abstract

The present disclosure provides methods of treating a human subject afflicted with lung cancer (e.g., non-small cell lung cancer (NSCLC)) with a PD-1 (programmed death-1) pathway inhibitor (e.g., an anti-PD-1 antibody) and concurrent chemoradiotherapy (CCRT, e.g., platinum-doublet chemotherapy (PDCT) and radiation therapy), followed by a combination of a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) and a lymphocyte-activation gene 3 (LAG-3) antagonist (e.g., an anti-LAG-3 antibody). In some embodiments, the methods include a recovery period that begins upon completion of treatment with the PD-1 pathway inhibitor and CCRT and ends upon initiation of treatment with the combination of the PD-1 pathway inhibitor and the LAG-3 antagonist.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This PCT application claims priority benefit of U.S. Provisional Application No. 63 / 476,596, filed December 21, 2022, which is incorporated herein by reference in its entirety.

[0002] Reference to an electronically submitted sequence listing The contents of the electronically submitted sequence listing (Name: 3338_323PC01_Seqlisting_ST26; Size: 102,064 bytes; Created December 13, 2023) are incorporated herein by reference in their entirety.

[0003] The present disclosure provides a method of treating a human subject afflicted with lung cancer, comprising administering a PD-1 (programmed death-1) pathway inhibitor and concurrent chemoradiotherapy, followed by administering a PD-1 pathway inhibitor and a lymphocyte-activation gene 3 (LAG-3) antagonist. [Background technology]

[0004] Lung cancer is the leading cause of cancer death worldwide (Non-Patent Document 1). An estimated 236,740 people will be diagnosed with lung cancer in the United States in 2022 (Non-Patent Document 2). More than 350 people will die from lung cancer every day, which is more than breast cancer, prostate cancer, and pancreatic cancer combined, and 2.5 times more than colorectal cancer, the second leading cause of cancer death (Non-Patent Document 3).

[0005] Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all lung cancers, with 30% of patients presenting with unresectable, locally advanced (stage III) disease (NPL 1; NPL 2; NPL 3; NPL 4). Unresectable stage III NSCLC represents a heterogeneous disease requiring a challenging multi-modality treatment paradigm. Historically, the prognosis for this population has been suboptimal, with 5-year survival rates ranging from 10% to 30% (NPL 5; NPL 6). Patient outcomes after definitive concurrent chemoradiotherapy followed by 12 months of durvalumab maintenance therapy are considered the new standard of care, yet the majority of patients with stage III locally advanced NSCLC remain without adequate treatment options (NPL 7). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] International Agency for Research on Cancer,GLOBOCAN Cancer Facts Sheet:Lung Cancer,2020 [Non-patent document 2] American Cancer Society,Cancer Facts and Figures,2022. [Non-patent document 3] Siegel et al.,CA Cancer J.Clin.2022;72:7-33 [Non-patent document 4] Islami et al.,CA Cancer J.Clin.2018;68:31-54 [Non-Patent Document 5] Curran et al.,J.Natl.Cancer Inst.2011;103:1452-60 [Non-patent document 6] Bradley et al.,Lancet Oncol.2015;16:187-99 [Non-Patent Document 7] Spigel et al.,J.Clin.Oncol.2022;40:1301-11 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need for improved methods for treating human subjects with lung cancer. [Means for solving the problem]

[0008] The present disclosure relates to a method of treating a human subject suffering from lung cancer, comprising administering to the subject: (a) a PD-1 (programmed death-1) pathway inhibitor and concurrent chemoradiotherapy (CCRT), followed by (b) a PD-1 pathway inhibitor and a lymphocyte-activation gene 3 (LAG-3) antagonist.

[0009] In some embodiments, the method further includes providing the subject with a recovery period beginning upon completion of administration in (a) and ending upon initiation of administration in (b). In some embodiments, the recovery period is sufficient to allow the subject to recover from CCRT-associated toxicities other than fatigue, esophagitis, or alopecia. In some embodiments, the recovery period is about 1 week to about 12 weeks, about 1 week to about 9 weeks, about 1 week to about 6 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 9 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 12 weeks, about 3 weeks to about 9 weeks, about 3 weeks to about 6 weeks, about 18 days to about 12 weeks from the final administration of the PD-1 pathway inhibitor in (a), about 18 days to about 9 weeks from the final administration of the PD-1 pathway inhibitor in (a), or about 18 days to about 6 weeks from the final administration of the PD-1 pathway inhibitor in (a).

[0010] In some embodiments, the method is a first line therapy.

[0011] In some embodiments, the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

[0012] In some embodiments, the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

[0013] In some aspects, the subject is naive to a previous immuno-oncology therapy, the subject is naive to a previous immuno-oncology therapy for the lung cancer, or the lung cancer is naive to a previous immuno-oncology therapy.

[0014] In some embodiments, the method is a second-line therapy. In some embodiments, the method is a third-line therapy. In some embodiments, the subject has progressed on a previous treatment. In some embodiments, the lung cancer recurs after multimodal treatment for locally advanced lung cancer.

[0015] In some embodiments, the lung cancer is unresectable, advanced, recurrent and / or metastatic.

[0016] In some embodiments, the lung cancer comprises small cell lung cancer.

[0017] In some embodiments, the lung cancer comprises non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC has squamous or non-squamous histology. In some embodiments, the NSCLC comprises locally advanced stage IIIA, IIIB, or IIIC NSCLC.

[0018] In some embodiments, the subject does not have progressive lung cancer during CCRT or recovery.

[0019] In some embodiments, the PD-1 pathway inhibitors of (a) and (b) are the same.

[0020] In some embodiments, the PD-1 pathway inhibitors of (a) and (b) are different.

[0021] In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0022] In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody comprises a full-length antibody. In some embodiments, the anti-PD-1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a dual affinity retargeting antibody (DART), a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide. In some embodiments, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen-binding portion thereof. In some embodiments, the anti-PD-1 antibody comprises nivolumab or an antigen-binding portion thereof. In some embodiments, the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively. In some embodiments, the anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 11 and 12, respectively.

[0023] In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) comprises a soluble PD-L2 polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a fusion polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some embodiments, the soluble PD-L2 polypeptide further comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble PD-L2 polypeptide comprises AMP-224.

[0024] In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody comprises a full-length antibody. In some embodiments, the anti-PD-L1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide. In some embodiments, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen-binding portion thereof.

[0025] In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) comprises BMS-986189.

[0026] In some embodiments, the PD-1 pathway inhibitor (a) and / or (b) is administered at a fixed dose of at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 1000 mg, about 0.25 mg to about 500 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 1000 mg, about 0.25 ... It is administered at about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg. In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) is about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg g, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7m g, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 The compound is administered at a dose of about 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0027] In some embodiments, the PD-1 pathway inhibitor in (a) and / or (b) is administered as a body weight-based dose. ... 03mg / kg~about 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.003mg / kg~about 0.4mg / kg, about 0.003mg / kg~about 0.3mg / kg, about 0.003mg / kg~about 0.2mg / kg, about 0.003mg / kg~about 0.1mg / kg, about 0.1mg / kg~about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1mg / kg, about 1mg / kg to about 25mg / kg, about 1mg / kg to about 20mg / kg, about 1mg / kg to about 15mg / kg, about 1mg / kg to about 10mg / kg, about 1mg / kg to about 5mg / kg, about 5 The dose is administered at a range of about 100 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.In some embodiments, the PD-1 pathway inhibitor of (a) and / or (b) is about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg g / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0028] In some embodiments, the doses of the PD-1 pathway inhibitor in (a) and (b) are different.

[0029] In some embodiments, the dose of the PD-1 pathway inhibitor of (a) and / or (b) is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0030] In some embodiments, CCRT includes platinum-doublet chemotherapy (PDCT). In some embodiments, PDCT includes a platinum agent in combination with a nucleoside analog, antimetabolite, taxane, vinca alkaloid, or topoisomerase inhibitor. In some embodiments, the platinum agent includes cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenanthriplatin. In some embodiments, the platinum agent includes cisplatin. In some embodiments, the platinum agent includes carboplatin. In some embodiments, the nucleoside analog includes cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some embodiments, the nucleoside analog includes gemcitabine. In some embodiments, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some embodiments, the antimetabolite comprises pemetrexed. In some embodiments, the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, or cabazitaxel. In some embodiments, the vinca alkaloid comprises vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinbrunin. In some embodiments, the vinca alkaloid comprises vinorelbine or vinblastine. In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some embodiments, the topoisomerase inhibitor comprises etoposide. In some embodiments, the topoisomerase inhibitor comprises irinotecan. In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan. In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with pemetrexed. In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with etoposide.

[0031] In some embodiments, CCRT includes thoracic radiation therapy and / or volumetric modulated arc therapy (VMAT), intensity modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT).

[0032] In some embodiments, the LAG-3 antagonist comprises an anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody comprises a full-length antibody. In some embodiments, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide. In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yeramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen-binding portion thereof. In some embodiments, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:4. In some embodiments, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively.In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively.

[0033] In some embodiments, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some embodiments, the soluble LAG-3 polypeptide comprises a fusion polypeptide. In some embodiments, the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. In some embodiments, the ligand-binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 22. In some embodiments, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble LAG-3 polypeptide comprises IMP321 (efthirazimod alfa).

[0034] In some embodiments, the LAG-3 antagonist is administered at a fixed dose, such as at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, or about 20 mg to about 400 mg. mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg. In some embodiments, the LAG-3 antagonist is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, or about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 The compound is administered at a dose of about 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0035] In some embodiments, the LAG-3 antagonist is administered in a weight-based dose, such as about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, or about 0.003 mg / kg. g~about 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.003mg / kg~about 0.4mg / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 25mg / k g, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1mg / kg to about 25mg / kg, about 1mg / kg to about 20mg / kg, about 1mg / kg to about 15mg / kg, about 1mg / kg to about 10mg / kg, about 1mg / kg to about 5mg / kg, about 5mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.In some embodiments, the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg g, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0036] In some embodiments, the dose of the LAG-3 antagonist is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0037] In some embodiments, the (a) PD-1 pathway inhibitor, CCRT, (b) PD-1 pathway inhibitor, and / or LAG-3 antagonist are formulated for intravenous administration.

[0038] In some embodiments, the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are formulated separately. In some embodiments, the PD-1 pathway inhibitor of (b) is administered before the LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor of (b). In some embodiments, the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are administered simultaneously.

[0039] In some embodiments, the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are formulated together.

[0040] In some embodiments, the PD-1 pathway inhibitor and LAG-3 antagonist of (b) are administered as maintenance therapy. In some embodiments, the maintenance therapy is administered for up to about 1 year.

[0041] The present disclosure provides a method of treating a human subject afflicted with NSCLC having squamous or non-squamous histology, comprising: (a) administering to the subject approximately 360 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and CCRT, including PDCT and radiation therapy; (b) providing the subject with a recovery period beginning upon completion of administration of (a); and (c) administering to the subject approximately 360 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 14, and CCRT, including PDCT and radiation therapy; The present invention relates to a method for administering to a subject a maintenance therapy comprising approximately 480 mg of an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and approximately 480 mg of an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4.

[0042] In some embodiments, the PDCT comprises cisplatin and etoposide. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is administered at about 100 mg / m 2 etoposide was administered on days 1, 2, and 3 of each cycle, followed by anti-PD-1 antibody on day 1 of each cycle, at a dose of approximately 80 mg / m 2 The cisplatin is administered after the etoposide on day 1 of each cycle. In some embodiments, the cisplatin and etoposide are each administered intravenously over about 60 minutes.

[0043] In some embodiments, the PDCT comprises carboplatin and paclitaxel. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is about 175 mg / m 2 or about 200 mg / m 2 of paclitaxel was administered on day 1 of the first cycle at approximately 45 mg / m 2 or about 50 mg / m 2 paclitaxel is administered on days 1, 8, and 15 of the second and third cycles, with paclitaxel administered after the anti-PD-1 antibody on day 1 of each cycle, carboplatin at a target AUC of about 5 mg / mL·min or about 6 mg / mL·min is administered on day 1 of the first cycle, and carboplatin at a target AUC of about 2 mg / mL·min is administered on days 1, 8, and 15 of the second and third cycles, with carboplatin administered after paclitaxel in each cycle. In some embodiments, carboplatin is administered intravenously over about 30 minutes, and paclitaxel is administered intravenously over about 180 minutes in the first cycle and about 60 minutes in the second and third cycles.

[0044] In some embodiments, the PDCT comprises cisplatin and pemetrexed. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is at about 500 mg / m 2 Pemetrexed is administered on day 1 of each cycle after the anti-PD-1 antibody at approximately 75 mg / m 2Cisplatin is administered after pemetrexed on day 1 of each cycle. In some embodiments, cisplatin is administered intravenously over about 60 minutes, and pemetrexed is administered intravenously over about 10 minutes. In some embodiments, if cisplatin is not tolerated by the subject, cisplatin is replaced with carboplatin at a target area under the concentration-time curve (AUC) of about 5 mg / mL·min. In some embodiments, carboplatin is administered intravenously over about 30 minutes. In some embodiments, if pemetrexed is not tolerated by the subject, pemetrexed is replaced with etoposide.

[0045] In some embodiments, the anti-PD-1 antibody in (a) is administered intravenously over about 30 minutes.

[0046] In some embodiments, radiation therapy is administered after PDCT and comprises a dose of about 60 Gy to about 66 Gy. In some embodiments, radiation therapy comprises chest radiation therapy and / or volumetric modulated arc therapy (VMAT), intensity-modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT). In some embodiments, radiation therapy begins on day 1 of the second and third cycles and comprises about 30 to about 33 daily doses of 2 Gy on an about 5-day on, 2-day off schedule over about 6 to about 7 weeks.

[0047] In some embodiments, the recovery period is sufficient for the subject to recover from CCRT-related toxicities other than fatigue, esophagitis, or alopecia. In some embodiments, the recovery period is about 1 week to about 12 weeks, about 1 week to about 9 weeks, about 1 week to about 6 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 9 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 12 weeks, about 3 weeks to about 9 weeks, about 3 weeks to about 6 weeks, about 18 days to about 12 weeks from the final administration of the anti-PD-1 antibody in (a), about 18 days to about 9 weeks from the final administration of the anti-PD-1 antibody in (a), or about 18 days to about 6 weeks from the final administration of the anti-PD-1 antibody in (a).

[0048] In some embodiments, the method is a first line therapy.

[0049] In some embodiments, the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

[0050] In some embodiments, the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

[0051] In some aspects, the subject is naive to a previous immuno-oncology therapy, the subject is naive to a previous immuno-oncology therapy for the lung cancer, or the lung cancer is naive to a previous immuno-oncology therapy.

[0052] In some embodiments, the method is a second-line therapy. In some embodiments, the method is a third-line therapy. In some embodiments, the subject has progressed on a previous treatment. In some embodiments, the NSCLC recurs after multimodal therapy for locally advanced NSCLC.

[0053] In some embodiments, the NSCLC is unresectable, advanced, recurrent and / or metastatic.

[0054] In some embodiments, the NSCLC has squamous or non-squamous histology.

[0055] In some embodiments, the NSCLC comprises locally advanced stage IIIA, IIIB, or IIIC NSCLC.

[0056] In some embodiments, the subject does not have progressive NSCLC during CCRT or in recovery.

[0057] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered about once every four weeks.

[0058] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated separately. In some embodiments, the anti-PD-1 antibody of (b) is administered before the anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody is administered before the anti-PD-1 antibody of (b). In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered simultaneously.

[0059] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated together.

[0060] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered intravenously over about 30 minutes.

[0061] In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a full-length antibody. In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide. In some embodiments, the anti-PD-1 antibody of (a) and / or (b) comprises an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a heavy chain variable region and a light chain variable region comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively. In some embodiments, the anti-PD-1 antibody of (a) and / or (b) comprises a heavy chain and a light chain comprising the sequences as set forth in SEQ ID NOs: 11 and 12, respectively.

[0062] In some embodiments, the anti-LAG-3 antibody comprises a full-length antibody. In some embodiments, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide. In some embodiments, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0063] In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some embodiments, at least about 1% of the immune cells express LAG-3. In some embodiments, the immune cells comprise tumor-infiltrating lymphocytes. In some embodiments, the tumor-infiltrating lymphocytes are CD8 + Contains cells.

[0064] In some embodiments, one or more nucleated cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express LAG-3. In some embodiments, at least about 1% of the nucleated cells express LAG-3.

[0065] In some embodiments, one or more tumor cells in tumor tissue from a subject express PD-L1. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. In some embodiments, at least about 1% of the tumor cells express PD-L1.

[0066] In some embodiments, any of the methods further comprises administering an additional therapeutic agent to the subject. In some embodiments, the additional therapeutic agent comprises an anti-cancer agent. In some embodiments, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof. In some embodiments, the tyrosine kinase inhibitor comprises afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, larotrectinib, or any combination thereof. In some embodiments, the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase containing Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof. In some aspects, the antiangiogenic agent comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.In some embodiments, the checkpoint inhibitor is a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T-cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B-cell and T-cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T-cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor, a phenotype inhibitor, or a phenotype inhibitor. The checkpoint inhibitors include transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-inducible TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death 1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof. In some embodiments, the checkpoint inhibitor comprises a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody comprises a full-length antibody. In some embodiments, the anti-CTLA-4 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some embodiments, the anti-CTLA-4 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.In some embodiments, the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen-binding portion thereof. DETAILED DESCRIPTION OF THE INVENTION

[0067] The present disclosure provides methods of treating a human subject afflicted with lung cancer (e.g., non-small cell lung cancer (NSCLC)), comprising: (a) administering to the subject a PD-1 (programmed death-1) pathway inhibitor (e.g., an anti-PD-1 antibody) and concurrent chemoradiotherapy (CCRT, e.g., platinum-doublet chemotherapy (PDCT) and radiation therapy), followed by (b) administering to the subject a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) and a lymphocyte-activation gene-3 (LAG-3) antagonist (e.g., an anti-LAG-3 antibody). In some embodiments, the method includes a recovery period (e.g., about 3 weeks to about 6 weeks) that begins upon completion of administration of the PD-1 pathway inhibitor and CCRT in (a) and ends upon initiation of administration of the PD-1 pathway inhibitor and LAG-3 antagonist in (b). In some embodiments, the PD-1 pathway inhibitor and LAG-3 antagonist in (b) are administered as maintenance therapy (e.g., for up to 1 year).

[0068] I. Terminology In order to make this disclosure more readily understandable, certain terms are first defined. As used herein, unless otherwise expressly provided herein, each of the following terms shall have the meaning indicated below. Additional definitions are provided throughout this application. It should be noted that the term "a" or "an" entity refers to one or more of that entity. For example, a "nucleotide sequence" is understood to represent one or more nucleotide sequences. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0069] The term "and / or," as used herein, should be interpreted as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or," when used herein in phrases such as "A and / or B," is intended to include "A and B," "A or B," "A" (alone) and "B" (alone). Similarly, the term "and / or," as used in phrases such as "A, B, and / or C," is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B, or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0070] Whenever an embodiment is described herein with the term "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0071] The terms "about" or "essentially consisting of" refer to a value or composition that is within an acceptable range of error for a particular value or composition as determined by one of ordinary skill in the art; such error will depend, in part, on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially consisting of" can mean within one standard deviation or within more than one standard deviation, in accordance with practice in the art. Alternatively, "about" or "essentially consisting of" can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect to biological systems or processes, these terms can mean up to an order of magnitude or up to 5 times a value. When a specific value or composition is provided in the present application and claims, unless otherwise specified, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable range of error for that specific value or composition.

[0072] As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range and fractions thereof, where appropriate (such as tenths and hundredths of an integer), unless otherwise indicated.

[0073] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, 2006, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0074] Units, prefixes, and symbols are written in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0075] The headings provided herein are not limitations of the various aspects of this disclosure that can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification as a whole.

[0076] "Antagonist" includes, but is not limited to, any molecule that can block, reduce, or otherwise limit the interaction or activity of a target molecule (e.g., LAG-3). In some embodiments, the antagonist is an antibody. In other embodiments, the antagonist comprises a small molecule. The terms "antagonist" and "inhibitor" are used interchangeably herein.

[0077] "Antibody" (Ab) is intended to include, without limitation, a glycoprotein immunoglobulin that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain contains a heavy chain variable region (referred to herein as V H ) and a heavy chain constant region (abbreviated as C H The heavy chain constant region contains three constant domains: C H1 , C H2 and C H3 Each light chain comprises a light chain variable region (referred to herein as V L ) and a light chain constant region (abbreviated as C L The light chain constant region contains one constant domain, C L Includes V H and V L The regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with regions of greater conservedness called framework regions (FRs). H and V L contains three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The heavy chain may or may not have a C-terminal lysine. Unless otherwise specified herein, amino acids in the variable region are numbered using the Kabat numbering system, and amino acids in the constant region are numbered using the EU system.

[0078] Immunoglobulins can be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by heavy chain constant region genes. By way of example, the term "antibody" includes both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; single-chain antibodies; monospecific antibodies; bispecific antibodies; and multispecific antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless expressly specified and the context dictates otherwise, the term "antibody" also includes antigen-binding fragments or portions of any of the aforementioned immunoglobulins, including monovalent and bivalent fragments or portions that retain the ability to specifically bind to the antigen bound by the whole immunoglobulin. Examples of "antigen-binding portions" or "antigen-binding fragments" include: (1) Fab fragments (fragments from papain cleavage) or V L ,V H ,L C and C H1 (2) a F(ab')2 fragment (a fragment from pepsin cleavage) or a similar bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (3) an Fd fragment consisting of the VH and CH1 domains; (4) a single-arm V L and V H Fv fragment consisting of domains; (5) V H (6) single-domain antibody (dAb) fragments, which consist of two V domains (Ward et al., (1989) Nature 341:544-46); (7) two V domains connected by a hinge H (7) bi-single domain antibodies (dual affinity retargeting antibodies (DART)); or (8) dual variable domain immunoglobulins. Furthermore, the two domains V of the Fv fragment L and V Hare encoded by separate genes, but they can be joined together by synthetic linkers using recombinant methods, resulting in V L and V H These regions can be produced as single protein chains that pair to form monovalent molecules (known as single-chain Fvs (scFvs); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0079] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to LAG-3 is substantially free of antibodies that do not specifically bind to LAG-3). However, an isolated antibody that specifically binds to LAG-3 may have cross-reactivity to other antigens, such as LAG-3 molecules from different species. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0080] The term "monoclonal antibody" ("mAb") refers to antibody molecules of single molecular composition, i.e., a non-naturally occurring preparation of antibody molecules essentially identical in their primary sequence and displaying a single binding specificity and affinity for a particular epitope. A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0081] A "human" antibody (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro by random or site-specific mutagenesis or in vivo by somatic mutation). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human" antibody and "fully human" antibody are used synonymously.

[0082] A "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDR domains of a non-human antibody have been replaced with amino acids from the corresponding human immunoglobulin. In one embodiment of a humanized form of an antibody, some, most, or all of the amino acids outside the CDR domains have been replaced with amino acids from a human immunoglobulin, while some, most, or all of the amino acids within one or more CDR regions remain unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permissible as long as they do not abolish the ability of the antibody to bind to a specific antigen. A "humanized" antibody retains the same antigen specificity as the original antibody.

[0083] "Chimeric antibody" refers to an antibody whose variable region is derived from one species and whose constant region is derived from another species, such as an antibody whose variable region is derived from a murine antibody and whose constant region is derived from a human antibody.

[0084] An "anti-antigen" antibody refers to an antibody that specifically binds to an antigen. For example, an anti-LAG-3 antibody specifically binds to LAG-3.

[0085] "LAG-3" refers to lymphocyte activation gene 3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, an antibody specific for human LAG-3 protein may, in certain cases, cross-react with LAG-3 proteins from species other than human. In other embodiments, an antibody specific for human LAG-3 protein may be completely specific for human LAG-3 protein and exhibit no species or other types of cross-reactivity, or may cross-react with LAG-3 from certain other species but not with any other species (e.g., cross-react with monkey LAG-3 but not with mouse LAG-3). The term "human LAG-3" refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank accession number NP_002277. The term "mouse LAG-3" refers to the mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank Accession No. NP_032505. LAG-3 is also known in the art, for example, as CD223. A human LAG-3 sequence can differ from human LAG-3 of GenBank Accession No. NP_002277 by, for example, having conserved mutations or mutations in non-conserved regions, and the LAG-3 has substantially the same biological function as human LAG-3 of GenBank Accession No. NP_002277. For example, the biological function of human LAG-3 is that it has an epitope in the extracellular domain of LAG-3 to which an antibody of the present disclosure specifically binds, or the biological function of human LAG-3 is binding to an MHC class II molecule.

[0086] A particular human LAG-3 sequence will generally have an amino acid sequence that is at least about 90% identical to the human LAG-3 of GenBank Accession No. NP_002277 and contains amino acid residues that identify the amino acid sequence as human when compared to the LAG-3 amino acid sequence of another species (e.g., mouse). In certain cases, the human LAG-3 may have an amino acid sequence that is at least about 95%, or even at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the LAG-3 of GenBank Accession No. NP_002277. In certain embodiments, the human LAG-3 sequence will exhibit no more than 10 amino acid differences from the LAG-3 sequence of GenBank Accession No. NP_002277. In certain embodiments, the human LAG-3 may exhibit no more than 5 amino acid differences, or even no more than 4, 3, 2, or 1 amino acid differences, from the LAG-3 sequence of GenBank Accession No. NP_002277.

[0087] "PD-1 (Programmed Death-1)" refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is primarily expressed on pre-activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs that share at least one epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863. "PD-1" and "PD-1 receptor" are used interchangeably herein.

[0088] "Cytotoxic T-lymphocyte antigen 4 (CTLA-4)" refers to an immunosuppressive receptor belonging to the CD28 family. CTLA-4 is expressed exclusively on T cells in vivo and binds to two ligands, CD80 and CD86 (also known as B7-1 and B7-2, respectively). As used herein, the term "CTLA-4" includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologs of hCTLA-4, as well as analogs that share at least one epitope with hCTLA-4. The complete hCTLA-4 sequence can be found at GenBank accession number AAB59385.

[0089] "PD-L1 (Programmed Death Ligand-1)" is one of the two cell surface glycoprotein ligands for PD-1 (the other is PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, and analogs that share at least one epitope with hPD-L1. The complete hPD-L1 sequence can be found at GenBank Accession No. Q9NZQ7.

[0090] "PD-L2 (Programmed Death Ligand-2)", as used herein, includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs that share at least one epitope with hPD-L2. The complete hPD-L2 sequence can be found under GenBank Accession No. Q9BQ51.

[0091] As used herein, a "patient" includes any patient suffering from lung cancer (e.g., NSCLC). The terms "subject" and "patient" are used interchangeably herein.

[0092] "Administering" refers to the physical introduction of a therapeutic agent (e.g., a composition or formulation comprising a therapeutic agent) into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes, e.g., by injection or infusion. The phrase "parenteral administration," as used herein, refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. In some embodiments, the formulation is administered by a non-parenteral route, in some embodiments orally. Other non-parenteral routes include topical, epidermal, or mucosal routes of administration, e.g., intranasal, vaginal, rectal, sublingual, or topical. Administration can be, for example, one time, multiple times and / or over one or more successive periods of time.

[0093] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting, or slowing the progression, onset, severity, or recurrence of symptoms, complications, or conditions, or the biochemical markers associated with the disease. Response Evaluation Criteria in Solid Tumors (RECIST) are a measure of treatment effectiveness and established rules that define when a tumor responds, stabilizes, or progresses during treatment. RECIST 1.1 is the current guideline for solid tumor measurement and definition to objectively determine changes in tumor size used in adult and pediatric cancer clinical trials.

[0094] As used herein, "maintenance therapy" refers to treatment intended to prevent the development or recurrence of tumors.

[0095] As used herein, a "recovery period" is a duration that begins upon completion of one treatment and ends upon the initiation of another treatment (e.g., a period that begins upon completion of a CCRT disclosed herein and ends upon administration of a combination therapy and / or maintenance therapy disclosed herein, e.g., a combination of a PD-1 pathway inhibitor and a LAG-3 antagonist disclosed herein). In some embodiments, the recovery period is a period of time sufficient for the subject to recover from an adverse event or serious adverse event associated with the treatment (e.g., a period of time sufficient for the subject to recover from toxicities associated with a CCRT disclosed herein other than fatigue, esophagitis, or alopecia).

[0096] As used herein, "effective treatment" refers to treatment that results in a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement compared to baseline, i.e., an improvement compared to measurements or observations made before initiation of therapy according to the method. A beneficial effect can also take the form of a prevention, slowing, deceleration, or stabilization of adverse progression of solid tumor markers. Effective treatment can refer to a reduction in at least one symptom of a solid tumor. Such effective treatment can, for example, reduce a patient's pain, reduce the size and / or number of lesions, reduce or prevent tumor metastasis, and / or slow tumor growth.

[0097] The term "effective amount" refers to the amount of an agent that provides a desired biological, therapeutic, and / or prophylactic result. Such a result can be reduction, amelioration, alleviation, mitigation, delay, and / or relief of one or more of the signs, symptoms, or causes of a disease, or any other desired change to a biological system. In the context of solid tumors, an effective amount includes an amount sufficient to cause tumor shrinkage and / or a reduction in the rate of tumor growth (such as tumor growth inhibition) or other slowing of undesired cell proliferation. In some embodiments, an effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. An effective amount of a drug or composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, delay, slow to some extent, or stop cancer cell invasion of peripheral organs; (iv) inhibit (i.e., slow to some extent, or stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor onset and / or recurrence; and / or (vii) alleviate to some extent one or more symptoms associated with cancer. In one example, an "effective amount" is an amount of anti-LAG-3 antibody alone, or an amount of anti-LAG-3 antibody in combination with an additional therapeutic agent (e.g., an anti-PD-1 antibody), that has been clinically shown to affect a significant reduction in cancer or a slowing of cancer progression, such as advanced solid tumors.

[0098] As used herein, the terms "fixed dose," "constant dose," and "fixed fixed dose" are used interchangeably and refer to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed or constant dose is not provided as a mg / kg dose, but rather as an absolute amount of drug (e.g., an amount in μg or mg).

[0099] Use of the term "fixed dose combination" in reference to compositions of the invention means that two or more different inhibitors as described herein (e.g., an anti-LAG-3 antibody and an anti-PD-1 antibody) in a single composition are present in the composition in a specific (fixed) ratio relative to each other. In some embodiments, the fixed dose is based on the weight (e.g., mg) of the inhibitor. In certain embodiments, the fixed dose is based on the concentration (e.g., mg / ml) of the inhibitor. In some embodiments, the ratio is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200 , about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg of the first inhibitor to mg of the second inhibitor. For example, a 1:1 ratio of the first inhibitor to the second inhibitor can mean that a vial can contain about 480 mg of the first inhibitor and 480 mg of the second inhibitor, or about 12 mg / ml of the first inhibitor and 12 mg / ml of the second inhibitor.

[0100] The term "body weight-based dose" as referred to herein means that the dose administered to a patient is calculated based on the patient's body weight.

[0101] "Dosing interval," as used herein, refers to the amount of time that elapses between administration of multiple doses of the formulations disclosed herein to a subject. Dosing intervals may thus be indicated as ranges.

[0102] The term "dose frequency," as used herein, refers to the frequency with which doses of the formulations disclosed herein are administered within a given period of time. Dose frequency can be indicated as the number of doses per given period of time, such as, for example, once a week or once every two weeks.

[0103] The terms "about once a week," "about once every week," "about once every two weeks," or any other similar dosing interval term, as used herein, refer to approximations, and "about once a week" or "about once every week" can include every 7 days ± 2 days, i.e., every 5 to 9 days. A "weekly" dose administration frequency can thus be every 5, 6, 7, 8, or 9 days. "About once every 3 weeks" can include every 21 days ± 3 days, i.e., every 25 to 31 days. Similar approximations apply to, for example, about once every 2 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, about once every 7 weeks, about once every 8 weeks, about once every 9 weeks, about once every 10 weeks, about once every 11 weeks, and about once every 12 weeks. In some embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose can be administered on any day in week 1, followed by the next dose on any day in week 6 or week 12, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a particular day in week 1 (e.g., Monday), followed by the next dose on the same day in week 6 or week 12 (i.e., Monday), respectively.

[0104] An "adverse event" (AE), as used herein, is any unfavorable, generally unintended or undesirable, sign (including abnormal clinical laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be related to activation of the immune system or an increase in immune system cells (e.g., T cells) in response to the treatment. A medical treatment may be associated with one or more associated AEs, each of which may present with the same or different levels of severity.

[0105] The term "tumor," as used herein, refers to any mass of tissue resulting from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions.

[0106] The term "biological sample," as used herein, refers to biological material isolated from a subject. Biological samples can include any biological material suitable for analysis, for example, by sequencing nucleic acids of a tumor (or circulating tumor cells) and identifying genomic alterations in the sequenced nucleic acids. Biological samples can be any suitable biological tissue or body fluid, such as, for example, tumor tissue, blood, plasma, and serum. Biological samples can be test tissue samples (e.g., tissue samples containing tumor cells and tumor-infiltrating inflammatory cells). In one aspect, the sample is a tumor tissue biopsy, such as formalin-fixed, paraffin-embedded (FFPE) tumor tissue or fresh-frozen tumor tissue. In another aspect, the biological sample is a liquid biopsy, which in some embodiments includes one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.

[0107] By way of example, an "anti-cancer agent" promotes cancer regression in a subject. In a preferred embodiment, a therapeutically effective amount of the agent promotes cancer regression to the point where the cancer disappears. "Promoting cancer regression" means that administration of an effective amount of an anti-cancer agent, alone or in combination with another agent, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods, or prevention of disability or incapacity due to disease. Additionally, the terms "effective" and "effectiveness" in relation to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level resulting from the administration of the drug.

[0108] By way of example with respect to tumor treatment, a therapeutically effective amount of an anticancer agent can inhibit cell or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% compared to untreated subjects. In other aspects of the present disclosure, tumor regression can be observed and continue to regress over a period of at least about 20 days, more preferably at least about 40 days or at least about 60 days. Notwithstanding these measures of therapeutic efficacy, evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0109] As used herein, "immuno-oncology" therapy or "IO" or "IO" therapy refers to a therapy that involves harnessing the immune response to target and treat a tumor in a subject. Therefore, as used herein, IO therapy is a type of anti-cancer therapy. In some embodiments, IO therapy involves administering to the subject an antibody. In some embodiments, IO therapy involves administering to the subject immune cells, e.g., T cells, e.g., modified T cells, e.g., T cells modified to express a chimeric antigen receptor or a specific T cell receptor. In some embodiments, IO therapy involves administering to the subject a therapeutic vaccine. In some embodiments, IO therapy involves administering to the subject a cytokine or chemokine. In some embodiments, IO therapy involves administering to the subject an interleukin. In some embodiments, IO therapy involves administering to the subject an interferon. In some embodiments, IO therapy involves administering to the subject a colony-stimulating factor.

[0110] "Immune response" refers to the actions of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, and neutrophils) and soluble macromolecules (including antibodies, cytokines, and complement) produced by any of these cells or the liver, resulting in the selective targeting, binding to, damaging, destroying, and / or elimination from the vertebrate body of invading pathogens, pathogen-infected cells or tissues, cancerous or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

[0111] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are any type of cell that is typically involved in a subject's inflammatory response and that infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0112] The term "LAG-3 positive" or "positive for LAG-3 expression" with respect to LAG-3 expression refers to tumor tissue (e.g., a tissue sample tested) that is scored as expressing LAG-3 based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes such as CD8+ T cells) that express LAG-3 (e.g., expression of 1% or more) or based on the proportion (i.e., percentage) of nucleated cells that express LAG-3 (i.e., immune cells that express LAG-3 as a percentage of total nucleated cells, e.g., expression of 1% or more).

[0113] "LAG-3 negative" or "LAG-3 expression negative" refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing LAG-3 (e.g., less than 1% LAG-3 expression in immune cells and / or nucleated cells).

[0114] The terms "PD-1 positive" or "positive for PD-1 expression" with respect to PD-1 expression refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-1 based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes such as CD8+ T cells) that express PD-1 (e.g., 1% or greater expression) or the proportion (i.e., percentage) of nucleated cells that express PD-1 (i.e., immune cells that express PD-1 as a proportion of total nucleated cells, e.g., 1% or greater expression).

[0115] "PD-1 negative" or "PD-1 expression negative" refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing PD-1 (e.g., less than 1% PD-1 expression).

[0116] The terms "PD-L1 positive" or "positive for PD-L1 expression," with respect to cell surface PD-L1 expression, refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-L1 based on the proportion (i.e., percentage) of tumor cells that express PD-L1 (e.g., expression of 1% or greater) or the proportion (i.e., percentage) of nucleated cells that express PD-L1 (i.e., tumor cells that express PD-L1 as a proportion of total nucleated cells, e.g., expression of 1% or greater).

[0117] The terms "PD-L1 negative" or "PD-L1 expression negative" refer to tumor tissue (e.g., a tissue sample tested) that does not score as expressing PD-L1 (e.g., less than 1% expression).

[0118] Various aspects of the invention are described in further detail in the following subsections.

[0119] II. Methods of the Disclosure Provided herein are methods of treating a human subject afflicted with lung cancer, comprising administering to the subject (a) a PD-1 (programmed death-1) pathway inhibitor (e.g., an anti-PD-1 antibody) and concurrent chemoradiotherapy (CCRT, i.e., combination chemotherapy and radiation therapy, e.g., platinum-doublet chemotherapy (PDCT) and radiation therapy), followed by (b) a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody) and a lymphocyte-activation gene-3 (LAG-3) antagonist (e.g., an anti-LAG-3 antibody). The administration of (b) is also referred to interchangeably herein as combination therapy comprising a PD-1 pathway inhibitor and a LAG-3 antagonist (e.g., a fixed-dose combination comprising a PD-1 pathway inhibitor and a LAG-3 antagonist).

[0120] In some embodiments, the method further comprises providing the subject with a recovery period beginning at the completion of administering in (a) and ending at the start of administering in (b). In some embodiments, the recovery period is a period sufficient for the subject to recover from an adverse event associated with administering in (a). In some embodiments, the adverse event is a serious adverse event. In some embodiments, the recovery period is a period sufficient for the subject to recover from toxicity associated with CCRT other than fatigue, esophagitis, or alopecia. In some embodiments, the PD-1 pathway inhibitor in (a) is administered before CCRT. In some embodiments, the recovery period begins at the completion of CCRT. In some embodiments, the chemotherapy for CCRT is administered before the radiation therapy for CCRT. In some embodiments, the recovery period begins at the completion of radiation therapy. In some embodiments, the recovery period is from about 1 week to about 12 weeks, from about 1 week to about 9 weeks, from about 1 week to about 6 weeks, from about 2 weeks to about 12 weeks, from about 2 weeks to about 9 weeks, from about 2 weeks to about 6 weeks, from about 3 weeks to about 12 weeks, from about 3 weeks to about 9 weeks, from about 3 weeks to about 6 weeks, from about 18 days to about 12 weeks, from about 18 days to about 9 weeks from the last administration of the PD-1 pathway inhibitor in (a), or from about 18 days to about 6 weeks from the last administration of the PD-1 pathway inhibitor in (a).

[0121] In some embodiments, the method is a first line (1L) therapy.

[0122] In some embodiments, the method is a second line (2L) therapy.

[0123] In some embodiments, the method is a third line (3L) therapy.

[0124] In some embodiments, the subject has progressed on previous treatment (e.g., standard treatment). Standards of care for various types of cancer are well known to those skilled in the art. For example, the National Comprehensive Cancer Network (NCCN), a collaboration of 21 major cancer centers in the United States, publishes the NCCN Clinical Practice Guidelines in Oncology (NCCN GUIDELINES®), which provide detailed and up-to-date information on standard treatment for a wide variety of cancers. See NCCN GUIDELINES®, 2022-2023, https: / / www.nccn.org / guidelines / category_1, last accessed December 20, 2022.

[0125] In some aspects, the lung cancer recurs after multimodal treatment for locally advanced lung cancer.

[0126] In some embodiments, the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

[0127] In some embodiments, the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

[0128] In some embodiments, the subject has no prior immuno-oncology (IO) therapy. In some embodiments, the subject has not received IO therapy, has received IO therapy for a cancer other than lung cancer, or has received IO therapy for a previous lung cancer but not for the current lung cancer. In some embodiments, the subject is naive to prior IO therapy, the subject is naive to prior IO therapy for lung cancer, or the lung cancer is naive to prior IO therapy. In some embodiments, the prior IO therapy is an antibody. In some embodiments, the antibody binds to a checkpoint inhibitor. In some embodiments, the prior IO therapy is an anti-PD-1 antibody and / or a combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0129] In some aspects, the methods of the present disclosure extend progression-free survival (PFS), objective response rate (ORR), overall survival (OS), or any combination thereof, compared to the standard of care (e.g., CCRT followed by maintenance therapy with durvalumab) disclosed herein and / or a prior treatment.

[0130] In some aspects, the methods of the present disclosure reduce tumor size, inhibit tumor growth, eliminate tumors from a subject, prevent recurrence of lung cancer, induce remission of lung cancer, provide a complete or partial response, or any combination thereof.

[0131] In some embodiments, the methods of the present disclosure are administered to a subject based on the subject's performance status and / or cancer stage, which may be indicated by any one or more systems in the art.

[0132] In some embodiments, the lung cancer is unresectable, advanced, recurrent and / or metastatic.

[0133] In some embodiments, performance status is indicated by Eastern Cooperative Oncology Group Performance Status (ECOG PS), which uses standardized criteria to measure how disease affects a patient's ability to perform daily activities. Exemplary definitions of ECOG PS include: "0" for patients who are fully functional and can perform all the activities they were able to perform before the onset of disease without limitation; "1" for patients who are limited in physically strenuous activities but can walk and perform light or sedentary tasks; "2" for patients who are ambulatory and can take care of themselves completely, and can sit up and move around more than 50% of the day, but cannot perform any occupational activities; "3" for patients who can only take care of themselves to a limited extent and spend more than 50% of the day in bed or chair; and "4" for patients who are completely immobile, cannot take care of themselves at all, and spend the whole day in bed or chair.

[0134] In some embodiments, the subject has an ECOG PS of 0, 1, 2, 3, or 4. In some embodiments, the subject has an ECOG PS of 3 or less. In some embodiments, the subject has an ECOG PS of 2 or less. In some embodiments, the subject has an ECOG PS of 1 or less.

[0135] In some embodiments, lung cancer is staged based on a tumor (T) / lymph node (N) / metastasis (M) staging system (T / N / M), such as the American Joint Committee on Cancer (AJCC) classification. See, e.g., https: / / www.cancer.org / cancer / lung-cancer / detection-diagnosis-staging / staging-nsclc.html, last accessed December 20, 2022.

[0136] Stages of lung cancer (e.g., NSCLC) include: occult (hidden) stage, stage 0 (carcinoma in situ), stage I (e.g., stage IA1, stage IA2, stage IA3, and stage IB NSCLC), stage II (e.g., stage IIA and stage IIB NSCLC), stage III (e.g., stage IIIA, stage IIIB, and stage IIIC NSCLC), and stage IV (e.g., stage IVA and stage IVB NSCLC).

[0137] In some embodiments, the subject has lung cancer (e.g., NSCLC) in an occult (hidden) stage, where the cancer cannot be seen by imaging or bronchoscopy (TX), has not spread to lymph nodes (N0), and has not metastasized (TX / N0 / M0).

[0138] In some embodiments, the subject has stage 0 lung cancer (e.g., NSCLC). In stage 0 (Tis / N0 / M0), cancer cells are found only in the lining of the airways and have not infiltrated deep into other lung tissues (Tis). N0 and M0 are as described above.

[0139] In some embodiments, the subject has stage I lung cancer (e.g., NSCLC). Stage I lung cancer is divided into stage IA1, stage IA2, stage IA3, and stage IB, for example, for NSCLC. N0 and M0 are as described above. In stage IA1 (T1mi / N0 / M0), the cancer is a minimally invasive adenocarcinoma, with tumors 3 centimeters (cm) or less in diameter, some of which have invaded deeper lung tissues 0.5 cm (T1mi) or less in diameter. In stage IA1 (T1a / N0 / M0), the tumor is 1 cm or less in diameter, has not grown into the membrane surrounding the lung, and does not affect the main bronchial branches (T1a). In stage IA2 (T1b / N0 / M0), the tumor is greater than 1 cm in diameter but 2 cm or less in diameter, has not grown into the membrane surrounding the lung, and does not affect the main bronchial branches (T1b). In stage IA3 (T1c / N0 / M0), the tumor is larger than 2 cm in diameter but not larger than 3 cm in diameter, has not grown into the membrane surrounding the lung, and does not affect the main branch of the bronchus (T1c). In stage IB (T2a / N0 / M0), one or more of the following is true: 1) the tumor is larger than 3 cm in diameter but not larger than 4 cm in diameter; 2) cancer has spread to the main bronchus and is at least 2 cm below where the trachea joins the bronchi; 3) cancer has spread to the innermost layer of the membrane covering the lung and is not larger than 4 cm wide; or 4) the tumor is not larger than 4 cm in diameter but is partially blocking the airway (T2a).

[0140] In some embodiments, the subject has stage II lung cancer (e.g., NSCLC). Stage II is divided into stage IIA (T2b / N0 / M0) and stage IIB (T1a / T1b / T1c / N1 / M0 or T2a / T2b / N1 / M0 or T3 / N0 / M0), for example, for NSCLC. N0 and M0 are as defined above. In stage IIA, one or more of the following is true: 1) the tumor is larger than 4 cm in diameter but not larger than 5 cm in diameter; 2) the cancer has spread to the main bronchi and is at least 2 centimeters below where the trachea joins the bronchi, and the tumor is larger than 4 cm but not larger than 5 cm; 3) the cancer has spread to the innermost layer of the membrane covering the lung, and the tumor is larger than 4 cm but not larger than 5 cm; or 4) the tumor is larger than 4 cm but not larger than 5 cm and is partially obstructing the airway (T2b). In stage IIB, the cancer may or may not have spread to the lymph nodes. If the cancer has spread to the lymph nodes, it can only spread to lymph nodes on the same side of the chest as the tumor, and the lymph nodes with cancer are within the lung or near the bronchi (N1). In T1a / T1b / T1c / N1 / M0, the tumor is 3 cm or less in diameter, has not grown into the membrane surrounding the lung, and does not affect the main branches of the bronchi (T1a / T1b / T1c). For T2a / T2b / N1 / M0, one or more of the following is true: 1) the tumor is larger than 3 cm in diameter but not larger than 5 cm in diameter; 2) the cancer has spread to the main bronchus and is at least 2 centimeters below where the trachea joins the bronchi and the tumor is not larger than 5 cm across the bronchus; 3) the cancer has spread to the innermost layer of the membrane covering the lung and is not larger than 5 cm wide; or 4) the tumor is not larger than 5 cm in diameter and is partially blocking the airway (T2a / T2b). For T3 / N0 / M0, the cancer has not spread to lymph nodes or metastasized, but one or more of the following is true: 1) the cancer is larger than 5 cm in diameter but not larger than 7 cm in diameter; 2) the cancer has grown into the chest wall, parietal pleura, phrenic nerve, or parietal pericardium; or 3) the same lobe of the lung has two or more separate tumor nodules (T3).

[0141] In some embodiments, the subject is suffering from stage III lung cancer (e.g., NSCLC). Stage III is divided into, for example, stage IIIA (T1a / T1b / T1c / N2 / M0 or T2a / T2b / N2 / M0 or T3 / N1 / M0 or T4 / N0 or N1 / M0) for NSCLC, stage IIIB (T1a / T1b / T1c / N3 / M0 or T2a / T2b / N3 / M0 or T3 / N2 / M0 or T4 / N2 / M0) and stage IIIC (T3 / N3 / M0 or T4 / N3 / M0). T1a / T1b / T1c, T2a / T2b, T3, N0, N1 and M0 are as described above. In the case of N2, the cancer has spread to lymph nodes around the carina or in the mediastinum on the same side as the tumor. At N3, the cancer has spread to lymph nodes on both sides of the body near the collarbone and / or has spread from the main tumor to lymph nodes in the hilum or mediastinum on the other side of the body. At T4, one or more of the following is true: 1) the tumor is larger than 7 cm; 2) the tumor is growing in the mediastinum, heart, large blood vessels near the heart (e.g., the aorta), trachea, esophagus, diaphragm, spine, or tracheal bifurcation; or 3) two or more tumor nodules are in different lobes of the same lung.

[0142] In some embodiments, the subject has stage IV lung cancer (e.g., NSCLC). Stage IV is divided into stage IVA (Any T / Any N / M1a or Any T / Any N / M1b) and stage IVB (Any T / Any N / M1c) for NSCLC, for example. For any T, the tumor can be any size and may or may not have grown into nearby structures. For any N, the cancer may or may not have reached nearby lymph nodes. In the case of M1a, one or more of the following is true: 1) the cancer has spread to both lungs; 2) cancer cells are found in the fluid surrounding the lungs; 3) cancer cells are found in the fluid surrounding the heart. In the case of M1b, the cancer has spread as a single tumor to distant lymph nodes or another organ (e.g., the liver, bone, or brain). In M1c, the cancer has spread as two or more tumors to distant lymph nodes and / or other organs (eg, the liver, bone, or brain).

[0143] In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, the stage of SCLC is by T / N / M staging. In some embodiments, SCLC is staged as either limited-stage or extensive-stage rather than by T / N / M staging. Limited-stage SCLC is confined to one lung and / or regional lymph nodes. Extensive-stage SCLC is found in both the lung and / or distant sites in the body.

[0144] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). NSCLC includes NSCLC with histology "not otherwise specified" (NOS), NSCLC with squamous histology (SQ), and NSCLC with non-squamous histology (NSQ1, including adenocarcinoma, large cell carcinoma, and undifferentiated carcinoma). In some embodiments, the NSCLC has squamous histology. In some embodiments, the NSCLC has non-squamous histology. In some embodiments, the staging of the NSCLC is by T / N / M staging. In some embodiments, the NSCLC includes locally advanced stage IIIA, IIIB, or IIIC NSCLC. In some embodiments, the subject does not have progressive lung cancer during CCRT or the recovery period of the methods as disclosed herein.

[0145] Surgery (i.e., surgical resection), radiation therapy (RT, also referred to herein as radiotherapy), and chemotherapy are three modalities commonly used to treat patients with NSCLC. As a class, NSCLC is relatively insensitive to chemotherapy and RT compared with small cell carcinoma. Generally, for patients with stage I or II disease, surgical resection offers the best chance for cure, and chemotherapy is often used both preoperatively and postoperatively. RT can also be used as adjuvant therapy for patients with resectable NSCLC, as primary local treatment, or as palliative therapy for patients with incurable NSCLC. Patients with advanced or metastatic disease (e.g., stage IV NSCLC) who have a good performance status (PS) may benefit from chemotherapy.

[0146] Specific targeted therapies are also being developed for the treatment of advanced or metastatic NSCLC in subjects with sensitizing mutations in the genes for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS-1, neurotrophin receptor tyrosine kinase (NTRK), and B rapidly accelerating fibrosarcoma proto-oncogene (BRAF, e.g., BRAF V600E mutation).

[0147] In some embodiments, the subject has an EGFR, ALK, NTRK, ROS-1, or BRAF mutation that is susceptible to targeted inhibitor therapy.

[0148] In some embodiments, the subject does not have an EGFR, ALK, NTRK, ROS-1, or BRAF mutation that is susceptible to targeted inhibitor therapy.

[0149] II.A PD-1 pathway inhibitors In some embodiments, the PD-1 pathway inhibitor administered with CCRT in the disclosed methods is the same as the PD-1 pathway inhibitor administered with the LAG-3 antagonist in the disclosed methods.

[0150] In some embodiments, the PD-1 pathway inhibitor administered with CCRT in the disclosed methods is different from the PD-1 pathway inhibitor administered with the LAG-3 antagonist in the disclosed methods.

[0151] In some embodiments, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist comprises a PD-1 inhibitor and / or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor and / or PD-L1 inhibitor comprises a small molecule. In some embodiments, the PD-1 inhibitor and / or PD-L1 inhibitor comprises a millimolecule. In some embodiments, the PD-1 inhibitor and / or PD-L1 inhibitor comprises a macrocyclic peptide. In certain embodiments, the PD-1 inhibitor and / or PD-L1 inhibitor comprises BMS-986189. In some embodiments, the PD-1 inhibitor comprises an inhibitor disclosed in WO 2014 / 151634, which is incorporated herein by reference in its entirety. In some embodiments, the PD-1 inhibitor is INCMGA00012 (Insight Pharmaceuticals). In some embodiments, the PD-1 inhibitor comprises a combination of an anti-PD-1 antibody and a PD-1 small molecule inhibitor disclosed herein. In some embodiments, the PD-L1 inhibitor has Formula (I): [ka] (In the formula, R 1 -R 13 is the amino acid side chain, and R a -R n is hydrogen, methyl, or forms a ring with the adjacent R group; R 14 -C(O)NHR 15 where R 15 is hydrogen or a glycine residue optionally substituted with additional glycine residues and / or tails that can improve pharmacokinetic properties) In some embodiments, the PD-L1 inhibitor includes a compound disclosed in WO 2014 / 151634, which is incorporated by reference in its entirety. In some embodiments, the PD-L1 inhibitor comprises a compound disclosed in WO 2016 / 039749, WO 2016 / 149351, WO 2016 / 077518, WO 2016 / 100285, WO 2016 / 100608, WO 2016 / 126646, WO 2016 / 057624, WO 2017 / 151830, WO 2017 / 176608, WO 2018 / 085750, WO 2018 / 237153, or WO 2019 / 070643, each of which is incorporated by reference herein in its entirety. In some embodiments, the PD-L1 inhibitor comprises a small molecule PD-L1 inhibitor disclosed in WO2015 / 034820, WO2015 / 160641, WO2018 / 044963, WO2017 / 066227, WO2018 / 009505, WO2018 / 183171, WO2018 / 118848, WO2019 / 147662, or WO2019 / 169123, each of which is incorporated by reference in its entirety.

[0152] In some embodiments, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist comprises a soluble PD-L2 polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a fusion polypeptide. In some embodiments, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some embodiments, the soluble PD-L2 polypeptide further comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble PD-L2 polypeptide is AMP-224 (see, e.g., U.S. Patent Application Publication No. 2013 / 0017199).

[0153] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0154] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is administered at a fixed dose.

[0155] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, It is administered at a dose of about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0156] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg g, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg , about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.25mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 3 50mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, About 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg , about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 10 The compound is administered at a dose of about 80 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0157] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is administered as a body weight-based dose.

[0158] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is from about 0.003 mg / kg to about 25 mg / kg, from about 0.003 mg / kg to about 20 mg / kg, from about 0.003 mg / kg to about 15 mg / kg, from about 0.003 mg / kg to about 10 mg / kg, from about 0.003 mg / kg to about 5 mg / kg, from about 0.003 mg / kg to about 1 mg / kg, from about 0.003 mg / kg to about 0.9mg / kg, about 0.003mg / kg to about 0.8mg / kg, about 0.003mg / kg to about 0.7mg / kg, about 0.003mg / kg to about 0.6mg / kg, about 0.003mg / kg to about 0.5mg / kg, about 0.003mg / kg to about 0.4mg / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1 mg / kg~about 25mg / kg, about 0.1mg / kg~about 20mg / kg, about 0.1mg / kg~about 15mg / kg, about 0.1mg / kg~about 10mg / kg, about 0.1mg / kg~about 5mg / kg, about 0.1 mg / kg~about 1mg / kg, about 1mg / kg~about 25mg / kg, about 1mg / kg~about 20mg / kg, about 1mg / kg~about 15mg / kg, about 1mg / kg~about 10mg / kg, about 1mg / kg~about 5mg / kg The dose is administered at a dose of about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0159] In some embodiments, the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8mg / kg, about 0.9mg / kg, about 1.0mg / kg, about 2.0mg / kg, about 3.0mg / kg, about 4.0mg / kg, about 5.0mg / kg, about 6.0mg / kg, about 7.0mg / kg, about 8.0mg / kg, about 9.0mg / kg, about 10.0mg / kg, about 11.0mg / kg, about 12.0mg / kg, about 13.0mg / kg, about 14.0mg / kg, about 15.0mg / kg, about 16.0mg / kg, about 17.0mg / kg, about 18.0mg / kg, about 19.0mg / kg, about 20.0mg / kg, about 21.0mg / kg, about 22.0mg / kg, about 23.0mg / kg, about 24.0mg / kg, or about 25.0mg / kg.

[0160] In some embodiments, the dose of the PD-1 pathway inhibitor administered with the CCRT is different from the dose of the PD-1 pathway inhibitor administered with the LAG-3 antagonist.

[0161] In some embodiments, the dose of the PD-1 pathway inhibitor administered with the CCRT and / or LAG-3 antagonist is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0162] In some embodiments, the PD-1 pathway inhibitor is administered in three 21-day cycles with CCRT as disclosed herein.

[0163] In some embodiments, the PD-1 pathway inhibitor is administered with a LAG-3 antagonist disclosed herein about once every four weeks as maintenance therapy.

[0164] II.A.1 Anti-PD-1 antibody The methods of the present disclosure can use anti-PD-1 antibodies known in the art. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) 1×10 binding to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D (b) does not substantially bind to human CD28, CTLA-4, or ICOS; (c) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increases interferon-γ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus PD-1; (g) inhibits the binding of PD-L1 and / or PD-L2 to PD-1; and (h) stimulates an antigen-specific memory response; (i) stimulates an antibody response; and (j) inhibits tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0165] Other anti-PD-1 monoclonal antibodies that can be used in the methods of the disclosure are described in, for example, U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509; U.S. Patent Application Publication No. 2016 / 0272708; and WO 2012 / 145493, WO 2008 / 156712, WO 2015 / 044999, and WO 2016 / 0449999. / 112900 Brochure, 2012 / 145493 Brochure, 2015 / 112800 Brochure, 2014 / 206107 Brochure, 2015 / 35606 Brochure, 2015 / 085847 Brochure, 2014 / 179664 Brochure, 2017 / 020291 Brochure, 2017 / 020858 Brochure, 2016 / 19 Brochure No. 7367, Brochure No. 2017 / 024515, Brochure No. 2017 / 025051, Brochure No. 2017 / 123557, Brochure No. 2016 / 106159, Brochure No. 2014 / 194302, Brochure No. 2017 / 040790, Brochure No. 2017 / 133540, Brochure No. 2017 / 132827, Brochure No. 2017 / 024 Nos. 465, 2017 / 025016, 2017 / 106061, 2017 / 19846, 2017 / 024465, 2017 / 025016, 2017 / 132825, and 2017 / 133540 (each of which is incorporated by reference in its entirety).

[0166] Anti-PD-1 antibodies that can be used in the methods of the disclosure include nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK3475; see WO 2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO 2015 / 112900 and U.S. Patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostarlimab; see WO 2014 / 179664), cemiplimab (Regeneron; also known as LIBTAYO® or REGN2810; see WO 2015 / 112800 and U.S. Pat. No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; Si-Yang Liu et al. al., J. Hematol. Oncol. 10:136 (2017)), PF-06801591 (Pfizer; also known as sasanlimab; U.S. Patent Application Publication No. 2016 / 0159905), BGB-A317 (Beigene; also known as tislelizumab; see WO 2015 / 35606 and U.S. Patent Application Publication No. 2015 / 0079109), BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018); 78(13 supra): Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; International Publication No. 2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics; see WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018), IBI308 (Innovent; also known as sintilimab; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), and SSI-361 (Lyvgen Biopharma Holdings Limited, U.S. Patent Application Publication No. 2018 / 0346569).

[0167] Anti-PD-1 antibodies that can be used in the methods of the disclosure can also include isolated antibodies that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with any of the anti-PD-1 antibodies disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013 / 173223). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab.

[0168] In some embodiments, any of the anti-PD-1 antibodies disclosed herein, such as antibodies that cross-compete with nivolumab for binding to human PD-1 or that bind to the same epitope region as nivolumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0169] The ability of antibodies to cross-compete for binding to an antigen indicates that such antibodies bind to the same epitope region of the antigen and sterically hinder other cross-competing antibodies from binding to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of a reference antibody, such as nivolumab, due to their binding to the same epitope region. Cross-competing antibodies can be easily identified based on their ability to cross-compete in standard binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, for example, WO 2013 / 173223).

[0170] Anti-PD-1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies described above. It is well established that fragments of full-length antibodies can perform the antigen-binding function of an antibody.

[0171] Anti-PD-1 antibodies that can be used in the methods of the disclosure are antibodies that bind to PD-1 with high specificity and affinity, antibodies that block binding of PD-L1 and / or PD-L2, and antibodies that inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to a whole antibody in binding to the PD-1 receptor and inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0172] In some embodiments, the anti-PD-1 antibody comprises a full-length antibody.

[0173] In some embodiments, the anti-PD-1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a dual affinity retargeting antibody (DART), a DVD-Ig, or a bispecific antibody.

[0174] In some embodiments, the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0175] In some embodiments, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen-binding portion thereof.

[0176] In some embodiments, the anti-PD-1 antibody is formulated for intravenous administration.

[0177] In some embodiments, the anti-PD-1 antibody is administered intravenously over about 30 minutes.

[0178] In some embodiments, the anti-PD-1 antibody comprises nivolumab, a fully human IgG4(S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol. Res. 2(9):846-56).

[0179] In some embodiments, nivolumab is administered at a fixed dose of about 240 mg about once every two weeks. In some embodiments, nivolumab is administered at a fixed dose of about 240 mg about once every three weeks. In some embodiments, nivolumab is administered at a fixed dose of about 360 mg about once every three weeks. In some embodiments, nivolumab is administered at a fixed dose of about 480 mg about once every four weeks.

[0180] In some embodiments, nivolumab is administered intravenously over about 30 minutes at a dose of about 240 mg on day 1 of a two-week cycle.

[0181] In some embodiments, nivolumab is administered intravenously over about 30 minutes at a dose of about 360 mg on day 1 of a 3-week cycle.

[0182] In some embodiments, nivolumab is administered intravenously over about 30 minutes at a dose of about 480 mg on day 1 of a 4-week cycle.

[0183] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14.

[0184] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20.

[0185] In some embodiments, the methods of the disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

[0186] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively.

[0187] In some embodiments, the anti-PD-1 antibody is pembrolizumab, a humanized monoclonal IgG4(S228P) antibody directed against the human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0188] In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg about once every two weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg about once every three weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 400 mg about once every six weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 300 mg about once every four to five weeks.

[0189] In some embodiments, pembrolizumab is administered intravenously at a dose of about 200 mg on day 1, then about once every three weeks.

[0190] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:79, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:80.

[0191] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:81; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:82; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:83; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:84; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:85; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:86.

[0192] In some embodiments, the methods of the disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 79 and 80, respectively.

[0193] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 77 and 78, respectively.

[0194] In some embodiments, the anti-PD-1 antibody comprises cemiplimab (REGN2810), which is described, for example, in WO 2015 / 112800 and U.S. Pat. No. 9,987,500.

[0195] In some embodiments, cemiplimab is administered intravenously at a dose of about 3 mg / kg or about 350 mg about once every three weeks.

[0196] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:35, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:36.

[0197] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:37; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:38; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:39; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:40; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:41; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:42.

[0198] In some embodiments, the methods of the disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 35 and 36, respectively.

[0199] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 33 and 34, respectively.

[0200] In some embodiments, the anti-PD-1 antibody comprises spartalizumab (PDR001), which is described, for example, in WO 2015 / 112900 and U.S. Pat. No. 9,683,048.

[0201] In some embodiments, spartalizumab is administered intravenously at a dose of about 300 mg about once every three weeks or 400 mg about once every four weeks.

[0202] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:59, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:60.

[0203] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:61; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:62; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:63; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:64; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:65; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:66.

[0204] In some embodiments, the methods of the disclosure include anti-PD-1 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 59 and 60, respectively.

[0205] In some embodiments, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 57 and 58, respectively.

[0206] II.A.2 Anti-PD-L1 antibody The methods of the present disclosure may use anti-PD-L1 antibodies known in the art. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the present disclosure include the antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 has been demonstrated to exhibit one or more of the following characteristics: (a) a PD-L1 activity of 1×10 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D (b) bind to human PD-L1 in a mixed lymphocyte reaction (MLR) assay; (c) increase interferon-γ production in an MLR assay; (d) increase IL-2 secretion in an MLR assay; (e) stimulate antibody responses; and (f) reverse the effects of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one of the foregoing characteristics, and in some embodiments, at least five of the foregoing characteristics.

[0207] Anti-PD-L1 antibodies that can be used in the methods of the disclosure include BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO 2013 / 173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see, U.S. Patent No. 8,217,149; see also Herbst et al. (2013) J Clin Oncol 31 (supra):3000), durvalumab (AstraZeneca; IMFINZI, also known as MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; BAVENCIO, also known as MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO 2013 / 181634), CX-072 (Cytomx; see WO 2016 / 149201), KN035 (3DMed / Alphamab; Zhang et al., Cell Discov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO36 (15 supra):TPS3113 (2018)), ICO36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR: Abstract 4606 (Apr 2016)).

[0208] Anti-PD-L1 antibodies that can be used in the methods of the disclosure can also include isolated antibodies that specifically bind to human PD-L1 and cross-compete with any of the anti-PD-L1 antibodies disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1. In some embodiments, the anti-PD-L1 antibody binds to the same epitope as any of the anti-PD-L1 antibodies described herein, e.g., atezolizumab, durvalumab, and / or avelumab. In certain embodiments, antibodies that cross-compete with, or bind to the same epitope region as, any of the anti-PD-L1 antibodies disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1 are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, modified, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0209] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies listed above.

[0210] Anti-PD-L1 antibodies that can be used in the methods of the disclosure are antibodies that bind to PD-L1 with high specificity and affinity, antibodies that block PD-1 binding, and antibodies that inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to a whole antibody in that it binds to PD-L1 and inhibits receptor binding, and upregulates the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0211] In some embodiments, an anti-PD-L1 antibody is substituted for the anti-PD-1 antibody in any of the methods disclosed herein.

[0212] In some embodiments, the anti-PD-L1 antibody comprises a full-length antibody.

[0213] In some embodiments, the anti-PD-L1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0214] In some embodiments, the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0215] In some embodiments, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen-binding portion thereof.

[0216] In some embodiments, the PD-L1 antibody comprises atezolizumab. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some embodiments, atezolizumab is administered as a flat dose of about 800 mg about once every two weeks. In some embodiments, atezolizumab is administered as a flat dose of about 840 mg about once every two weeks.

[0217] In some embodiments, atezolizumab is administered intravenously on day 1 of a 3-week cycle at a dose of about 1,200 mg.

[0218] In some embodiments, the PD-L1 antibody comprises durvalumab. Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg about once every two weeks. In some embodiments, durvalumab is administered at a dose of about 10 mg / kg about once every two weeks for up to 12 months. In some embodiments, durvalumab is administered as a flat dose of about 800 mg / kg about once every two weeks. In some embodiments, durvalumab is administered as a flat dose of about 1200 mg / kg about once every three weeks.

[0219] In some embodiments, the PD-L1 antibody comprises avelumab. Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody. In some embodiments, avelumab is administered as a flat dose of about 800 mg about once every two weeks.

[0220] II.B CCRT Concurrent chemoradiotherapy (CCRT) known in the art as well as CCRT disclosed herein can be used in the disclosed methods.

[0221] In some embodiments, the CCRT comprises platinum-doublet therapy (PDCT).

[0222] In some embodiments, the PDCT comprises a platinum agent in combination with a nucleoside analog, antimetabolite, taxane, vinca alkaloid, or topoisomerase inhibitor.

[0223] In some embodiments, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenanthriplatin. In some embodiments, the platinum agent comprises cisplatin. In some embodiments, the platinum agent comprises carboplatin.

[0224] In some embodiments, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some embodiments, the nucleoside analog comprises gemcitabine.

[0225] In some embodiments, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some embodiments, the antimetabolite comprises pemetrexed.

[0226] In some embodiments, the taxane comprises paclitaxel, albumin-bound paclitaxel (also called nab-paclitaxel), docetaxel, or cabazitaxel. In some embodiments, the taxane comprises paclitaxel.

[0227] In some embodiments, the vinca alkaloid comprises vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinbrunin. In some embodiments, the vinca alkaloid comprises vinorelbine or vinblastine.

[0228] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some embodiments, the topoisomerase inhibitor comprises etoposide. In some embodiments, the topoisomerase inhibitor comprises irinotecan.

[0229] In some embodiments, PDCT is administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 weeks.

[0230] In some embodiments, PDCT is administered about every 3 weeks for about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 cycles. In some embodiments, PDCT is administered about every 3 weeks for about 1, about 2, about 3, about 4, about 5, or about 6 cycles. In some embodiments, PDCT is administered about every 3 weeks for about 1, about 2, about 3, or about 4 cycles. In some embodiments, PDCT is administered in three 21-day cycles.

[0231] In some embodiments, the platinum agent comprises cisplatin. In some embodiments, the cisplatin is administered at a concentration of about 25 mg / m 2 ~about 150mg / m 2 , about 50mg / m 2 ~about 100mg / m 2 , about 75mg / m 2 ~about 100mg / m 2 or about 75 mg / m 2 ~about 80mg / m 2 In some embodiments, cisplatin is administered at a dose of about 50 mg / m 2 , about 55mg / m 2 , about 60mg / m 2 , about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 76mg / m 2 , about 77mg / m 2 , about 78mg / m 2 , about 79mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 or about 100 mg / m 2 In some embodiments, cisplatin is administered intravenously over about 60 minutes. In some embodiments, cisplatin is administered on day 1 of each of three 21-day cycles.

[0232] In some embodiments, the platinum agent comprises carboplatin. In some embodiments, carboplatin is administered at a dose with an area under the concentration-time curve (AUC) of about 1 mg / mL·min to about 10 mg / mL·min. In some embodiments, carboplatin is administered at a dose with a target AUC of about 1 mg / mL·min, about 2 mg / mL·min, about 3 mg / mL·min, about 4 mg / mL·min, about 5 mg / mL·min, about 6 mg / mL·min, about 7 mg / mL·min, about 8 mg / mL·min, about 9 mg / mL·min, or about 10 mg / mL·min. In some embodiments, carboplatin is administered at a dose for a target AUC of about 2 mg / mL·min. In some embodiments, carboplatin is administered at a dose for a target AUC of about 5 mg / mL·min or about 6 mg / mL·min. In some embodiments, carboplatin is administered at a dose for a target AUC of about 5 mg / mL·min. In some embodiments, carboplatin is administered at a dose for a target AUC of about 6 mg / mL min. In some embodiments, carboplatin is administered intravenously over about 30 minutes. In some embodiments, carboplatin is administered on day 1 of each of three 21-day cycles. In some embodiments, carboplatin is administered on day 1 of the first 21-day cycle and days 1, 8, and 15 of each of the second and third 21-day cycles.

[0233] The carboplatin dose can be calculated according to methods known in the art. In some embodiments, the carboplatin dose is calculated using the Calvert formula as follows: Carboplatin dose (mg) = target AUC × (CrCl [mL / min] + 25). Creatine clearance (CrCl) calculation in the Calvert formula can be determined using the Cockcroft-Gault formula: Cockcroft-Gault CrCl = [(140 - age) × (weight (kg)) × (0.85 for women)] / (72 × Cr). The Cockcroft-Gault formula includes the subject's most recent body weight (kg) and most recent serum creatinine (Cr) concentration (mg / dL). In some embodiments, if calculating CrCl using the Cockcroft-Gault formula results in a rate greater than 125 mL / min, CrCl is calculated using an alternative formula according to facility standards or capped at 125 mL / min.

[0234] In some embodiments, PDCT comprises cisplatin or carboplatin in combination with gemcitabine, paclitaxel, albumin-bound paclitaxel, docetaxel, pemetrexed, vinorelbine, vinblastine, etoposide, or irinotecan.

[0235] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine. In some embodiments, the gemcitabine is administered at a dose of about 1,000 mg / m 2 ~Approx. 1,250mg / m 2 In some embodiments, gemcitabine is administered at a dose of about 1,000 mg / m 2 , about 1,050mg / m 2 , about 1,100mg / m 2 , about 1,150mg / m 2 , about 1,200mg / m 2 or approximately 1,250 mg / m 2 In some embodiments, gemcitabine is administered intravenously over about 30 minutes. In some embodiments, gemcitabine is administered on days 1, 8, and 15 of a three-week cycle for up to about 3, about 4, about 5, or about 6 cycles. In some embodiments, gemcitabine is administered on days 1 and 8 of a three-week cycle for up to about 3, about 4, about 5, or about 6 cycles. In some embodiments, PDCT is administered at a dose of about 1,000 mg / m administered on days 1 and 8 of a three-week cycle for about three cycles. 2 ~Approx. 1,250mg / m 2 gemcitabine at a dose of approximately 75 mg / m administered on day 1 of each cycle 2 ~about 80mg / m 2and cisplatin at a dose of about 1,000 mg / m administered on days 1, 8, and 15 of a 3-week cycle for about three cycles. In some embodiments, gemcitabine is administered intravenously over about 30 minutes and cisplatin is administered intravenously over about 60 minutes. In some embodiments, PDCT is administered at a dose of about 1,000 mg / m administered on days 1, 8, and 15 of a 3-week cycle for about three cycles. 2 and carboplatin administered at a dose of about 5 mg / mL min target AUC on day 1 of each cycle. In some embodiments, the gemcitabine and carboplatin are each administered intravenously over about 30 minutes.

[0236] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

[0237] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel. In some embodiments, paclitaxel is administered at a dose of about 45 mg / m 2 ~about 200mg / m 2 In some embodiments, paclitaxel is administered at a dose of about 45 mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg / m 2 , about 65mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 85mg / m 2 , about 90mg / m 2 , about 95mg / m 2 , about 100mg / m 2 , about 105mg / m 2 , about 110mg / m 2 , about 115mg / m 2 , about 120mg / m 2 , about 125mg / m 2 , about 130mg / m 2 , about 135mg / m 2 , about 140mg / m 2 , about 145mg / m 2 , about 150mg / m2 , about 155mg / m 2 , about 160mg / m 2 , about 165mg / m 2 , about 170mg / m 2 , about 175mg / m 2 , about 180mg / m 2 , about 185mg / m 2 , about 190mg / m 2 , about 195mg / m 2 , or about 200 mg / m 2 In some embodiments, paclitaxel is administered intravenously over about 60 minutes to about 180 minutes. In some embodiments, PDCT is administered at a dose of about 175 mg / m administered on day 1 of a 3-week cycle for about 3 cycles. 2 or about 200 mg / m 2 of paclitaxel dose and approximately 75 mg / m administered on day 1 of each cycle. 2 ~about 80mg / m 2 In some embodiments, the PDCT comprises a dose of about 135 mg / m administered on day 1 of a 3-week cycle for about 3 cycles. 2 dose of paclitaxel and approximately 75 mg / m administered on day 1 of each cycle 2 and a dose of cisplatin of about 175 mg / m administered on day 1 of the first 3-week cycle. In some embodiments, paclitaxel is administered intravenously over about 180 minutes and cisplatin is administered intravenously over about 60 minutes. In some embodiments, PDCT is administered at a dose of about 175 mg / m administered on day 1 of the first 3-week cycle. 2 or about 200 mg / m 2 and carboplatin administered at a dose of about 5 mg / mL·min or about 6 mg / mL·min on day 1 of the cycle. In some embodiments, paclitaxel is administered intravenously over about 180 minutes and carboplatin is administered intravenously over about 30 minutes in the first cycle. In some embodiments, PDCT comprises about 45 mg / m administered on days 1, 8, and 15 of the second and third 3-week cycles. 2 or about 50 mg / m 2and carboplatin administered at a dose of about 2 mg / mL·min on days 1, 8, and 15 of cycles 2 and 3, respectively. In some embodiments, paclitaxel is administered intravenously over about 60 minutes and carboplatin is administered intravenously over about 30 minutes in cycles 2 and 3. In some embodiments, carboplatin is administered after paclitaxel in each cycle.

[0238] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with albumin-bound paclitaxel. In some embodiments, the albumin-bound paclitaxel is at about 100 mg / m 2 In some embodiments, the albumin-bound paclitaxel is administered intravenously over about 30 minutes. In some embodiments, the PDCT is administered at a dose of about 100 mg / m administered on days 1, 8, and 15 of about three 3-weekly cycles. 2 of albumin-bound paclitaxel and approximately 75 mg / m administered on day 1 of each cycle. 2 ~about 80mg / m 2 and a dose of cisplatin of about 100 mg / m administered on days 1, 8, and 15 of about three 3-weekly cycles. In some embodiments, the PDCT comprises a dose of albumin-bound paclitaxel of about 100 mg / m administered on days 1, 8, and 15 of about three cycles of 3-weekly cycles, and carboplatin administered at a dose with a target AUC of about 6 mg / mL·min on day 1 of each cycle. In some embodiments, the albumin-bound paclitaxel and carboplatin are each administered intravenously over about 30 minutes.

[0239] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with docetaxel. In some embodiments, docetaxel is at about 75 mg / m 2In some embodiments, docetaxel is administered intravenously over about 60 minutes. In some embodiments, PDCT is administered at a dose of about 75 mg / m administered on day 1 of a 3-week cycle for about 3 cycles. 2 dose of docetaxel and approximately 75 mg / m administered on day 1 of each cycle 2 and a dose of cisplatin of about 75 mg / m administered on day 1 of about three 3-week cycles. In some embodiments, docetaxel and cisplatin are each administered intravenously over about 60 minutes. In some embodiments, PDCT is administered at a dose of about 75 mg / m administered on day 1 of about three 3-week cycles. 2 and carboplatin administered at a dose with a target AUC of about 6 mg / mL min on day 1 of each cycle. In some embodiments, docetaxel is administered intravenously over about 60 minutes and carboplatin is administered intravenously over about 30 minutes.

[0240] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with pemetrexed. In some embodiments, pemetrexed is at a dose of about 500 mg / m 2 In some embodiments, pemetrexed is administered intravenously over about 10 minutes. In some embodiments, PDCT is administered at a dose of about 500 mg / m administered on day 1 of a 3-week cycle for about 3 cycles. 2 pemetrexed at a dose of approximately 75 mg / m administered on day 1 of each cycle 2 and cisplatin at a dose of about 500 mg / m administered on day 1 of a 3-week cycle for about three cycles. In some embodiments, pemetrexed is administered intravenously over about 10 minutes and cisplatin is administered intravenously over about 60 minutes. In some embodiments, cisplatin is administered after pemetrexed. In some embodiments, if cisplatin is not tolerated by the subject, cisplatin is replaced with carboplatin. In some embodiments, PDCT is administered at a dose of about 500 mg / m administered on day 1 of a 3-week cycle for about three cycles. 2and carboplatin administered at a target AUC of about 5 mg / mL·min on day 1 of each cycle. In some embodiments, pemetrexed is administered intravenously over about 10 minutes and carboplatin is administered intravenously over about 30 minutes. In some embodiments, carboplatin is administered after pemetrexed. In some embodiments, if pemetrexed is not tolerated by the subject, pemetrexed is replaced with etoposide.

[0241] In some embodiments, the PDCT comprises cisplatin or carboplatin in combination with etoposide. In some embodiments, the etoposide is administered at a dose of about 50 mg / m 2 ~about 100mg / m 2 In some embodiments, etoposide is administered intravenously over about 30 minutes to about 60 minutes. In some embodiments, PDCT is administered at a dose of about 100 mg / m administered on days 1, 2, and 3 of about three 3-weekly cycles. 2 etoposide at a dose of approximately 80 mg / m administered on day 1 of each cycle 2 and cisplatin at a dose of about 100 mg / m administered on days 1, 2, and 3 of about three three-week cycles. In some embodiments, etoposide and cisplatin are each administered intravenously over about 60 minutes. In some embodiments, cisplatin is administered after etoposide. In some embodiments, PDCT is administered at a dose of about 100 mg / m administered on days 1, 2, and 3 of about three three-week cycles. 2 and carboplatin administered at a dose of about 5 mg / mL·min on day 1 of each cycle. In some embodiments, the etoposide and carboplatin are each administered intravenously over about 30 minutes. In some embodiments, the carboplatin is administered after the etoposide.

[0242] In some embodiments, the PDCT comprises cisplatin and vinorelbine. In some embodiments, the vinorelbine is at a dose of about 25 mg / m 2 ~about 30mg / m 2In some embodiments, vinorelbine is administered intravenously over about 5 minutes to about 10 minutes. In some embodiments, PDCT is administered at a dose of about 25 mg / m administered on days 1 and 8 of about three, three-week cycles. 2 ~about 30mg / m 2 Vinorelbine at a dose of approximately 75 mg / m administered on day 1 of each cycle 2 ~about 80mg / m 2 In some embodiments, the vinorelbine is administered intravenously over about 5 to about 10 minutes, and the cisplatin is administered intravenously over about 60 minutes. In some embodiments, the PDCT is administered at a dose of about 25 mg / m administered on days 1, 8, 15, and 22 of about three, three-week cycles. 2 and vinorelbine at a dose of about 50 mg / m administered on days 1 and 8 of each cycle. 2 In some embodiments, the vinorelbine is administered intravenously over about 5 to about 10 minutes, and the cisplatin is administered intravenously over about 60 minutes. In some embodiments, the PDCT is administered at a dose of about 30 mg / m administered on days 1, 8, 15, and 22 of about three, three-week cycles. 2 vinorelbine at a dose of approximately 100 mg / m administered on day 1 of each cycle 2 In some embodiments, the vinorelbine is administered intravenously over about 5 to about 10 minutes, and the cisplatin is administered intravenously over about 60 minutes.

[0243] In some embodiments, CCRT includes thoracic radiation therapy and / or volumetric modulated arc therapy (VMAT), intensity modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT).

[0244] In some embodiments, radiation therapy comprises about 30 to about 33 daily doses of 2 Gy on an about 5 days on and 2 days off schedule over about 6 to about 7 weeks, starting on day 1 of the second and third cycles.

[0245] II.C LAG-3 antagonists LAG-3 antagonists for use in the methods of the present disclosure include, but are not limited to, LAG-3 binding agents and soluble LAG-3 polypeptides. LAG-3 binding agents include antibodies that specifically bind to LAG-3 (i.e., "anti-LAG-3 antibodies"). As used herein, the term "LAG-3 antagonist" is interchangeable with the term "LAG-3 inhibitor."

[0246] In some embodiments, the LAG-3 antagonist comprises an anti-LAG-3 antibody.

[0247] Antibodies that bind to LAG-3 are described, for example, in International Publication No. WO 2015 / 042246 and U.S. Patent Application Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated by reference herein in its entirety.

[0248] Exemplary LAG-3 antibodies useful in the present disclosure include 25F7 (described in U.S. Patent Application Publication No. 2011 / 0150892). Additional exemplary LAG-3 antibodies useful in the present disclosure include BMS-986016 (relatolimab). In some embodiments, anti-LAG-3 antibodies useful in the present disclosure cross-compete with 25F7 or BMS-986016. In some embodiments, anti-LAG-3 antibodies useful in the present disclosure bind to the same epitope as 25F7 or BMS-986016. In some embodiments, anti-LAG-3 antibodies comprise the six CDRs of 25F7 or BMS-986016.

[0249] Other art-recognized anti-LAG-3 antibodies that can be used in the methods of the present disclosure include IMP731 (H5L7BW), described in U.S. Patent Application Publication No. 2011 / 007023; MK-4280 (28G-10, favezelimab), described in WO 2016028672 and U.S. Patent Application Publication No. 2020 / 0055938; Burova E, et al. al., J. Immunother. Cancer (2016); 4 (Supp. 1): P195 and REGN3767 (fianlimab) described in U.S. Pat. No. 10,358,495, humanized BAP050 described in International Publication No. WO 2017 / 019894, GSK2831781, IMP-701 (LAG-525; ielamilimab) described in U.S. Pat. No. 10,711,060 and U.S. Patent Application Publication No. 2020 / 0172617, aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007 and ABL501.These and other anti-LAG-3 antibodies useful in the claimed invention are described in, e.g., U.S. Pat. No. 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO 2017 / 062888, WO 2009 / 044273, WO 2018 / 069500, WO 2016 / 126858, WO 2014 / 179664, and the like. FRET, International Publication No. 2016 / 200782, International Publication No. 2015 / 200119, International Publication No. 2017 / 019846, International Publication No. 2017 / 198741, International Publication No. 2017 / 220555, International Publication No. 2017 / 220569, International Publication No. 2018 / 071500, International Publication No. 2017 / 015560, International Publication No. 2017 / 025498, International Publication No. 2017 / 087589, International Publication No. 2017 / 087901, International Publication No. 2018 / 083087, International Publication No. 2017 / 149143, International Publication No. 2017 / 219995, U.S. Patent Application Publication No. 2017 / 0260271, International Publication No. 2017 / 086367, International Publication No. 2017 / 086419, International Publication No. 2018 / 034227, International Publication No. Reference can be made to WO 2018 / 185046, WO 2018 / 185043, WO 2018 / 217940, WO 19 / 011306, WO 2018 / 208868, WO 2014 / 140180, WO 2018 / 201096, WO 2018 / 204374, and WO 2019 / 018730, the contents of each of which are incorporated by reference in their entirety.

[0250] Anti-LAG-3 antibodies that can be used in the methods of the disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete with any of the anti-LAG-3 antibodies disclosed herein, e.g., leratolimab, for binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, e.g., leratolimab.

[0251] In some embodiments, any of the anti-LAG-3 antibodies disclosed herein, such as antibodies that cross-compete with leratolimab for binding to human LAG-3 or that bind to the same epitope region as leratolimab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0252] Anti-LAG-3 antibodies that can be used in the methods of the disclosure also include antigen-binding portions of any of the full-length antibodies described above.

[0253] In some embodiments, the anti-LAG-3 antibody comprises a full-length antibody.

[0254] In some embodiments, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0255] In some embodiments, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0256] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yeramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen-binding portion thereof.

[0257] In some embodiments, the anti-LAG-3 antibody is formulated for intravenous administration.

[0258] In some embodiments, the anti-LAG-3 antibody is administered intravenously over about 30 minutes.

[0259] In some embodiments, the anti-LAG-3 antibody comprises leratolimab.

[0260] In some aspects, the methods of the present disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4.

[0261] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 10.

[0262] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

[0263] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 1 and 2, respectively.

[0264] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively.

[0265] In some embodiments, the anti-LAG-3 antibody comprises MGD013 (tebotelimab), which is a bispecific PD-1 x LAG-3 DART. In some embodiments, teboterimab is administered intravenously at a dose of about 300 mg or about 600 mg about once every two or three weeks. In some embodiments, teboterimab is administered intravenously at a dose of about 300 mg about once every two weeks. In some embodiments, teboterimab is administered intravenously at a dose of about 600 mg about once every three weeks.

[0266] In some embodiments, the anti-LAG-3 antibody comprises REGN3767 (fianlimab). In some embodiments, fianlimab is administered intravenously at a dose of about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 20 mg / kg about once every three weeks. In some embodiments, fianlimab is administered intravenously at a dose of about 1600 mg about once every three weeks.

[0267] In some aspects, the methods of the present disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 25, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 26.

[0268] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 27; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 28; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 29; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 30; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 31; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 32.

[0269] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 25 and 26, respectively.

[0270] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 23 and 24, respectively.

[0271] In some embodiments, the anti-LAG-3 antibody comprises LAG525 (Ielamirimab). In some embodiments, Ielamirimab is administered intravenously at a dose of 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, or about 1300 mg once about every 2, 3, or 4 weeks.

[0272] In some aspects, the methods of the present disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 47, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 49.

[0273] In some aspects, the methods of the present disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 48 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 50.

[0274] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 51; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 52; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 53; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 54; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 55; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 56.

[0275] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 47 and 49, respectively.

[0276] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 48 and 50, respectively.

[0277] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 43 and 45, respectively.

[0278] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 44 and 46, respectively.

[0279] In some embodiments, the anti-LAG-3 antibody comprises MK4280 (fabezelimab). In some embodiments, favezelimab is administered intravenously at a dose of about 7 mg, about 21 mg, about 70 mg, about 210 mg, about 700 mg, or about 800 mg about once every three weeks or about once every six weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 200 mg about once every three weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg about once every six weeks. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg on day 1, then about once every three weeks. In some embodiments, favezelimab is administered for up to 35 cycles. In some embodiments, favezelimab is administered intravenously at a dose of about 800 mg over about 30 minutes on day 1 of a 3-week cycle for up to 35 cycles.

[0280] In some aspects, the methods of the present disclosure include an anti-LAG-3 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 69 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 70.

[0281] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 71; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 72; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 73; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 74; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 75; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 76.

[0282] In some aspects, the methods of the disclosure include an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 69 and 70, respectively.

[0283] In some embodiments, the methods of the disclosure include an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 67 and 68, respectively.

[0284] In some embodiments, LAG-3 expression is determined using an anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody is selected for its ability to bind to LAG-3 in formalin-fixed, paraffin-embedded (FFPE) tissue specimens. In some embodiments, the anti-LAG-3 antibody is capable of binding to LAG-3 in frozen tissue. In some embodiments, the anti-LAG-3 antibody has the ability to distinguish between membrane-bound, cytoplasmic, and / or soluble forms of LAG-3.

[0285] In some embodiments, an anti-LAG-3 antibody useful for assaying, detecting, and / or quantifying LAG-3 expression according to the methods disclosed herein is the 17B4 mouse IgG1 anti-human LAG-3 monoclonal antibody. See, e.g., Matsuzaki, J et al., PNAS (2010); 107:7875.

[0286] In some embodiments, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some embodiments, the soluble LAG-3 polypeptide is a fusion polypeptide, e.g., a fusion protein comprising the extracellular portion of LAG-3. In some embodiments, the soluble LAG-3 polypeptide is a LAG-3-Fc fusion polypeptide capable of binding to MHC class II. In some embodiments, the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. In some embodiments, the ligand-binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO: 22. In some embodiments, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some embodiments, the half-life extending moiety comprises an immunoglobulin constant region or portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PAS moiety, a HES moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some embodiments, the soluble LAG-3 polypeptide is IMP321 (efthirazimod alfa). See, e.g., Brignone C, et al., J. Immunol. (2007); 179:4202-4211 and WO 2009 / 044273. In some embodiments, efthirazimod alfa is administered at a dose of about 30 mg. In some embodiments, eftirazimod alpha is administered subcutaneously at a dose of about 30 mg about once every two weeks.

[0287] In some embodiments, the LAG-3 antagonist is administered in a fixed dose.

[0288] In some embodiments, the LAG-3 antagonist is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, It is administered at a dose of about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0289] In some embodiments, the LAG-3 antagonist is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, or about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m g, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0290] In some embodiments, the LAG-3 antagonist is administered in a body weight-based dose.

[0291] In some embodiments, the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, or about 0.003 mg / kg. g~about 0.8mg / kg, about 0.003mg / kg~about 0.7mg / kg, about 0.003mg / kg~about 0.6mg / kg, about 0.003mg / kg~about 0.5mg / kg, about 0.003mg / kg~about 0.4mg / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 25mg / k g, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1mg / kg to about 25mg / kg, about 1mg / kg to about 20mg / kg, about 1mg / kg to about 15mg / kg, about 1mg / kg to about 10mg / kg, about 1mg / kg to about 5mg / kg, about 5mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0292] In some embodiments, the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg g, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0293] In some embodiments, the dose is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

[0294] In some embodiments, the PD-1 pathway inhibitor administered with CCRT, the PD-1 pathway inhibitor administered with CCRT, the LAG-3 antagonist, and / or the LAG-3 antagonist are formulated for intravenous administration.

[0295] In some embodiments, a PD-1 pathway inhibitor administered with a LAG-3 antagonist is formulated separately from the LAG-3 antagonist. In some embodiments, the PD-1 pathway inhibitor is administered before the LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor. In some embodiments, the PD-1 pathway inhibitor and the LAG-3 antagonist are administered simultaneously.

[0296] In some embodiments, the PD-1 pathway inhibitor administered with a LAG-3 antagonist is formulated with the LAG-3 antagonist (e.g., a fixed-dose combination comprising a PD-1 pathway inhibitor and a LAG-3 antagonist).

[0297] In some embodiments, the PD-1 pathway inhibitor is administered with the LAG-3 antagonist about once every four weeks. In some embodiments, the PD-1 pathway inhibitor is administered with the LAG-3 antagonist as maintenance therapy. In some embodiments, the maintenance therapy is administered for up to about one year.

[0298] In some embodiments, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the disclosure includes nivolumab and leratolimab.

[0299] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14; and (b) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4.

[0300] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20, respectively; and (b) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively.

[0301] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

[0302] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 1 and 2, respectively.

[0303] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 21 and 2, respectively.

[0304] In some embodiments, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the disclosure includes pembrolizumab and favezelimab.

[0305] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 79 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 80; and (b) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 69 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 70.

[0306] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; and (b) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively.

[0307] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 79 and 80, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 69 and 70, respectively.

[0308] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 77 and 78, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 67 and 68, respectively.

[0309] In some embodiments, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the disclosure includes cemiplimab and fianlimab.

[0310] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 35, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 36; and (b) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 25, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 26.

[0311] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:37, SEQ ID NO:38, and SEQ ID NO:39, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:40, SEQ ID NO:41, and SEQ ID NO:42, respectively; and (b) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:27, SEQ ID NO:28, and SEQ ID NO:29, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:30, SEQ ID NO:31, and SEQ ID NO:32, respectively.

[0312] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 35 and 36, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 25 and 26, respectively.

[0313] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 33 and 34, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 23 and 24, respectively.

[0314] In some embodiments, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the disclosure includes spartalizumab and yelamirimab.

[0315] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:59 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:60; and (b) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:47 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:49.

[0316] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:59 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:60; and (b) an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:48 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:50.

[0317] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:64, SEQ ID NO:65, and SEQ ID NO:66, respectively; and (b) an anti-LAG-3 antibody comprising heavy chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively, and light chain variable regions CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively.

[0318] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 59 and 60, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 47 and 49, respectively.

[0319] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 59 and 60, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 48 and 50, respectively.

[0320] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 57 and 58, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 43 and 45, respectively.

[0321] In some embodiments, the PD-1 antagonist administered in conjunction with the LAG-3 antagonist in the methods of the disclosure comprises: (a) an anti-PD-1 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs: 57 and 58, respectively, and (b) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs: 44 and 46, respectively.

[0322] Provided herein is a method for treating a human subject suffering from NSCLC having squamous or non-squamous histology, comprising: (a) administering to the subject about 360 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and CCRT, including PDCT and radiation therapy; (b) providing the subject with a recovery period beginning upon completion of the administration of (a); and (c) administering to the subject an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 14, and CCRT, including PDCT and radiation therapy. and about 480 mg of an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 4.

[0323] In some embodiments, the PDCT comprises cisplatin and etoposide. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is administered at about 100 mg / m 2 etoposide was administered on days 1, 2, and 3 of each cycle, followed by anti-PD-1 antibody on day 1 of each cycle, at a dose of approximately 80 mg / m 2 The cisplatin is administered after the etoposide on day 1 of each cycle. In some embodiments, the cisplatin and etoposide are each administered intravenously over about 60 minutes.

[0324] In some embodiments, the PDCT comprises carboplatin and paclitaxel. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is about 175 mg / m 2 or about 200 mg / m 2 of paclitaxel was administered on day 1 of the first cycle at approximately 45 mg / m 2or about 50 mg / m 2 paclitaxel is administered on days 1, 8, and 15 of the second and third cycles, with paclitaxel administered after the anti-PD-1 antibody on day 1 of each cycle, carboplatin at a target AUC of about 5 mg / mL·min or about 6 mg / mL·min is administered on day 1 of the first cycle, and carboplatin at a target AUC of about 2 mg / mL·min is administered on days 1, 8, and 15 of the second and third cycles, with carboplatin administered after paclitaxel in each cycle. In some embodiments, carboplatin is administered intravenously over about 30 minutes, and paclitaxel is administered intravenously over about 180 minutes in the first cycle and about 60 minutes in the second and third cycles.

[0325] In some embodiments, the PDCT comprises cisplatin and pemetrexed. In some embodiments, (a) comprises three 21-day cycles, and the anti-PD-1 antibody is administered on day 1 of each cycle and is at about 500 mg / m 2 Pemetrexed is administered on day 1 of each cycle after the anti-PD-1 antibody at approximately 75 mg / m 2 Cisplatin is administered after pemetrexed on day 1 of each cycle. In some embodiments, cisplatin is administered intravenously over about 60 minutes, and pemetrexed is administered intravenously over about 10 minutes. In some embodiments, if cisplatin is not tolerated by the subject, cisplatin is replaced with carboplatin at a target area under the concentration-time curve (AUC) of about 5 mg / mL·min. In some embodiments, carboplatin is administered intravenously over about 30 minutes. In some embodiments, if pemetrexed is not tolerated by the subject, pemetrexed is replaced with etoposide.

[0326] In some embodiments, the anti-PD-1 antibody in (a) is administered intravenously over about 30 minutes.

[0327] In some embodiments, radiation therapy is administered after PDCT and comprises a dose of about 60 Gy to about 66 Gy.

[0328] In some embodiments, the radiation therapy comprises chest radiation therapy and / or volumetric modulated arc therapy (VMAT), intensity-modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT). In some embodiments, the radiation therapy comprises about 30 to about 33 daily doses of 2 Gy on an about 5-day on, 2-day off schedule over about 6 to about 7 weeks, starting on day 1 of the second and third cycles.

[0329] In some embodiments, the recovery period is sufficient for the subject to recover from CCRT-related toxicities other than fatigue, esophagitis, or alopecia. In some embodiments, the recovery period is about 1 week to about 12 weeks, about 1 week to about 9 weeks, about 1 week to about 6 weeks, about 2 weeks to about 12 weeks, about 2 weeks to about 9 weeks, about 2 weeks to about 6 weeks, about 3 weeks to about 12 weeks, about 3 weeks to about 9 weeks, about 3 weeks to about 6 weeks, about 18 days to about 12 weeks from the final administration of the anti-PD-1 antibody in (a), about 18 days to about 9 weeks from the final administration of the anti-PD-1 antibody in (a), or about 18 days to about 6 weeks from the final administration of the anti-PD-1 antibody in (a).

[0330] In some embodiments, the method is a first line therapy.

[0331] In some embodiments, the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

[0332] In some embodiments, the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

[0333] In some aspects, the subject is naive to a previous immuno-oncology therapy, the subject is naive to a previous immuno-oncology therapy for the lung cancer, or the lung cancer is naive to a previous immuno-oncology therapy.

[0334] In some embodiments, the method is a second line therapy.

[0335] In some embodiments, the method is a third line therapy.

[0336] In some embodiments, the subject has progressed on a previous treatment.

[0337] In some embodiments, the NSCLC recurs after multimodal therapy for locally advanced NSCLC.

[0338] In some embodiments, the NSCLC is unresectable, advanced, recurrent and / or metastatic.

[0339] In some embodiments, the NSCLC has squamous or non-squamous histology.

[0340] In some embodiments, the NSCLC comprises locally advanced stage IIIA, IIIB, or IIIC NSCLC.

[0341] In some embodiments, the subject does not have progressive NSCLC during CCRT or in recovery.

[0342] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered about once every four weeks.

[0343] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated separately. In some embodiments, the anti-PD-1 antibody of (b) is administered before the anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody is administered before the anti-PD-1 antibody of (b). In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered simultaneously.

[0344] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated together.

[0345] In some embodiments, the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered intravenously over about 30 minutes.

[0346] In some embodiments, the anti-PD-1 antibody of (a) and / or (b) comprises a full-length antibody.

[0347] In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0348] In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0349] In some embodiments, the anti-PD-1 antibody of (a) and / or (b) comprises an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody in (a) and / or (b) comprises a heavy chain variable region and a light chain variable region comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively. In some embodiments, the anti-PD-1 antibody of (a) and / or (b) comprises a heavy chain and a light chain comprising the sequences as set forth in SEQ ID NOs: 11 and 12, respectively.

[0350] In some embodiments, the anti-LAG-3 antibody comprises a full-length antibody.

[0351] In some embodiments, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0352] In some embodiments, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0353] In some embodiments, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively. In some embodiments, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0354] II.D LAG-3 and / or PD-L1 Expression In some aspects, one or more immune cells in the tumor tissue from the subject in the methods disclosed herein express LAG-3 (i.e., the tumor tissue from the patient is LAG-3 positive), and / or one or more nucleated cells in the tumor tissue from the subject express LAG-3 (i.e., the tumor tissue from the patient is LAG-3 positive), and / or one or more tumor cells in the tumor tissue from the subject express PD-L1 (i.e., the tumor tissue from the patient is PD-L1 positive).

[0355] In some embodiments, one or more immune cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some embodiments, at least about 1% of the immune cells express LAG-3. In some embodiments, more than about 1% of the immune cells express LAG-3. In some embodiments, at least about 5% of the immune cells express LAG-3. In some embodiments, the immune cells comprise tumor-infiltrating lymphocytes. In some embodiments, the tumor-infiltrating lymphocytes are CD8 + Contains cells.

[0356] In some embodiments, one or more nucleated cells in tumor tissue from a subject express LAG-3. In some embodiments, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express LAG-3. In some embodiments, at least about 1% of the nucleated cells express LAG-3. In some embodiments, more than about 1% of the nucleated cells express LAG-3. In some embodiments, at least about 5% of the nucleated cells express LAG-3.

[0357] In some embodiments, one or more tumor cells in tumor tissue from a subject express PD-L1. In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. In some embodiments, at least about 1% of the tumor cells express PD-L1. In some embodiments, more than about 1% of the tumor cells express PD-L1. In some embodiments, at least about 5% of the tumor cells express PD-L1.

[0358] In some embodiments, one or more nucleated cells in tumor tissue from a subject express PD-L1. In some embodiments, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express PD-L1. In some embodiments, at least about 1% of the nucleated cells express PD-L1. In some embodiments, more than about 1% of the nucleated cells express PD-L1. In some embodiments, at least about 5% of the nucleated cells express PD-L1.

[0359] In some embodiments, any value of "at least about X%" is "≧X%."

[0360] In some embodiments, tumor tissue from a patient is LAG-3 negative. In some embodiments, tumor tissue is LAG-3 negative when less than about 1% of immune cells express LAG-3. In some embodiments, tumor tissue is LAG-3 negative when less than about 1% of nucleated cells express LAG-3.

[0361] In some embodiments, the tumor tissue from the patient is PD-1 negative. In some embodiments, the tumor tissue is PD-1 negative when less than about 1% of immune cells express PD-1. In some embodiments, the tumor tissue is PD-1 negative when less than about 1% of nucleated cells express PD-1.

[0362] In some embodiments, tumor tissue from a patient is PD-L1 negative. In some embodiments, tumor tissue is PD-L1 negative if less than about 1% of tumor cells express PD-L1. In some embodiments, tumor tissue is PD-L1 negative if less than about 1% of nucleated cells express PD-L1.

[0363] In some embodiments, the expression of LAG-3, PD-1, and / or PD-L1 in a subject's tumor tissue is determined from a test tissue sample. In some embodiments, the test tissue sample includes any clinically relevant tissue sample, such as, but not limited to, a tumor biopsy, core biopsy, incisional biopsy, excision biopsy, surgical specimen, fine needle aspirate, or a sample of bodily fluid, e.g., blood, plasma, serum, lymph, ascites, cyst fluid, or urine. In some embodiments, the test tissue sample is from a primary tumor. In some embodiments, the test tissue sample is from a metastasis. In some embodiments, the test tissue sample is from multiple time points, e.g., before, during, and / or after treatment. In some embodiments, the test tissue samples are from different locations in the subject, e.g., from a primary tumor and from a metastasis.

[0364] In some embodiments, the test tissue sample is a paraffin-embedded, fixed tissue sample. In some embodiments, the test tissue sample is a formalin-fixed, paraffin-embedded (FFPE) tissue sample. In some embodiments, the test tissue sample is a fresh tissue (e.g., tumor) sample. In some embodiments, the test tissue sample is a frozen tissue sample. In some embodiments, the test tissue sample is a fresh-frozen (FF) tissue (e.g., tumor) sample. In some embodiments, the test tissue sample is cells isolated from a fluid. In some embodiments, the test tissue sample comprises circulating tumor cells (CTCs). In some embodiments, the test tissue sample comprises tumor-infiltrating lymphocytes (TILs). In some embodiments, the test tissue sample comprises tumor cells and tumor-infiltrating lymphocytes (TILs). In some embodiments, the test tissue sample comprises circulating lymphocytes. In some embodiments, the test tissue sample is an archived tissue sample. In some embodiments, the test tissue sample is an archived tissue sample with a known diagnostic, treatment, and / or outcome history. In some embodiments, the sample is a block of tissue. In some embodiments, the test tissue sample is dispersed cells. In some embodiments, the sample size is from about 1 cell to about 1 x 10 6 In some embodiments, the sample size is from about 1 cell to about 1 x 10 5 In some embodiments, the sample size is from about 1 cell to about 10,000 cells. In some embodiments, the sample size is from about 1 cell to about 1,000 cells. In some embodiments, the sample size is from about 1 cell to about 100 cells. In some embodiments, the sample size is from about 1 cell to about 10 cells. In some embodiments, the sample size is a single cell.

[0365] In some embodiments, the expression of LAG-3, PD-1, and / or PD-L1 is assessed by performing an assay to detect the presence of LAG-3, PD-1, and / or PD-L1 RNA, respectively. In some embodiments, the presence of LAG-3, PD-1, and / or PD-L1 RNA is detected by RT-PCR, in situ hybridization, or RNase protection.

[0366] In some embodiments, LAG-3, PD-1, and / or PD-L1 expression is assessed by performing an assay to detect the presence of LAG-3, PD-1, and / or PD-L1 polypeptides, respectively. In some embodiments, the presence of LAG-3, PD-1, and / or PD-L1 polypeptides is detected by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.

[0367] II.E. Additional Therapeutic Agents The methods disclosed herein can include additional therapeutic agents and / or anti-cancer therapies, which can include any known therapeutic agents or anti-cancer therapies, including standard care in the art for treating subjects with lung cancer.In some embodiments, the therapeutic agents and / or therapies are described by the NCCN Guidelines for the Treatment of NSCLC.For example, see the therapeutic agents and therapies listed below: https: / / www.cancertherapyadvisor.com / home / cancer-topics / lung-cancer / lung-cancer-treatment-regimens-landing-page / non-small-cell-lung-cancer-treatment-regimens / , Last accessed December 20, 2022.

[0368] II.E.1. Therapeutic Agents In some embodiments, the additional therapeutic agent comprises an anti-cancer agent, hi some embodiments, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

[0369] In some embodiments, the tyrosine kinase inhibitor is sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®), lenvatinib (e.g., lenvatinium mesylate, also known as LENVIMA®), regorafenib (e.g., STIVARGA®), carbozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX®), sunitinib (e.g., sunitinib malate, also known as SUTENT®), brivanib, linifex, nibs, pemigatinib (also known as PEMAZYRE™), everolimus (also known as AFINITOR® or ZORTRESS®), gefitinib (IRESSA®, a small molecule TKI for EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinium ditosylate, also known as TYKERB®), nilotinib (e.g., nilotinib hydrochloride, also known as TASIGNA®), pazopanib (e.g., VOTRIENT®), and pazopanib hydrochloride, also known as TEVA®), temsirolimus (also known as TORISEL®), erlotinib (e.g., erlotinib hydrochloride, also known as TARCEVA®, an EGFR small molecule TKI), afatinib (GILOTRIF®, an EGFR small molecule TKI), dacomitinib (VIZIMPRO®, an EGFR small molecule TKI), osimeritinib (TAGRISSO®, an EGFR small molecule TKI), alectinib (ALECENSA®, ALK small molecule TKI), ceritinib (ZYKADIA (registered trademark), ALK and ROS-1 small molecule TKI), brigatinib (ALUNBRIG (registered trademark), ALK small molecule TKI), crizotinib (XALKORI (registered trademark), ALK and ROS-1 small molecule TKI), lorlatinib (LORBRENA (registered trademark), ALK and ROS-1 small molecule TKI), entrectinib (ROZLYTREK (registered trademark), ROS-1 and NTRK small molecule TKI), dabrafenib (TAFINLAR (registered trademark), BRAF small molecule TKI),Trametinib (MEKINIST®, a BRAF-directed small molecule TKI), vemurafenib (ZELBORAF®, a BRAF-directed small molecule TKI), larotrectinib (ROZLYTREK®, an NTRK-directed small molecule TKI), or any combination thereof.

[0370] In some embodiments, the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase containing Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGFR, or any combination thereof. In some embodiments, the antiangiogenic agent comprises bevacizumab (also known as AVASTIN®), ramucirumab (also known as CYRAMZA®), aflibercept (also known as EYLEA® or ZALTRAP®), tanibirumab, olaratumab (also known as LARTRUVO™), nesbacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0371] In some embodiments, the antiangiogenic agent is bevacizumab. In some embodiments, the bevacizumab is administered at a dose of about 15 mg / kg. In some embodiments, the bevacizumab is administered at a dose of about 15 mg / kg on day 1 of a 3-week cycle.

[0372] In some aspects, checkpoint stimulators include agonists of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell costimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), CD28H, or any combination thereof.

[0373] In some embodiments, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an anti-neoplastic antibiotic, an antimitotic, a hormone or hormone-modulating agent, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, another neoplastic agent, or any combination thereof.

[0374] In some aspects, the immunotherapeutic agent comprises an antibody that specifically binds to EGFR (e.g., cetuximab (ERBITUX®)), ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, GITR, herpes virus entry mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, killer cell lectin-like receptor G1 (KLRG-1), natural killer cell receptor 2B4 (CD244), CD160, TIGIT, VISTA, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

[0375] In some embodiments, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (eg, triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.

[0376] In some embodiments, the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.

[0377] In some embodiments, the taxane comprises paclitaxel (ie, nab-paclitaxel), albumin-bound paclitaxel, docetaxel, cabazitaxel, or any combination thereof.

[0378] In some embodiments, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0379] In some embodiments, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0380] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0381] In some aspects, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0382] In some embodiments, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, vinbrunin, or any combination thereof.

[0383] II.E.2. Checkpoint Inhibitors In some aspects, the anti-cancer agent administered as an additional therapeutic agent in the methods of the present disclosure is a checkpoint inhibitor.

[0384] In some embodiments, the checkpoint inhibitor is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T-cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B-cell and T-cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T-cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor (e.g., an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, epacadostat (INCB24360), navoximod (GDC-0919), or linrodostat (BMS-986205), including a linrodostat salt, e.g., linrodostat mesylate), a nicotinamide adenine dinucleotide phosphate oxidase isoform inhibitor, ... form 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta (TGF-β) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-inducible TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat dominant (GARP) inhibitors, 2B4 inhibitors, programmed death 1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0385] In some embodiments, the checkpoint inhibitor is formulated for intravenous administration.

[0386] In some embodiments, the checkpoint inhibitor is administered in a fixed dose.

[0387] In some embodiments, the checkpoint inhibitor is administered in an amount of at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, It is administered at a dose of about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0388] In some embodiments, the checkpoint inhibitor is administered at a concentration of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, or about 9.75mg, about 10mg, about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 18 0mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 35 0mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg, approx. 420mg, approx. 430mg, approx. 440mg, approx. 450mg, approx. 20mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 6 90mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080m g, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0389] In some embodiments, the checkpoint inhibitor is administered as a weight-based dose.

[0390] In some embodiments, the checkpoint inhibitor is administered at a dose of about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, or about 0.003 mg / kg ~0.8mg / kg, 0.003mg / kg~0.7mg / kg, 0.003mg / kg~0.6mg / kg, 0.003mg / kg~0.5mg / kg, 0.003mg / kg~0 .4mg / kg, about 0.003mg / kg to about 0.3mg / kg, about 0.003mg / kg to about 0.2mg / kg, about 0.003mg / kg to about 0.1mg / kg, about 0.1mg / kg to about 25mg / kg , about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0391] In some embodiments, the checkpoint inhibitor is administered at a concentration of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, The compound is administered at a dose of about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0392] In some embodiments, the dose of checkpoint inhibitor is administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, every 10 weeks, every 11 weeks, or every 12 weeks.

[0393] II.E.3 CTLA-4 inhibitors In some embodiments, a checkpoint inhibitor as disclosed herein comprises a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody.

[0394] Anti-CTLA-4 antibodies that can be used in the methods of the present disclosure bind to human CTLA-4 and disrupt the interaction between CTLA-4 and human B7 receptors. When CTLA-4 interacts with B7, a signal is transmitted that leads to the inactivation of T cells that bear the CTLA-4 receptor, and disruption of this interaction effectively induces, enhances, or prolongs the activation of such T cells, and thus effectively induces, enhances, or prolongs the immune response.

[0395] Human monoclonal antibodies that specifically bind to CTLA-4 with high affinity are disclosed in U.S. Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies are described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121 and WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504 (each of which is incorporated by reference in its entirety). The anti-CTLA-4 human monoclonal antibodies disclosed in U.S. Pat. No. 6,984,720 have been demonstrated to exhibit one or more of the following characteristics: (a) a specific binding affinity of at least about 10 to human CTLA-4 as determined by Biacore analysis; 7 M -1 , or about 10 9 M -1 , or about 10 10 M -1 ~10 11 M -1 or higher equilibrium binding constant (K a (b) specifically binds with a binding affinity reflected by at least about 10 3 , about 10 4 , or about 10 5 m -1 s -1 The kinetic binding constant (k a );(c) at least about 10 3 , about 10 4 , or about 10 5 m-1 s -1 The kinetic dissociation constant (k d and (d) inhibit the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the aforementioned characteristics.

[0396] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure include ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO 2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3):133-39 (2007)).

[0397] In some embodiments, the anti-CTLA-4 antibody specifically binds to human CTLA-4 and cross-competes with any of the anti-CTLA-4 antibodies disclosed herein, e.g., ipilimumab and / or tremelimumab, for binding to human CTLA-4. In some embodiments, the anti-CTLA-4 antibody binds to the same epitope as any of the anti-CTLA-4 antibodies described herein, e.g., ipilimumab and / or tremelimumab.

[0398] In some embodiments, any of the anti-CTLA-4 antibodies disclosed herein, such as antibodies that cross-compete with ipilimumab and / or tremelimumab for binding to human CTLA-4 or that bind to the same epitope region as ipilimumab and / or tremelimumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies.

[0399] Anti-CTLA-4 antibodies that can be used in the methods of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above.

[0400] In some embodiments, the anti-CTLA-4 antibody comprises a full-length antibody. In some embodiments, the anti-CTLA-4 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0401] In some embodiments, the anti-CTLA-4 antibody comprises an F(ab')2 fragment, an Fab' fragment, an Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0402] In some embodiments, the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen-binding portion thereof.

[0403] In some embodiments, the anti-CTLA-4 antibody comprises ipilimumab. Ipilimumab is a fully human IgG1 monoclonal antibody that stimulates T cell activation by blocking the binding of CTLA-4 to its B7 ligand. In some embodiments, ipilimumab is administered at a dose of about 3 mg / kg about once every three weeks. In some embodiments, ipilimumab is administered at a dose of about 10 mg / kg about once every three weeks. In some embodiments, ipilimumab is administered at a dose of about 10 mg / kg about once every 12 weeks. In some embodiments, ipilimumab is administered over four doses. In some embodiments, ipilimumab is administered on day 1 of each cycle.

[0404] II.E.4. Treatments for Sensitizing Mutations In some aspects, the methods of the disclosure include treating a subject with a mutation that is susceptible to targeted inhibitor therapy, such as a sensitizing mutation in a gene such as EGFR, ALK, ROS-1, NTRK, or BRAF. Such methods can further include administering a targeted inhibitor of the mutant gene, including standard of care therapy for subjects with such mutations who are afflicted with NSCLC.

[0405] In some embodiments, the methods of the disclosure comprise administering afatinib (e.g., 40 mg orally once daily), erlotinib (e.g., 150 mg orally once daily), dacomitinib (e.g., 45 mg orally once daily), gefitinib (e.g., 250 mg orally once daily), or osimertinib (e.g., 80 mg orally once daily) to a subject suffering from advanced or metastatic NSCLC with a sensitizing EGFR mutation.

[0406] In some embodiments, the methods of the disclosure involve administering afatinib and cetuximab (e.g., 40 mg afatinib orally once daily on days 1-14 and 500 mg / m 2 cetuximab on day 1 of a 2-week cycle) or osimertinib (e.g., 80 mg orally once daily).

[0407] In some embodiments, the methods of the disclosure comprise administering alectinib (e.g., 600 mg orally twice daily), brigatinib (e.g., 90 mg orally once daily on days 1-7, 180 mg orally once daily on days 8-28, followed by a 4-week cycle of 180 mg orally once daily on days 29-56), ceritinib (e.g., 450 mg orally once daily), or crizotinib (e.g., 250 mg orally twice daily) to a subject afflicted with advanced or metastatic NSCLC harboring a sensitizing ALK mutation (e.g., an ALK rearrangement).

[0408] In some embodiments, the methods of the disclosure include administering lorlatinib (e.g., 100 mg orally once daily) to a subject suffering from advanced or metastatic NSCLC with a sensitizing ALK mutation (e.g., an ALK rearrangement).

[0409] In some embodiments, the methods of the disclosure comprise administering ceritinib (e.g., 450 mg orally once daily), crizotinib (e.g., 250 mg orally twice daily), or entrectinib (e.g., 600 mg orally once daily) to a subject with advanced or metastatic NSCLC harboring a sensitizing ROS-1 mutation (e.g., ROS-1 rearrangement). In some embodiments, the methods of the disclosure comprise administering lorlatinib (e.g., 100 mg orally once daily) to a subject with advanced or metastatic NSCLC harboring a sensitizing ROS-1 mutation (e.g., ROS-1 rearrangement).

[0410] In some embodiments, the methods of the disclosure comprise administering dabrafenib (e.g., 150 mg orally twice daily), dabrafenib and trametinib (e.g., trametinib 150 mg orally twice daily and 2 mg orally once daily), or vemurafenib (e.g., 960 mg orally once daily) to a subject with advanced or metastatic NSCLC harboring a sensitizing BRAF mutation (e.g., BRAF V600E).

[0411] In some embodiments, the methods of the disclosure include administering entrectinib (e.g., 600 mg orally once daily) or larotrectinib (e.g., 100 mg orally twice daily) to a subject suffering from advanced or metastatic NSCLC harboring a sensitizing NTRK mutation (e.g., an NTRK gene fusion).

[0412] III. Pharmaceutical Compositions Therapeutic agents of the present disclosure can be components of compositions, e.g., pharmaceutical compositions, containing inhibitors, antibodies, and / or drugs as disclosed herein and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0413] In some embodiments, the carrier for a composition containing an inhibitor, antibody, and / or agent as disclosed herein is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). In some embodiments, the carrier is suitable for non-parenteral administration, e.g., oral administration. In some embodiments, subcutaneous injection is based on Halozyme Therapeutics' ENHANZE® drug delivery technology (see U.S. Pat. No. 7,767,429, which is incorporated herein by reference in its entirety). ENHANZE® uses a co-formulation of an antibody with a recombinant human hyaluronidase enzyme (rHuPH20), which eliminates the previous limitations imposed by the extracellular matrix on the volume of biologics and drugs that can be delivered subcutaneously (see U.S. Pat. No. 7,767,429). Pharmaceutical compositions of the disclosure may include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers, and / or adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents, etc. In some aspects, pharmaceutical compositions of the disclosure may further include a recombinant human hyaluronidase enzyme, e.g., rHuPH20.

[0414] Treatment is continued as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs. The dosage and frequency vary depending on the half-life of the inhibitor, antibody, and / or drug in the subject. Generally, human antibodies exhibit the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The dosage and frequency of administration can vary depending on whether the treatment is preventive or therapeutic. In preventive applications, relatively low dosages are typically administered relatively infrequently over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, relatively high dosages at relatively short intervals may sometimes be required until disease progression is reduced or halted, preferably until the patient shows partial or complete improvement in disease symptoms. The patient can then be administered a preventive regime.

[0415] The actual dosage level of the active ingredient (i.e., inhibitor, antibody, and / or drug) in the pharmaceutical compositions of the present disclosure can be varied to achieve an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without undue toxicity to the patient. The selected dosage level will depend on various pharmacokinetic factors, including the activity of the particular composition of the present disclosure used, the route of administration, the timing of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular composition used, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts. The compositions of the present disclosure can be administered by one or more routes of administration using one or more of a variety of methods well known in the art. As will be appreciated by those of skill in the art, the route and / or mode of administration will vary depending on the desired results.

[0416] Provided herein are pharmaceutical compositions comprising an anti-LAG-3 antibody and an anti-PD-1 antibody described herein, in any dose or dose combination described herein.

[0417] In some embodiments, the pharmaceutical composition is for treating (eg, as maintenance therapy) a human subject with a lung cancer described herein.

[0418] In some aspects, the methods of treating a human subject with lung cancer described herein comprise administering a pharmaceutical composition described herein.

[0419] In some embodiments, the pharmaceutical composition comprises a dose of leratolimab and a dose of an anti-PD-1 antibody as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.

[0420] In some embodiments, the pharmaceutical composition comprises favezelimab in a dose described herein and an anti-PD-1 antibody in a dose described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0421] In some embodiments, the pharmaceutical composition comprises a dose of fianlimab and a dose of an anti-PD-1 antibody described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is cemiplimab.

[0422] In some embodiments, the pharmaceutical composition comprises yeramirimab in a dose and an anti-PD-1 antibody in a dose as described herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, or spartalizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab.

[0423] In some embodiments, the pharmaceutical composition comprises about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about The anti-LAG-3 antibody and the anti-PD-1 antibody are present in a ratio of about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1.

[0424] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody in a ratio of about 1:3.

[0425] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody in a ratio of about 1:1.

[0426] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody in a ratio of about 2:1.

[0427] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody and an anti-PD-1 antibody in a ratio of about 4:1.

[0428] In some embodiments, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 50 mg / mL, approx. 135 mg / mL, approx. 140 mg / mL, approx. 145 mg / mL, approx. 150 mg / mL, approx. 155 mg / mL, approx. 160 mg / mL, approx. 165 mg / mL, approx. 195mg / mL, about 200mg / mL, about 205mg / mL, about 210mg / mL, about 215mg / mL, about 220mg / mL, about 225mg / mL, about 230mg / mL, about 235mg / mL, about 240mg / mL, about 245mg / mL, about 250mg / mL, about 255mg / mL, approximately 260mg / mL, approximately 265mg / mL, approximately 270mg / mL, approximately 275mg / mL, approximately 280mg / mL, approximately 285mg / mL, approximately 290mg / mL, approximately 295mg / mL, approximately 300mg / mL, approximately 305mg / mL, approximately 310mg / mL, approximately 315mg / mL, Approx. 320 mg / mL, approx. 325 mg / mL, approx. 330 mg / mL, approx. 335 mg / mL, approx. 340 mg / mL, approx. 345 mg / mL, approx. 350 mg / mL, approx. 355 mg / mL, approx. 360 mg / mL, approx. 365 mg / mL, approx. g / mL, approximately 385 mg / mL, approximately 390 mg / mL, approximately 395 mg / mL, approximately 400 mg / mL, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg,Approximately 350mg, approximately 360mg, approximately 370mg, approximately 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg, approximately 440mg, approximately 450mg, approximately 460mg, approximately 470mg, approximately 480mg, approximately 490mg, approximately 500mg, approximately 510mg, approximately 520mg, approximately 530mg, approximately 540mg, approximately 550mg, approximately 560mg, approximately 570mg, approximately 580mg, approximately 590mg, approximately 600mg, approximately 610mg, approximately 620mg, approximately 630mg, approximately 640mg, approximately 650mg, approximately 660mg, approximately 670mg, approximately 680mg, approximately 690mg, approximately 700mg mg, approximately 710mg, approximately 720mg, approximately 730mg, approximately 740mg, approximately 750mg, approximately 760mg, approximately 770mg, approximately 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg, approximately 840mg, approximately 850mg, approximately 860mg, approximately 870mg, approximately 880mg, approximately 890mg, approximately 900mg, approximately 910mg, approximately 920mg, approximately 930mg, approximately 940mg, approximately 950mg, approximately 960mg, approximately 970mg, approximately 980mg, approximately 990mg, approximately 1000mg, approximately 1010mg, approximately 1020mg, approximately 1030mg, approximately 1040mg, approximately 105 0mg, approximately 1060mg, approximately 1070mg, approximately 1080mg, approximately 1090mg, approximately 1100mg, approximately 1110mg, approximately 1120mg, approximately 1130mg, approximately 1140mg, approximately 1150mg, approximately 1160mg, approximately 1170mg, approximately 1180mg, approximately 1190mg, approximately 1200mg, approximately 1210mg, approximately 1220mg, approximately 1230mg, approximately 1240mg, approximately 1250mg, approximately 1260mg, approximately 1270mg, approximately 1280mg, approximately 1290mg, approximately 1300mg, approximately 1310mg, approximately 1320mg, approximately 1330mg, approximately 1340mg, approximately 1350mg, approximately 1360mg g, approximately 1370mg, approximately 1380mg, approximately 1390mg, approximately 1400mg, approximately 1410mg, approximately 1420mg, approximately 1430mg, approximately 1440mg, approximately 1450mg, approximately 1460mg, approximately 1470mg, approximately 1480mg, approximately 1490mg, approximately 1500mg, approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg, approximately 1560mg, approximately 1570mg, approximately 1580mg, approximately 1590mg, approximately 1600mg, approximately 1610mg, approximately 1620mg, approximately 1630mg, approximately 1640mg, approximately 1650mg, approximately 1660mg, approximately 1670mg,About 1680 mg, about 1690 mg, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, or about 1780 mg.

[0429] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 25 mg / mL.

[0430] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 50 mg / mL.

[0431] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 150 mg / mL.

[0432] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 50 mg.

[0433] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 320 mg.

[0434] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 640 mg.

[0435] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 720 mg.

[0436] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 960 mg.

[0437] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 1000 mg.

[0438] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 1080 mg.

[0439] In some embodiments, the total amount of anti-LAG-3 and anti-PD-1 antibody in the pharmaceutical composition is about 1440 mg.

[0440] In some embodiments, the pharmaceutical composition comprises about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL, about 47.5 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, About 125mg / mL, 130mg / mL, about 135mg / mL, about 140mg / mL, about 145mg / mL, about 150mg / mL, about 155mg / mL, about 160mg / mL, Approx. 165mg / mL, approx. 170mg / mL, approx. 175mg / mL, approx. 180mg / mL, approx. 185mg / mL, approx. 190mg / mL, approx. 195mg / mL, approx. 200mg / mL, The composition contains about 7 mg, about 21 mg, about 40 mg, about 70 mg, about 80 mg, about 160 mg, about 200 mg, about 210 mg, about 300 mg, about 400 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 960 mg, about 1000 mg, about 1100 mg, about 1200 mg, or about 1300 mg of anti-LAG-3 antibody.In some embodiments, the pharmaceutical composition comprises about 5 mg / mL, about 10 mg / mL, about 12.5 mg / mL, about 15 mg / mL, about 17.5 mg / mL, about 20 mg / mL, about 22.5 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 42.5 mg / mL, about 45 mg / mL, about 47.5 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL mL, about 105 mg / mL, about 110 mg / mL, about 115 mg / mL, about 120 mg / mL, about 125 mg / mL, 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, about 200 mg / mL, about 10 mg, about 40 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, or about 480 mg of anti-PD-1 antibody.

[0441] In some embodiments, the pharmaceutical composition comprises about 12.5 mg / mL of an anti-LAG-3 antibody and about 37.5 mg / mL of an anti-PD-1 antibody.

[0442] In some embodiments, the pharmaceutical composition comprises about 20 mg / mL of an anti-LAG-3 antibody and about 5 mg / mL of an anti-PD-1 antibody.

[0443] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL of an anti-LAG-3 antibody and about 75 mg / mL of an anti-PD-1 antibody.

[0444] In some embodiments, the pharmaceutical composition comprises about 100 mg / mL of an anti-LAG-3 antibody and about 50 mg / mL of an anti-PD-1 antibody.

[0445] In some embodiments, the pharmaceutical composition comprises about 80 mg of an anti-LAG-3 antibody and about 240 mg of an anti-PD-1 antibody.

[0446] In some embodiments, the pharmaceutical composition comprises about 160 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody.

[0447] In some embodiments, the pharmaceutical composition comprises about 360 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody.

[0448] In some embodiments, the pharmaceutical composition comprises about 480 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody.

[0449] In some embodiments, the pharmaceutical composition comprises about 720 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody.

[0450] In some embodiments, the pharmaceutical composition comprises about 800 mg of an anti-LAG-3 antibody and about 200 mg of an anti-PD-1 antibody.

[0451] In some embodiments, the pharmaceutical composition comprises about 960 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody.

[0452] In some embodiments, the pharmaceutical composition comprises about 5 mM to about 50 mM histidine, about 50 mM to about 300 mM sucrose, about 5 μM to about 1 mM diethylenetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA), and about 0.001% to about 1% (w / v) polysorbate or poloxamer (e.g., polysorbate 80 (PS80), polysorbate 20 (PS20), poloxamer 188 (PX188), or any combination thereof).

[0453] In some embodiments, the pharmaceutical composition comprises about 20 mM histidine, about 250 mM sucrose, about 50 μM DTPA, and 0.05% PS80.

[0454] In some embodiments, the pH of the pharmaceutical composition is about 5 to about 6.5. In some embodiments, the pH is about 5.3 to about 6.3. In some embodiments, the pH is 5.8. In some embodiments, the pH is 5.7.

[0455] Provided herein is a vial, syringe, or intravenous bag containing a pharmaceutical composition as described herein. In some aspects, the present disclosure includes an autoinjector containing a pharmaceutical composition as described herein.

[0456] In some embodiments, a vial contains a pharmaceutical composition as described herein, and the vial further comprises a stopper and a seal. In some embodiments, the total volume within the vial is about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, or about 20 mL.

[0457] Also within the scope of the invention are kits for treating a human subject with lung cancer that comprise any of the antibodies, therapeutic agents and / or anti-cancer therapies described herein.

[0458] Kits typically include labeling and instructions directing the intended use of the contents of the kit. The term "labeling" includes any written or recorded material supplied on or with the kit, or which otherwise accompanies the kit. In some embodiments, the kit includes instructions for using the kit components in a method of treating a human subject afflicted with lung cancer.

[0459] The antibody can be provided in any of the doses or combinations of doses described herein.

[0460] In some embodiments, the kit comprises one dose of leratolimab and one dose of an anti-PD-1 antibody described herein, or two different doses of an anti-PD-1 antibody described herein, which can be the same or different anti-PD-1 antibodies.

[0461] In some embodiments, doses of an anti-LAG-3 antibody and an anti-PD-1 antibody disclosed herein are co-packaged in a single unit dosage form.

[0462] In some embodiments, all doses of antibody are packaged as separate unit dosage forms.

[0463] In some embodiments, the kit further comprises one or more PDCT therapeutic agents disclosed herein. In some embodiments, the one or more PDCT therapeutic agents are carboplatin and paclitaxel, carboplatin and albumin-bound paclitaxel, carboplatin and pemetrexed, and / or cisplatin and pemetrexed. In some embodiments, the therapeutic agents are carboplatin, cisplatin, paclitaxel, albumin-bound paclitaxel, and pemetrexed.

[0464] All of the references cited above and all of the references cited herein are incorporated herein by reference in their entirety.

[0465] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0466] Example 1 Anti-PD-1 antibody plus anti-LAG-3 antibody combined with anti-PD-1 antibody following concurrent chemoradiotherapy for the treatment of lung cancer This multicenter, double-blind, randomized, global phase 3 trial will evaluate the efficacy and safety of chemoradiotherapy (CCRT) plus nivolumab followed by maintenance therapy with a fixed-dose combination (FDC) of nivolumab and leratolimab versus CCRT plus placebo followed by maintenance therapy with durvalumab in subjects with previously untreated, unresectable, stage IIIA, IIIB, or IIIC locally advanced non-small cell lung cancer (NSCLC).

[0467] Approximately 850 male and female adults aged 18 years or older, or of local age of consent within the jurisdiction where the trial is being conducted at the time of signing the informed consent form, will be randomized (1:1) across two treatment arms (Arms A and B) and stratified by PD-L1 expression level (≥1%, <1%, or not quantifiable [NQ]) and disease stage (IIIA, IIIB, IIIC) according to the American Joint Committee on Cancer (AJCC) 8th edition of TNM (tumor, node, metastases) in lung cancer (Amin et al., AJCC Cancer Staging Manual (8th edition). Springer International Publishing: American Joint Commission on Cancer; 2017).

[0468] Each arm includes a CCRT phase, a recovery period, and a maintenance phase.

[0469] Arm A CCRT phase (3 cycles of 21 days): Nivolumab (360 mg intravenously infused over 30 ± 5 minutes (Q3W) for ± 3 days every 3 weeks) plus platinum-doublet chemotherapy (PDCT, IV Q3W) in cycles 1, 2, and 3, respectively, plus radiation therapy (60–66 Gy) in cycles 2 and 3. Maintenance phase (28-day cycles for up to 1 year of treatment): Nivolumab 480 mg + Leratolimab 480 mg FDC intravenously infused Q4W over 60 minutes

[0470] Arm B CCRT phase (3 21-day cycles): placebo (IV infusion over 30 ± 5 minutes Q3W ± 3 days) in cycles 1, 2, and 3 and PDCT (IV Q3W) + radiotherapy (dose of 60–66 Gy) in cycles 2 and 3. Maintenance phase (28-day cycles for up to 1 year of treatment): Durvalumab 1500 mg IV infusion over 60 minutes Q4W.

[0471] During the CCRT phase, nivolumab (Arm A) or placebo (Arm B) will be administered on day 1 of each cycle before the administration of chemotherapy (i.e., PDCT).

[0472] Subjects with squamous histology NSCLC receive cisplatin / etoposide or carboplatin / paclitaxel as PDCT during the CCRT phase.

[0473] Subjects with non-squamous histology NSCLC receive either cisplatin / etoposide, carboplatin / paclitaxel, or cisplatin / pemetrexed as PDCT during the CCRT phase.

[0474] For cisplatin / etoposide PDCT, 80 mg / m over 60 minutes (or per local standard) 2 of cisplatin IV infusion was administered on Day 1 of each of Cycles 1, 2, and 3, at a dose of 100 mg / m over 60 minutes (or per local standard). 2 Etoposide IV infusions of 5 mg / mL per minute will be administered on days 1, 2, and 3 of each of Cycles 1, 2, and 3. Days 2 and 3 may be interrupted, delayed, or discontinued depending on how well the participant tolerates treatment and at the investigator's discretion. Etoposide will be infused before cisplatin. If cisplatin is not tolerated, it may be replaced with carboplatin at an area under the concentration-time curve (AUC) of 5 mg / mL per minute IV infusion over 30 minutes (or per local standard).

[0475] For carboplatin / paclitaxel PDCT, IV infusion of carboplatin AUC 5 mg / mL·min or 6 mg / mL·min over 30 minutes (or per local standard) and 175 or 200 mg / m over 180 minutes (or per local standard) 2 of paclitaxel IV infusion was administered on day 1 of cycle 1, while carboplatin AUC 2 mg / mL min IV infusion over 30 minutes (or per local standard) and 45 or 50 mg / m IV infusion over 60 minutes (or per local standard) were administered. 2Paclitaxel IV infusions of 100 mg / kg / day will be administered on days 1, 8, and 15 of cycles 2 and 3. Paclitaxel infusions will be administered before carboplatin in cycles 1, 2, and 3. Days 8 and 15 of cycles 2 and 3 may be interrupted, delayed, or discontinued depending on how well the participant tolerates treatment and at the investigator's discretion. Carboplatin doses must be calculated according to the Calvert formula. When calculating creatinine clearance (CrCl), the Cockcroft-Gault (see below) formula must be used or local standards must be followed: Calvert formula: Dose (mg) = Target AUC × (Glomerular Filtration Rate + 25) Cockcroft-Gault: CrCl (mL / min) = ([140 - age (years) x actual weight (kg)] / [72 x serum creatinine (mg / dL)]) x {0.85 for women}

[0476] For cisplatin / pemetrexed PDCT, 75 mg / m over 60 minutes (or per local standard) 2 of cisplatin IV infusion and 500 mg / m over 10 minutes (or per local standard) 2 Pemetrexed IV infusion of 5 mg / mL per minute will be administered on Day 1 of each of Cycles 1, 2, and 3. Pemetrexed will be infused before cisplatin. If cisplatin is not tolerated, cisplatin may be replaced with carboplatin at an AUC of 5 mg / mL per minute IV infusion over 30 minutes (or per local standard). If pemetrexed is not tolerated, pemetrexed may be replaced with etoposide.

[0477] The recovery period in each arm is the time between the CCRT and maintenance phases. The recovery period will vary depending on adverse events / serious adverse events and required treatment, but is expected to last approximately 3-6 weeks, but not less than 18 days, from the previous administration of nivolumab (Arm A) or placebo (Arm B) during the Q3W cycle.

[0478] Radiation therapy in each arm will be administered at a dose of 60 Gy to 66 Gy in 30 to 33 daily fractions of 2 Gy each, typically on a 5-day-on / 2-day-off schedule as needed, over 6 to 7 weeks. Each subject will receive chest radiation therapy in the form of intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or three-dimensional conformal radiation therapy (3DRT). Irradiation will begin on day 1 of cycle 2 of the CCRT phase.

[0479] Key selection criteria for CCRT Locally advanced stage IIIA, IIIB, or IIIC (T1-2 N2-3 M0, T3 N1-3 M0, or T4 N0-3 M0) pathologically confirmed NSCLC (including cytology) according to AJCC 8th edition TNM in lung cancer eligible for definitive CCRT. Participants without planned potentially curative surgical resection are eligible. Eastern Cooperative Oncology Group performance status ≤ 1. Treatment-naive, with no prior local or systemic anti-cancer therapy as first-line therapy for locally advanced disease. · Measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria. All participants must have sufficient fresh or archived tumor tissue available for biomarker analysis. Investigators shall advise participants who are women of childbearing potential (WOCBP) and sexually active male participants who are WOCBP about the importance of pregnancy prevention, the consequences of unintended pregnancy, and the potential for fetal toxicity resulting from transmission of the study intervention present in semen, even if the participant has undergone a successful vasectomy or their partner is pregnant.

[0480] Important exclusion criteria for CCRT Participants with a history of myocarditis, regardless of etiology. · History of a concurrent malignancy requiring treatment (present at screening) or a previous malignancy that was active within 2 years prior to randomization. Participants with active, known, or suspected autoimmune disease. Participants with conditions requiring systemic treatment with either corticosteroids (>10 mg / day prednisone equivalent) or other immunosuppressive drugs within 14 days of the start of randomization. · Presence of pleural / pericardial effusion on computed tomography (CT) scan and / or X-ray.

[0481] Important inclusion criteria for maintenance No BICR-confirmed progressive disease by RECIST v1.1 during CCRT or recovery period. No current or previous use of immunosuppressive medications (not to exceed 10 mg / day daily prednisone or its equivalent) within 14 days prior to the first dose of maintenance. Toxicity from CCRT must be resolved to grade 1 or baseline (excluding grade 2 fatigue, esophagitis, or alopecia).

[0482] Important Exclusion Criteria for Maintenance · Serum creatinine > 1.5 × upper limit of normal (ULN) unless creatinine clearance ≥ 40 mL / min (measured or calculated using the Cockcroft-Gault formula). · Aspartate aminotransferase / alanine aminotransferase >3.0 × ULN. Total bilirubin >1.5 × ULN (except for participants with Gilbert's syndrome, who must have a total bilirubin level <3.0 × ULN). Troponin T or I > 2 × institutional ULN.

[0483] This study will demonstrate that nivolumab plus CCRT followed by maintenance with nivolumab and leratolimab FDC (arm A) compared with CCRT plus placebo, followed by maintenance with durvalumab (arm B), improves progression-free survival (PFS) in patients with locally advanced, previously untreated, unresectable stage III NSCLC.

[0484] array SEQ ID NO: 1: Heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) [ka] SEQ ID NO: 2: Light chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) [ka] SEQ ID NO: 3: Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (BMS-986016) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS SEQ ID NO: 4: Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (BMS-986016) EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK SEQ ID NO: 5: Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (BMS-986016) DYYWN SEQ ID NO: 6: Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (BMS-986016) EINHRGSTNSNPSLKS SEQ ID NO: 7: Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (BMS-986016) GYSDYEYNWFDP SEQ ID NO: 8 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (BMS-986016) RASQSISSYLA SEQ ID NO: 9 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (BMS-986016) DASNRAT SEQ ID NO: 10 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (BMS-986016) QQRSNWPLT SEQ ID NO: 11: Heavy chain amino acid sequence; anti-PD-1 mAb (BMS-936558) [ka] SEQ ID NO: 12 Light chain amino acid sequence; anti-PD-1 mAb (BMS-936558) [ka] SEQ ID NO: 13: Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (BMS-936558) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS SEQ ID NO: 14: Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (BMS-936558) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK SEQ ID NO: 15: Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (BMS-936558) NSGMH SEQ ID NO: 16: Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (BMS-936558) VIWYDGSKRYYADSVKG SEQ ID NO: 17: Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (BMS-936558) NDDY SEQ ID NO: 18 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (BMS-936558) RASQSVSSYLA SEQ ID NO: 19 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (BMS-936558) DASNRAT SEQ ID NO: 20 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (BMS-936558) QQSSNWPRT SEQ ID NO: 21 Heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) without terminal lysine [ka] SEQ ID NO: 22 Lymphocyte activation gene 3 protein amino acid sequence (Homo Sapiens, NP_002277) [ka] SEQ ID NO: 23 Heavy chain amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 24 Light chain amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 25: Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (REGN3767) [ka] SEQ ID NO: 26: Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPARFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK SEQ ID NO: 27 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (REGN3767) GFTFSSYG SEQ ID NO: 28 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (REGN3767) IWYDGSNK SEQ ID NO: 29 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (REGN3767) ASVATSGDFDYYGMDV SEQ ID NO: 30 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (REGN3767) QRISTY SEQ ID NO: 31 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (REGN3767) DAS SEQ ID NO: 32 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (REGN3767) QQRSNWPLT SEQ ID NO: 33 Heavy chain amino acid sequence; anti-PD-1 mAb (REGN2810) [ka] SEQ ID NO: 34 Light chain amino acid sequence; anti-PD-1 mAb (REGN2810) [ka] SEQ ID NO: 35: Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (REGN2810) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYFADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS SEQ ID NO: 36: Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (REGN2810) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFR SEQ ID NO: 37: Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (REGN2810) GFTFSNFG SEQ ID NO: 38: Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (REGN2810) ISGGGRDT SEQ ID NO: 39: Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (REGN2810) VKWGNIYFDY SEQ ID NO: 40 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (REGN2810) LSINTF SEQ ID NO: 41 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (REGN2810) AAS SEQ ID NO: 42 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (REGN2810) QQSSNTPFT SEQ ID NO: 43 Heavy chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 44 Heavy chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 45 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 46 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 47: Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 48: Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) [ka] SEQ ID NO: 49 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 50 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 51 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (LAG525) NYGMN SEQ ID NO: 52 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (LAG525) WINTDTGEPTYADDFKG SEQ ID NO: 53 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (LAG525) NPPYYYGTNNAEAMDY SEQ ID NO: 54 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (LAG525) SSSQDISNYLN SEQ ID NO: 55 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (LAG525) YTSTLHL SEQ ID NO: 56 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (LAG525) QQYYNLPWT SEQ ID NO: 57 Heavy chain amino acid sequence; anti-PD-1 mAb (PDR001) [ka] SEQ ID NO: 58 Light chain amino acid sequence; anti-PD-1 mAb (PDR001) [ka] SEQ ID NO: 59: Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (PDR001) EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 60 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (PDR001) EIVLTQSPATLLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 61 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (PDR001) TYWMH SEQ ID NO: 62 Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (PDR001) NIYPGTGGSNFDEKFKN SEQ ID NO: 63 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (PDR001) WTGTGAY SEQ ID NO: 64 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (PDR001) KSSQSLLDSGNQKNFLT SEQ ID NO: 65 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (PDR001) WASTRES SEQ ID NO: 66 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (PDR001) QNDYSYPYT SEQ ID NO: 67 Heavy chain amino acid sequence; anti-LAG-3 mAb (MK4280) [ka] SEQ ID NO: 68 Light chain amino acid sequence; anti-LAG-3 mAb (MK4280) [ka] SEQ ID NO: 69: Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (MK4280) QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIYAQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSS SEQ ID NO: 70 Light chain variable region (VL) amino acid sequence; anti-LAG-3 anti-LAG-3 mAb (MK4280) DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK SEQ ID NO: 71 Heavy chain CDR1 amino acid sequence; anti-LAG-3 mAb (MK4280) DYNVD SEQ ID NO: 72 Heavy chain CDR2 amino acid sequence; anti-LAG-3 mAb (MK4280) DINPNDGGTIYAQKFQE SEQ ID NO: 73 Heavy chain CDR3 amino acid sequence; anti-LAG-3 mAb (MK4280) NYRWFGAMDH SEQ ID NO: 74 Light chain CDR1 amino acid sequence; anti-LAG-3 mAb (MK4280) KASQSLDYEGDSDMN SEQ ID NO: 75 Light chain CDR2 amino acid sequence; anti-LAG-3 mAb (MK4280) GASNLES SEQ ID NO: 76 Light chain CDR3 amino acid sequence; anti-LAG-3 mAb (MK4280) QQSTEDPRT SEQ ID NO: 77 Heavy chain amino acid sequence; anti-PD-1 mAb (MK3475) [ka] SEQ ID NO: 78 Light chain amino acid sequence; anti-PD-1 mAb (MK3475) [ka] SEQ ID NO: 79: Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (MK3475) QVQLVQSVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNFNEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS SEQ ID NO: 80 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (MK3475) EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLESGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGGTKVEIK SEQ ID NO: 81 Heavy chain CDR1 amino acid sequence; anti-PD-1 mAb (MK3475) NYYMY SEQ ID NO: 82 Heavy chain CDR2 amino acid sequence; anti-PD-1 mAb (MK3475) GINPSNGGTNFNEKFKN SEQ ID NO: 83 Heavy chain CDR3 amino acid sequence; anti-PD-1 mAb (MK3475) RDYRFDMGFDY SEQ ID NO: 84 Light chain CDR1 amino acid sequence; anti-PD-1 mAb (MK3475) RASKGVSTSGYSYLH SEQ ID NO: 85 Light chain CDR2 amino acid sequence; anti-PD-1 mAb (MK3475) LASYLES SEQ ID NO: 86 Light chain CDR3 amino acid sequence; anti-PD-1 mAb (MK3475) QHSRDLPLT

[0485]

Claims

1. 1. A method of treating a human subject suffering from lung cancer, comprising administering to said subject (a) PD-1 (programmed death-1) pathway inhibitor and concurrent chemoradiotherapy (CCRT), followed by (b) PD-1 pathway inhibitors and lymphocyte-activation gene 3 (LAG-3) antagonists The method of claim 1, wherein the

2. 10. The method of claim 1, further comprising providing the subject with a recovery period beginning upon completion of the administering in (a) and ending upon initiation of the administering in (b).

3. 3. The method of claim 2, wherein the recovery period is a period of time sufficient for the subject to recover from toxicities associated with the CCRT other than fatigue, esophagitis, or alopecia.

4. 4. The method of claim 2 or 3, wherein the recovery period is from about 1 week to about 12 weeks, from about 1 week to about 9 weeks, from about 1 week to about 6 weeks, from about 2 weeks to about 12 weeks, from about 2 weeks to about 9 weeks, from about 2 weeks to about 6 weeks, from about 3 weeks to about 12 weeks, from about 3 weeks to about 9 weeks, from about 3 weeks to about 6 weeks, from about 18 days to about 12 weeks, from about 18 days to about 9 weeks, from about 18 days to about 6 ...9 weeks, from about 18 days to about 6 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days to about 9 weeks, from about 18 days

5. The method according to any one of claims 1 to 4, which is a first line therapy.

6. 6. The method of any one of claims 1 to 5, wherein the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

7. 7. The method of any one of claims 1 to 6, wherein the subject has not received prior systemic therapy for cancer, the subject has not received prior systemic therapy for lung cancer, or the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

8. 8. The method of any one of claims 1 to 7, wherein the subject has no prior immuno-oncology therapy, the subject has no prior immuno-oncology therapy for the lung cancer, or the lung cancer has no prior immuno-oncology therapy.

9. The method of any one of claims 1 to 4, which is a second line therapy.

10. The method of any one of claims 1 to 4, which is a third line therapy.

11. 11. The method of claim 9 or 10, wherein the subject has progressed on a previous treatment.

12. The method of any one of claims 9 to 11, wherein the lung cancer recurs after multimodal treatment for locally advanced lung cancer.

13. The method of any one of claims 1 to 12, wherein the lung cancer is unresectable, advanced, recurrent and / or metastatic.

14. The method of any one of claims 1 to 13, wherein the lung cancer comprises small cell lung cancer.

15. The method of any one of claims 1 to 14, wherein the lung cancer comprises non-small cell lung cancer (NSCLC).

16. 16. The method of claim 15, wherein the NSCLC has squamous or non-squamous histology.

17. 17. The method of claim 15 or 16, wherein the NSCLC comprises locally advanced stage IIIA, IIIB or IIIC NSCLC.

18. 18. The method of any one of claims 2 to 17, wherein the subject does not have progressive lung cancer during the CCRT or during the recovery period.

19. 19. The method of any one of claims 1-18, wherein the PD-1 pathway inhibitors of (a) and (b) are the same.

20. 19. The method of any one of claims 1-18, wherein the PD-1 pathway inhibitors of (a) and (b) are different.

21. 21. The method of any one of claims 1 to 20, wherein the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

22. 22. The method of any one of claims 1 to 21, wherein the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-1 antibody.

23. The method of claim 21 or 22, wherein the anti-PD-1 antibody comprises a full-length antibody.

24. 24. The method of any one of claims 21 to 23, wherein the anti-PD-1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

25. 25. The method of claim 24, wherein the multispecific antibody comprises a dual affinity retargeting antibody (DART), a DVD-binding protein (DVD-Ig), or a bispecific antibody.

26. The anti-PD-1 antibody is F(ab') ２ 23. The method of claim 21 or 22, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

27. 27. The method of any one of claims 21 to 26, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen-binding portion thereof.

28. 28. The method of any one of claims 21 to 27, wherein the anti-PD-1 antibody comprises nivolumab or an antigen-binding portion thereof.

29. The method of any one of claims 21 to 28, wherein the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:

14.

30. the anti-PD-1 antibody: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20 30. The method of any one of claims 21 to 29, comprising:

31. 31. The method of any one of claims 21 to 30, wherein the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

32. 32. The method of any one of claims 21-25 or 27-31, wherein the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively.

33. 21. The method of any one of claims 1-20, wherein the PD-1 pathway inhibitor of (a) and / or (b) comprises a soluble PD-L2 polypeptide.

34. 34. The method of claim 33, wherein the soluble PD-L2 polypeptide comprises a fusion polypeptide.

35. 35. The method of claim 33 or 34, wherein the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain.

36. 36. The method of any one of claims 33-35, wherein the soluble PD-L2 polypeptide further comprises a half-life extending moiety.

37. 37. The method of claim 36, wherein the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof.

38. 38. The method of any one of claims 33-37, wherein the soluble PD-L2 polypeptide comprises AMP-224.

39. 22. The method of any one of claims 1 to 21, wherein the PD-1 pathway inhibitor of (a) and / or (b) comprises an anti-PD-L1 antibody.

40. 40. The method of claim 21 or 39, wherein the anti-PD-L1 antibody comprises a full-length antibody.

41. 41. The method of any one of claims 21 or 39-40, wherein the anti-PD-L1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

42. 42. The method of claim 41 , wherein the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

43. The anti-PD-L1 antibody is F(ab') ２ 40. The method of any one of claims 21 or 39, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

44. 44. The method of any one of claims 21 or 39-43, wherein the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen-binding portion thereof.

45. 21. The method of any one of claims 1-20, wherein the PD-1 pathway inhibitor of (a) and / or (b) comprises BMS-986189.

46. 46. ​​The method of any one of claims 1-45, wherein the PD-1 pathway inhibitor of (a) and / or (b) is administered at a fixed dose.

47. The PD-1 pathway inhibitor of (a) and / or (b) is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 47. The method of any one of claims 1 to 46, wherein the medicament is administered at a dose of about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

48. The PD-1 pathway inhibitor of (a) and / or (b) is about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.25mg, about 9.5mg, about 9.75mg, about 10mg, about 20mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, Approximately 130mg, approximately 140mg, approximately 150mg, approximately 160mg, approximately 170mg, approximately 180mg, approximately 190mg, approximately 200mg, approximately 210mg , about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg , about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390m g, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 m g, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 75 0mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 84 0mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 9 30mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg,48. The method of any one of claims 1 to 47, wherein the compound is administered at a dose of about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

49. 46. ​​The method of any one of claims 1-45, wherein the PD-1 pathway inhibitor of (a) and / or (b) is administered as a body weight-based dose.

50. The PD-1 pathway inhibitor of (a) and / or (b) is from about 0.003 mg / kg to about 25 mg / kg, from about 0.003 mg / kg to about 20 mg / kg, from about 0.003 mg / kg to about 15 mg / kg, from about 0.003 mg / kg to about 10 mg / kg, from about 0.003 mg / kg to about 5 mg / kg, from about 0.003 mg / kg to about 1 mg / kg, from about 0.003 mg / kg to about 0.9 mg / kg, from about 0.003 mg / kg to about 0.8 mg / kg g / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20mg / kg, about 0.1mg / kg to about 15mg / kg, about 0.1mg / kg to about 10mg / kg, about 0.1mg / kg to about 5mg / kg, about 0.1mg / kg to about 1mg / kg, about 1mg / kg to about 25m g / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg 50. The method of any one of claims 1-45 or 49, wherein the patient is administered at a dose of about 10 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

51. The PD-1 pathway inhibitor of (a) and / or (b) is at least about 0.003 mg / kg, at least about 0.004 mg / kg, at least about 0.005 mg / kg, at least about 0.006 mg / kg, at least about 0.007 mg / kg, at least about 0.008 mg / kg, at least about 0.009 mg / kg, at least about 0.01 mg / kg, at least about 0.02 mg / kg, at least about 0.03 mg / kg, at least about 0.04 mg / kg, at least about 0.05 mg / kg, at least about 0.06 mg / kg, at least about 0.07 mg / kg, at least about 0.08 mg / kg, at least about 0.09 mg / kg, at least about 0.1 mg / kg, at least about 0.2 mg / kg, at least about 0.3 mg / kg, at least about 0.4 mg / kg, at least about 0.5 mg / kg, at least about 0.6 mg / kg, at least about 0.7 mg / kg, at least about 0.8 mg / kg, at least about 0.9 mg / kg, at least about 1.

51. The method of any one of claims 1-45 or 49-50, wherein the compound is administered at a dose of about 0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

52. 52. The method of any one of claims 46-51, wherein the doses of the PD-1 pathway inhibitors in (a) and (b) are different.

53. 53. The method of any one of claims 46-52, wherein the dose of the PD-1 pathway inhibitor of (a) and / or (b) is administered about once every week, about once every two weeks, about once every three weeks, about once every four weeks, about once every five weeks, about once every six weeks, about once every seven weeks, about once every eight weeks, about once every nine weeks, about once every ten weeks, about once every eleven weeks, or about once every twelve weeks.

54. 54. The method of any one of claims 1 to 53, wherein the CCRT comprises platinum-doublet chemotherapy (PDCT).

55. 55. The method of claim 54, wherein the PDCT comprises a platinum agent in combination with a nucleoside analog, antimetabolite, taxane, vinca alkaloid, or topoisomerase inhibitor.

56. 56. The method of claim 55, wherein the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenanthriplatin.

57. 57. The method of claim 55 or 56, wherein the platinum agent comprises cisplatin.

58. 57. The method of claim 55 or 56, wherein the platinum agent comprises carboplatin.

59. 59. The method of any one of claims 55 to 58, wherein the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine.

60. 60. The method of claim 59, wherein the nucleoside analog comprises gemcitabine.

61. 59. The method of any one of claims 55 to 58, wherein the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine.

62. 62. The method of claim 61, wherein the antimetabolite comprises pemetrexed.

63. 59. The method of any one of claims 55 to 58, wherein the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, or cabazitaxel.

64. 59. The method of any one of claims 55 to 58, wherein the vinca alkaloid comprises vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridin, or vinbrunin.

65. 65. The method of claim 64, wherein the vinca alkaloid comprises vinorelbine or vinblastine.

66. 59. The method of any one of claims 55 to 58, wherein the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin.

67. 67. The method of claim 66, wherein the topoisomerase inhibitor comprises etoposide.

68. 67. The method of claim 66, wherein the topoisomerase inhibitor comprises irinotecan.

69. 70. The method of any one of claims 54 to 69, wherein the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan.

70. 70. The method of any one of claims 54 to 69, wherein the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel.

71. 70. The method of any one of claims 54 to 69, wherein the PDCT comprises cisplatin or carboplatin in combination with pemetrexed.

72. 70. The method of any one of claims 54 to 69, wherein the PDCT comprises cisplatin or carboplatin in combination with etoposide.

73. 73. The method of any one of claims 1 to 72, wherein the CCRT comprises chest radiotherapy and / or volumetric modulated arc therapy (VMAT), intensity modulated radiotherapy (IMRT), or three-dimensional conformal radiotherapy (3DRT).

74. 74. The method of any one of claims 1 to 73, wherein the LAG-3 antagonist comprises an anti-LAG-3 antibody.

75. 75. The method of claim 74, wherein the anti-LAG-3 antibody comprises a full-length antibody.

76. 76. The method of claim 74 or 75, wherein the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

77. 75. The method of claim 74, wherein said multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

78. The anti-LAG-3 antibody is F(ab') ２ 75. The method of claim 74, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

79. The anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (relatolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yelamilimab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen-binding portion thereof.

80. 80. The method of any one of claims 74 to 79, wherein the anti-LAG-3 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:

4.

81. The anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 10 81. The method of any one of claims 74 to 80, comprising:

82. 82. The method of any one of claims 74 to 81, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

83. 83. The method of any one of claims 74-77 and 79-82, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 1 and 2, respectively.

84. 83. The method of any one of claims 74-77 and 79-82, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively.

85. 74. The method of any one of claims 1 to 73, wherein the LAG-3 antagonist comprises a soluble LAG-3 polypeptide.

86. 86. The method of claim 85, wherein the soluble LAG-3 polypeptide comprises a fusion polypeptide.

87. 87. The method of claim 85 or 86, wherein the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain.

88. 88. The method of claim 87, wherein the ligand-binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:

22.

89. 89. The method of any one of claims 85-88, wherein the soluble LAG-3 polypeptide further comprises a half-life extending moiety.

90. 90. The method of claim 89, wherein the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, immunoglobulin G (IgG), an albumin-binding polypeptide (ABP), a PAS-modified moiety, a HES-modified moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof.

91. 91. The method of any one of claims 85 to 90, wherein the soluble LAG-3 polypeptide comprises IMP321 (efthirazimod alfa).

92. 92. The method of any one of claims 1 to 91, wherein the LAG-3 antagonist is administered in a fixed dose.

93. The LAG-3 antagonist is at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 93. The method of any one of claims 1 to 92, wherein the compound is administered at a dose of 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

94. Preface LAG-3 Antigonist, approximately 0.25 mg, approximately 0.5 mg, approximately 0.75 mg, approximately 1 mg, approximately 1.25 mg, approximately 1.5 mg, approximately 1.75 mg, approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3.25 mg, approximately 3.5 mg, approximately 3.75 mg, approximately 4 mg, approximately 4.25 mg, approximately 4.5 mg, approximately 4.75 mg, approximately 5 mg, approximately 5.25 mg, approximately 5.5 mg, approximately 5.75 mg, approximately 6 mg, approximately 6.25 mg, approximately 6.5 mg, approximately 6.75 mg, approximately 7 mg, approximately 7.25 mg, approximately 7.5 mg, approximately 7.75 mg, approximately 8 mg, approximately 8.25 mg, approximately 8.5 mg, approximately 8.75 mg, approximately 9 mg, approximately 9.25 mg, approximately 9.5 mg, approximately 9.75 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg Approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg Approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg g, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1000 mg, approximately 1040 mg, approximately 1080 mg94. The method of any one of claims 1 to 93, wherein the compound is administered at a dose of about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

95. 92. The method of any one of claims 1 to 91, wherein the LAG-3 antagonist is administered in a body weight-based dose.

96. The LAG-3 antagonist is selected from the group consisting of about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0 .. 003mg / kg to about 0.7mg / kg, about 0.003mg / kg to about 0.6mg / kg, about 0.003mg / kg to about 0.5mg / kg, about 0.003mg / kg to about 0.4mg / kg, about 0.003mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg , about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to 96. The method of any one of claims 1 -91 or 95, wherein the compound is administered at a dose of about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

97. The LAG-3 antagonist is at least about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, or about 1.0 mg / kg 97. The method of any one of claims 1-91 or 95-96, wherein the medicament is administered at a dose of about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

98. 98. The method of any one of claims 92-97, wherein said dose of the LAG-3 antagonist is administered about once per week, about once per 2 weeks, about once per 3 weeks, about once per 4 weeks, about once per 5 weeks, about once per 6 weeks, about once per 7 weeks, about once per 8 weeks, about once per 9 weeks, about once per 10 weeks, about once per 11 weeks, or about once per 12 weeks.

99. 99. The method of any one of claims 1-98, wherein (a) the PD-1 pathway inhibitor, the CCRT, (b) the PD-1 pathway inhibitor and / or the LAG-3 antagonist are formulated for intravenous administration.

100. 100. The method of any one of claims 1-99, wherein the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are formulated separately.

101. 101. The method of claim 100, wherein the PD-1 pathway inhibitor of (b) is administered prior to the LAG-3 antagonist.

102. 101. The method of claim 100, wherein the LAG-3 antagonist is administered prior to the PD-1 pathway inhibitor of (b).

103. 101. The method of claim 100, wherein the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are administered simultaneously.

104. 100. The method of any one of claims 1-99, wherein the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are formulated together.

105. The method of any one of claims 1 to 104, wherein the PD-1 pathway inhibitor and the LAG-3 antagonist of (b) are administered as maintenance therapy.

106. 106. The method of claim 105, wherein the maintenance therapy is administered for up to about one year.

107. 1. A method of treating a human subject suffering from NSCLC having squamous or non-squamous histology, comprising: (a) administering to the subject approximately 360 mg of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and CCRT, including PDCT and radiation therapy; (b) providing the subject with a recovery period beginning upon completion of the administering in (a); thereafter (c) administering to the subject a maintenance therapy comprising about 480 mg of an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 13 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 14, and about 480 mg of an anti-LAG-3 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO:

4. A method comprising:

108. 108. The method of claim 107, wherein the PDCT comprises cisplatin and etoposide.

109. (a) comprises three 21-day cycles; the anti-PD-1 antibody is administered on day 1 of each cycle; Approximately 100mg / m ２ the etoposide is administered after the anti-PD-1 antibody on days 1, 2, and 3 of each cycle, and on day 1 of each cycle; Approximately 80mg / m ２ 109. The method of claim 108, wherein the cisplatin is administered on day 1 of each cycle after the etoposide.

110. 110. The method of claim 108 or 109, wherein each of the cisplatin and the etoposide is administered intravenously over a period of about 60 minutes.

111. 108. The method of claim 107, wherein the PDCT comprises carboplatin and paclitaxel.

112. (a) comprises three 21-day cycles; the anti-PD-1 antibody is administered on day 1 of each cycle; Approximately 175mg / m ２ or about 200 mg / m ２ of said paclitaxel is administered on day 1 of the first cycle and is about 45 mg / m ２ or about 50 mg / m ２ the paclitaxel is administered on days 1, 8, and 15 of a second cycle and a third cycle, and the paclitaxel is administered after the anti-PD-1 antibody on day 1 of each cycle; 112. The method of claim 111, wherein the carboplatin at a target AUC of about 5 mg / mL min or about 6 mg / mL min is administered on day 1 of a first cycle, and the carboplatin at a target AUC of about 2 mg / mL min is administered on days 1, 8, and 15 of a second and third cycle, wherein the carboplatin is administered after the paclitaxel in each cycle.

113. 113. The method of claim 111 or 112, wherein the carboplatin is administered intravenously over about 30 minutes and the paclitaxel is administered intravenously over about 180 minutes in the first cycle and over about 60 minutes in the second and third cycles.

114. 108. The method of claim 107, wherein the PDCT comprises cisplatin and pemetrexed.

115. (a) comprises three 21-day cycles; the anti-PD-1 antibody is administered on day 1 of each cycle; Approximately 500mg / m ２ is administered on day 1 of each cycle after the anti-PD-1 antibody; Approximately 75mg / m ２ 115. The method of claim 114, wherein the cisplatin is administered on day 1 of each cycle after the pemetrexed.

116. 116. The method of claim 114 or 115, wherein the cisplatin is administered intravenously over about 60 minutes and the pemetrexed is administered intravenously over about 10 minutes.

117. 117. The method of any one of claims 108-110 or 114-116, wherein if the cisplatin is not tolerated by the subject, the cisplatin is replaced with carboplatin at a target area under the concentration-time curve (AUC) of about 5 mg / mL min.

118. 118. The method of claim 117, wherein the carboplatin is administered intravenously over a period of about 30 minutes.

119. 119. The method of any one of claims 114 to 118, wherein the pemetrexed is replaced with etoposide if the pemetrexed is not tolerated by the subject.

120. 120. The method of any one of claims 107-119, wherein the anti-PD-1 antibody of (a) is administered intravenously over about 30 minutes.

121. 121. The method of any one of claims 107-120, wherein the radiation therapy is administered after the PDCT and comprises a dose of about 60 Gy to about 66 Gy.

122. 122. The method of any one of claims 107 to 121, wherein the radiotherapy comprises chest radiotherapy and / or volumetric modulated arc therapy (VMAT), intensity modulated radiotherapy (IMRT), or three-dimensional conformal radiotherapy (3DRT).

123. 123. The method of any one of claims 107-122, wherein said radiation therapy comprises about 30 to about 33 daily doses of 2 Gy on about a 5 days on and 2 days off schedule for about 6 to about 7 weeks starting on day 1 of the second and third cycles.

124. 124. The method of any one of claims 107-123, wherein the recovery period is a period of time sufficient for the subject to recover from toxicity associated with the CCRT other than fatigue, esophagitis, or alopecia.

125. The method of any one of claims 107 to 124, wherein the recovery period is from about 1 week to about 12 weeks, from about 1 week to about 9 weeks, from about 1 week to about 6 weeks, from about 2 weeks to about 12 weeks, from about 2 weeks to about 9 weeks, from about 2 weeks to about 6 weeks, from about 3 weeks to about 12 weeks, from about 3 weeks to about 9 weeks, from about 3 weeks to about 6 weeks, from about 18 days to about 12 weeks, from about 18 days to about 9 weeks from the final administration of the anti-PD-1 antibody in (a), or from about 18 days to about 6 weeks from the final administration of the anti-PD-1 antibody in (a).

126. 126. The method of any one of claims 107 to 125, which is a first line therapy.

127. 127. The method of any one of claims 107-126, wherein the subject has not received prior local or systemic anti-cancer therapy given as primary therapy for locally advanced disease.

128. 128. The method of any one of claims 107-127, wherein the subject has not received prior systemic therapy for cancer, wherein the subject has not received prior systemic therapy for lung cancer, or wherein the subject has not received prior systemic therapy for advanced or metastatic lung cancer.

129. 129. The method of any one of claims 107-128, wherein the subject has no prior immuno-oncology therapy, the subject has no prior immuno-oncology therapy for the lung cancer, or the lung cancer has no prior immuno-oncology therapy.

130. 126. The method of any one of claims 107 to 125, which is a second line therapy.

131. 126. The method of any one of claims 107 to 125, which is a third line therapy.

132. 132. The method of claim 130 or 131, wherein the subject has progressed on a previous treatment.

133. 133. The method of any one of claims 130-132, wherein the NSCLC recurs after multimodal treatment for locally advanced NSCLC.

134. The method of any one of claims 107 to 133, wherein the NSCLC is unresectable, advanced, recurrent and / or metastatic.

135. 135. The method of any one of claims 107 to 134, wherein the NSCLC has squamous or non-squamous histology.

136. 136. The method of any one of claims 107-135, wherein the NSCLC comprises locally advanced stage IIIA, IIIB or IIIC NSCLC.

137. 137. The method of any one of claims 107-136, wherein the subject does not have progressive NSCLC during the CCRT or during the recovery period.

138. 138. The method of any one of claims 107-137, wherein the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered about once every four weeks.

139. 139. The method of any one of claims 107-138, wherein the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated separately.

140. 140. The method of claim 139, wherein the anti-PD-1 antibody of (b) is administered before the anti-LAG-3 antibody.

141. 140. The method of claim 139, wherein the anti-LAG-3 antibody is administered before the anti-PD-1 antibody of (b).

142. 140. The method of claim 139, wherein the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered simultaneously.

143. 139. The method of any one of claims 107-138, wherein the anti-PD-1 and anti-LAG-3 antibodies of (b) are formulated together.

144. 144. The method of any one of claims 107-143, wherein the anti-PD-1 and anti-LAG-3 antibodies of (b) are administered intravenously over about 30 minutes.

145. 145. The method of any one of claims 107-144, wherein the anti-PD-1 antibody of (a) and / or (b) comprises a full-length antibody.

146. 146. The method of any one of claims 107-145, wherein the anti-PD-1 antibody of (a) and / or (b) comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

147. 147. The method of claim 146, wherein said multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

148. The anti-PD-1 antibody of (a) and / or (b) is F(ab') ２ 145. The method of any one of claims 107 to 144, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

149. The anti-PD-1 antibody of (a) and / or (b) is: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 20 149. The method of any one of claims 107 to 148, comprising:

150. 150. The method of any one of claims 107-149, wherein the anti-PD-1 antibody of (a) and / or (b) comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 13 and 14, respectively.

151. 151. The method of any one of claims 107-147 and 149-150, wherein the anti-PD-1 antibody of (a) and / or (b) comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 11 and 12, respectively.

152. The method of any one of claims 107 to 151, wherein the anti-LAG-3 antibody comprises a full-length antibody.

153. The method of any one of claims 107 to 152, wherein the anti-LAG-3 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

154. 154. The method of claim 153, wherein said multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

155. The anti-LAG-3 antibody is F(ab') ２ 152. The method of any one of claims 107 to 151, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

156. The anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 10 156. The method of any one of claims 107 to 155, comprising:

157. The method of any one of claims 107 to 156, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 3 and 4, respectively.

158. 158. The method of any one of claims 107-154 and 156-157, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 1 and 2, respectively.

159. 158. The method of any one of claims 107-154 and 156-157, wherein the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively.

160. The method of any one of claims 1 to 159, wherein one or more immune cells in tumor tissue from the subject express LAG-3.

161. 161. The method of claim 160, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3.

162. 162. The method of claim 160 or 161, wherein at least about 1% of the immune cells express LAG-3.

163. 163. The method of any one of claims 160 to 162, wherein the immune cells comprise tumor-infiltrating lymphocytes.

164. The tumor-infiltrating lymphocytes are CD8 ＋ 164. The method of claim 163, comprising cells.

165. The method of any one of claims 1 to 159, wherein one or more nucleated cells in tumor tissue from the subject express LAG-3.

166. 166. The method of claim 165, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express LAG-3.

167. 167. The method of claim 165 or 166, wherein at least about 1% of the nucleated cells express LAG-3.

168. The method of any one of claims 1 to 167, wherein one or more tumor cells in the tumor tissue from the subject express PD-L1.

169. 169. The method of claim 168, wherein at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1.

170. 170. The method of claim 168 or 169, wherein at least about 1% of the tumor cells express PD-L1.

171. 171. The method of any one of claims 1 to 170, further comprising administering to the subject an additional therapeutic agent.

172. 172. The method of claim 171, wherein the additional therapeutic agent comprises an anti-cancer agent.

173. The method of claim 172, wherein the anticancer agent comprises a tyrosine kinase inhibitor, an antiangiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

174. 174. The method of claim 173, wherein the tyrosine kinase inhibitor comprises afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, larotrectinib, or any combination thereof.

175. 174. The method of claim 173, wherein the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase containing Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.

176. 176. The method of claim 173 or 175, wherein the antiangiogenic agent comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesbacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

177. The checkpoint inhibitors include cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T-cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B-cell and T-cell lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta ( 174. The method of claim 173, comprising an inhibitor of a tumour necrosis factor-β (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid-inducible TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repeat dominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death 1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof.

178. 178. The method of any one of claims 173 or 177, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

179. 179. The method of claim 178, wherein the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody.

180. 180. The method of claim 179, wherein the anti-CTLA-4 antibody comprises a full-length antibody.

181. 181. The method of any one of claims 179 or 180, wherein the anti-CTLA-4 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

182. 182. The method of claim 181, wherein said multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

183. The anti-CTLA-4 antibody is an F(ab') ２ 180. The method of claim 179, comprising a fragment, a Fab' fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single chain binding polypeptide.

184. 184. The method of any one of claims 179-183, wherein the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen-binding portion thereof.

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