Combination therapy for lung cancer

Abstract

The present disclosure provides methods of treating a human subject suffering from lung cancer (e.g., non-small cell lung cancer (NSCLC)) using a programmed death-1 (PD-1) pathway inhibitor (e.g., an anti-PD-1 antibody) and synchronous chemoradiotherapy (CCRT, e.g., platinum-based dual drug chemotherapy (PDCT) and radiotherapy), 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) is then used. In some aspects, the methods include a recovery phase that begins after completion of treatment with a PD-1 pathway inhibitor and CCRT, and ends at the beginning of treatment with a combination of a PD-1 pathway inhibitor and a LAG-3 antagonist.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the benefit of priority to U.S. Provisional Application No. 63 / 476,596, filed on December 21, 2022, which is incorporated herein by reference in its entirety. References to electronically submitted sequence listings

[0002] The contents of the electronically submitted Sequence Listing (Name: 3338_323PC01_Seqlisting_ST26; Size: 102,064 bytes; Creation Date: December 13, 2023) are incorporated herein by reference in their entirety. Technical Field

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

[0004] Lung cancer is the leading cause of cancer death worldwide (International Agency for Research on Cancer, GLOBOCAN Cancer Facts Sheet: Lung Cancer, 2020). An estimated 236,740 people will be diagnosed with lung cancer in the United States in 2022 (American Cancer Society, Cancer Facts and Figures, 2022). Lung cancer kills more than 350 people every day, more than breast, prostate, and pancreatic cancer combined, and 2.5 times more than colorectal cancer, the second leading cause of cancer death (Siegel et al., CA Cancer J Clin 2022;72:7-33).

[0005] Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of all lung cancers, and 30% of patients have unresectable, locally advanced (stage III) disease (GLOBOCAN Cancer Facts Sheet: Lung Cancer, 2020; Cancer Facts and Figures, 2022; Siegel et al.; Islami et al., CA Cancer J Clin 2018;68:31-54). Unresectable, stage III NSCLC represents a heterogeneous disease requiring challenging multimodal treatment strategies. Historically, the prognosis for this population has been suboptimal, with 5-year survival rates ranging from 10% to 30% (Curran et al., J Natl Cancer Inst 2011;103:1452-60; Bradley et al., Lancet Oncol 2015;16:187-99). Although considered the new standard of care, outcomes for patients with stage III locally advanced NSCLC following definitive concurrent chemoradiotherapy with 12 months of durvalumab maintenance therapy still leave a significant proportion of patients without suitable treatment options (Spigel et al., J Clin Oncol 2022;40:1301-11).

[0006] There is a need for improved methods for treating human subjects suffering from lung cancer. Summary of the Invention

[0007] The present disclosure relates to methods of treating a human subject having lung cancer, the methods comprising administering to the subject: (a) a programmed death-1 (PD-1) pathway inhibitor and concurrent chemoradiotherapy (CCRT), followed by (b) a PD-1 pathway inhibitor and a lymphocyte activation gene-3 (LAG-3) antagonist.

[0008] In some aspects, the method further includes providing a recovery period to the subject, which begins when the application in (a) is completed, and ends when the application in (b) begins. In some aspects, the recovery period is the duration sufficient to allow the subject to recover from the toxicity associated with CCRT except fatigue, esophagitis or alopecia. In some aspects, 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 (a) PD-1 pathway inhibitors finally use after about 18 days to about 12 weeks, from (a) PD-1 pathway inhibitors finally use after about 18 days to about 9 weeks or from (a) PD-1 pathway inhibitors finally use after about 18 days to about 6 weeks.

[0009] In some aspects, the method is first-line therapy.

[0010] In some aspects, the subject has not received prior local or systemic anti-cancer therapy administered as primary therapy for locally advanced disease.

[0011] In some aspects, 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.

[0012] In some aspects, the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

[0013] In some aspects, the method is a second-line therapy. In some aspects, the method is a third-line therapy. In some aspects, the subject has progressed on previous therapy. In some aspects, the lung cancer has recurred after multimodality therapy for locally advanced lung cancer.

[0014] In some aspects, the lung cancer is unresectable, advanced, recurrent, and / or metastatic.

[0015] In some aspects, the lung cancer comprises small cell lung cancer.

[0016] In some aspects, lung cancer includes non-small cell lung cancer (NSCLC). In some aspects, NSCLC has squamous or non-squamous histology. In some aspects, NSCLC includes locally advanced IIIA, IIIB or IIIC stage NSCLC.

[0017] In some aspects, the subject has not had lung cancer progression during CCRT or recovery.

[0018] In some aspects, the PD-1 pathway inhibitors in (a) and (b) are the same.

[0019] In some aspects, the PD-1 pathway inhibitors in (a) and (b) are different.

[0020] In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0021] In some aspects, the PD-1 pathway inhibitors in (a) and / or (b) include anti-PD-1 antibodies. In some aspects, anti-PD-1 antibodies include full-length antibodies. In some aspects, anti-PD-1 antibodies include monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies or multispecific antibodies. In some aspects, multispecific antibodies include dual affinity retargeting antibodies (DART), DVD-Ig or bispecific antibodies. In some aspects, anti-PD-1 antibodies include F(ab')2 fragments, Fab' fragments, Fab fragments, Fv fragments, scFv fragments, dsFv fragments, dAb fragments or single-chain binding polypeptides. In some aspects, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplizumab, 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 aspects, the anti-PD-1 antibody comprises nivolumab or an antigen-binding portion thereof. In some aspects, the anti-PD-1 antibody comprises a heavy chain variable region CDR1, CDR2, and CDR3 domain having the sequence set forth in SEQ ID NO: 13, and a light chain variable region CDR1, CDR2, and CDR3 domain having the sequence set forth in SEQ ID NO: 14. In some aspects, 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 aspects, 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 aspects, the anti-PD-1 antibody comprises heavy and light chains comprising the sequences shown in SEQ ID NOs: 11 and 12, respectively.

[0022] In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) comprises a soluble PD-L2 polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a fusion polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a ligand-binding fragment of the PD-L2 extracellular domain. In some aspects, the soluble PD-L2 polypeptide further comprises a half-life extending portion. In some aspects, the half-life extending portion comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin binding polypeptide, immunoglobulin G (IgG), an albumin binding polypeptide (ABP), a PASylated portion, a HESylated portion, an XTEN, a PEGylated portion, an Fc region, or any combination thereof. In some aspects, the soluble PD-L2 polypeptide comprises AMP-224.

[0023] In some aspects, the PD-1 pathway inhibitors in (a) and / or (b) include anti-PD-L1 antibodies. In some aspects, anti-PD-L1 antibodies include full-length antibodies. In some aspects, anti-PD-L1 antibodies include monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies or multispecific antibodies. In some aspects, multispecific antibodies include DART, DVD-Ig or bispecific antibodies. In some aspects, anti-PD-L1 antibodies include F(ab')2 fragments, Fab' fragments, Fab fragments, Fv fragments, scFv fragments, dsFv fragments, dAb fragments or single-chain binding polypeptides. In some aspects, anti-PD-L1 antibodies include BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301 or antigen-binding portions thereof.

[0024] In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) comprises BMS-986189.

[0025] In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at a steady dose. In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at a steady 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 400 mg. In some embodiments, the present invention provides a dosage 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. In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at 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 4.5mg, 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 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

[0026] In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at a dose based on body weight. In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at a dose based on body weight. In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) 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, 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 10 mg / kg. / kg to about 0.8 mg / 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. g / 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, 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.In some aspects, the PD-1 pathway inhibitor in (a) and / or (b) is administered at 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 / 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.

[0027] In some aspects, the dosage of the PD-1 pathway inhibitor in (a) and (b) is different.

[0028] In some aspects, the dose of the PD-1 pathway inhibitor in (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.

[0029] In some aspects, CCRT includes platinum doublet chemotherapy (PDCT). In some aspects, PDCT includes a combination of platinum agents and nucleoside analogs, antimetabolites, taxanes, vinca alkaloids or topoisomerase inhibitors. In some aspects, platinum agents include cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposome cisplatin (lipoplatin) or phenoplatin. In some aspects, platinum agents include cisplatin. In some aspects, platinum agents include carboplatin. In some aspects, nucleoside analogs include cytarabine, gemcitabine, lamivudine, entecavir or telbivudine. In some aspects, nucleoside analogs include gemcitabine. In some aspects, antimetabolites include capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate or thioguanine. In some aspects, antimetabolites include pemetrexed. In some aspects, taxanes include paclitaxel, albumin-bound paclitaxel, docetaxel, or cabazitaxel. In some aspects, vinca alkaloids include vinblastine, vincristine, vinorelbine, vindesine, vinaminol, vinnepine, or vinbutrin. In some aspects, vinca alkaloids include vinorelbine or vinblastine. In some aspects, topoisomerase inhibitors include etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some aspects, topoisomerase inhibitors include etoposide. In some aspects, topoisomerase inhibitors include irinotecan. In some aspects, PDCT includes a combination of cisplatin or carboplatin with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan. In some aspects, PDCT comprises a combination of cisplatin or carboplatin and paclitaxel or nab-paclitaxel. In some aspects, PDCT comprises a combination of cisplatin or carboplatin and pemetrexed. In some aspects, PDCT comprises a combination of cisplatin or carboplatin and etoposide.

[0030] In some aspects, CCRT includes thoracic radiation therapy and / or volumetric arc modulated radiation therapy (VMAT), intensity modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT).

[0031] In some aspects, the LAG-3 antagonist comprises an anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody comprises a full-length antibody. In some aspects, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some aspects, the anti-LAG-3 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 aspects, the anti-LAG-3 antibodies include BMS-986016 (relatlimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramilimab), 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 aspects, the anti-LAG-3 antibody comprises a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 3, and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 4. In some aspects, 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 aspects, 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 aspects, 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 aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences shown in SEQ ID NOs: 21 and 2, respectively.

[0032] In some aspects, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide comprises a fusion polypeptide. In some aspects, the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. In some aspects, 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 aspects, the soluble LAG-3 polypeptide further comprises a half-life-extending moiety. In some aspects, 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 PASylated moiety, a HESylated moiety, an XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide comprises IMP321 (Eftilagimod Alpha).

[0033] In some aspects, the LAG-3 antagonist is administered at a steady state dose. In some aspects, the LAG-3 antagonist is administered at a steady state 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 400 mg, about 20 In some embodiments, the present invention provides a dosage of about 100 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 aspects, the LAG-3 antagonist is administered at 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, 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

[0034] In some aspects, the LAG-3 antagonist is administered at a weight-based dose. In some aspects, 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, 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 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 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 The invention also provides a dosage of about 15 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 aspects, the LAG-3 antagonist is administered at 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 or about 25.0 mg / kg.

[0035] In some aspects, the dose of the LAG-3 antagonist 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.

[0036] In some aspects, the PD-1 pathway inhibitor, CCRT in (a), the PD-1 pathway inhibitor in (b), and / or the LAG-3 antagonist are formulated for intravenous administration.

[0037] In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist in (b) are formulated separately. In some aspects, the PD-1 pathway inhibitor in (b) is administered before the LAG-3 antagonist. In some aspects, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor in (b). In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist in (b) are administered simultaneously.

[0038] In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist in (b) are formulated together.

[0039] In some aspects, the PD-1 pathway inhibitor and LAG-3 antagonist in (b) is administered as maintenance therapy. In some aspects, the maintenance therapy is administered for up to about 1 year.

[0040] The present disclosure relates to methods of treating a human subject having NSCLC with squamous or non-squamous histology, the methods comprising: (a) administering to the subject about 360 mg of an anti-PD-1 antibody comprising a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 13 and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 14, and CCRT, the CCRT comprising PDCT and radiation therapy; (b) providing the subject with a recovery period, the recovery period beginning after completion of the administration in (a); and subsequently (c) administering to the subject a maintenance therapy comprising about 480 mg of the anti-PD-1 antibody comprising a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 13 and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence shown in SEQ ID NO: 14, and about 480 mg of an anti-LAG-3 antibody. The anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 4.

[0041] In some aspects, PDCT comprises cisplatin and etoposide. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 100 mg / m2 is administered on days 1, 2, and 3 of each cycle. 2 etoposide, and the etoposide is administered after the anti-PD-1 antibody on day 1 of each cycle, and wherein about 80 mg / m2 is administered after etoposide on day 1 of each cycle 2 In some aspects, cisplatin and etoposide are each administered intravenously over about 60 minutes.

[0042] In some aspects, PDCT comprises carboplatin and paclitaxel. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 175 mg / m2 is administered on day 1 of the first cycle. 2 or about 200 mg / m 2Paclitaxel, with approximately 45 mg / m2 administered on days 1, 8, and 15 of the second and third cycles 2 or about 50 mg / m 2 In some aspects, the present invention provides a method for treating a patient with paclitaxel, wherein the paclitaxel is administered after the anti-PD-1 antibody on day 1 of each cycle, and wherein carboplatin is administered at a target AUC of about 5 mg / mL·min or about 6 mg / mL·min on day 1 of the first cycle, wherein carboplatin is administered at a target AUC of about 2 mg / mL·min on days 1, 8, and 15 of the second and third cycles, and wherein carboplatin is administered after paclitaxel in each cycle. In some aspects, carboplatin is administered intravenously over about 30 minutes, and paclitaxel is administered intravenously over about 180 minutes in the first cycle, and over about 60 minutes in the second and third cycles.

[0043] In some aspects, PDCT comprises cisplatin and pemetrexed. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 500 mg / m 2 is administered after the anti-PD-1 antibody on day 1 of each cycle. 2 and wherein about 75 mg / m is administered after pemetrexed on day 1 of each cycle. 2 In some aspects, cisplatin is administered intravenously over about 60 minutes, and pemetrexed is administered intravenously over about 10 minutes. In some aspects, if the subject is intolerant to cisplatin, cisplatin is replaced with carboplatin, with a target concentration-time area under the curve (AUC) of about 5 mg / mL min. In some aspects, carboplatin is administered intravenously over about 30 minutes. In some aspects, if the subject is intolerant to pemetrexed, pemetrexed is replaced with etoposide.

[0044] In some aspects, the anti-PD-1 antibody in (a) is administered intravenously over about 30 minutes.

[0045] In some respects, radiotherapy is used after PDCT, and comprises the dosage of about 60Gy to about 66Gy. In some respects, radiotherapy comprises chest radiotherapy and / or volumetric arc modulated radiation therapy (VMAT), intensity modulated radiation therapy (IMRT) or three-dimensional conformal radiation therapy (3DRT). In some respects, radiotherapy starts on the 1st day of the second and third cycle, and comprises the daily portion of about 30 to about 33 times 2Gy, and its scheme is about 5 days irradiation and 2 days rest, continues about 6 weeks to about 7 weeks.

[0046] In some aspects, the recovery period is a duration sufficient for the subject to recover from CCRT-related toxicities other than fatigue, esophagitis, or alopecia. In some aspects, 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 after the last administration of the anti-PD-1 antibody in (a), about 18 days to about 9 weeks after the last administration of the anti-PD-1 antibody in (a), or about 18 days to about 6 weeks after the last administration of the anti-PD-1 antibody in (a).

[0047] In some aspects, the method is first-line therapy.

[0048] In some aspects, the subject has not received prior local or systemic anti-cancer therapy administered as primary therapy for locally advanced disease.

[0049] In some aspects, 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.

[0050] In some aspects, the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

[0051] In some aspects, the method is a second-line therapy. In some aspects, the method is a third-line therapy. In some aspects, the subject has disease progression on prior therapy. In some aspects, the NSCLC has recurred after multimodality therapy for locally advanced NSCLC.

[0052] In some aspects, the NSCLC is unresectable, advanced, recurrent, and / or metastatic.

[0053] In some aspects, the NSCLC has squamous or non-squamous histology.

[0054] In some aspects, the NSCLC comprises locally advanced stage IIIA, IIIB, or IIIC NSCLC.

[0055] In some aspects, the subject has not had NSCLC progression during CCRT or recovery.

[0056] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are administered about once every 4 weeks.

[0057] In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are formulated separately. In some aspects, the anti-PD-1 antibody in (b) is administered before the anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody is administered before the anti-PD-1 antibody in (b). In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are administered simultaneously.

[0058] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are formulated together.

[0059] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are administered intravenously over about 30 minutes.

[0060] In some aspects, the anti-PD-1 antibodies in (a) and / or (b) include full-length antibodies. In some aspects, the anti-PD-1 antibodies in (a) and / or (b) include monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies or multispecific antibodies. In some aspects, multispecific antibodies include DART, DVD-Ig or bispecific antibodies. In some aspects, the anti-PD-1 antibodies in (a) and / or (b) include F(ab')2 fragments, Fab' fragments, Fab fragments, Fv fragments, scFv fragments, dsFv fragments, dAb fragments or single-chain binding polypeptides. In some aspects, the anti-PD-1 antibody of (a) and / or (b) 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 aspects, 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. In some aspects, 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.

[0061] In some aspects, the anti-LAG-3 antibody comprises a full-length antibody. In some aspects, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody. In some aspects, the anti-LAG-3 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 aspects, 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 aspects, 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 aspects, 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 aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively.

[0062] In some aspects, one or more immune cells in a tumor tissue from a subject express LAG-3. In some aspects, 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 aspects, at least about 1% of the immune cells express LAG-3. In some aspects, the immune cells include tumor infiltrating lymphocytes. In some aspects, the tumor infiltrating lymphocytes include CD8 + cell.

[0063] In some aspects, one or more nucleated cells in a tumor tissue from a subject express LAG-3. In some aspects, 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 aspects, at least about 1% of the nucleated cells express LAG-3.

[0064] In some aspects, one or more tumor cells in a tumor tissue from a subject express PD-L1. In some aspects, 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 aspects, at least about 1% of the tumor cells express PD-L1.

[0065] In some aspects, any of these methods further includes administering another therapeutic agent to the subject. In some aspects, the other therapeutic agent includes an anticancer agent. In some aspects, the anticancer agent includes 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 aspects, the tyrosine kinase inhibitor includes afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, alectinib, brigatinib, ceritinib, crizotinib, lorlatinib, entrectinib, dabrafenib, trametinib, vemurafenib, larotrectinib, or any combination thereof. In some aspects, the anti-angiogenic agent includes an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase with 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), multimeric protein 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof. In some aspects, the anti-angiogenic agent comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, olaratumab, nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.In some aspects, 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-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B 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 (TGF-β) inhibitors. ) 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-induced 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 advantage (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors or any combination thereof. In some aspects, checkpoint inhibitors include CTLA-4 inhibitors. In some aspects, CTLA-4 inhibitors include anti-CTLA-4 antibodies. In some aspects, anti-CTLA-4 antibodies include full-length antibodies. In some aspects, anti-CTLA-4 antibodies include monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies or multispecific antibodies. In some aspects, multispecific antibodies include DART, DVD-Ig or bispecific antibodies. In some aspects, anti-CTLA-4 antibodies include F(ab')2 fragments, Fab' fragments, Fab fragments, Fv fragments, scFv fragments, dsFv fragments, dAb fragments or single-chain binding polypeptides. In some aspects, anti-CTLA-4 antibodies include ipilimumab, tremelimumab, MK-1308, AGEN-1884 or their antigen-binding portions. DETAILED DESCRIPTION

[0066] The present disclosure provides a method for treating a human subject having lung cancer (e.g., non-small cell lung cancer (NSCLC)), the method comprising administering to the subject: (a) a programmed death-1 (PD-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) 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 aspects, the method comprises a recovery period (e.g., about 3 weeks to about 6 weeks) that begins when administration of the PD-1 pathway inhibitor and CCRT in (a) is completed and ends when administration of the PD-1 pathway inhibitor and LAG-3 antagonist in (b) begins. In some aspects, the PD-1 pathway inhibitor and LAG-3 antagonist in (b) are administered as maintenance therapy (e.g., for up to one year). I. Terminology

[0067] In order to be able to more easily understand this disclosure, first define some terms. As used in this application, unless otherwise clearly provided in the text, each of the following terms should have the implication of the following statement. Other definitions are set forth in the entire application. It should be noted that the term "one / kind (a or an)" entity refers to one or more entities; for example, "nucleotide sequence" should be construed as representing one or more nucleotide sequences. Therefore, the terms "one / kind (a or an)", "one / kind or more / kind" and "at least one / kind" can be used interchangeably in this article.

[0068] As used herein, the term "and / or" should be taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as 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 cover each of the following: 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).

[0069] It should be understood that any aspect described herein using the word "comprising" also provides other similar aspects described as "consisting of" and / or "consisting essentially of.

[0070] The term "about" or "consisting essentially of..." refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which 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 "consisting essentially of..." can mean within 1 or more than 1 standard deviations according to practice in the art. Alternatively, "about" or "consisting essentially of..." can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). For example, about 3 mg can include any value between 2.7 mg and 3.3 mg (for 10%) or 2.4 mg and 3.6 mg (for 20%). In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. When a specific value or composition is provided in the present application and claims, unless otherwise stated, the meaning of "about" or "consisting essentially of..." should be assumed to be within an acceptable error range for that specific value or composition.

[0071] As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the range, and where appropriate, fractions thereof (e.g., tenths and hundredths of integers).

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. 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 a general dictionary for many of the terms used in this disclosure.

[0073] Units, prefixes, and symbols are denoted in their SI accepted form. Numerical ranges are inclusive of the numbers defining the range.

[0074] The headings provided herein are not limitations of the various aspects of the disclosure, which can be obtained by reference to the specification as a whole. Accordingly, the terms defined below are more fully defined by reference to the entire content of the specification.

[0075] "Antagonists" shall include, but are 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 aspects, antagonists are antibodies. In other aspects, antagonists include small molecules. The terms "antagonist" and "inhibitor" are used interchangeably herein.

[0076] "Antibody" (Ab) shall include, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen and comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as V H ) and the heavy chain constant region (abbreviated herein as C H The heavy chain constant region includes three constant domains C H1 、C H2 and C H3 Each light chain includes a light chain variable region (abbreviated herein as V L ) and the light chain constant region (abbreviated herein as C L The light chain constant region contains a constant domain C L . V H and V L The V region can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It comprises three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxyl terminus: 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 an antibody can 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 indicated herein, the amino acids in the variable region are numbered using the Kabat numbering system, and the amino acids in the constant region are numbered using the EU system.

[0077] Immunoglobulin can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art, including but not limited to human IgG1, IgG2, IgG3 and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene. The term "antibody" includes, for example, naturally occurring antibodies and non-naturally occurring antibodies; monoclonal antibodies and polyclonal antibodies; chimeric antibodies and humanized antibodies; human antibodies or non-human antibodies; fully synthetic antibodies; single-chain antibodies; monospecific antibodies; bispecific antibodies; and multispecific antibodies. Non-human antibodies can be humanized to reduce their immunogenicity in humans by recombinant methods. In the absence of explicit instructions, and unless the context indicates otherwise, the term "antibody" also includes the antigen-binding fragment or antigen-binding portion of any of the above-mentioned immunoglobulins, and includes 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 derived from papain cleavage) or fragments consisting of V L 、V H , L C and C H1 (2) F(ab')2 fragments (fragments derived from pepsin cleavage) or similar bivalent fragments, which contain two Fab fragments connected by a disulfide bond at the hinge region; (3) Fd fragments consisting of VH and CH1 domains; (4) Fd fragments consisting of a single-arm V L and V H (5) single domain antibody (dAb) fragments (Ward et al., (1989) Nature 341:544-46), which are composed of V H domain; (6) consists of two V H domains (dual affinity retargeting antibodies (DARTs)); or (7) dual variable domain immunoglobulins. In addition, although the two domains V L and V H are encoded by separate genes, but they can be joined using recombinant methods by a synthetic linker that enables them to be made into a single protein chain, where V L and V H The domains pair to form monovalent molecules (termed single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0078] An "isolated antibody" is an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds LAG-3 is substantially free of antibodies that do not specifically bind LAG-3). However, an isolated antibody that specifically binds LAG-3 may have cross-reactivity with other antigens (e.g., LAG-3 molecules from different species). Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0079] The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules that are substantially identical in primary sequence and exhibit a single binding specificity and affinity for a particular epitope. mAbs are examples of isolated antibodies. mAbs can be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0080] "HuMAb" refers to an antibody with a variable region, wherein the framework region and the CDR region are derived from human germline immunoglobulin sequences. In addition, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species (e.g., mouse) have been transplanted onto human framework sequences. The terms "human" antibody and "fully human" antibody are used synonymously.

[0081] 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 are replaced with corresponding amino acids derived from human immunoglobulins. In one aspect of the humanized form of an antibody, some, most, or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, while some, most, or all of the amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permitted as long as they do not eliminate the ability of the antibody to bind to a specific antigen. A "humanized" antibody retains antigenic specificity similar to that of the original antibody.

[0082] A "chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species, eg, an antibody in which the variable region is derived from a mouse antibody and the constant region is derived from a human antibody.

[0083] An "anti-antigen" antibody is an antibody that specifically binds to an antigen. For example, an anti-LAG-3 antibody specifically binds to LAG-3.

[0084] "LAG-3" refers to lymphocyte activation gene-3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, in some cases, antibodies specific for human LAG-3 protein may cross-react with LAG-3 proteins from species other than human. In other aspects, antibodies 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 all other species (e.g., cross-react with monkey LAG-3 but not mouse LAG-3). The term "human LAG-3" refers to the complete amino acid sequence of human LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank Accession No. NP_002277. The term "mouse LAG-3" refers to the complete amino acid sequence of mouse 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 as CD223, for example. The human LAG-3 sequence may differ from the human LAG-3 of GenBank Accession No. NP_002277, for example, by having a conservative mutation or a mutation in a non-conserved region, and the LAG-3 may have substantially the same biological function as the human LAG-3 of GenBank Accession No. NP_002277. For example, the biological function of human LAG-3 may be to have an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the disclosure, or the biological function of human LAG-3 may be to bind to an MHC class II molecule.

[0085] A specific human LAG-3 sequence will generally be at least about 90% identical in amino acid sequence to the human LAG-3 of GenBank Accession No. NP_002277 and contain amino acid residues that identify the amino acid sequence as human when compared to LAG-3 amino acid sequences of other species (e.g., mouse). In some cases, the human LAG-3 may be 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 in amino acid sequence to the LAG-3 of GenBank Accession No. NP_002277. In certain aspects, 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 aspects, the human LAG-3 sequence will exhibit no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the LAG-3 sequence of GenBank Accession No. NP_002277.

[0086] "Programmed death-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is primarily expressed on previously 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 common 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.

[0087] "Cytotoxic T lymphocyte antigen-4 (CTLA-4)" refers to an immunoinhibitory 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 common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank accession number AAB59385.

[0088] "Programmed death ligand-1 (PD-L1)" is one of the two cell surface glycoprotein ligands of PD-1 (the other is PD-L2), which downregulates T cell activation and cytokine secretion after 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 have at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank accession number Q9NZQ7.

[0089] As used herein, "programmed death ligand-2 (PD-L2)" includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, as well as analogs that share at least one common epitope with hPD-L2. The complete hPD-L2 sequence can be found under GenBank accession number Q9BQ51.

[0090] As used herein, "patient" includes any patient with lung cancer (eg, NSCLC). The terms "subject" and "patient" are used interchangeably herein.

[0091] " administration " refers to any one of various methods well known to persons skilled in the art and delivery system by which therapeutic agent is physically introduced into a subject (for example, a composition or formulation comprising a therapeutic agent). Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, phrase " parenteral administration " refers to a mode of administration except enteral and topical administration, typically by injection, and includes but is not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion and in vivo electroporation. In some aspects, formulation is administered via non-parenteral route, in some aspects, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, such as intranasal, vaginal, rectal, sublingual or topical. Administration can also be carried out, such as once, repeatedly and / or in one or more extended time periods.

[0092] "Treatment" or "therapy" of a subject refers to any type of intervention or procedure performed on a subject, or the administration of an active agent to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing the progression, development, severity, or recurrence of a symptom, complication, or condition, or a biochemical marker associated with the disease. Response Evaluation Criteria in Solid Tumors (RECIST) is a measure of treatment efficacy and is an established rule for determining when a tumor responds, stabilizes, or progresses during treatment. RECIST 1.1 is the current guideline for the measurement and definition of solid tumors used in adult and pediatric cancer clinical trials for objective assessment of changes in tumor size.

[0093] As used herein, "maintenance therapy" refers to therapy intended to prevent the development or recurrence of a tumor.

[0094] As used herein, a "recovery period" is a duration that begins upon completion of one therapy and ends upon initiation of another therapy (e.g., a duration that begins upon completion of CCRT as disclosed herein and ends upon administration of a combination therapy and / or maintenance therapy as disclosed herein (e.g., a combination of a PD-1 pathway inhibitor and a LAG-3 antagonist as disclosed herein). In some aspects, the recovery period is a duration sufficient for a subject to recover from an adverse event or serious adverse event associated with the therapy (e.g., a duration sufficient for a subject to recover from a toxicity associated with CCRT as disclosed herein other than fatigue, esophagitis, or alopecia).

[0095] As used herein, "effective treatment" refers to treatment that produces a beneficial effect, such as an improvement in at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement relative to a baseline, i.e., an improvement relative to a measurement or observation made before initiation of therapy according to the method. A beneficial effect can also take the form of preventing, slowing, delaying, or stabilizing the adverse progression of a solid tumor marker. Effective treatment can refer to alleviation of at least one symptom of a solid tumor. Such effective treatment can, for example, relieve pain in the patient, reduce the size and / or number of lesions, reduce or prevent metastasis of the tumor, and / or slow tumor growth.

[0096] The term "effective amount" refers to the amount of a pharmaceutical agent that provides a desired biological, therapeutic and / or preventive result. The result can be a reduction, improvement, alleviation, reduction, delay and / or alleviation of one or more signs, symptoms or causes of a disease, or any other desired change in a biological system. With respect to solid tumors, an effective amount includes an amount sufficient to shrink the tumor and / or reduce the tumor growth rate (e.g., inhibit tumor growth) or delay other unwanted cell proliferation. In some aspects, 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 down and prevent cancer cells from infiltrating into peripheral organs to a certain extent; (iv) inhibit (i.e., slow down and prevent tumor metastasis to a certain extent); (v) inhibit tumor growth; (vi) prevent or delay the occurrence and / or recurrence of a tumor; and / or (vii) alleviate one or more of the symptoms associated with cancer to a certain extent. In one example, an "effective amount" is an amount of an anti-LAG-3 antibody alone or in combination with an additional therapeutic agent (e.g., an anti-PD-1 antibody) that clinically demonstrates a significant reduction in cancer or slows the progression of cancer (e.g., an advanced solid tumor).

[0097] As used herein, the terms "fixed dose," "stable dose," and "stable fixed dose" are used interchangeably and refer to a dose that is administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed or steady dose is not provided in mg / kg doses, but rather in absolute amounts of the agent (e.g., in μg or mg).

[0098] The use of the term "fixed dose combination" with respect to the compositions of the present invention means that two or more different inhibitors described herein (e.g., an anti-LAG-3 antibody and an anti-PD-1 antibody) are present in a single composition at a specific (fixed) ratio relative to one another. In some aspects, the fixed dose is based on the weight of the inhibitor (e.g., mg). In certain aspects, the fixed dose is based on the concentration of the inhibitor (e.g., mg / ml). In some aspects, 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 1: 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 ratio of mg first inhibitor to mg 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.

[0099] The term "weight-based dose" referred to herein means a dose administered to a patient calculated based on the patient's weight.

[0100] As used herein, "dosing interval" refers to the amount of time that passes between administration of multiple doses of a formulation disclosed herein to a subject. Thus, the dosing interval can be expressed as a range.

[0101] As used herein, the term "dosing frequency" refers to the frequency at which a dosage of a formulation disclosed herein is administered within a given time. Dosing frequency can be expressed as the number of doses per given time, such as once a week or once every two weeks, etc.

[0102] As used herein, the terms "about once a week," "about once a week," "about once every two weeks," or any other similar dosing interval terms mean approximate quantities, and "about once a week" or "about once a week" can include every seven days ± two days, i.e., every five days to every nine days. Thus, a dosing frequency of "once a week" can be every five days, every six days, every seven days, every eight days, or every nine days. "About once every three weeks" can include every 21 days ± 3 days, i.e., every 25 days to every 31 days. Similar approximations apply, for example, about once every two 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, and about once every twelve weeks. In some aspects, a dosing interval of about once every six weeks or about once every twelve weeks means that the first dose can be administered on any day of the first week, and then the next dose can be administered on any day of the sixth week or the twelfth week, respectively. In other aspects, a dosing interval of about once every six weeks or about once every twelve weeks means that the first dose is administered on a particular day (e.g., Monday) of the first week, and the next dose is administered on the same day (i.e., Monday) of the sixth or twelfth week, respectively.

[0103] As used herein, an "adverse event (AE)" is any unfavorable and generally unintended or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to treatment. A medical treatment may have one or more associated AEs, each of which may have the same or different severity.

[0104] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, whether benign (non-cancerous) or malignant (cancerous), including precancerous lesions.

[0105] As used herein, the term "biological sample" refers to a biological material separated from a subject. A biological sample can contain any biological substance suitable for analysis, for example, by sequencing the nucleic acid in a tumor (or circulating tumor cells), and identifying the genomic changes in the sequenced nucleic acid. A biological sample can be any suitable biological tissue or fluid, such as tumor tissue, blood, plasma, and serum. A biological sample can be a test tissue sample (for example, a tissue sample comprising tumor cells and tumor-infiltrating inflammatory cells). On the one hand, the sample is a tumor tissue biopsy, such as formalin-fixed, paraffin-embedded (FFPE) tumor tissue or freshly frozen tumor tissue, etc. On the other hand, a biological sample is a liquid biopsy, and in some aspects, a liquid biopsy includes one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.

[0106] For example, an "anticancer agent" promotes the regression of cancer in a subject. In preferred aspects, a therapeutically effective amount of an agent promotes the regression of cancer to the extent that the cancer is eliminated. "Promoting cancer regression" means that the administration of an effective amount of an anticancer agent, alone or in combination with another drug, results in slowing tumor growth or reducing tumor size, tumor necrosis, reducing the severity of at least one disease symptom, increasing the frequency and duration of disease-free periods, or preventing damage or disability caused by disease affliction. In addition, the terms "effective" and "effectiveness" with respect to treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of an agent to promote the regression of cancer in a patient. Physiological safety refers to the level of toxicity caused by the administration of an agent or other adverse physiological effects (adverse effects) at the cell, organ and / or organism level.

[0107] For example, for the treatment of tumors, a therapeutically effective amount of an anticancer agent can inhibit cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject. In other aspects of the present disclosure, tumor regression can be observed and persists for a period of at least about 20 days, more preferably at least about 40 days, or at least about 60 days. Despite these measures of therapeutic effectiveness, the evaluation of immunotherapy drugs must also take into account immune-related response patterns.

[0108] As used herein, "immuno-oncology" therapy or "IO" or "IO" therapy refers to a therapy that includes the use of an immune response to target and treat a subject's tumor. Therefore, as used herein, IO therapy is an anti-cancer therapy. In some aspects, IO therapy includes administering an antibody to a subject. In some aspects, IO therapy includes administering an immune cell, such as a T cell, such as a modified T cell, such as a T cell modified to express a chimeric antigen receptor or a specific T cell receptor, to a subject. In some aspects, IO therapy includes administering a therapeutic vaccine to a subject. In some aspects, IO therapy includes administering a cytokine or chemokine to a subject. In some aspects, IO therapy includes administering an interleukin to a subject. In some aspects, IO therapy includes administering an interferon to a subject. In some aspects, IO therapy includes administering a colony stimulating factor to a subject.

[0109] "Immune response" refers to the action 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 produced by any of these cells or the liver (including antibodies, cytokines, and complement) that result in the selective targeting, binding, damage, destruction, and / or elimination from the body of a vertebrate of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or (in the case of autoimmunity or pathological inflammation) normal human cells or tissues.

[0110] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are any type of cell that typically participates in the inflammatory response in a subject and infiltrates tumor tissue. These cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0111] The terms "LAG-3 positive" or "LAG-3 expression positive" in relation to LAG-3 expression refer to tumor tissue (e.g., a test tissue sample) 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., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells that express LAG-3 (i.e., the ratio of LAG-3-expressing immune cells to total nucleated cells, e.g., greater than or equal to 1% expression).

[0112] "LAG-3 negative" or "LAG-3 expression negative" refers to tumor tissue (eg, a test tissue sample) that is not assessed as expressing LAG-3 (eg, less than 1% LAG-3 expression in immune cells and / or nucleated cells).

[0113] The terms "PD-1 positive" or "PD-1 expression positive" in relation 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., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells that express PD-1 (i.e., the ratio of immune cells expressing PD-1 to total nucleated cells, e.g., greater than or equal to 1% expression).

[0114] "PD-1 negative" or "PD-1 expression negative" refers to a tumor tissue (eg, a test tissue sample) that is not scored as expressing PD-1 (eg, less than 1% PD-1 expression).

[0115] The terms "PD-L1 positive" or "PD-L1 expression positive" in relation 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 expressing PD-L1 (e.g., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells expressing PD-L1 (i.e., the proportion of tumor cells expressing PD-L1 to total nucleated cells, e.g., greater than or equal to 1% expression).

[0116] The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (eg, a test tissue sample) that is not scored as expressing PD-L1 (eg, less than 1% expression).

[0117] Various aspects of the invention are described in further detail in the following subsections. II. Methods of the Disclosure

[0118] Provided herein are methods for treating human subjects with lung cancer, comprising administering to the subject: (a) a programmed death-1 (PD-1) pathway inhibitor (e.g., an anti-PD-1 antibody) and concurrent chemoradiotherapy (CCRT, i.e., concurrent chemotherapy and radiotherapy, such as platinum-doublet chemotherapy (PDCT) and radiotherapy), 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 in (b) is also interchangeably referred to herein as a 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).

[0119] In some aspects, the method further includes providing a recovery period to the subject, which begins when the administration in (a) is completed and ends when the administration in (b) begins. In some aspects, the recovery period is a duration sufficient for the subject to recover from adverse events associated with the administration in (a). In some aspects, the adverse event is a serious adverse event. In some aspects, the recovery period is a duration sufficient for the subject to recover from toxicities associated with CCRT other than fatigue, esophagitis or alopecia. In some aspects, the PD-1 pathway inhibitor in (a) is administered before CCRT. In some aspects, the recovery period begins when CCRT is completed. In some aspects, the chemotherapy of CCRT is administered before the radiotherapy of CCRT. In some aspects, the recovery period begins after radiotherapy is completed. In some aspects, the recovery period is from 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 from the last administration of the PD-1 pathway inhibitor in (a) (e.g., from the last dose of the PD-1 pathway inhibitor when the administration in (a) comprises multiple doses of the PD-1 pathway inhibitor) to about 12 weeks, about 18 days to about 9 weeks from the last administration of the PD-1 pathway inhibitor in (a), or about 18 days to about 6 weeks from the last administration of the PD-1 pathway inhibitor in (a).

[0120] In some aspects, the method is first-line (1L) therapy.

[0121] In some aspects, the method is a second-line (2L) therapy.

[0122] In some aspects, the method is a third-line (3L) therapy.

[0123] In some aspects, the subject has progressed on previous therapy (e.g., standard of care therapy). Standard of care therapy for different types of cancer is well known to those skilled in the art. For example, the National Comprehensive Cancer Network (NCCN), an alliance of 21 major cancer centers in the United States, has published the NCCN Clinical Practice Guidelines in Oncology (NCCN). ), which provide detailed, up-to-date information on standard-of-care treatments for various cancers. See NCCN 2022-2023, https: / / www.nccn.org / guidelines / category_1, last accessed December 20, 2022.

[0124] In some aspects, the lung cancer relapses after multimodality therapy for locally advanced lung cancer.

[0125] In some aspects, the subject has not received prior local or systemic anti-cancer therapy administered as primary therapy for locally advanced disease.

[0126] In some aspects, 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.

[0127] In some aspects, the subject has not received previous immuno-oncology (IO) therapy. In some aspects, the subject has never received IO therapy, has received IO therapy for cancers other than lung cancer, or has received IO therapy for previous lung cancer rather than current lung cancer. In some aspects, the subject has not received previous IO therapy, the subject has not received previous IO therapy for lung cancer, or their lung cancer has not received previous IO therapy. In some aspects, previous IO therapy is an antibody. In some aspects, the antibody binds to a checkpoint inhibitor. In some aspects, previous IO therapy is a combination of an anti-PD-1 antibody and / or an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0128] In some aspects, the methods of the present disclosure may increase the duration of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), or any combination thereof, compared to standard of care therapy (e.g., maintenance therapy with durvalumab following CCRT) and / or prior therapies as disclosed herein.

[0129] In some aspects, the methods of the present disclosure reduce tumor size, inhibit tumor growth, eliminate a tumor in a subject, prevent recurrence of lung cancer, induce remission of lung cancer, provide complete remission or partial remission, or any combination thereof.

[0130] In some aspects, the methods of the present disclosure are administered to a subject based on the subject's performance status and / or cancer stage.Performance status and / or cancer stage can be indicated by any one or more systems known in the art.

[0131] In some aspects, the lung cancer is unresectable, advanced, recurrent, and / or metastatic.

[0132] In some aspects, performance status is indicated by the Eastern Cooperative Oncology Group Performance Status (ECOG PS), which utilizes standardized criteria to measure how the disease affects a patient's ability to perform daily activities. Example definitions of ECOGPS include: "0" indicating that the patient is fully active and able to perform all pre-disease manifestations without limitation; "1" indicating that the patient is limited in vigorous physical activity but is ambulatory and able to perform light or sedentary work; "2" indicating that the patient is ambulatory, able to perform self-care, and is out of bed and active for more than 50% of waking hours, but is unable to perform any work activities; "3" indicating that the patient is able to perform only limited self-care and is confined to a bed or chair for more than 50% of waking hours; and "4" indicating that the patient is completely disabled, unable to perform any self-care, and is completely bedridden or in a wheelchair.

[0133] In some aspects, the subject has an ECOGPS of 0, 1, 2, 3, or 4. In some aspects, the subject has an ECOGPS of ≤ 3. In some aspects, the subject has an ECOGPS of ≤ 2. In some aspects, the subject has an ECOGPS of ≤ 1.

[0134] In some aspects, lung cancer is staged based on the tumor (T) / node (N) / metastasis (M) staging system (T / N / M), such as the American Joint Committee on Cancer (AJCC) classification. See, for example, https: / / www.cancer.org / cancer / lung-cancer / detection-diagnosis-staging / staging-nsclc.html, last accessed December 20, 2022.

[0135] Stages of lung cancer (e.g., NSCLC) include: occult (hidden) stage, stage 0 (carcinoma in situ), stage I (e.g., stage IA1, IA2, IA3, and IB NSCLC), stage II (e.g., stage IIA and IIB NSCLC), stage III (e.g., stage IIIA, IIIB, and IIIC NSCLC), and stage IV (e.g., stage IVA and IVB NSCLC).

[0136] In some aspects, the subject has occult (hidden) stage lung cancer (e.g., NSCLC). In the occult stage, the cancer cannot be observed by imaging or bronchoscopy (TX), has not spread to lymph nodes (N0), and has not metastasized (M0) (TX / N0 / M0).

[0137] In some aspects, the subject has stage 0 lung cancer (e.g., NSCLC). In stage 0 (Tis / N0 / M0), cancer cells are only found in the lining of the airways and have not yet invaded deeper into other lung tissues (Tis). N0 and M0 are as described above.

[0138] In some aspects, the subject suffers from stage I lung cancer (e.g., NSCLC). For NSCLC, stage I lung cancer is divided into, for example, stage IA1, stage IA2, stage IA3, and stage IB. N0 and M0 are as described above. In stage IA1 (T1mi / N0 / M0), the cancer is a microinvasive adenocarcinoma, and the tumor transverse diameter is no more than 3 centimeters (cm), wherein the transverse diameter of the part invading deeper lung tissue is no more than 0.5 cm (T1mi). In stage IA1 (T1a / N0 / M0), the tumor transverse diameter is no more than 1 cm, does not grow into the membrane surrounding the lung, and does not affect the main branches of the bronchus (T1a). In stage IA2 (T1b / N0 / M0), the tumor transverse diameter is greater than 1 cm but no more than 2 cm, does not grow into the membrane surrounding the lung, and does not affect the main branches of the bronchus (T1b). In stage IA3 (T1c / N0 / M0), the tumor is larger than 2 cm but no larger than 3 cm across, has not grown into the membrane surrounding the lung, and does not affect the main branches of the bronchi (T1c). In stage IB (T2a / N0 / M0), one or more of the following must be met: 1) the tumor is larger than 3 cm but no larger than 4 cm across; 2) the cancer has spread to the main bronchi and is at least 2 cm below where the trachea joins the bronchus; 3) the cancer has spread to the innermost layer of the membrane covering the lung and is no larger than 4 cm across; or 4) the tumor is no larger than 4 cm across but partially blocks the airway (T2a).

[0139] In some aspects, the subject suffers from stage II lung cancer (e.g., NSCLC). For NSCLC, stage II is divided into, for example, stage IIA (T2b / N0 / M0) and stage IIB (T1a / T1b / T1c / N1 / M0 or T2a / T2b / N1 / M0 or T3 / N0 / M0). N0 and M0 are as described above. In stage IIA, one or more of the following is met: 1) the tumor is greater than 4 cm in transverse diameter but not greater than 5 cm in transverse diameter; 2) the cancer has spread to the main bronchi, located at least 2 centimeters below the trachea where the bronchus is connected, and the tumor is greater than 4 cm in transverse diameter but not greater than 5 cm in transverse diameter; 3) the cancer has spread to the innermost layer of the membrane covering the lungs, and the tumor is greater than 4 cm in transverse diameter but not greater than 5 cm in transverse diameter; or 4) the tumor is greater than 4 cm in transverse diameter but not greater than 5 cm in transverse diameter and partially blocks the airway (T2b). In stage IIB, the cancer has spread to or has not yet spread to the lymph nodes. If cancer has spread to the lymph nodes, it must have spread only to lymph nodes on the same side of the chest as the tumor, and the lymph nodes with cancer are located inside a lung or near a bronchus (N1). For T1a / T1b / T1c / N1 / M0, the tumor is no larger than 3 cm across, 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 must be met: 1) the tumor is larger than 3 cm but no larger than 5 cm across; 2) the cancer has spread to the main bronchus, at least 2 cm below where the trachea joins the bronchus, and the tumor is no larger than 5 cm across; 3) the cancer has spread to the innermost layer of the membrane covering the lung and is no larger than 5 cm across; or 4) the tumor is no larger than 5 cm across and partially blocks the airway (T2a / T2b). In 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 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) there are two or more separate tumor nodules in the same lobe of the lung (T3).

[0140] In some aspects, the subject suffers from stage III lung cancer (e.g., NSCLC). For NSCLC, the 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), 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. For N2, cancer has spread to the lymph nodes around the carina or in the mediastinum on the same side of the tumor. For N3, the cancer has spread to lymph nodes near the clavicle on either side of the body and / or has spread from the primary tumor to the hilar or mediastinal lymph nodes on the other side of the body. For T4, one or more of the following is true: 1) the tumor is larger than 7 cm in diameter; 2) the tumor has grown into the mediastinum, heart, large blood vessels near the heart (such as the aorta), trachea, esophagus, diaphragm, spine, or carina; or 3) there are two or more tumor nodules in different lobes of the same lung.

[0141] In some aspects, the subject has stage IV lung cancer (e.g., NSCLC). For NSCLC, stage IV is divided into, for example, stage IVA (any T / any N / M1a or any T / any N / M1b) and stage IVB (any T / any N / M1c). For any T, the tumor can be any size and may have grown into nearby structures or not yet grown. For any N, the cancer may have reached or not yet reached nearby lymph nodes. For M1a, one or more of the following is met: 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. For M1b, the cancer has spread as a single tumor to distant lymph nodes or another organ (e.g., liver, bones, or brain). For M1c, the cancer has spread as two or more tumors to distant lymph nodes and / or another organ (e.g., liver, bones, or brain).

[0142] In some aspects, the lung cancer is small cell lung cancer (SCLC). In some aspects, SCLC is staged using the T / N / M classification. In some aspects, SCLC is staged as limited-stage or extensive-stage, rather than using the T / N / M classification. Limited-stage SCLC is confined to one lung and / or regional lymph nodes. Extensive-stage SCLC is found in both lungs and / or distant sites in the body.

[0143] In some aspects, lung cancer is non-small cell lung cancer (NSCLC). NSCLC includes NSCLC with "not otherwise specified" (NOS) histology, NSCLC with squamous histology (SQ) and NSCLC with non-squamous histology (NSQ, including adenocarcinoma, large cell carcinoma and undifferentiated carcinoma). In some aspects, NSCLC has squamous histology. In some aspects, NSCLC has non-squamous histology. In some aspects, the staging of NSCLC adopts T / N / M staging. In some aspects, NSCLC includes locally advanced IIIA, IIIB or IIIC stage NSCLC. In some aspects, the subject does not experience lung cancer progression during CCRT or the recovery period of the method disclosed herein.

[0144] Surgery (i.e., surgical resection), radiotherapy (RT, also referred to interchangeably herein as radiotherapy) and chemotherapy are three common modalities for treating patients with NSCLC. As a category, NSCLC is relatively insensitive to chemotherapy and RT compared to small cell carcinoma. In general, for patients with stage I or II disease, surgical resection offers the best chance of cure, and chemotherapy is usually used before and after surgery. RT can also be used as an adjuvant therapy for patients with resectable NSCLC, as a primary local treatment, or as palliative therapy for patients with incurable NSCLC. Patients with good performance status (PS) who have advanced or metastatic disease (e.g., stage IV NSCLC) may benefit from chemotherapy.

[0145] Specific targeted therapies have also been 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 accelerated fibrosarcoma proto-oncogene (BRAF, e.g., BRAF V600E mutation).

[0146] In some aspects, the subject has an EGFR, ALK, NTRK, ROS-1, or BRAF mutation that is sensitive to targeted inhibitor therapy.

[0147] In some aspects, the subject does not have an EGFR, ALK, NTRK, ROS-1, or BRAF mutation that is sensitive to targeted inhibitor therapy. II.A PD-1 pathway inhibitors

[0148] In some aspects, 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.

[0149] In some aspects, 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.

[0150] In some aspects, the PD-1 pathway inhibitors administered with CCRT and / or LAG-3 antagonists include PD-1 inhibitors and / or PD-L1 inhibitors. In some aspects, the PD-1 inhibitors and / or PD-L1 inhibitors include small molecules. In some aspects, the PD-1 inhibitors and / or PD-L1 inhibitors include millimolecular molecules. In some aspects, the PD-1 inhibitors and / or PD-L1 inhibitors include macrocyclic peptides. In some aspects, the PD-1 inhibitors and / or PD-L1 inhibitors include BMS-986189. In some aspects, the PD-1 inhibitors include inhibitors disclosed in International Publication No. WO 2014 / 151634, which are incorporated herein by reference in their entirety. In some aspects, the PD-1 inhibitor is INCMGA00012 (Insight Pharmaceuticals). In some aspects, the PD-1 inhibitors include a combination of anti-PD-1 antibodies and PD-1 small molecule inhibitors disclosed herein. In some aspects, the PD-L1 inhibitors include millimolecular molecules having the formula shown in formula (I): where R 1 -R 13 is the amino acid side chain; R a -R n is hydrogen, methyl, or forms a ring with an adjacent R group, and R 14 Yes – C(O)NHR 15 , where R 15is hydrogen or a glycine residue, which is optionally substituted with another glycine residue and / or a tail that can improve pharmacokinetic properties. In some aspects, PD-L1 inhibitors include compounds disclosed in International Publication No. WO 2014 / 151634, which is incorporated herein by reference in its entirety. In some aspects, the PD-L1 inhibitors include compounds disclosed in International Publication Nos. 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 herein incorporated by reference in its entirety. In some aspects, the PD-L1 inhibitor includes a small molecule PD-L1 inhibitor disclosed in International Publication Nos. WO 2015 / 034820, WO 2015 / 160641, WO 2018 / 044963, WO 2017 / 066227, WO 2018 / 009505, WO 2018 / 183171, WO 2018 / 118848, WO 2019 / 147662, or WO 2019 / 169123, each of which is herein incorporated by reference in its entirety.

[0151] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or LAG-3 antagonists comprises a soluble PD-L2 polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a fusion polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a ligand binding fragment of the PD-L2 extracellular domain. In some aspects, the soluble PD-L2 polypeptide further comprises a half-life extending portion. In some aspects, the half-life extending portion comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin binding polypeptide, immunoglobulin G (IgG), an albumin binding polypeptide (ABP), a PASylated portion, a HESylated portion, an XTEN, a PEGylated portion, an Fc region, or any combination thereof. In some aspects, the soluble PD-L2 polypeptide is AMP-224 (see, e.g., US2013 / 0017199).

[0152] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0153] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist is administered at a leveling dose.

[0154] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist is administered at a 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 400 mg. The present invention relates to a pharmaceutical composition comprising the pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises a pharmaceutical composition comprising: ...

[0155] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist is administered 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, about 4.2 5mg, 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 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

[0156] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist is administered at a weight-based dose.

[0157] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a 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, about 0.003 mg / kg to about 0.8 mg / 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 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 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 The invention also provides a method for the administration of a dosage of about 1 mg / kg to about 2 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.

[0158] In some aspects, the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist is administered at 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, 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 25.0 mg / kg.

[0159] In some aspects, the dose of the PD-1 pathway inhibitor administered with CCRT is different than the dose of the PD-1 pathway inhibitor administered with the LAG-3 antagonist.

[0160] In some aspects, the dose of the PD-1 pathway inhibitor administered with CCRT and / or a LAG-3 antagonist 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.

[0161] In some aspects, a PD-1 pathway inhibitor is administered with CCRT as disclosed herein for three 21-day cycles.

[0162] In some aspects, a PD-1 pathway inhibitor is administered with a LAG-3 antagonist as disclosed herein approximately once every four weeks as maintenance therapy. II.A.1 Anti-PD-1 Antibodies

[0163] Anti-PD-1 antibodies known in the art can be used in the methods disclosed herein. U.S. Patent No. 8,008,449 discloses various human monoclonal antibodies that specifically bind to PD-1 with high affinity. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been shown to exhibit one or more of the following characteristics: (a) a 1×10 -7 M or lower K D Binds to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; (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 monkey PD-1; (g) inhibits the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulates an antigen-specific memory response; (i) stimulates an antibody response; and (j) inhibits tumor cell growth in vivo. Anti-PD-1 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some aspects at least five, of the aforementioned characteristics.

[0164] Other anti-PD-1 monoclonal antibodies that can be used in the methods of the present disclosure have been described, for example, in U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. Publication No. 2016 / 0272708, and PCT Publication Nos. WO 2012 / 145493, WO 2008 / 156712, WO 2015 / 112900, WO 2012 / 145493, WO 2015 / 112800, WO 2014 / 206107, WO 2015 / 35606, WO 2015 / 085847, WO 2014 / 179664, WO 2017 / 020291, WO 2017 / 020858, WO 2016 / 197367, WO 2017 / 024515, WO 2017 / 025051, WO 2017 / 123557, WO 2016 / 106159, WO 2014 / 194302, WO 2017 / 040790, WO 2017 / 133540, WO 2017 / 132827, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 106061, WO 2017 / 19846, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825 and WO 2017 / 133540, each of which is incorporated by reference in its entirety.

[0165] Anti-PD-1 antibodies that can be used in the methods of the present disclosure include nivolumab (also known as 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as 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 Biopharmaceuticals; also known as ANB011 or dostarlimab; see WO 2014 / 179664), cemiplizumab (Regeneron; also known as or REGN2810; see WO 2015 / 112800 and U.S. Patent No. 9,987,500), JS001 (TAIZHOU JUNSHIPHARMA); also known as toripalimab; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), PF-06801591 (Pfizer; also known as sasanlimab; US2016 / 0159905), BGB-A317 (BeiGene; also known as tislelizumab; see WO 2015 / 35606 and US2015 / 0079109), BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018); 78(13 Suppl):Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; see WO 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.[Journal of Hematology and Oncology] 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 [monoclonal antibodies] 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, US2018 / 0346569).

[0166] Anti-PD-1 antibodies useful in the methods of the present disclosure also include isolated antibodies that specifically bind to human PD-1 and cross-compete 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) for binding to human PD-1. In some aspects, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein (e.g., nivolumab).

[0167] In some aspects, antibodies that cross-compete for binding to human PD-1 or bind to the same epitope region as any of the anti-PD-1 antibodies disclosed herein (e.g., nivolumab) are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, 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.

[0168] The ability of an antibody to cross-compete for binding to an antigen indicates that the antibody binds to the same epitope region of the antigen and sterically hinders other cross-competing antibodies from binding to that specific epitope region. It is expected that these cross-competing antibodies have very similar functional properties to the reference antibody (e.g., nivolumab) due to binding to the same epitope region. Cross-competing antibodies can be easily identified based on their cross-competitive ability in standard binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO 2013 / 173223).

[0169] Anti-PD-1 antibodies useful in the disclosed methods also include antigen-binding portions of any of the above-described full-length antibodies. It has been well documented that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0170] The anti-PD-1 antibodies that can be used in the methods of the present disclosure are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any composition or method disclosed herein, the anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of the intact antibody in inhibiting ligand binding and upregulating the immune system. In certain aspects, the anti-PD-1 antibody or its antigen-binding portion cross-competes with nivolumab for binding to human PD-1.

[0171] In some aspects, the anti-PD-1 antibody comprises a full-length antibody.

[0172] In some aspects, the anti-PD-1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a dual affinity retargeting antibody (DART), a DVD-Ig, or a bispecific antibody.

[0173] In some aspects, the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0174] In some aspects, the anti-PD-1 antibody includes nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplizumab, 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.

[0175] In some aspects, the anti-PD-1 antibody is formulated for intravenous administration.

[0176] In some aspects, the anti-PD-1 antibody is administered intravenously for about 30 minutes.

[0177] In some aspects, the anti-PD-1 antibody includes nivolumab. Nivolumab is 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 the downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol. Res. [Cancer Immunology Research] 2(9):846-56).

[0178] In some aspects, nivolumab is administered at a steady-state dose of about 240 mg approximately once every 2 weeks. In some aspects, nivolumab is administered at a steady-state dose of about 240 mg approximately once every 3 weeks. In some aspects, nivolumab is administered at a steady-state dose of about 360 mg approximately once every 3 weeks. In some aspects, nivolumab is administered at a steady-state dose of about 480 mg approximately once every 4 weeks.

[0179] In some aspects, nivolumab is administered intravenously over about 30 minutes on day 1 of a two-week cycle at a dose of about 240 mg.

[0180] In some aspects, nivolumab is administered intravenously over about 30 minutes on day 1 of a three-week cycle at a dose of about 360 mg.

[0181] In some aspects, nivolumab is administered intravenously over about 30 minutes on day 1 of a four-week cycle at a dose of about 480 mg.

[0182] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 13 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 14.

[0183] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 20.

[0184] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 13 and 14, respectively.

[0185] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 11 and 12, respectively.

[0186] In some aspects, the anti-PD-1 antibody includes pembrolizumab. Pembrolizumab is 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.

[0187] In some aspects, pembrolizumab is administered approximately once every 2 weeks at a steady-state dose of about 200 mg. In some aspects, pembrolizumab is administered approximately once every 3 weeks at a steady-state dose of about 200 mg. In some aspects, pembrolizumab is administered approximately once every 6 weeks at a steady-state dose of about 400 mg. In some aspects, pembrolizumab is administered approximately once every 4-5 weeks at a steady-state dose of about 300 mg.

[0188] In some aspects, pembrolizumab is administered intravenously at a dose of about 200 mg on day 1 and about every 3 weeks thereafter.

[0189] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO:79 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO:80.

[0190] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 81; (b) a heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 82; (c) a heavy chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 83; (d) a light chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 84; (e) a light chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 85; and (f) a light chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 86.

[0191] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 79 and 80, respectively.

[0192] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 77 and 78, respectively.

[0193] In some aspects, the anti-PD-1 antibody comprises cemiplimab (REGN2810). Cemiplimab is described, for example, in WO 2015 / 112800 and U.S. Pat. No. 9,987,500.

[0194] In some aspects, cemiplimab is administered intravenously at a dose of about 3 mg / kg or about 350 mg about once every 3 weeks.

[0195] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 35 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 36.

[0196] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 37; (b) a heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 38; (c) a heavy chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 39; (d) a light chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 40; (e) a light chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 41; and (f) a light chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 42.

[0197] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 35 and 36, respectively.

[0198] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 33 and 34, respectively.

[0199] In some aspects, the anti-PD-1 antibody comprises spartalizumab (PDR001). Spartalizumab is described, for example, in WO 2015 / 112900 and U.S. Pat. No. 9,683,048.

[0200] In some aspects, spartalizumab is administered intravenously at a dose of about 300 mg about once every 3 weeks or at a dose of 400 mg about once every 4 weeks.

[0201] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 59 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 60.

[0202] In some aspects, the methods of the present disclosure include an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 61; (b) a heavy chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 62; (c) a heavy chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 63; (d) a light chain variable region CDR1 comprising the sequence shown in SEQ ID NO: 64; (e) a light chain variable region CDR2 comprising the sequence shown in SEQ ID NO: 65; and (f) a light chain variable region CDR3 comprising the sequence shown in SEQ ID NO: 66.

[0203] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 59 and 60, respectively.

[0204] In some aspects, the methods of the disclosure include an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 57 and 58, respectively. II.A.2 Anti-PD-L1 Antibodies

[0205] Anti-PD-L1 antibodies known in the art can be used in the methods of the present disclosure. Examples of anti-PD-L1 antibodies that can be used in the compositions and methods of the present disclosure include antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibodies disclosed in U.S. Patent No. 9,580,507 have been shown to exhibit one or more of the following characteristics: (a) a 1×10 -7 M or lower K D Binds to human PD-L1 as measured by surface plasmon resonance using a Biacore biosensor system; (b) increases T cell proliferation in a mixed lymphocyte reaction (MLR) assay; (c) increases interferon-γ production in an MLR assay; (d) increases IL-2 secretion in an MLR assay; (e) stimulates an antibody response; and (f) reverses the effects of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one of the aforementioned characteristics, and in some aspects at least five.

[0206] Anti-PD-L1 antibodies that can be used in the methods of the present 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 MPDL3280A, RG7446; see US 8,217,149; see also Herbst et al. (2013) J Clin Oncol 31(Suppl):3000), durvalumab (AstraZeneca; also known as IMFINZI TM , MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; also known as MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO 2013 / 181634), CX-072 (Cytomx; see WO 2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017)), LY3300054 (Eli Lilly and Company; see, e.g., WO 2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO 36(15 Suppl):TPS3113 (2018)), ICO 36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see, e.g., WO 2017 / 034916). Therapeutics); see Gorelik et al., AACR: Abstract 4606 (April 2016).

[0207] Anti-PD-L1 antibodies that can be used in the present disclosure methods also include antibodies that specifically bind to human PD-L1 and cross-compete with any anti-PD-L1 antibody disclosed herein (e.g., atezolizumab, durvalumab and / or avelumab) for binding to human PD-L1. In some aspects, the anti-PD-L1 antibody binds to the same epitope as any anti-PD-L1 antibody described herein (e.g., atezolizumab, durvalumab and / or avelumab). In certain aspects, the antibody that cross-competes with any anti-PD-L1 antibody disclosed herein (e.g., atezolizumab, durvalumab and / or avelumab) for binding to human PD-L1 or binds to the same epitope region is a monoclonal antibody. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, 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.

[0208] Anti-PD-L1 antibodies useful in the methods of the disclosure also include antigen-binding portions of any of the above-described full-length antibodies.

[0209] The anti-PD-L1 antibodies that can be used in the methods of the present disclosure are antibodies that bind to PD-L1 with high specificity and affinity, block the binding of PD-1, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any composition or method disclosed herein, the anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to those of the intact antibody in inhibiting receptor binding and upregulating the immune system. In certain aspects, the anti-PD-L1 antibody or its antigen-binding portion cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0210] In some aspects, in any of the methods disclosed herein, an anti-PD-L1 antibody is substituted for an anti-PD-1 antibody.

[0211] In some aspects, the anti-PD-L1 antibody comprises a full-length antibody.

[0212] In some aspects, the anti-PD-L1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0213] In some aspects, the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0214] In some aspects, the anti-PD-L1 antibody includes BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen-binding portion thereof.

[0215] In some aspects, the PD-L1 antibody comprises atezolizumab. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some aspects, atezolizumab is administered approximately once every two weeks at a steady dose of about 800 mg. In some aspects, atezolizumab is administered approximately once every two weeks at a steady dose of about 840 mg.

[0216] In some aspects, atezolizumab is administered intravenously on day 1 of a three-week cycle at a dose of about 1,200 mg.

[0217] In some aspects, the PD-L1 antibody comprises Imfinzi. Imfinzi is a human IgG1κ monoclonal anti-PD-L1 antibody. In some aspects, Imfinzi is administered approximately every 2 weeks at a dose of about 10 mg / kg. In some aspects, Imfinzi is administered approximately every 2 weeks at a dose of about 10 mg / kg for up to 12 months. In some aspects, Imfinzi is administered approximately every 2 weeks at a steady-state dose of about 800 mg / kg. In some aspects, Imfinzi is administered approximately every 3 weeks at a steady-state dose of about 1200 mg / kg.

[0218] In some aspects, the PD-L1 antibody comprises avelumab. Avelumab is a human IgG1λ monoclonal anti-PD-L1 antibody. In some aspects, avelumab is administered at a steady dose of about 800 mg approximately once every 2 weeks. II.B CCRT

[0219] Concurrent chemoradiotherapy (CCRT) known in the art as well as CCRT disclosed herein can be used in the disclosed methods.

[0220] In some aspects, CCRT comprises platinum-doublet chemotherapy (PDCT).

[0221] In some aspects, PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topoisomerase inhibitor.

[0222] In some aspects, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, liposomal cisplatin, or phenanthreneplatin. In some aspects, the platinum agent comprises cisplatin. In some aspects, the platinum agent comprises carboplatin.

[0223] In some aspects, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some aspects, the nucleoside analog comprises gemcitabine.

[0224] In some aspects, antimetabolites include capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some aspects, antimetabolites include pemetrexed.

[0225] In some aspects, the taxane comprises paclitaxel, nab-paclitaxel (also known as nab-paclitaxel), docetaxel, or cabazitaxel. In some aspects, the taxane comprises paclitaxel.

[0226] In some aspects, the vinca alkaloid comprises vinblastine, vincristine, vinorelbine, vindesine, vinaminol, vindesine, or vinbutrin. In some aspects, the vinca alkaloid comprises vinorelbine or vinblastine.

[0227] In some aspects, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan or camptothecin. In some aspects, the topoisomerase inhibitor comprises etoposide. In some aspects, the topoisomerase inhibitor comprises irinotecan.

[0228] In some aspects, PDCT administration continues 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.

[0229] In some aspects, PDCT is administered about every three weeks for about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 cycles. In some aspects, PDCT is administered about every three weeks for about 1, about 2, about 3, about 4, about 5, or about 6 cycles. In some aspects, PDCT is administered about every three weeks for about 1, about 2, about 3, about 4, about 5, or about 6 cycles. In some aspects, PDCT is administered about every three weeks for about 1, about 2, about 3, or about 4 cycles. In some aspects, PDCT is administered for three 21-day cycles.

[0230] In some aspects, the platinum agent comprises cisplatin. In some aspects, cisplatin is administered at about 25 mg / m 2 Up to about 150 mg / m 2 , about 50mg / m 2 to about 100 mg / m 2 , about 75mg / m 2 to about 100 mg / m 2 or about 75 mg / m 2 Up to about 80 mg / m 2 In some aspects, 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 2In some aspects, cisplatin is administered intravenously over a period of about 60 minutes. In some aspects, cisplatin is administered on day 1 of each of three 21-day cycles.

[0231] In some aspects, platinum agents include carboplatin. In some aspects, carboplatin is administered at a dosage of about 1 mg / mL min to about 10 mg / mL min of the target concentration-time area under the curve (AUC). In some aspects, carboplatin is administered at a dosage 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 of the target AUC. In some aspects, carboplatin is administered at a dosage of about 2 mg / mL min of the target AUC. In some aspects, carboplatin is administered at a dosage of about 5 mg / mL min or about 6 mg / mL min of the target AUC. In some aspects, carboplatin is administered at a dosage of about 5 mg / mL min of the target AUC. In some aspects, carboplatin is administered at a dosage of about 6 mg / mL min of the target AUC. In some aspects, carboplatin is administered intravenously for about 30 minutes. In some aspects, carboplatin is administered on day 1 of each of three 21-day cycles. In some aspects, carboplatin is administered on day 1 of the first 21-day cycle and on days 1, 8, and 15 of each of the second and third 21-day cycles.

[0232] Carboplatin dosage can be calculated according to methods known in the art. In some aspects, the carboplatin dosage is calculated using the following Calvert formula: Carboplatin dose (mg) = target AUC x (CrCl [mL / min] + 25). Creatinine clearance (CrCl) calculation in the Calvert formula can be determined using the Cockcroft-Gault formula: Cockcroft-Gault CrCl = [(140 - age) x (weight (kg)) x (0.85 (if female))] / (72 x Cr). The Cockcroft-Gault formula includes the subject's most recent weight (kg) and most recent serum creatinine (Cr) concentration (mg / dL). In some aspects, if the CrCl calculated by the Cockcroft-Gault formula produces a result >125 mL / min, the CrCl is calculated by an alternative formula or capped at 125 mL / min according to institutional standards.

[0233] In some aspects, PDCT comprises cisplatin or carboplatin in combination with gemcitabine, paclitaxel, nab-paclitaxel, docetaxel, pemetrexed, vinorelbine, vinblastine, etoposide, or irinotecan.

[0234] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and gemcitabine. In some aspects, gemcitabine is administered at about 1,000 mg / m 2 to about 1,250 mg / m 2 In some aspects, 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 about 1,250 mg / m 2 In some aspects, gemcitabine is administered intravenously over about 30 minutes. In some aspects, 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 aspects, 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 aspects, PDCT comprises administering about 1,000 mg / m2 of gemcitabine on days 1 and 8 of a three-week cycle for about 3 cycles. 2 to about 1,250 mg / m 2 The dose of gemcitabine was approximately 75 mg / m2 administered on day 1 of each cycle. 2 Up to about 80 mg / m 2 In some aspects, gemcitabine is administered intravenously over about 30 minutes and cisplatin is administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 1,000 mg / m 2 administered on days 1, 8, and 15 of a three-week cycle for about three cycles. 2 A dose of gemcitabine and carboplatin is administered at a dose of about 5 mg / mL·min with a target AUC on day 1 of each cycle. In some aspects, gemcitabine and carboplatin are each administered intravenously over about 30 minutes.

[0235] In some aspects, PDCT comprises cisplatin or carboplatin in combination with paclitaxel or nab-paclitaxel.

[0236] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and paclitaxel. In some aspects, paclitaxel is administered at a dose of about 45 mg / m 2 to about 200 mg / m 2 In some aspects, 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 / m 2 , 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 aspects, paclitaxel is administered intravenously over about 60 minutes to about 180 minutes. In some aspects, PDCT comprises administering on day 1 of a three-week cycle for about three cycles of about 175 mg / m 2 or about 200 mg / m 2 The dose of paclitaxel was approximately 75 mg / m2 administered on day 1 of each cycle. 2 Up to about 80 mg / m 2 In some aspects, PDCT comprises about 135 mg / m 2 administered on day 1 of a three-week cycle for about three cycles. 2 The dose of paclitaxel was approximately 75 mg / m2 administered on day 1 of each cycle. 2 In some aspects, paclitaxel is administered intravenously over about 180 minutes and cisplatin is administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 175 mg / m 2 administered on day 1 of the first three-week cycle.2 or about 200 mg / m 2 In some aspects, PDCT comprises a dose of paclitaxel and carboplatin administered at a target AUC of about 5 mg / mL·min or about 6 mg / mL·min on day 1 of the cycle. In some aspects, in the first cycle, paclitaxel is administered intravenously over about 180 minutes and carboplatin is administered intravenously over about 30 minutes. In some aspects, PDCT comprises about 45 mg / mL·min administered on days 1, 8, and 15 of the second and third three-week cycles. 2 or about 50 mg / m 2 In some aspects, the paclitaxel is administered intravenously over about 60 minutes and the carboplatin is administered intravenously over about 30 minutes on days 1, 8, and 15 of each of the second and third cycles. In some aspects, the carboplatin is administered after the paclitaxel in each cycle.

[0237] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and nab-paclitaxel. In some aspects, nab-paclitaxel is administered at a dose of about 100 mg / m 2 In some aspects, nab-paclitaxel is administered intravenously over about 30 minutes. In some aspects, PDCT comprises administering about 100 mg / m2 on days 1, 8, and 15 of a three-week cycle for about three cycles. 2 The dose of nab-paclitaxel is approximately 75 mg / m2 administered on day 1 of each cycle. 2 Up to about 80 mg / m 2 In some aspects, nab-paclitaxel is administered intravenously over about 30 minutes and cisplatin is administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 100 mg / m 2 administered on days 1, 8, and 15 of a three-week cycle for about three cycles. 2 A dose of nab-paclitaxel and carboplatin is administered at a dose with a target AUC of about 6 mg / mL·min on day 1 of each cycle. In some aspects, nab-paclitaxel and carboplatin are each administered intravenously over about 30 minutes.

[0238] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and docetaxel. In some aspects, docetaxel is administered at a dose of about 75 mg / m 2 In some aspects, docetaxel is administered intravenously over about 60 minutes. In some aspects, PDCT comprises administering on day 1 of a three-week cycle for about three cycles of about 75 mg / m 2 Docetaxel doses were approximately 75 mg / m2 administered on day 1 of each cycle. 2In some aspects, docetaxel and cisplatin are each administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 75 mg / m 2 administered on day 1 of a three-week cycle for about three cycles. 2 A dose of docetaxel and carboplatin is administered at a dose of about 6 mg / mL·min at a target AUC on day 1 of each cycle. In some aspects, docetaxel is administered intravenously over about 60 minutes and carboplatin is administered intravenously over about 30 minutes.

[0239] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and pemetrexed. In some aspects, pemetrexed is administered at about 500 mg / m 2 In some aspects, pemetrexed is administered intravenously over about 10 minutes. In some aspects, PDCT comprises administering about 500 mg / m 2 on day 1 of a three-week cycle for about three cycles. 2 The dose of pemetrexed is approximately 75 mg / m2 administered on day 1 of each cycle. 2 In some aspects, pemetrexed is administered intravenously over about 10 minutes and cisplatin is administered intravenously over about 60 minutes. In some aspects, cisplatin is administered after pemetrexed. In some aspects, if the subject is intolerant to cisplatin, carboplatin is substituted for cisplatin. In some aspects, PDCT comprises about 500 mg / m 2 administered on day 1 of a three-week cycle for about three cycles. 2 In some aspects, the subject is administered a dose of pemetrexed and carboplatin at a target AUC of about 5 mg / mL min on day 1 of each cycle. In some aspects, the pemetrexed is administered intravenously over about 10 minutes, and the carboplatin is administered intravenously over about 30 minutes. In some aspects, the carboplatin is administered after the pemetrexed. In some aspects, if the subject is intolerant to pemetrexed, etoposide is substituted for pemetrexed.

[0240] In some aspects, PDCT comprises a combination of cisplatin or carboplatin and etoposide. In some aspects, etoposide is administered at a dose of about 50 mg / m 2 to about 100 mg / m 2 In some aspects, etoposide is administered intravenously over about 30 minutes to about 60 minutes. In some aspects, PDCT comprises administering about 100 mg / m2 on days 1, 2, and 3 of a three-week cycle for about three cycles. 2 The dose of etoposide is approximately 80 mg / m2 administered on day 1 of each cycle. 2 In some aspects, etoposide and cisplatin are each administered intravenously over about 60 minutes. In some aspects, cisplatin is administered after etoposide. In some aspects, PDCT comprises about 100 mg / m 2 administered on days 1, 2, and 3 of a three-week cycle for about three cycles. 2In some aspects, etoposide and carboplatin are administered intravenously over about 30 minutes, with a dose of etoposide and a target AUC of about 5 mg / mL·min on day 1 of each cycle. In some aspects, etoposide and carboplatin are each administered intravenously over about 30 minutes. In some aspects, carboplatin is administered after etoposide.

[0241] In some aspects, PDCT comprises cisplatin and vinorelbine. In some aspects, vinorelbine is administered at a dose of about 25 mg / m 2 to about 30 mg / m 2 In some aspects, vinorelbine is administered intravenously over about 5 minutes to about 10 minutes. In some aspects, PDCT comprises administering about 25 mg / m2 on days 1 and 8 of a three-week cycle for about 3 cycles. 2 to about 30 mg / m 2 The dose of vinorelbine was approximately 75 mg / m2 on day 1 of each cycle. 2 Up to about 80 mg / m 2 In some aspects, vinorelbine is administered intravenously over about 5 minutes to about 10 minutes, and cisplatin is administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 25 mg / m 2 administered on days 1, 8, 15, and 22 of a three-week cycle for about three cycles. 2 The dose of vinorelbine was approximately 50 mg / m2 on days 1 and 8 of each cycle. 2 In some aspects, vinorelbine is administered intravenously over about 5 minutes to about 10 minutes, and cisplatin is administered intravenously over about 60 minutes. In some aspects, PDCT comprises about 30 mg / m 2 administered on days 1, 8, 15, and 22 of a three-week cycle for about three cycles. 2 The dose of vinorelbine was approximately 100 mg / m2 on day 1 of each cycle. 2 Dosage of Cisplatin. In some aspects, vinorelbine is administered intravenously over about 5 minutes to about 10 minutes, and cisplatin is administered intravenously over about 60 minutes.

[0242] In some aspects, CCRT includes thoracic radiation therapy and / or volumetric arc modulated radiation therapy (VMAT), intensity modulated radiation therapy (IMRT), or three-dimensional conformal radiation therapy (3DRT).

[0243] In some aspects, radiation therapy begins on day 1 of the second and third cycles and comprises about 30 to about 33 daily fractions of 2 Gy, with a schedule of about 5 days of radiation and 2 days of rest, for about 6 to about 7 weeks. II.C LAG-3 antagonists

[0244] 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."

[0245] In some aspects, the LAG-3 antagonist comprises an anti-LAG-3 antibody.

[0246] Antibodies that bind to LAG-3 have been disclosed, for example, in International Publication No. WO / 2015 / 042246 and U.S. Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is herein incorporated by reference in its entirety.

[0247] Exemplary LAG-3 antibodies useful in the present disclosure include 25F7 (described in U.S. Publication No. 2011 / 0150892). Another exemplary LAG-3 antibody useful in the present disclosure includes BMS-986016 (relalizumab). In some aspects, the anti-LAG-3 antibodies useful in the present disclosure can cross-compete with 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibodies useful in the present disclosure can bind to the same epitope as 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibodies include the six CDRs of 25F7 or BMS-986016.

[0248] Other art-recognized anti-LAG-3 antibodies that can be used in the methods of the present disclosure include IMP731 (H5L7BW, described in US2011 / 007023), MK-4280 (28G-10, mavezelimab, described in WO 2016 / 028672 and U.S. Publication No. 2020 / 0055938), REGN3767 (furanlimab, described in Burova E et al., J. Immunother. Cancer (2016); 4(Suppl 1): P195 and U.S. Patent No. 10,358,495), humanized BAP050 (described in WO 2017 / 019894), GSK2831781, IMP-701 (LAG525; elalimumab, described in U.S. Patent No. 10,711,060 and U.S. Publication No. 2020 / 0172617), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tepolizumab), 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 present invention can be found, for example, in US 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO 2017 / 062888, WO 2009 / 044273, WO 2018 / 069500, WO 2016 / 126858, WO 2014 / 179664, WO 2016 / 200782, WO 2015 / 200119, WO 2017 / 019846, WO 2017 / 198741, WO 2017 / 220555, WO 2017 / 220569, WO 2018 / 071500, WO 2017 / 015560, WO 2017 / 025498, WO 2017 / 087589, WO 2017 / 087901, WO 2018 / 083087, WO 2017 / 149143, WO 2017 / 219995, US 2017 / 0260271, WO 2017 / 086367, WO 2017 / 086419, WO 2018 / 034227, 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 these references are incorporated by reference in their entirety.

[0249] Anti-LAG-3 antibodies useful in the methods of the present disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete for binding to human LAG-3 with any of the anti-LAG-3 antibodies disclosed herein (e.g., relalizumab). In some aspects, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein (e.g., relalizumab).

[0250] In some aspects, antibodies that cross-compete for binding to human LAG-3 or bind to the same epitope region as any of the anti-LAG-3 antibodies disclosed herein (e.g., relalizumab) 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.

[0251] Anti-LAG-3 antibodies useful in the methods of the disclosure also include antigen-binding portions of any of the above-described full-length antibodies.

[0252] In some aspects, the anti-LAG-3 antibody comprises a full-length antibody.

[0253] In some aspects, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0254] In some aspects, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0255] In some aspects, the anti-LAG-3 antibodies include BMS-986016 (relalizumab), IMP731 (H5L7BW), MK4280 (28G-10, mavezilimab), REGN3767 (furanlizumab), GSK2831781, humanized BAP050, IMP-701 (LAG525, elalimumab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tepolizumab), 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.

[0256] In some aspects, the anti-LAG-3 antibody is formulated for intravenous administration.

[0257] In some aspects, the anti-LAG-3 antibody is administered intravenously for about 30 minutes.

[0258] In some aspects, the anti-LAG-3 antibody comprises relalizumab.

[0259] In some aspects, the methods of the disclosure include 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.

[0260] 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.

[0261] In some aspects, the methods of the disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 3 and 4, respectively.

[0262] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 1 and 2, respectively.

[0263] In some aspects, the methods of the disclosure comprise 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.

[0264] In some aspects, anti-LAG-3 antibodies include MGD013 (Tepolizumab), which is a bispecific PD-1×LAG-3 DART. In some aspects, Tepolizumab is administered intravenously at a dose of about 300 mg or about 600 mg approximately once every 2 or 3 weeks. In some aspects, Tepolizumab is administered intravenously at a dose of about 300 mg approximately once every 2 weeks. In some aspects, Tepolizumab is administered intravenously at a dose of about 600 mg approximately once every 3 weeks.

[0265] In some aspects, the anti-LAG-3 antibody comprises REGN3767 (Fulimumab). In some aspects, Fulimumab is administered intravenously at a dose of about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 20 mg / kg approximately once every three weeks. In some aspects, Fulimumab is administered intravenously at a dose of about 1600 mg approximately once every three weeks.

[0266] In some aspects, the methods of the disclosure include 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.

[0267] 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.

[0268] In some aspects, the methods of the disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 25 and 26, respectively.

[0269] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 23 and 24, respectively.

[0270] In some aspects, the anti-LAG-3 antibody comprises LAG525 (elalimumab). In some aspects, elalimumab 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 about once every 2, 3, or 4 weeks.

[0271] In some aspects, the methods of the disclosure include 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.

[0272] In some aspects, the methods of the disclosure include 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.

[0273] 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.

[0274] In some aspects, the methods of the disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 47 and 49, respectively.

[0275] In some aspects, the methods of the disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs: 48 and 50, respectively.

[0276] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 43 and 45, respectively.

[0277] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 44 and 46, respectively.

[0278] In some aspects, the anti-LAG-3 antibody comprises MK4280 (mavezimalimab). In some aspects, mavezimalimab 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 approximately once every three weeks or approximately once every six weeks. In some aspects, mavezimalimab is administered intravenously at a dose of about 200 mg approximately once every three weeks. In some aspects, mavezimalimab is administered intravenously at a dose of about 800 mg approximately once every six weeks. In some aspects, mavezimalimab is administered intravenously at a dose of about 800 mg on day 1 and approximately every three weeks thereafter. In some aspects, mavezimalimab is administered for up to 35 cycles. In some aspects, mavezimalimab is administered intravenously on day 1 of a three-week cycle at a dose of about 800 mg for about 30 minutes for up to 35 cycles.

[0279] In some aspects, the methods of the disclosure include 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.

[0280] 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.

[0281] In some aspects, the methods of the disclosure include anti-LAG-3 antibodies comprising heavy and light chain variable regions comprising the sequences shown in SEQ ID NOs: 69 and 70, respectively.

[0282] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 67 and 68, respectively.

[0283] In some aspects, LAG-3 expression is determined using an anti-LAG-3 antibody. In some aspects, 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 aspects, the anti-LAG-3 antibody is capable of binding to LAG-3 in frozen tissue. In some aspects, the anti-LAG-3 antibody is capable of distinguishing between membrane-bound, cytoplasmic, and / or soluble forms of LAG-3.

[0284] In some aspects, the anti-LAG-3 antibody that can be used to analyze, detect, and / or quantify 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 [Proceedings of the National Academy of Sciences of the United States of America] (2010); 107:7875.

[0285] In some aspects, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide is a fusion polypeptide, such as a fusion protein comprising the extracellular portion of LAG-3. In some aspects, the soluble LAG-3 polypeptide is a LAG-3-Fc fusion polypeptide capable of binding to MHC class II. In some aspects, the soluble LAG-3 polypeptide comprises a ligand-binding fragment of the LAG-3 extracellular domain. In some aspects, 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 aspects, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some aspects, 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 PASylated moiety, a HESylated moiety, an XTEN, a PEGylated moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide is IMP321 (etilimod α). See, for example, Brignone C et al., J. Immunol. (2007); 179: 4202-4211 and WO2009 / 044273. In some aspects, etilimod α is administered at a dose of about 30 mg. In some aspects, etilimod α is administered subcutaneously at a dose of about 30 mg approximately once every two weeks.

[0286] In some aspects, the LAG-3 antagonist is administered in a steady dose.

[0287] In some aspects, the LAG-3 antagonist 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, about 20 In some embodiments, the present invention provides a dosage of about 100 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.

[0288] In some aspects, the LAG-3 antagonist is administered at 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, 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

[0289] In some aspects, the LAG-3 antagonist is administered at a weight-based dose.

[0290] In some aspects, 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, 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 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 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 The invention also provides a dosage of about 15 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.

[0291] In some aspects, the LAG-3 antagonist is administered at 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 or about 25.0 mg / kg.

[0292] In some aspects, the dose 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.

[0293] In some aspects, the PD-1 pathway inhibitor administered with CCRT, CCRT, the PD-1 pathway inhibitor administered with a LAG-3 antagonist, and / or the LAG-3 antagonist are formulated for intravenous administration.

[0294] In some aspects, the PD-1 pathway inhibitor administered with the LAG-3 antagonist is formulated separately from the LAG-3 antagonist. In some aspects, the PD-1 pathway inhibitor is administered before the LAG-3 antagonist. In some aspects, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor. In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist are administered simultaneously.

[0295] In some aspects, the PD-1 pathway inhibitor administered with the LAG-3 antagonist is formulated together with the LAG-3 antagonist (e.g., a fixed-dose combination comprising the PD-1 pathway inhibitor and the LAG-3 antagonist).

[0296] In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist are administered approximately once every four weeks. In some aspects, the PD-1 pathway inhibitor and the LAG-3 antagonist are administered together as maintenance therapy. In some aspects, maintenance therapy is administered for up to about 1 year.

[0297] In some aspects, the PD-1 antagonists administered with the LAG-3 antagonist in the methods of the disclosure include nivolumab and relalizumab.

[0298] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (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.

[0299] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown 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 region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively.

[0300] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown 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 shown in SEQ ID NOs: 3 and 4, respectively.

[0301] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 11 and 12, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 1 and 2, respectively.

[0302] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 11 and 12, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 21 and 2, respectively.

[0303] In some aspects, the PD-1 antagonists administered with the LAG-3 antagonist in the methods of the disclosure include pembrolizumab and mavezelizumab.

[0304] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (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.

[0305] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown 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 region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:71, SEQ ID NO:72, and SEQ ID NO:73, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:74, SEQ ID NO:75, and SEQ ID NO:76, respectively.

[0306] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown 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 shown in SEQ ID NOs: 69 and 70, respectively.

[0307] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 77 and 78, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 67 and 68, respectively.

[0308] In some aspects, the PD-1 antagonists administered with the LAG-3 antagonist in the methods of the disclosure include cemiplizumab and foranlimab.

[0309] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (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.

[0310] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 37, SEQ ID NO: 38, and SEQ ID NO: 39, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown 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 region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 27, SEQ ID NO: 28, and SEQ ID NO: 29, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO: 30, SEQ ID NO: 31, and SEQ ID NO: 32, respectively.

[0311] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown 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 shown in SEQ ID NOs: 25 and 26, respectively.

[0312] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 33 and 34, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 23 and 24, respectively.

[0313] In some aspects, the PD-1 antagonists administered with the LAG-3 antagonist in the methods of the disclosure include spartalizumab and elalimumab.

[0314] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (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.

[0315] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (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.

[0316] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:61, SEQ ID NO:62, and SEQ ID NO:63, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown 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 region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:51, SEQ ID NO:52, and SEQ ID NO:53, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences shown in SEQ ID NO:54, SEQ ID NO:55, and SEQ ID NO:56, respectively.

[0317] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown 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 shown in SEQ ID NOs: 47 and 49, respectively.

[0318] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences shown 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 shown in SEQ ID NOs: 48 and 50, respectively.

[0319] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 57 and 58, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 43 and 45, respectively.

[0320] In some aspects, the PD-1 antagonist administered with the LAG-3 antagonist in the methods of the present disclosure includes: (a) an anti-PD-1 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 57 and 58, respectively; and (b) an anti-LAG-3 antibody comprising a heavy chain and a light chain comprising the sequences shown in SEQ ID NOs: 44 and 46, respectively.

[0321] Provided herein are methods of treating a human subject having NSCLC with squamous or non-squamous histology, the methods comprising: (a) administering to the subject about 360 mg of an anti-PD-1 antibody comprising a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence set forth in SEQ ID NO: 13 and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence set forth in SEQ ID NO: 14, and CCRT, the CCRT comprising PDCT and radiation therapy; (b) providing the subject with a recovery period, the recovery period beginning after completion of the administration in (a); and subsequently (c) administering to the subject a maintenance therapy comprising about 480 mg of the anti-PD-1 antibody comprising a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence set forth in SEQ ID NO: 13 and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the sequence set forth in SEQ ID NO: 14, and about 480 mg of an anti-LAG-3 antibody. The anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence shown in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence shown in SEQ ID NO: 4.

[0322] In some aspects, PDCT comprises cisplatin and etoposide. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 100 mg / m2 is administered on days 1, 2, and 3 of each cycle. 2 etoposide, and the etoposide is administered after the anti-PD-1 antibody on day 1 of each cycle, and wherein about 80 mg / m2 is administered after etoposide on day 1 of each cycle 2 In some aspects, cisplatin and etoposide are each administered intravenously over about 60 minutes.

[0323] In some aspects, PDCT comprises carboplatin and paclitaxel. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 175 mg / m2 is administered on day 1 of the first cycle. 2 or about 200 mg / m 2 Paclitaxel, with approximately 45 mg / m2 administered on days 1, 8, and 15 of the second and third cycles 2 or about 50 mg / m 2In some aspects, the present invention provides a method for treating a patient with paclitaxel, wherein the paclitaxel is administered after the anti-PD-1 antibody on day 1 of each cycle, and wherein carboplatin is administered at a target AUC of about 5 mg / mL·min or about 6 mg / mL·min on day 1 of the first cycle, wherein carboplatin is administered at a target AUC of about 2 mg / mL·min on days 1, 8, and 15 of the second and third cycles, and wherein carboplatin is administered after paclitaxel in each cycle. In some aspects, carboplatin is administered intravenously over about 30 minutes, and paclitaxel is administered intravenously over about 180 minutes in the first cycle, and over about 60 minutes in the second and third cycles.

[0324] In some aspects, PDCT comprises cisplatin and pemetrexed. In some aspects, (a) comprises three 21-day cycles, wherein the anti-PD-1 antibody is administered on day 1 of each cycle, wherein about 500 mg / m 2 is administered after the anti-PD-1 antibody on day 1 of each cycle. 2 and wherein about 75 mg / m is administered after pemetrexed on day 1 of each cycle. 2 In some aspects, cisplatin is administered intravenously over about 60 minutes, and pemetrexed is administered intravenously over about 10 minutes. In some aspects, if the subject is intolerant to cisplatin, cisplatin is replaced with carboplatin, with a target concentration-time area under the curve (AUC) of about 5 mg / mL min. In some aspects, carboplatin is administered intravenously over about 30 minutes. In some aspects, if the subject is intolerant to pemetrexed, pemetrexed is replaced with etoposide.

[0325] In some aspects, the anti-PD-1 antibody in (a) is administered intravenously over about 30 minutes.

[0326] In some aspects, radiation therapy is administered after PDCT and comprises a dose of about 60 Gy to about 66 Gy.

[0327] In some aspects, radiotherapy includes chest radiotherapy and / or volumetric arc modulated radiation therapy (VMAT), intensity modulated radiation therapy (IMRT) or three-dimensional conformal radiation therapy (3DRT). In some aspects, radiotherapy starts on the 1st day of the second and third cycles and comprises about 30 to about 33 daily doses of 2Gy with a scheme of about 5 days of irradiation and 2 days of rest for about 6 weeks to about 7 weeks.

[0328] In some aspects, the recovery period is a duration sufficient for the subject to recover from CCRT-related toxicities other than fatigue, esophagitis, or alopecia. In some aspects, 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 after the last administration of the anti-PD-1 antibody in (a), about 18 days to about 9 weeks after the last administration of the anti-PD-1 antibody in (a), or about 18 days to about 6 weeks after the last administration of the anti-PD-1 antibody in (a).

[0329] In some aspects, the method is first-line therapy.

[0330] In some aspects, the subject has not received prior local or systemic anti-cancer therapy administered as primary therapy for locally advanced disease.

[0331] In some aspects, 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.

[0332] In some aspects, the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

[0333] In some aspects, the method is a second-line therapy.

[0334] In some aspects, the method is a third-line therapy.

[0335] In some aspects, the subject has disease progression on prior therapy.

[0336] In some aspects, the NSCLC has recurred following multimodality therapy for locally advanced NSCLC.

[0337] In some aspects, the NSCLC is unresectable, advanced, recurrent, and / or metastatic.

[0338] In some aspects, the NSCLC has squamous or non-squamous histology.

[0339] In some aspects, the NSCLC comprises locally advanced stage IIIA, IIIB, or IIIC NSCLC.

[0340] In some aspects, the subject has not had NSCLC progression during CCRT or recovery.

[0341] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are administered about once every 4 weeks.

[0342] In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are formulated separately. In some aspects, the anti-PD-1 antibody in (b) is administered before the anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody is administered before the anti-PD-1 antibody in (b). In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are administered simultaneously.

[0343] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are formulated together.

[0344] In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody in (b) are administered intravenously over about 30 minutes.

[0345] In some aspects, the anti-PD-1 antibody in (a) and / or (b) comprises a full-length antibody.

[0346] In some aspects, 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 aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0347] In some aspects, the anti-PD-1 antibody in (a) and / or (b) comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0348] In some aspects, the anti-PD-1 antibody of (a) and / or (b) 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 aspects, 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. In some aspects, 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.

[0349] In some aspects, the anti-LAG-3 antibody comprises a full-length antibody.

[0350] In some aspects, the anti-LAG-3 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0351] In some aspects, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0352] In some aspects, 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 aspects, 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 aspects, 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 aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs: 21 and 2, respectively. II.D LAG-3 and / or PD-L1 expression

[0353] In some aspects, in the methods disclosed herein, one or more immune 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 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).

[0354] In some aspects, one or more immune cells in a tumor tissue from a subject express LAG-3. In some aspects, 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 aspects, at least about 1% of the immune cells express LAG-3. In some aspects, greater than about 1% of the immune cells express LAG-3. In some aspects, at least about 5% of the immune cells express LAG-3. In some aspects, the immune cells include tumor infiltrating lymphocytes. In some aspects, the tumor infiltrating lymphocytes include CD8 + cell.

[0355] In some aspects, one or more nucleated cells in a tumor tissue from a subject express LAG-3. In some aspects, 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 aspects, at least about 1% of the nucleated cells express LAG-3. In some aspects, greater than about 1% of the nucleated cells express LAG-3. In some aspects, at least about 5% of the nucleated cells express LAG-3.

[0356] In some aspects, one or more tumor cells in a tumor tissue from a subject express PD-L1. In some aspects, 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 aspects, at least about 1% of the tumor cells express PD-L1. In some aspects, at least about 1% of the tumor cells express PD-L1. In some aspects, greater than about 1% of the tumor cells express PD-L1. In some aspects, at least about 5% of the tumor cells express PD-L1.

[0357] In some aspects, one or more nucleated cells in a tumor tissue from a subject express PD-L1. In some aspects, 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 nucleated cells express PD-L1. In some aspects, at least about 1% of nucleated cells express PD-L1. In some aspects, at least about 1% of nucleated cells express PD-L1. In some aspects, greater than about 1% of nucleated cells express PD-L1. In some aspects, at least about 5% of nucleated cells express PD-L1.

[0358] In some aspects, any value of "at least about X%" is "≥ X%."

[0359] In some aspects, tumor tissue from a patient is LAG-3 negative. In some aspects, tumor tissue is LAG-3 negative when less than about 1% of immune cells express LAG-3. In some aspects, tumor tissue is LAG-3 negative when less than about 1% of nucleated cells express LAG-3.

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

[0361] In some aspects, tumor tissue from a patient is PD-L1 negative. In some aspects, tumor tissue is PD-L1 negative when less than about 1% of tumor cells express PD-L1. In some aspects, tumor tissue is PD-L1 negative when less than about 1% of nucleated cells express PD-L1.

[0362] In some aspects, LAG-3, PD-1 and / or PD-L1 expression in the subject's tumor tissue is determined from a test tissue sample. In some aspects, the test tissue sample includes but is not limited to any clinically relevant tissue sample, such as a tumor biopsy, core biopsy, incisional biopsy, excisional biopsy, surgical specimen, fine needle aspirate or body fluid sample, such as blood, plasma, serum, lymph, ascites, cystic fluid or urine. In some aspects, the test tissue sample is from a primary tumor. In some aspects, the test tissue sample is from metastasis. In some aspects, the test tissue sample is from multiple time points, for example, before treatment, during treatment and / or after treatment. In some aspects, the test tissue sample is from different locations in the subject, for example, from a primary tumor and from metastasis.

[0363] In some aspects, the test tissue sample is a paraffin-embedded fixed tissue sample. In some aspects, the test tissue sample is a formalin-fixed paraffin-embedded (FFPE) tissue sample. In some aspects, the test tissue sample is a fresh tissue (e.g., tumor) sample. In some aspects, the test tissue sample is a frozen tissue sample. In some aspects, the test tissue sample is a fresh frozen (FF) tissue (e.g., tumor) sample. In some aspects, the test tissue sample is a cell separated from a fluid. In some aspects, the test tissue sample includes circulating tumor cells (CTCs). In some aspects, the test tissue sample includes tumor infiltrating lymphocytes (TILs). In some aspects, the test tissue sample includes tumor cells and tumor infiltrating lymphocytes (TILs). In some aspects, the test tissue sample includes circulating lymphocytes. In some aspects, the test tissue sample is an archived tissue sample. In some aspects, the test tissue sample is an archived tissue sample with a known diagnosis, treatment, and / or outcome history. In some aspects, the sample is a tissue block. In some aspects, the test tissue sample is a dispersed cell. In some aspects, the sample size is from about 1 cell to about 1×10 6 cells or more. In some aspects, the sample size is from about 1 cell to about 1×10 5 In some aspects, the sample size is about 1 cell to about 10,000 cells. In some aspects, the sample size is about 1 cell to about 1,000 cells. In some aspects, the sample size is about 1 cell to about 100 cells. In some aspects, the sample size is about 1 cell to about 10 cells. In some aspects, the sample size is a single cell.

[0364] In some aspects, 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 RNA, respectively. In some aspects, the presence of LAG-3, PD-1, and / or PD-L1 RNA is detected by RT-PCR, in situ hybridization, or RNase protection.

[0365] In some aspects, 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 aspects, 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. II.E. Additional Therapeutic Agents

[0366] The methods disclosed herein may include additional therapeutic agents and / or anti-cancer therapies, which may include any therapeutic agent or anti-cancer therapy known in the art, including standard of care for treating subjects with lung cancer. In some aspects, the therapeutic agents and / or therapies are selected from the NCCN Guidelines for the Treatment of NSCLC. See, e.g., the therapeutic agents and therapies described in: 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. II.E.1. Therapeutic Agents

[0367] In some aspects, the additional therapeutic agent comprises an anticancer agent. In some aspects, the anticancer 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.

[0368] In some aspects, the tyrosine kinase inhibitor includes sorafenib (e.g., sorafenib tosylate, also known as ), lenvatinib (eg, lenvatinib mesylate, also known as ), regorafenib (e.g., ), cabozantinib (e.g., cabozantinib S-malate, also known as ), sunitinib (eg, sunitinib malate, also known as ), brivanib, linifanib, pemigatinib (also known as PEMAZYRE TM ), everolimus (also known as or ), gefitinib ( a small molecule TKI for EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as ), nilotinib (e.g., nilotinib hydrochloride, also known as ), pazopanib (eg, pazopanib hydrochloride, also known as ), temsirolimus (also known as ), erlotinib (e.g., erlotinib hydrochloride, also known as A small molecule TKI for EGFR), afatinib ( A small molecule TKI for EGFR), dacomitinib ( A small molecule TKI for EGFR), osimertinib ( A small molecule TKI for EGFR), alectinib ( a small molecule TKI of ALK), ceritinib ( a small molecule TKI for ALK and ROS-1), brigatinib ( A small molecule TKI of ALK), crizotinib ( a small molecule TKI for ALK and ROS-1), lorlatinib ( a small molecule TKI of ALK and ROS-1), entrectinib ( a small molecule TKI for ROS-1 and NTRK), dabrafenib ( A small molecule TKI of BRAF), trametinib ( A small molecule TKI of BRAF), vemurafenib ( A small molecule TKI of BRAF), larotrectinib ( a small molecule TKI of an NTRK) or any combination thereof.

[0369] In some aspects, 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 with 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), multimeric protein 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGFR, or any combination thereof. In some aspects, the anti-angiogenic agent comprises bevacizumab (also known as ), ramucirumab (also known as ), Aflibercept (also known as or ), tanibizumab, olatumomab (also known as LARTRUVO TM ), nevacuzumab, AMG780, MEDI3617, vanucezumab, rilotuzumab, filatuzumab, TAK-701, onatuzumab, imatinib, or any combination thereof.

[0370] In some aspects, the anti-angiogenic agent is bevacizumab. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg. In some aspects, bevacizumab is administered on day 1 of a three-week cycle at a dose of about 15 mg / kg.

[0371] In some aspects, the checkpoint stimulators include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell co-stimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), an agonist of CD28H, or any combination thereof.

[0372] In some aspects, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a hormone or hormone modulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other antitumor agents, or any combination thereof.

[0373] In some aspects, the immunotherapeutic agent includes an antibody that specifically binds to EGFR (e.g., cetuximab). ), 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.

[0374] In some aspects, the platinum-based agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (eg, triplatin tetranitrate), liposomal cisplatin, phenanthreneplatin, or any combination thereof.

[0375] In some aspects, 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.

[0376] In some aspects, the taxane includes paclitaxel, nab-paclitaxel (ie, nab-paclitaxel), docetaxel, cabazitaxel, or any combination thereof.

[0377] In some aspects, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0378] In some aspects, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0379] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0380] In some aspects, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0381] In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vinaminol, vindesine, vinbutine, or any combination thereof. II.E.2. Checkpoint Inhibitors

[0382] In some aspects, the anti-cancer agent administered as an additional therapeutic agent in the methods of the disclosure is a checkpoint inhibitor.

[0383] In some aspects, 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-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V domain Ig suppressor of T cell activation (VISTA ) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors (e.g., indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors), epacadostat (INCB24360), navoximod (GDC-0919) or linrodostat (BMS-986205) (including linrodostat salts (e.g., linrodostat mesylate)), 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 (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-induced 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 protein (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0384] In some aspects, the checkpoint inhibitor is formulated for intravenous administration.

[0385] In some aspects, the checkpoint inhibitor is administered as a steady dose.

[0386] In some aspects, the checkpoint inhibitor is administered at a dosage 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, about 20 mg to about The present invention also provides a method for the administration of a dosage of about 100 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.

[0387] In some aspects, the checkpoint inhibitor is administered at 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, 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

[0388] In some aspects, the checkpoint inhibitor is administered at a weight-based dose.

[0389] In some aspects, the checkpoint inhibitor is administered at 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. 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 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.6 ... .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 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 The present invention also provides a dosage of about 15 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.

[0390] In some aspects, the checkpoint inhibitor is administered at 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, about 10 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg or about 25.0 mg / kg.

[0391] In some aspects, a dose of the checkpoint inhibitor is administered every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks. II.E.3 CTLA-4 inhibitors

[0392] In some aspects, the checkpoint inhibitors disclosed herein include CTLA-4 inhibitors. In some aspects, the CTLA-4 inhibitors include anti-CTLA-4 antibodies.

[0393] Anti-CTLA-4 antibodies useful in the methods of the present disclosure bind to human CTLA-4 and disrupt the interaction of CTLA-4 with the human B7 receptor. Because the interaction of CTLA-4 with B7 transduces a signal that results in the inactivation of T cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing, or prolonging an immune response.

[0394] 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 have been described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, and International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504, each of which is incorporated herein by reference in its entirety. The anti-CTLA-4 human monoclonal antibodies disclosed in U.S. Patent No. 6,984,720 have been shown to exhibit one or more of the following characteristics: (a) binding to CTLA-4 by at least about 10 7 M -1 , or about 10 9 M -1 , or about 10 10 M -1 to 10 11 M -1 or higher equilibrium association constant (K a ) specifically binds to human CTLA-4 as determined by Biacore analysis; (b) at least about 10 3 , about 10 4 or about 10 5 m -1 s -1 The kinetic association 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) inhibiting 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.

[0395] Anti-CTLA-4 antibodies that can be used in the methods of the present disclosure include ipilimumab (also known as MDX-010, 10D1; see U.S. Patent No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Aginas; see WO 2016 / 196237), and tremelimumab (AstraZeneca; also known as tesimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3):133-39 (2007)).

[0396] In some aspects, the anti-CTLA-4 antibody specifically binds to human CTLA-4 and cross-competes for binding to human CTLA-4 with any of the anti-CTLA-4 antibodies disclosed herein (e.g., ipilimumab and / or tremelimumab). In some aspects, 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).

[0397] In some aspects, antibodies that cross-compete for binding to human CTLA-4 or bind to the same epitope region as any of the anti-CTLA-4 antibodies disclosed herein (e.g., ipilimumab and / or tremelimumab) are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.

[0398] Anti-CTLA-4 antibodies useful in the disclosed methods also include antigen-binding portions of any of the above-described full-length antibodies.

[0399] In some aspects, the anti-CTLA-4 antibody comprises a full-length antibody. In some aspects, the anti-CTLA-4 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-Ig, or a bispecific antibody.

[0400] In some aspects, the anti-CTLA-4 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0401] In some aspects, the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen-binding portion thereof.

[0402] In some aspects, anti-CTLA-4 antibodies include ipilimumab. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation. In some aspects, ipilimumab is administered approximately once every three weeks at a dose of about 3 mg / kg. In some aspects, ipilimumab is administered approximately once every three weeks at a dose of about 10 mg / kg. In some aspects, ipilimumab is administered approximately once every 12 weeks at a dose of about 10 mg / kg. In some aspects, ipilimumab is administered four times. In some aspects, ipilimumab is administered on day 1 of each cycle. II.E.4. Therapies for Sensitizing Mutations

[0403] In some aspects, the methods of the present disclosure include treating subjects with mutations that are sensitive to targeted inhibitor therapy, such as sensitive mutations in genes such as EGFR, ALK, ROS-1, NTRK, or BRAF. Such methods may further include administering targeted inhibitors of the mutant gene, including standard of care therapies for subjects with NSCLC who have such mutations.

[0404] In some aspects, the methods of the present 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 with advanced or metastatic NSCLC with a sensitizing EGFR mutation.

[0405] In some aspects, the methods of the present disclosure comprise administering afatinib and cetuximab (e.g., 40 mg afatinib orally once daily on days 1-14 and 500 mg / m2 orally on day 1) to a subject with advanced or metastatic NSCLC who has a sensitizing EGFR mutation. 2 cetuximab) or osimertinib (e.g., 80 mg orally once daily).

[0406] In some aspects, the methods of the present 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 180 mg orally once daily on days 29-56 in a 4-week cycle), ceritinib (e.g., 450 mg orally once daily), or crizotinib (e.g., 250 mg orally twice daily) to a subject with advanced or metastatic NSCLC with a sensitizing ALK mutation (e.g., ALK rearrangement).

[0407] In some aspects, the methods of the disclosure comprise administering lorlatinib (eg, 100 mg orally once daily) to a subject with advanced or metastatic NSCLC having a sensitizing ALK mutation (eg, ALK rearrangement).

[0408] In some aspects, the methods of the present disclosure include 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 that has a sensitizing ROS-1 mutation (e.g., ROS-1 rearrangement). In some aspects, the methods of the present disclosure include administering lorlatinib (e.g., 100 mg orally once daily) to a subject with advanced or metastatic NSCLC that has a sensitizing ROS-1 mutation (e.g., ROS-1 rearrangement).

[0409] In some aspects, the methods of the disclosure comprise administering dabrafenib (e.g., 150 mg orally twice daily), dabrafenib and trametinib (e.g., 150 mg dabrafenib orally twice daily and 2 mg trametinib orally once daily), or vemurafenib (e.g., 960 mg orally once daily) to a subject with advanced or metastatic NSCLC with a sensitizing BRAF mutation (e.g., BRAF V600E).

[0410] In some aspects, the methods of the disclosure comprise administering entrectinib (e.g., 600 mg orally once daily) or larotrectinib (e.g., 100 mg orally twice daily) to a subject with advanced or metastatic NSCLC with a sensitizing NTRK mutation (e.g., NTRK gene fusion). III. Pharmaceutical Compositions

[0411] The therapeutic agents disclosed herein can be formulated in compositions, for example, pharmaceutical compositions containing the inhibitors, antibodies, and / or agents 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.

[0412] In some aspects, the carrier for a composition containing an inhibitor, antibody, and / or agent disclosed herein is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion). In some aspects, the carrier is suitable for non-parenteral administration, such as oral administration. In some aspects, subcutaneous injection is based on Halozyme Therapeutics' Drug delivery technology (see US Pat. No. 7,767,429, which is incorporated herein by reference in its entirety). Use the total preparation of antibody and recombinant human hyaluronidase (rHuPH20), this eliminates the traditional restriction (referring to U.S. Patent number 7,767,429) of the volume of biological preparation and medicine that can be delivered subcutaneously due to extracellular matrix.The pharmaceutical composition of present disclosure can include one or more pharmaceutically acceptable salts, antioxidants, aqueous and non-aqueous carriers and / or adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants.In some aspects, the pharmaceutical composition of present disclosure can further include recombinant human hyaluronidase, such as rHuPH20.

[0413] As long as clinical benefit is observed, or until unacceptable toxicity or disease progression occurs, treatment continues. Dosage and frequency are different, and this depends on the half-life of inhibitor, antibody and / or medicament in the experimenter. Usually, human antibodies show the longest half-life, followed by humanized antibodies, chimeric antibodies and non-human antibodies. The dosage and frequency used can depend on whether treatment is preventive or therapeutic and change. In preventive applications, relatively low dosage is usually used at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment in their remaining lives. In therapeutic applications, it is sometimes necessary to use relatively high dosage at relatively short intervals, until the progression of the disease reduces or terminates, and preferably until the patient shows partial or complete improvement of symptoms of the disease. After this, preventive regimens can be used to the patient.

[0414] The actual dosage level of the active ingredient (i.e., inhibitor, antibody and / or agent) in the pharmaceutical composition of the present disclosure can be changed so as to obtain an amount of active ingredient whose amount effectively achieves the desired therapeutic response for a specific patient, composition and mode of administration without excessive toxicity to the patient. The selected dosage level will depend on various pharmacokinetic factors, including the activity of the specific composition of the present disclosure adopted, the route of administration, the time of administration, the excretion rate of the specific compound adopted, the duration of treatment, other drugs, compounds and / or substances used in combination with the specific composition used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field. The composition of the present disclosure can be administered via one or more routes of administration using one or more of the various methods well known in the art. As will be understood by those skilled in the art, the route of administration and / or mode will vary depending on the desired result.

[0415] Provided herein are pharmaceutical compositions comprising an anti-LAG-3 antibody and an anti-PD-1 antibody as described herein at any dose or dose combination described herein.

[0416] In some aspects, the pharmaceutical composition is used to treat a human subject having lung cancer as described herein (eg, as maintenance therapy).

[0417] In some aspects, methods for treating a human subject having lung cancer as described herein comprise administering a pharmaceutical composition as described herein.

[0418] In some aspects, the pharmaceutical composition comprises a dose of relalizumab and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplizumab, or spartalizumab. In some aspects, the anti-PD-1 antibody is nivolumab.

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

[0420] In some aspects, the pharmaceutical composition comprises a dose of foramulizumab and a dose of an anti-PD-1 antibody as described herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplizumab, or spartalizumab. In some aspects, the anti-PD-1 antibody is cemiplizumab.

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

[0422] In some aspects, the pharmaceutical composition comprises a ratio of 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 1:20 In some embodiments, the present invention relates to an anti-LAG-3 antibody and an anti-PD-1 antibody in an amount of about 0, 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.

[0423] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody at a ratio of about 1:3.

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

[0425] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody at a ratio of about 2:1.

[0426] In some aspects, the pharmaceutical composition comprises an anti-LAG-3 antibody to an anti-PD-1 antibody at a ratio of about 4:1.

[0427] In some aspects, 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 136 mg / mL, about 140 mg / mL, about 147 mg / mL, about 150 mg / mL, about 151 mg / mL, about 152 mg / mL, about 153 mg / mL, about 154 mg / mL, about 156 mg / mL, about 157 mg / mL, about 158 ​​mg / mL, about 159 mg / mL, about 160 mg / mL, about 161 mg / mL, about 162 mg / mL, about 163 mg / mL, about 164 mg / mL, about 165 mg / mL, about 166 mg / mL, about 167 mg / mL, about 168 mg / mL, about 169 mg / mL, about 170 mg / mL, about 171 5 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 205 mg / mL, about 210 mg / mL, about 215 mg / mL, about 220 mg / mL, about 225 mg / mL, about 230 mg / mL, about 235 mg / mL, about 240 mg / mL, about 245 mg / mL, about 250 mg / mL, about 255 mg / mL, about 26 0 mg / mL, about 265 mg / mL, about 270 mg / mL, about 275 mg / mL, about 280 mg / mL, about 285 mg / mL, about 290 mg / mL, about 295 mg / mL, about 300 mg / mL, about 305 mg / mL, about 310 mg / mL, about 315 mg / mL, about 320 mg / mL, about 325 mg / mL, about 330 mg / mL, about 335 mg / mL, about 340 mg / mL, about 345 mg / mL, about 350 mg / mL, about 355 mg / mL, about 360 mg / mL, about 365 mg / mL, about 370 mg / mL, about 375 mg / mL, about 380 mg / mL, about 3 85mg / mL, about 390mg / mL, about 395mg / mL, about 400mg / mL, 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 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, about 350mg,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 g, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg 0mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg, about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg, about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg, about 1360mg, about 1370mg g, about 1380mg, about 1390mg, about 1400mg, about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, about 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg,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.

[0428] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 25 mg / mL.

[0429] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 50 mg / mL.

[0430] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 150 mg / mL.

[0431] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 50 mg.

[0432] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 320 mg.

[0433] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 640 mg.

[0434] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 720 mg.

[0435] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 960 mg.

[0436] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 1000 mg.

[0437] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 1080 mg.

[0438] In some aspects, the total amount of anti-LAG-3 antibody and anti-PD-1 antibody in the pharmaceutical composition is about 1440 mg.

[0439] In some aspects, 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 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 mL, 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 aspects, 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. In some embodiments, the present invention relates to an anti-PD-1 antibody in an amount of about 1 mg / 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 an anti-PD-1 antibody.

[0440] In some aspects, the pharmaceutical composition comprises about 12.5 mg / mL of the anti-LAG-3 antibody and about 37.5 mg / mL of the anti-PD-1 antibody.

[0441] In some aspects, the pharmaceutical composition comprises about 20 mg / mL of the anti-LAG-3 antibody and about 5 mg / mL of the anti-PD-1 antibody.

[0442] In some aspects, the pharmaceutical composition comprises about 75 mg / mL of the anti-LAG-3 antibody and about 75 mg / mL of the anti-PD-1 antibody.

[0443] In some aspects, the pharmaceutical composition comprises about 100 mg / mL of the anti-LAG-3 antibody and about 50 mg / mL of the anti-PD-1 antibody.

[0444] In some aspects, the pharmaceutical composition comprises about 80 mg of the anti-LAG-3 antibody and about 240 mg of the anti-PD-1 antibody.

[0445] In some aspects, the pharmaceutical composition comprises about 160 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody.

[0446] In some aspects, the pharmaceutical composition comprises about 360 mg of an anti-LAG-3 antibody and about 360 mg of an anti-PD-1 antibody.

[0447] In some aspects, the pharmaceutical composition comprises about 480 mg of an anti-LAG-3 antibody and about 480 mg of an anti-PD-1 antibody.

[0448] In some aspects, the pharmaceutical composition comprises about 720 mg of the anti-LAG-3 antibody and about 360 mg of the anti-PD-1 antibody.

[0449] In some aspects, the pharmaceutical composition comprises about 800 mg of the anti-LAG-3 antibody and about 200 mg of the anti-PD-1 antibody.

[0450] In some aspects, the pharmaceutical composition comprises about 960 mg of the anti-LAG-3 antibody and about 480 mg of the anti-PD-1 antibody.

[0451] In some aspects, 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).

[0452] In some aspects, the pharmaceutical composition comprises about 20 mM histidine, about 250 mM sucrose, about 50 μM DTPA, and 0.05% PS80.

[0453] In some aspects, the pH of the pharmaceutical composition is from about 5 to about 6.5. In some aspects, the pH is from about 5.3 to about 6.3. In some aspects, the pH is 5.8. In some aspects, the pH is 5.7.

[0454] Provided herein are vials, syringes, or intravenous bags comprising a pharmaceutical composition described herein. In some aspects, the disclosure includes an autoinjector comprising a pharmaceutical composition described herein.

[0455] In some aspects, the vial comprises a pharmaceutical composition as described herein, and the vial further comprises a stopper and a seal. In some aspects, the total volume in 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.

[0456] Also within the scope of the present invention are kits for treating a human subject having lung cancer comprising any of the antibodies, therapeutic agents, and / or anti-cancer therapies described herein.

[0457] The kit typically includes a label indicating the intended use of the kit contents and instructions for use. The term label includes any written or recorded material on or provided with the kit or otherwise accompanying the kit. In some aspects, the kit includes instructions for using the kit components in a method for treating a human subject with lung cancer.

[0458] The antibodies may be provided in any dose or combination of doses described herein.

[0459] In some aspects, the kit comprises a dose of relalizumab and a dose of an anti-PD-1 antibody as described herein, or two different doses of an anti-PD-1 antibody as described herein, wherein the two different doses can be the same or different doses of the anti-PD-1 antibody.

[0460] In some aspects, doses of an anti-LAG-3 antibody and an anti-PD-1 antibody as disclosed herein are co-packaged in a single unit dosage form.

[0461] In some aspects, all doses of the antibody are packaged as separate unit dosage forms.

[0462] In some aspects, the kit further comprises a therapeutic agent for one or more PDCT as disclosed herein. In some aspects, the therapeutic agent for one or more PDCT is carboplatin and paclitaxel, carboplatin and nab-paclitaxel, carboplatin and pemetrexed, and / or cisplatin and pemetrexed. In some aspects, the therapeutic agent is carboplatin, cisplatin, paclitaxel, nab-paclitaxel, and pemetrexed.

[0463] All references cited above and all references cited herein are incorporated by reference in their entirety.

[0464] The following examples are offered by way of illustration and not limitation. Examples Example 1 Anti-PD-1 antibody plus concurrent chemoradiotherapy, followed by anti-LAG-3 antibody combined with anti-PD-1 antibody for the treatment of lung cancer

[0465] A multicenter, double-blind, randomized, phase 3 global trial will evaluate the efficacy and safety of concurrent chemoradiotherapy (CCRT) plus nivolumab followed by maintenance with a fixed-dose combination (FDC) of nivolumab and relarilimab compared with CCRT plus placebo followed by maintenance with durvalumab in participants with previously untreated, unresectable, stage IIIA, IIIB, or IIIC locally advanced non-small cell lung cancer (NSCLC).

[0466] Approximately 850 adult men and women who were 18 years of age or older at the time of informed consent or who reached the local consent age in the jurisdiction where the study was conducted were randomly assigned (1:1) to two treatment groups (Group A and Group B) and stratified according to PD-L1 expression level (≥1%, <1%, or not quantifiable [NQ]) and disease stage (IIIA, IIIB, IIIC) according to the 8th edition of the American Joint Commission on Cancer (AJCC) TNM (Tumor, Node, Metastasis) classification for lung cancer (Amin et al., AJCC Cancer Staging Manual (8th ed.). Springer International Publishing: American Joint Commission on Cancer; 2017).

[0467] Each group will include a CCRT phase, a recovery phase, and a maintenance phase.

[0468] Group A · CCRT phase (three 21-day cycles) : Nivolumab (360 mg, IV infusion over 30 ± 5 minutes, once every three weeks (Q3W) ± 3 days) in each of cycles 1, 2, and 3 and platinum-doublet chemotherapy (PDCT, IV Q3W) plus radiotherapy (dose 60-66 Gy) in cycles 2 and 3. · Maintenance phase (28-day cycles, up to one year of treatment) Nivolumab 480 mg + relalizumab 480 mg FDC IV infusion over 60 minutes, every 4 weeks

[0469] Group B · CCRT phase (three 21-day cycles) : Placebo in each of cycles 1, 2, and 3 (IV infusion 30±5 minutes, Q3W±3 days) and PDCT (IV Q3W) + radiotherapy (dose 60-66 Gy) in cycles 2 and 3. · Maintenance phase (28-day cycles, up to one year of treatment) : Imfinzi 1500 mg IV infusion over 60 minutes, every 4 weeks.

[0470] During the CCRT phase, nivolumab (Arm A) or placebo (Arm B) will be administered on day 1 of each cycle, before chemotherapy (ie, PDCT).

[0471] Subjects with NSCLC of squamous histology will receive cisplatin / etoposide or carboplatin / paclitaxel as PDCT during the CCRT phase.

[0472] Subjects with NSCLC of non-squamous histology will receive cisplatin / etoposide, carboplatin / paclitaxel, or cisplatin / pemetrexed as PDCT during the CCRT phase.

[0473] For cisplatin / etoposide PDCT, 80 mg / m2 will be administered by IV infusion on day 1 of each of cycles 1, 2, and 3. 2 Cisplatin (over 60 minutes or according to local standards) and 100 mg / m2 will be administered by IV infusion on days 1, 2, and 3 of each of cycles 1, 2, and 3. 2 Etoposide (over 60 minutes or according to local standards). Days 2 and 3 may be interrupted, delayed, or terminated 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, carboplatin can be substituted for cisplatin, with a target area under the concentration-time curve (AUC) of 5 mg / mL·min, administered as an IV infusion (over 30 minutes or according to local standards).

[0474] For carboplatin / paclitaxel PDCT, carboplatin AUC 5 mg / mL·min or 6 mg / mL·min will be administered by IV infusion (over 30 minutes or according to local standards) and 175 or 200 mg / m2 will be administered by IV infusion on Day 1 of Cycle 1. 2 Paclitaxel (over 180 minutes or according to local standards) will be administered concurrently with carboplatin (over 30 minutes or according to local standards) and 45 or 50 mg / m2 of AUC administered by IV infusion on days 1, 8, and 15 of cycles 2 and 3. 2 Paclitaxel (over 60 minutes or according to local standards). In cycles 1, 2, and 3, the paclitaxel infusion will be administered before the carboplatin infusion. Days 8 and 15 of cycles 2 and 3 may be interrupted, delayed, or terminated depending on how well the participant tolerates treatment and at the discretion of the investigator. The carboplatin dose must be calculated according to the Calvert formula. Creatinine clearance (CrCl) should be calculated using the Cockcroft-Gault formula (see below) or according to local standards: Calvert formula: Dose (mg) = target AUC × (glomerular filtration rate + 25) Cockcroft-Gault: CrCl (mL / min) = ([140 - age (years) × actual weight (kg)] / [72 × serum creatinine (mg / dL)]) × {0.85, if female}

[0475] For cisplatin / pemetrexed PDCT, 75 mg / m2 will be administered by IV infusion on day 1 of each of cycles 1, 2, and 3. 2Cisplatin (over 60 minutes or according to local standards) and 500 mg / m by IV infusion 2 Pemetrexed (over 10 minutes or according to local standards). Pemetrexed will be infused before cisplatin. If cisplatin is not tolerated, carboplatin can be substituted for cisplatin, AUC 5 mg / mL·min, IV infusion (over 30 minutes or according to local standards). If pemetrexed is not tolerated, etoposide can be substituted for pemetrexed.

[0476] The recovery period in each group is the time between the CCRT phase and the maintenance phase. The recovery period varies depending on adverse events / serious adverse events and the treatment required, but is expected to last approximately 3 to 6 weeks and be no less than 18 days from the last dose of nivolumab (Arm A) or placebo (Arm B) during the Q3W cycle.

[0477] Radiation therapy in each group will be administered at a dose of 60-66 Gy (30-33 2 Gy daily fractions), typically on a 5-day treatment / 2-day rest schedule (if applicable), for 6 to 7 weeks. Each subject will receive thoracic radiation therapy in the form of intensity-modulated radiation therapy (IMRT), volumetric arc-modulated radiation therapy (VMAT), or three-dimensional conformal radiation therapy (3DRT). Irradiation will begin on day 1 of cycle 2 of the CCRT phase.

[0478] Key inclusion criteria for CCRT Patients with locally advanced stage IIIA, IIIB, or IIIC (T1-2 N2-3 M0, T3 N1-3 M0, or T4 N0-3M0) NSCLC confirmed by pathology (including cytology) according to the 8th edition of the AJCC TNM staging system for lung cancer who are candidates for curative CCRT. Participants who are not planning potentially curative surgical resection are eligible. Eastern Cooperative Oncology Group performance status ≤1. Treatment naive, with no prior local or systemic anticancer therapy given as primary therapy for locally advanced disease. Measurable disease according to 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 should inform female participants of childbearing potential (WOCBP) and male participants who are sexually active with WOCBP about the importance of contraception, the consequences of unintended pregnancy, and the potential for fetal toxicity due to transmission of the study intervention (present in semen) to the developing fetus, even if the participant has undergone a successful vasectomy or their partner is pregnant.

[0479] Key exclusion criteria for CCRT Participants with a history of myocarditis, regardless of etiology. Concurrent malignancy requiring treatment (present during screening) or history of active prior malignancy within 2 years prior to randomization. Participants with active, known, or suspected autoimmune disease. Participants had a condition requiring systemic treatment with corticosteroids (prednisone equivalents >10 mg daily) or other immunosuppressive drugs within 14 days before randomization. Computed tomography (CT) and / or x-ray showing the presence of pleural / pericardial effusion.

[0480] Key inclusion criteria for the maintenance phase No BICR-confirmed disease progression according to RECIST v1.1 during CCRT or recovery period. No current or previous use of immunosuppressive medications (daily prednisone or equivalent not exceeding 10 mg / day) within 14 days prior to the first dose of maintenance therapy. Toxicity due to CCRT must resolve to grade 1 or baseline (except for grade 2 fatigue, esophagitis, or alopecia).

[0481] Key exclusion criteria for the maintenance phase Serum creatinine >1.5 × upper limit of normal (ULN), unless creatinine clearance is ≥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 Syndrome, who must have a total bilirubin level <3.0×ULN). Troponin T or I > 2× institutional ULN.

[0482] The study will demonstrate that nivolumab plus CCRT followed by maintenance therapy with nivolumab and relarilimab FDC (Arm A) improves progression-free survival (PFS) in participants with locally advanced, previously untreated, unresectable, Stage III NSCLC compared with CCRT plus placebo followed by maintenance therapy with durvalumab (Arm B). sequence SEQ ID NO: 1 Heavy chain amino acid sequence; anti-LAG-3 mAb (BMS-986016) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:2 Amino acid sequence of the light chain; anti-LAG-3 mAb (BMS-986016)<000127​​​​​​​​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) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:12 Amino acid sequence of light chain; anti-PD-1 mAb (BMS-936558) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:13 Amino acid sequence of heavy chain variable region (VH); anti-PD-1 mAb (BMS-936558) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS SEQ ID NO:14 Amino acid sequence of light chain variable region (VL); anti-PD-1 mAb (BMS-93655)8 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 QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 22 Amino acid sequence of lymphocyte activation gene 3 protein (Homo sapiens, NP_002277) MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL SEQ ID NO: 23 Heavy chain amino acid sequence; anti-LAG-3 mAb (REGN3767) QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:24 Light chain amino acid sequence; anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:25 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (REGN3767) QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT VSS SEQ ID NO:26 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK 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) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:34 Light chain amino acid sequence; anti-PD-1 mAb (REGN2810) DIQMTQSPSSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRRTAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:35 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (REGN2810) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLE WVSGISGGGRDTYF ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS SEQ ID NO:36 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (REGN2810) DIQMTQSPSSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFPGPGTVVDFR 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) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO:44 Heavy chain amino acid sequence; anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO:45 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:46 Light chain amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:47 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSS SEQ ID NO:48 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSS SEQ ID NO:49 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIK SEQ ID NO: 50 Light chain variable region (VL) amino acid sequence; anti-LAG-3 mAb (LAG525) DIQMTQSPSSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIK 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) EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNF DEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLG SEQ ID NO:58 Light chain amino acid sequence; anti-PD-1 mAb (PDR001) EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:59 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (PDR001) EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNF DEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO:60 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (PDR001) EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTR ESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK 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) WTTGTGAY 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) QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIY AQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGN VFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:68 Light chain amino acid sequence; anti-LAG-3 mAb (MK4280) DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLES GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:69 Heavy chain variable region (VH) amino acid sequence; anti-LAG-3 mAb (MK4280) QMQLVQSGPEVKKPGTSVKVSCKASGYTFTDYNVDWVRQARGQRLEWIGDINPNDGGTIY AQKFQERVTITVDKSTSTAYMELSSLRSEDTAVYYCARNYRWFGAMDHWGQGTTVTVSS SEQ ID NO:70 Light chain variable region (VL) amino acid sequence; Anti-LAG-3 mAb (MK4280) DIVMTQTPLSLSVTPGQPASISCKASQSLDYEGDSDMNWYLQKPGQPPQLLIYGASNLES GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQSTEDPRTFGGGTKVEIK 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) QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 78 Light chain amino acid sequence; anti-PD-1 mAb (MK3475) EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 79 Heavy chain variable region (VH) amino acid sequence; anti-PD-1 mAb (MK3475) QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF NEKFKNRVTTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS SEQ ID NO:80 Light chain variable region (VL) amino acid sequence; anti-PD-1 mAb (MK3475) EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIK 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

Claims

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

2. The method of claim 1, further comprising providing the subject with a recovery period that begins when the administration in (a) is completed and ends when the administration in (b) begins.

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

4. The method of claim 2 or 3, wherein 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 last administration of the PD-1 pathway inhibitor in (a), about 18 days to about 9 weeks from the last administration of the PD-1 pathway inhibitor in (a), or about 18 days to about 6 weeks from the last administration of the PD-1 pathway inhibitor in (a).

5. The method of any one of claims 1 to 4, wherein the method is first-line therapy.

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

7. The method of any one of claims 1-6, 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. The method of any one of claims 1-7, wherein the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

9. The method of any one of claims 1-4, wherein the method is a second-line therapy.

10. The method of any one of claims 1-4, wherein the method is third-line therapy.

11. The method of claim 9 or 10, wherein the subject has disease progression on prior therapy.

12. The method of any one of claims 9-11, wherein the lung cancer relapses after multimodality therapy for locally advanced lung cancer.

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

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

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

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

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

18. The method of any one of claims 2-17, wherein the subject does not experience lung cancer progression during the CCRT or the recovery period.

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

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

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

22. The method of any one of claims 1-21, wherein the PD-1 pathway inhibitor in (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. The method of any one of claims 21-23, wherein the anti-PD-1 antibody comprises a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody.

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

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

27. The method of any one of claims 21-26, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplizumab, 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. The method of any one of claims 21-27, wherein the anti-PD-1 antibody comprises nivolumab or an antigen-binding portion thereof.

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

14.

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

20.

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

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

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

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

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

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

37. The method of claim 36, wherein 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 PASylated moiety, a HESylated moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof.

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

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

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

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

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

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

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

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

47. The method of any one of claims 1-46, wherein the PD-1 pathway inhibitor in (a) and / or (b) 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, In some embodiments, the present invention provides a dosage 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.

48. The method of any one of claims 1-47, wherein the PD-1 pathway inhibitor in (a) and / or (b) is administered in an amount 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, 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

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

50. The method of any one of claims 1-45 or 49, wherein the PD-1 pathway inhibitor in (a) and / or (b) 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, about 0.003 mg / kg to about 0.8 mg / 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 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 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 The invention also provides a method for the administration of a dosage of about 1 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.

51. The method of any one of claims 1-45 or 49-50, wherein the PD-1 pathway inhibitor in (a) and / or (b) is administered at 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. or about 25.0 mg / kg.

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

53. The method of any one of claims 46-52, wherein the dose of the PD-1 pathway inhibitor in (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. The method of any one of claims 1-53, wherein the CCRT comprises platinum-doublet chemotherapy (PDCT).

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

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

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

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

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

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

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

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

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

64. The method of any one of claims 55-58, wherein the vinca alkaloid comprises vinblastine, vincristine, vinorelbine, vindesine, vinaminol, vindesine, or vinbutine.

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

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

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

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

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

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

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

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

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

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

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

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

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

79. The method of any one of claims 74-78, wherein the anti-LAG-3 antibody comprises BMS-986016 (relalizumab), IMP731 (H5L7BW), MK4280 (28G-10, mavezilimab), REGN3767 (furanlizumab), GSK2831781, humanized BAP050, IMP-701 (LAG525, elalimumab), aLAG3 (0414), aLAG3 (0416 ), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tepolizumab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or antigen-binding portions thereof.

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

4.

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

10.

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

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

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

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

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

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

90. The method of claim 89, wherein 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 PASylated moiety, a HESylated moiety, XTEN, a PEGylated moiety, an Fc region, or any combination thereof.

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

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

93. The method of any one of claims 1-92, wherein the LAG-3 antagonist 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 In some embodiments, the present invention provides a dosage of 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.

94. The method of any one of claims 1-93, wherein the LAG-3 antagonist is administered at 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 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg g, 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, 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 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, about 350mg, 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 The present invention relates to a pharmaceutical composition comprising: ...

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

96. The method of any one of claims 1-91 or 95, wherein 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, about 0.003 mg / kg to about 0.8 mg / 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 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 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 The invention also provides a method for the administration of a dosage of about 1 mg / kg to about 2 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.

97. The method of any one of claims 1-91 or 95-96, wherein the LAG-3 antagonist is administered at 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, 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.

98. The method of any one of claims 92-97, wherein the dose of the LAG-3 antagonist 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.

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

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

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

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

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

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

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

106. The method of claim 105, wherein the maintenance therapy is administered for up to about 1 year.

107. A method of treating a human subject having NSCLC having squamous or non-squamous histology, the method comprising: (a) administering to the subject approximately 360 mg of an anti-PD-1 antibody comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 13 and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 14, and CCRT comprising PDCT and radiotherapy, (b) providing the subject with a recovery period, which begins after the administration in (a) is completed, and is followed by (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.

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

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

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

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

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

113. The method of claim 111 or 112, wherein the carboplatin is administered intravenously over about 30 minutes, wherein 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. The method of claim 107, wherein the PDCT comprises cisplatin and pemetrexed.

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

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. The method of any one of claims 108-110 or 114-116, wherein if the subject is intolerant to cisplatin, the cisplatin is replaced with carboplatin with a target area under the concentration time curve (AUC) of about 5 mg / mL·min.

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

119. The method of any one of claims 114-118, wherein if the subject is intolerant to pemetrexed, the pemetrexed is replaced with etoposide.

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

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

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

123. The method of any one of claims 107-122, wherein the radiotherapy begins on day 1 of the second and third cycles and comprises about 30 to about 33 daily fractions of 2 Gy, with a schedule of about 5 days of irradiation and 2 days of rest, for about 6 to about 7 weeks.

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

125. The method of any one of claims 107-124, wherein 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 last administration of the anti-PD-1 antibody in (a), about 18 days to about 9 weeks from the last administration of the anti-PD-1 antibody in (a), or about 18 days to about 6 weeks from the last administration of the anti-PD-1 antibody in (a).

126. The method of any one of claims 107-125, wherein the method is first-line therapy.

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

128. The method of any one of claims 107-127, 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.

129. The method of any one of claims 107-128, wherein the subject has not received prior immuno-oncology therapy, the subject has not received prior immuno-oncology therapy for lung cancer, or the lung cancer has not received prior immuno-oncology therapy.

130. The method of any one of claims 107-125, wherein the method is a second-line therapy.

131. The method of any one of claims 107-125, wherein the method is third-line therapy.

132. The method of claim 130 or 131, wherein the subject has disease progression on prior therapy.

133. The method of any one of claims 130-132, wherein the NSCLC has relapsed following multimodality therapy for locally advanced NSCLC.

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

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

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

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

138. The method of any one of claims 107-137, wherein the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are administered about once every 4 weeks.

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

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

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

142. The method of claim 139, wherein the anti-PD-1 antibody and the anti-LAG-3 antibody in (b) are administered concurrently.

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

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

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

146. The method of any one of claims 107-145, wherein 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.

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

148. The method of claims 107-144, wherein the anti-PD-1 antibody in (a) and / or (b) comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

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

20.

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

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

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

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

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

155. The method of claims 107-151, wherein the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

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

10.

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

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

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

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

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

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

164. The method of claim 163, wherein the tumor infiltrating lymphocytes comprise CD8 + cell.

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

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. 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 1-167, wherein one or more tumor cells in tumor tissue from the subject express PD-L1.

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

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

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 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.

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. 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 with 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), multimeric protein 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGF receptor (EGFR), or any combination thereof.

176. The method of claim 173 or 175, wherein the anti-angiogenic agent comprises bevacizumab, ramucirumab, aflibercept, tanibirumab, alucuzumab, nevacuzumab, AMG780, MEDI3617, vanucuzumab, rilotuzumab, filatuzumab, TAK-701, onatuzumab, imatinib, or any combination thereof.

177. The method of claim 173, wherein the checkpoint inhibitor comprises 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-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B 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 transforming growth factor-β inhibitor, or a cytotoxic T cell receptor antagonist. a transforming growth 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-induced 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 predominant (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. The method of any one of claims 173 or 177, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

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

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

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

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

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

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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