Combination of PD-1 inhibitors and LAG-3 inhibitors for enhanced efficacy in treating lung cancer

Abstract

The present disclosure provides methods for treating or inhibiting the growth of lung cancer in a subject in need thereof comprising administering a LAG-3 inhibitor (e.g., an anti-LAG-3 antibody or antigen-binding fragment thereof) in combination with a PD-1 inhibitor (e.g., an anti-PD-1 antibody or antigen-binding fragment thereof). In certain embodiments, the administration of the PD-1 inhibitor enhances the efficacy of the LAG-3 inhibitor in inhibiting the growth of lung cancer. In certain embodiments, the administration of the PD-1 inhibitor and LAG-3 inhibitor in combination with platinum-doublet chemotherapy enhances the efficacy in treating lung cancer. In certain embodiments, administration of the PD-1 inhibitor and LAG-3 inhibitor in combination with platinum-doublet chemotherapy can be followed by surgery to resect the cancer and adjuvant treatment comprising further administration of the PD-1 inhibitor and LAG-3 inhibitor.

Description

COMBINATION OF PD-1 INHIBITORS AND LAG-3 INHIBITORS FOR ENHANCED EFFICACY IN TREATING LUNG CANCERTECHNICAL FIELD

[0001] The present disclosure provides, in part, compositions, including inhibitors of LAG-3 and PD-1 , and methods for treating lung cancer.SEQUENCE LISTING

[0002] An official copy of the sequence listing is submitted concurrently with the specification electronically via Patent Center. The contents of the electronic sequence listing (11616WO01_Sequence_Listing_ST26.xml; Size: 28,672 bytes; and Date of Creation: November 14, 2024) is herein incorporated by reference in its entirety.BACKGROUND

[0003] Programmed death-1 (PD-1 ) receptor signaling in the tumor microenvironment plays a key role in allowing tumor cells to escape immune surveillance by the host immune system. The PD-1 receptor has two ligands, PD-ligand-1 (PD-L1) and PD-L2. Blockade of the PD-1 signaling pathway has demonstrated clinical activity in patients with multiple tumor types, and antibody therapeutics that block PD-1 / PDL1 signaling (e.g., nivolumab, pembrolizumab, atezolizumab, durvalumab, and cemiplimab) have been approved for the treatment of various cancers including, for example, metastatic melanoma and metastatic squamous non-small cell lung cancer.

[0004] Like PD-1 , lymphocyte activation gene-3 (LAG-3) negatively regulates T-cell activity. LAG-3 (also called CD223) is a 503 amino acid transmembrane protein receptor expressed on activated CD4 and CD8 T cells, yd T cells, natural killer T cells, B-cells, natural killer cells, plasmacytoid dendritic cells and regulatory T cells. LAG-3 is a member of the immunoglobulin (Ig) superfamily. The primary function of LAG-3 is to attenuate the immune response. LAG-3 binding to MHC class II molecules results in delivery of a negative signal to LAG-3-expressing cells and down-regulates antigendependent CD4 and CD8 T cell responses. LAG-3 negatively regulates the ability of T cells to proliferate, produce cytokines and lyse target cells, termed as ‘exhaustion’ of T cells. LAG-3 is also reported to play a role in enhancing T regulatory (Treg) cell function (Pardoll 2012, Nature Reviews Cancer 12: 252-264).

[0005] Since both PD-1 and LAG-3 play important roles in tumor immunity, they are ideal targets for immunotherapy. Targeting both LAG-3 and PD-1 (including in anti-PD-1 resistant tumors) may result in objective responses in patients across several tumortypes.SUMMARY

[0006] The present disclosure relates to methods for treating lung cancer and methods for inhibiting tumor growth.

[0007] Provided herein are methods for treating, ameliorating at least one symptom or indication, or inhibiting lung cancer in a subject. The methods according to this aspect of the disclosure comprise administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1 ) in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to LAG-3 to a subject in need thereof. In the methods disclosed herein, the inhibition achieved with the combination therapy is more efficacious than administration of either antibody as a monotherapy.

[0008] Provided herein are methods of treating lung cancer or inhibiting the growth and / or metastasis of lung cancer in a subject. The methods according to this aspect of the disclosure comprise administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed death 1 (PD-1 ) in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to LAG-3 to a subject in need thereof. In the methods disclosed herein, the inhibition achieved with the combination therapy is more efficacious than administration of either antibody as a monotherapy.

[0009] Further provided herein are methods of treating lung cancer or inhibiting the growth of lung cancer comprising administering to a subject in need thereof:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1); and(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3), wherein the subject suffers from advanced untreated lung cancer and wherein the lung cancer expresses PD-L1 in >50% of cancer cells as determined by immunohistochemistry.

[0010] In some aspects, the lung cancer is unresectable. In some aspects, the lung cancer is locally advanced lung cancer. In some aspects, the lung cancer is metastatic lung cancer.

[0011] A subject can be selected on the basis of one or more of the following criteria:• (i) the subject is at least 18 years of age;• (ii) the subject has non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage III B or stage I IIC disease and not a candidate for surgical resection or definitive chemoradiation;• (iii) the subject has non-squamous or squamous histology NSCLC stage IV (metastatic disease) and has not received prior systemic treatment for recurrent or metastatic NSCLC;• (iv) the subject has at least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria;• (v) the subject has Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and• (vi) the subject has adequate organ and bone marrow function.

[0012] In some embodiments, one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 50 to 1500 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg. In some embodiments, one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350mg.

[0013] In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 to 8000 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 2000 mg, or about 2500 mg, or about 3000 mg, or about 4000 mg, or about 5000 mg, or about 6000 mg, or about 7000 mg, or about 8000 mg. In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg. In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

[0014] In some embodiments, the lung cancer expresses PD-L1 in >55%, in >60%, in >65%, in >70%, or in >75% of cancer cells as determined by immunohistochemistry.

[0015] In some embodiments, > 1% LAG3 is present in the cancer tissue.

[0016] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered prior to, concurrent with or after the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered to the same day as the anti-PD-1antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered as a co-infusion with the anti-PD-1 antibody or antigen-binding fragment thereof.

[0017] In some embodiments, two or more doses of the anti-LAG-3 antibody or antigenbinding fragment thereof are administered in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0018] In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350 mg.

[0019] In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 and 8000 mg.

[0020] In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

[0021] In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.

[0022] In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 200 mg, 250 mg or 350 mg and each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

[0023] In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in three weeks.

[0024] The antibodies can be administered intravenously, subcutaneously, or intraperitoneally.

[0025] In some aspects, the methods provided herein produce a therapeutic effect selected from the group consisting of delay in cancer growth, reduction in cancer cell number, cancer regression, increase in survival, partial response, and complete response. In some aspects, cancer growth is delayed by at least 10 days as comparedto an untreated subject. In some aspects, cancer growth is inhibited by at least 50% as compared to an untreated subject. In some aspects, the cancer growth is inhibited by at least 20% as compared to a subject administered with either antibody as monotherapy. In some aspects, the inhibition is more efficacious than administration of either antibody as a monotherapy.

[0026] In some aspects, the methods provided herein further comprise administering to the subject an additional therapeutic agent or therapy. In some embodiments, the additional therapy is radiation. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is administration of a therapeutic agent. The additional therapeutic agent can be selected from the group consisting of a cancer vaccine, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a CD28 agonist, a CD38 inhibitor, an indoleamine-2,3- dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGF|3) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor, an oncolytic virus, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-21 , IL-12, IL-15, an antibody-drug conjugate, a GITR agonist, a 4-1 BB agonist, and an anti-inflammatory drug.

[0027] According to the methods provided herein, the anti-PD-1 antibody or antigenbinding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0028] In some aspects, the anti-PD-1 antibody comprises the HCVR amino acid sequence of SEQ ID NO: 1 and the LCVR amino acid sequence of SEQ ID NO: 2.

[0029] In some aspects, the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0030] According to the methods provided herein, the anti-LAG-3 antibody or antigenbinding fragment thereof comprises the heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) of a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) of a LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0031] In some aspects, the anti-LAG3 antibody comprises an HCVR amino acid sequence of SEQ ID NO: 11 and an LCVR amino acid sequence of SEQ ID NO: 12.

[0032] In some aspects, the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0033] In some embodiments, the method comprises administering to the subject (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12. The administering can occur once every 3 weeks; the administering can occur once every 6 weeks.

[0034] Provided herein are methods of treating lung cancer or inhibiting the growth of lung cancer comprising administering to a subject in need thereof:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3); and(c) platinum-based doublet chemotherapy; wherein the subject suffers from advanced untreated lung cancer.

[0035] The platinum-based doublet chemotherapy can be any such chemotherapy combination used by clinicians in the treatment of cancer. In some embodiments, the platinum-based doublet chemotherapy is selected from the group consisting of paclitaxel, carboplatin, cisplatin, gemcitabine and pemetrexed.

[0036] In some embodiments, the lung cancer is unresectable. In some embodiments, the lung cancer is locally advanced lung cancer. In some embodiments, the lung cancer is metastatic lung cancer.

[0037] In some aspects, the subject is further selected as having one or more of the following:• (i) at least 18 years of age;• (ii) has non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage I II B or stage IIIC disease and not a candidate for surgical resection or definitive chemoradiation;• (iii) has non-squamous or squamous histology NSCLC stage IV (metastatic disease) and has not received prior systemic treatment for recurrent or metastatic NSCLC;• (iv) has at least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria;• (v) Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and• (vi) Adequate organ and bone marrow function.

[0038] Provided herein are methods for treating, ameliorating at least one symptom or indication, or inhibiting growth of lung cancer in a subject. The methods according to this aspect of the disclosure comprise:(i) selecting a subject with resectable lung cancer; and(ii) administering to the subject a neo-adjuvant treatment comprising:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3); and(c) platinum-based doublet chemotherapy.

[0039] In some aspects, the lung cancer is non-squamous or squamous histology non- small cell lung cancer (NSCLC) with stage II to stage I II B (N2) disease.

[0040] In some aspects, the lung cancer is newly diagnosed, i.e. , untreated or naive.

[0041] In some aspects, the subject is further selected as having one or more of the following criteria:• (i) at least 18 years of age;• (ii) no evidence of distant metastases;• (iii) evaluable PD-L1 IHC result;• (iv) Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and• (v) adequate kidney, liver, and bone marrow function.

[0042] In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately precedingdose. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in three weeks. In some embodiments, the subject is administered the anti-PD-1 antibody or antigen-binding fragment thereof once every three weeks up to 15 weeks. In some embodiments, the subject is administered the anti-PD-1 antibody or antigen-binding fragment thereof once every three weeks up to 12 weeks. In some embodiments, the subject is administered the anti-LAG-3 antibody or antigen-binding fragment thereof once every three weeks up to 15 weeks. In some embodiments, the subject is administered the anti-LAG-3 antibody or antigen-binding fragment thereof once every three weeks up to 12 weeks. In some embodiments, the subject is administered chemotherapy once every three weeks up to 15 weeks. In some embodiments, the subject is administered the chemotherapy once every three weeks up to 12 weeks.

[0043] The cancer can be assessed radiologically after treatment, e.g., after neoadjuvant treatment. In some aspects, the subject undergoes surgery to resect the cancer. In some aspects, the cancer is assessed radiologically after the subject undergoes surgery to resect the cancer. In some aspects, the surgery occurs 1 to 10 weeks after administration of the anti-PD-1 antibody or antigen-binding fragment thereof, 1 to 10 weeks after administration of the anti-LAG-3 antibody or antigen-binding fragment thereof, and / or 1 to 10 weeks after administration of the chemotherapy. In some aspects, the surgery occurs 1 to 6 weeks after administration of the anti-PD-1 antibody or antigen-binding fragment thereof, 1 to 6 weeks after administration of the anti-LAG-3 antibody or antigen-binding fragment thereof, and / or 1 to 6 weeks after administration of the chemotherapy.

[0044] In some embodiments, the method further comprises administering to the subject adjuvant treatment comprising the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof. In some aspects, the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG- 3 antibody or antigen-binding fragment thereof is administered once every three weeks up to 45 weeks.

[0045] In some embodiments, one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 50 to 1500 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg. In some embodiments, one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350mg.

[0046] In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 to 8000 mg, or about 100 mg, or about 200 mg, or about 300 mg, or about 350 mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900 mg, or about 1000 mg, or about 1100 mg, or about 1200 mg, or about 1300 mg, or about 1400 mg, or about 1500 mg, or about 1600 mg, or about 2000 mg, or about 2500 mg, or about 3000 mg, or about 4000 mg, or about 5000 mg, or about 6000 mg, or about 7000 mg, or about 8000 mg. In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg. In some embodiments, one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

[0047] In some embodiments, the subject shows > 1% LAG3 in the cancer tissue.

[0048] In some embodiments, the subject shows <1%, 1% to 49%, >50% to <75%, or >75% PD-L1 in the cancer tissue.

[0049] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered the same day as the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered as a co-infusion with the anti-PD-1 antibody or antigenbinding fragment thereof. In some embodiments, the chemotherapy is administered after the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the chemotherapy is administered prior to the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the chemotherapy is administered the same day as the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigenbinding fragment thereof.

[0050] As provided herein, two or more doses of the anti-LAG-3 antibody or antigenbinding fragment thereof can be administered in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof. In some embodiments, eachdose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350 mg. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 and 8000 mg. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 200 mg, 250 mg or 350 mg and each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

[0051] In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks. In some embodiments, each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks. In some embodiments, each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in three weeks.

[0052] The antibodies can be administered intravenously, subcutaneously, or intraperitoneally.

[0053] According to the methods provided herein, the treatment produces a therapeutic effect selected from the group consisting of delay in cancer growth, reduction in cancer cell number, cancer regression, increase in survival, partial response, and complete response. In some aspects, cancer growth is delayed by at least 10 days as compared to an untreated subject. In some aspects, cancer growth is inhibited by at least 50% as compared to an untreated subject. In some aspects, cancer growth is inhibited by at least 20% as compared to a subject administered with either antibody as monotherapy. In some aspects, the inhibition is more efficacious than administration of either antibody as a monotherapy.

[0054] According to the methods provided herein, the anti-PD-1 antibody or antigenbinding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of alight chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4;HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

[0055] In some aspects, the anti-PD-1 antibody comprises the HCVR amino acid sequence of SEQ ID NO: 1 and the LCVR amino acid sequence of SEQ ID NO: 2.

[0056] In some aspects, the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

[0057] According to the methods provided herein, the anti-LAG-3 antibody or antigenbinding fragment thereof comprises the heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) of a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) of a LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

[0058] In some embodiments, the anti-LAG3 antibody comprises an HCVR amino acid sequence of SEQ ID NO: 11 and an LCVR amino acid sequence of SEQ ID NO: 12.

[0059] In some embodiments, the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

[0060] In some embodiments, the methods provided herein comprising administering to the subject (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12. The step of administering can occur as needed, or once every 3 weeks, or once every 6 weeks.

[0061] In some embodiments, the anti-PD-1 antibody is cemiplimab.

[0062] In some embodiments, the anti-LAG-3 antibody is fianlimab.

[0063] Other embodiments will become apparent from a review of the ensuing detailed description.BRIEF DESCRIPTION OF THE FIGURES

[0064] Figure 1 depicts a study flow diagram for Example 1 .

[0065] Figure 2 depicts a study flow diagram for Example 2.

[0066] Figure 3 depicts a study flow diagram for Example 3.DETAILED DESCRIPTION

[0067] It is to be understood that this invention is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0068] Unless defined otherwise, 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 belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1 , 99.2, 99.3, 99.4, etc.).

[0069] The term "antibody," as used herein, includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI , CH2 and CHS- Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CLI). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the disclosure, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0070] The term "antibody," as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigenbinding fragment" of an antibody, and the like, as used herein, include any naturallyoccurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0071] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.

[0072] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0073] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Nonlimiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) VH-CHI ; (ii) VH-CH2; (iii) VH-CHS; (iv) VH-CHI-CH2; (V) VH-CHI -CH2-CH3; (vi) VH-CH2-CH3; (vii)VH-CL; (viii) VL-CHI ; (ix) VL-CH2; (X) VL-CHS; (xi) VL-CHI-CHZ; (xii) VL-CH-I-CHZ-CHS; (xiii) VL- CH2-CH3; and (xiv) VI_-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present disclosure may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0074] The term "antibody," as used herein, also includes multispecific (e.g., bispecific) antibodies. A multispecific antibody or antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format may be adapted for use in the context of an antibody or antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art. For example, the present disclosure includes methods comprising the use of bispecific antibodies wherein one arm of an immunoglobulin is specific for PD-1 or LAG-3, or fragments thereof, and the other arm of the immunoglobulin is specific for a second therapeutic target or is conjugated to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes, etc.), CrossMab, CrossFab, (SEED) body, leucine zipper, Duobody, IgG 1 / lgG2, dual acting Fab (DAF)- IgG, and Mab2bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1 -11 , and references cited therein, for a review of the foregoing formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugation, e.g., wherein unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates which then self-assemble into multimeric complexes with defined composition, valency and geometry. (See, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0075] The antibodies used in the methods of the present disclosure may be human antibodies. The term "human antibody," as used herein, is intended to include antibodieshaving variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the disclosure may nonetheless 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 mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0076] The antibodies used in the methods of the present disclosure may be recombinant human antibodies. The term "recombinant human antibody," as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) NucL Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0077] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, exemplary methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.General Methods

[0078] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 1989 2ndEdition, 2001 3rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Sambrook and Russell (2001 ) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, Calif.). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols. 1 -4, John Wiley and Sons, Inc. New York, N.Y., which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1 ), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0079] Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1 , John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see, e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001 ) Products for Life Science Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech (2001 ) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001 ) Current Protocols in Immunology, Vol. 1 , John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0080] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, N.Y.; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).

[0081] An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995) Nature Medicine 1 :837-839; Mendez et al. (1997) Nature Genetics 15:146-156; Hoogenboom and Chames (2000) Immunol. Today21 :371-377; Barbas et al. (2001 ) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, Calif.; de Bruin et al. (1999) Nature Biotechnol. 17:397-399). Single chain antibodies and diabodies are described (see, e.g., Malecki et al. (2002) Proc. Natl. Acad. Sci. USA 99:213-218; Conrath et al. (2001) J. Biol. Chem. 276:7346-7350; Desmyter et al. (2001 ) J. Biol. Chem. 276:26285-26290; Hudson and Kortt (1999) J. Immunol. Methods 231 :177-189; and U.S. Pat. No. 4,946,778). Bifunctional antibodies are provided (see, e.g., Mack, et al. (1995) Proc. Natl. Acad. Sci. USA 92:7021 -7025; Carter (2001 ) J. Immunol. Methods 248:7-15; Volkel, et al. (2001 ) Protein Engineering 14:815-823; Segal, et al. (2001) J. Immunol. Methods 248:1 -6; Brennan, et al. (1985) Science 229:81-83; Raso, et al. (1997) J. Biol. Chem. 272:27623; Morrison (1985) Science 229:1202-1207; Traunecker, et al. (1991 ) EMBO J. 10:3655-3659; and U.S. Pat. Nos. 5,932,448, 5,532,210, and 6,129,914). Fully human antibodies may also be developed in genetically engineered mice such as the VelociMouse. See e.g., DeChiara et al., Producing fully ES cell-derived mice from eight-cell stage embryo injections, Methods Enzymol, 476:285-94 (2010); Dechiara et al., VelociMouse: fully ES cell-derived Regeneration mice obtained from the injection of ES cells into eight-cell-stage embryos. Methods Mol Biol, 530:311 -24 (2009); U.S. patent nos. 7576259; 7659442; or 7294754, and US2008 / 0078000A1 .

[0082] Purification of antigen is not typically necessary for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana et al. (1999) J. Immunol. 163:5157-5164).

[0083] Antibodies can be conjugated, e.g., to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g., colloidal gold (see, e.g., Le Doussal et al. (1991 ) J. Immunol. 146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891 -3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811 ; Everts et al. (2002) J. Immunol. 168:883-889).

[0084] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g., Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, N.J.; Givan (2001) FlowCytometry, 2nd ed.; Wiley-Liss, Hoboken, N.J.; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, N.J.). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

[0085] Standard methods of histology of the immune system are described (see, e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, N.Y.; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, N.Y.).

[0086] Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g., GenBank, Vector NTI® Suite (Informax, Inc, Bethesda, Md.); GCG Wisconsin Package (Accelrys, Inc., San Diego, Calif.);DeCypher® (TimeLogic Corp., Crystal Bay, Nev.); Menne, et al. (2000) Bioinformatics 16: 741 -742; Menne, et al. (2000) Bioinformatics Applications Note 16:741 -742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68:177-181 ; von Heijne (1983) Eur. J. Biochem. 133:17-21 ; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).PD-1 Inhibitors

[0087] According to certain exemplary embodiments of the present disclosure, the methods comprise administering a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof. The term "PD-1" refers to the programmed death-1 protein, a T-cell co-inhibitor, also known as CD279. The amino acid sequence of full-length PD-1 is provided in GenBank as accession number NP 005009.2. PD-1 is a member of the CD28 / CTLA-4 / ICOS family of T-cell co-inhibitors. PD-1 is a 288-amino acid protein with an extracellular N-terminal domain which is IgV-like, a transmembrane domain and an intracellular domain containing an immunoreceptor tyrosine-based inhibitory (ITIM) motif and an immunoreceptor tyrosine-based switch (ITSM) motif (Chattopadhyay et al 2009, Immunol. Rev.). The PD-1 receptor has two ligands, PD- ligand-1 (PD-L1 ) and PD-L2.

[0088] PD-L1 is a 290 amino acid protein with an extracellular IgV-like domain, a transmembrane domain and a highly conserved intracellular domain of approximately 30 amino acids. PD-L1 is constitutively expressed on many cells such as antigen presentingcells (e.g., dendritic cells, macrophages, and B-cells) and on hematopoietic and non- hematopoietic cells (e.g., vascular endothelial cells, pancreatic islets, and sites of immune privilege). PD-L1 is also expressed on a wide variety of tumors, virally-infected cells and autoimmune tissue, and is a component of the immunosuppressive milieu (Ribas 2012, NEJM 366: 2517-2519).

[0089] PD-1 inhibitors include antibodies and antigen-binding fragments thereof and other substances (e.g., peptides and small molecules) that specifically bind to PD-1 and antagonize one or more biological activities of PD-1 . Molecules that specifically bind to PD-1 may be referred to as “anti-PD-1”. In an embodiment of the disclosure, the PD-1 inhibitor is an antibody or antigen-binding fragment thereof that binds PD-L1 or PD-L2.

[0090] In an embodiment of the disclosure, the PD-1 inhibitor is an antibody or antigenbinding fragment thereof as set forth in U.S. 9,987,500.

[0091] According to certain embodiments, the antibodies used in the methods of the present disclosure specifically bind PD-1 . The term "specifically binds," or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" PD-1 , as used in the context of the present disclosure, includes antibodies that bind PD-1 or portion thereof with a KD of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay. An isolated antibody that specifically binds human PD-1 may, however, have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.

[0092] According to certain exemplary embodiments of the present disclosure, the anti- PD-1 antibody, or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-PD-1 antibodies as set forth in US Patent No. 9,987,500.

[0093] In certain exemplary embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the presentdisclosure comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 1 and an LCVR comprising SEQ ID NO: 2. In certain embodiments, the methods of the present disclosure comprise the use of an anti-PD-1 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PD-1 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. An exemplary antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2 is the fully human anti-PD-1 antibody known as REGN2810 (cemiplimab; LIBTAYO®).

[0094] According to certain exemplary embodiments, the methods of the present disclosure comprise the use of REGN2810, or a bioequivalent thereof. The term "bioequivalent", as used herein, refers to anti-PD-1 antibodies or PD-1 -binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and / or extent of absorption do not show a significant difference with that of REGN2810 when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose. In the context of the disclosure, the term refers to antigen-binding proteins that bind to PD-1 which do not have clinically meaningful differences with REGN2810 in their safety, purity and / or potency.

[0095] Other anti-PD-1 antibodies that can be used in the context of the methods of the present disclosure include, e.g., the antibodies referred to and known in the art as nivolumab (U.S. Pat. No. 8,008,449), pembrolizumab (U.S. Pat. No. 8,354,509), MEDI0608 (U.S. Pat. No. 8,609,089), pidilizumab (U.S. Pat. No. 8,686,119), or any of the anti-PD-1 antibodies as set forth in U.S. Pat. Nos. 6,808,710, 7,488,802, 8,168,757,8,354,509, 8,779,105, or 8900587. In an embodiment of the disclosure, a PD-1 inhibitor is as set forth in any of U.S. 20110008369, U.S. 20130017199, U.S. 20130022595, W02006121168, W020091154335, WO2012145493, WO2013014668, W02009101611 , EP2262837, and EP2504028.LAG-3 Inhibitors

[0096] The term “LAG-3” refers to the lymphocyte activation gene-3 protein, an immune checkpoint receptor or T cell co-inhibitor, also known as CD223. The amino acid sequence of full-length LAG-3 is provided in GenBank as accession number NP 002277.4. LAG-3 is a member of the immunoglobulin (Ig) superfamily. LAG-3 is a 503-amino acid type-1 transmembrane protein with four extracellular Ig-like domains D1 to D4 and is expressed on activated T cells, natural killer cells, B cells, plasmacytoid dendritic cells, and regulatory T cells. The LAG-3 receptor binds to MHC class II molecules present on antigen presenting cells (APCs).

[0097] As used herein, the term “T cell co-inhibitor” refers to a ligand and / or receptor which modulates the immune response via T cell activation or suppression. The term “T cell co-inhibitor”, also known as T cell co-signaling molecule, includes, but is not limited to, programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), B and T lymphocyte attenuator (BTLA), CD-28, 2B4, LY108, T cell immunoglobulin and mucin 3(TIM3), T cell immunoreceptor with immunoglobulin and ITIM (TIGIT; also known as VSIG9), leucocyte associated immunoglobulin-like receptor 1 (LAIR1 ; also known as CD305), inducible T cell costimulator (ICOS; also known as CD278), V-domain Ig suppressor of T cell activation (VISTA) and CD160.

[0098] LAG-3 inhibitors include antibodies and antigen-binding fragments thereof and other substances (e.g., peptides and small molecules) that specifically bind to LAG-3 and antagonize one or more biological activities of LAG-3. Molecules that specifically bind to LAG-3 may be referred to as “anti-LAG-3”.

[0099] In an embodiment of the disclosure, the LAG-3 inhibitor is an antibody or antigenbinding fragment thereof as set forth in U.S. 20170101472.

[0100] According to certain embodiments, the antibodies used in the methods of the present disclosure specifically bind LAG-3. The term "specifically binds," or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. Forexample, an antibody that "specifically binds" LAG-3, as used in the context of the present disclosure, includes antibodies that bind LAG-3 or portion thereof with a KD of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay. An isolated antibody that specifically binds human LAG-3 may, however, have cross-reactivity to other antigens, such as LAG-3 molecules from other (non-human) species.

[0101] According to certain exemplary embodiments of the present disclosure, the anti-LAG-3 antibody, or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti- LAG-3 antibodies as set forth in U.S. 20170101472.

[0102] In certain exemplary embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 11 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 12. According to certain embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 18. In yet other embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 11 and an LCVR comprising SEQ ID NO: 12. In certain embodiments, the methods of the present disclosure comprise the use of an anti-LAG-3 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-LAG-3 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 20. An exemplary antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12 is the fully human anti-LAG-3 antibody known as REGN3767 (fianlimab).

[0103] According to certain exemplary embodiments, the methods of the present disclosure comprise the use of REGN3767, or a bioequivalent thereof. The term "bioequivalent", as used herein, refers to anti-LAG-3 antibodies or LAG-3-binding proteins or fragments thereof that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and / or extent of absorption do not show a significant difference with that of REGN3767 when administered at the same molar dose under similar experimental conditions, either single dose or multiple dose. In the context of the disclosure, the term refers to antigen-binding proteins that bind to LAG-3 which do not have clinically meaningful differences with REGN3767 in their safety, purity and / or potency.

[0104] Other anti-LAG-3 antibodies that can be used in the context of the methods of the present disclosure include, e.g., the antibodies referred to and known in the art as relatlimab (U.S. 20110150892), LAG525 (WO2017 / 037203), GSK2831781 (U.S. 2016 / 0017037), Sym022 (WO2018 / 069500), INCAGN02385 (U.S. 20180127499) or any of the anti-LAG-3 antibodies as set forth in US Patent / Publication Nos. 5976877, 6143273, 6197524, 8551481 , 20110070238, 20110150892, 20130095114, 20140093511 , 20140127226, 20140286935, and in WQ95 / 30750, WO97 / 03695, WO98 / 58059, WG2004 / 078928, WG2008 / 132601 , WO2010 / 019570, WO2014 / 008218, EP0510079B1 , EP0758383B1 , EP0843557B1 , EP0977856B1 , EP1897548B2, EP2142210A1 , and EP2320940B1.Methods for Treating Lung Cancer or Inhibiting Lung Cancer Metastasis

[0105] The present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of lung cancer in a subject. The methods according to this aspect comprise administering an antibody or antigen-binding fragment thereof that specifically binds PD-1 in combination with an antibody or antigen-binding fragment thereof that specifically binds LAG-3 to a subject in need thereof. In some aspects, the methods comprise administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds PD-1 in combination with a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds LAG-3 to a subject in need thereof. As used herein, the terms "treat", "treating", or the like, mean to alleviatesymptoms, eliminate the causation of symptoms either on a temporary or permanent basis, to delay or inhibit lung cancer growth, to reduce lung cancer cell load or tumor burden, to promote lung cancer regression, to cause lung cancer shrinkage, necrosis and / or disappearance, to prevent lung cancer recurrence, and / or to increase duration of survival of the subject.

[0106] As used herein, the expression "a subject in need thereof" means a human or non-human mammal that exhibits one or more symptoms or indications of lung cancer, and / or who has been diagnosed with lung cancer, and who needs treatment for the same. In many embodiments, the term "subject" may be interchangeably used with the term "patient". For example, a human subject may be diagnosed with a primary or a metastatic lung cancer and / or with one or more symptoms or indications including, but not limited to, enlarged lymph node(s), swollen abdomen, chest pain / pressure, unexplained weight loss, fever, night sweats, persistent fatigue, loss of appetite, enlargement of spleen, itching. In specific embodiments, the expression includes human subjects that have and need treatment for unresectable locally advanced lung cancer or metastatic lung cancer. In some embodiments, the human subjects have not received a previous systemic treatment for advanced disease. In some embodiments, the expression includes human subjects that have and need treatment for resectable stage II to II IB (N2) non-small cell lung cancer.

[0107] In some instances, a subject having locally advanced lung cancer or metastatic lung cancer is further selected as having one or more of the following criteria:• (i) at least 18 years of age;• (ii) has non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage I II B or stage IIIC disease and not a candidate for surgical resection or definitive chemoradiation;• (iii) has non-squamous or squamous histology NSCLC stage IV (metastatic disease) and has not received prior systemic treatment for recurrent or metastatic NSCLC;• (iv) has at least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria;• (v) an Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and• (vi) adequate organ and bone marrow function.

[0108] In some instances, a subject having resectable stage II to IIIB (N2) NSCLC is further selected as having one or more of the following criteria:(i) at least 18 years of age (or the legal age of adults to consent to participate in a clinical study per country-specific regulations);(ii) newly diagnosed, histologically confirmed, fully resectable stage II to IIIB (N2) NSCLC;(iii) for patients with evidence of mediastinal adenopathy on imaging, mediastinal lymph node sampling is required;(iv) no evidence of distant metastases;(v) an evaluable PD-L1 IHC result;(vi) an ECOG performance status of < 1 ; and(vii) adequate organ and bone marrow function.

[0109] The expression "a subject in need thereof" also includes subjects who are at risk of developing lung cancer, e.g., persons with a family history of lung cancer, persons with a past lung cancer occurrence, or persons with a compromised immune system. In some aspects, the subject is resistant or inadequately responsive to, or relapsed after prior therapy.

[0110] In certain embodiments, the methods provided herein may be used to treat patients that show elevated levels of one or more cancer-associated biomarkers (e.g., PD-L1 , or LAG-3). For example, the methods of the present invention comprise administering a therapeutically effective amount of an anti-LAG-3 antibody in combination with an anti-PD-1 antibody to a patient with an elevated level of LAG-3 and / or PD-L1 . In one embodiment, the present methods are used in patients with lung cancer that are selected on the basis of PD-L1 expression in cancer tissue, wherein the cancer tissue comprises lung cancer cells and tumor-infiltrating immune cells. In certain embodiments, the present methods are used to treat patients with lung cancer wherein the patients are selected on the basis of <1%, 1% to 49%, 50%, >50%, >50% to <75%, >75%, or >80% PD-L1 expression in cancer tissue and / or immune cells. In one embodiment, the present methods are used in patients with lung cancer that are selected on the basis of LAG-3 expression in cancer tissue, wherein the cancer tissue comprises lung cancer cells and tumor-infiltrating immune cells. In certain embodiments, the present methods are used to treat patients with lung cancer wherein the patients show >1% LAG-3 expression in cancer tissue and / or immune cells. Methods to determine LAG-3 or PD-L1 expression in cancer tissue and / or tumor-associated immune cells are well-known in the art. In certain embodiments, the expression of LAG-3 or PD-L1 in tumor tissue is determined by any assay known in the art, for example, by an ELISA assay or by an immunohistochemistry (IHC) assay (e.g., as described in He et al 2017, J. Thoracic Oncol. 12: 814-823; WO2016124558 or WO2016191751 ). In certain embodiments, the expression of LAG-3 or PD-L1 is determined by quantitating RNA expression, for example, by in situ hybridization or by RT-PCR. In certain embodiments, the expression of LAG-3 is determined by imaging with a labeled anti-LAG-3 antibody, for example, by immuno-positron emission tomography or iPET [See, e.g., The Oncologist, 12: 1379 (2007); Journal of Nuclear Medicine, 52(8): 1171 (2011); US Patent Application Publication 2018 / 0228926]. In certain embodiments, the expression of PD-L1 is determined by imaging with a labeled anti-PD-L1 antibody, for example, by immuno-positron emission tomography or iPET (US Patent Application Publication 2018 / 0161464). In certain embodiments, the expression of PD-L1 is determined by a College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (CLIA) (or equivalently licensed, according to local regulations) accredited laboratory. In some embodiments, the expression of PD-L1 is obtained using the VENTANA PD-L1 (SP263) assay.

[0111] In certain embodiments, the methods provided herein are used in a subject with a cancer. The terms "tumor", "cancer" and "malignancy" are interchangeably used herein.

[0112] In certain embodiments, the cancer or tumor is a lung cancer. Reference to “tumor” or “cancer” throughout is inclusive of lung cancer, e.g., the tumor or cancer is lung cancer, for example, squamous or non-squamous non-small cell lung cancer (NSCLC). In some aspects, the lung cancer is unresectable locally advanced lung cancer. In some aspects, the lung cancer is metastatic lung cancer. In some aspects, the patient has not received a previous systemic treatment for advanced disease. In some aspects, the patient has received prior, systemic treatment.

[0113] According to certain embodiments, the present disclosure includes methods for treating, or delaying or inhibiting the growth of lung cancer. In certain embodiments, this includes methods to promote lung cancer regression. In certain embodiments, this includes methods to reduce tumor cell load or to reduce tumor burden. In certain embodiments, the present disclosure includes methods to prevent lung cancer recurrence. The methods, according to this aspect, comprise sequentially administering a therapeutically effective amount of an anti-PD-1 antibody in combination with anti- LAG-3 antibody to a subject in need thereof, wherein each antibody is administered to the subject in multiple doses, e.g., as part of a specific therapeutic dosing regimen. Forexample, the therapeutic dosing regimen may comprise administering one or more doses of an anti-PD-1 antibody to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, or less frequently. In certain embodiments, the one or more doses of anti-PD-1 antibody are administered in combination with one or more doses of a therapeutically effective amount of anti-LAG-3 antibody, wherein the one or more doses of the anti-LAG-3 antibody are administered to the subject at a frequency of about once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every six weeks, once every two months, once every three months, once every four months, or less frequently.

[0114] In certain embodiments, the present disclosure includes methods to inhibit, retard or stop lung cancer metastasis or infiltration into peripheral organs. The methods, according to this aspect, comprise administering a therapeutically effective amount of an anti-PD-1 antibody to a subject in need thereof. In certain embodiments, the anti-PD-1 antibody is administered in combination with an anti-LAG-3 antibody.

[0115] In specific embodiments, the present disclosure provides methods for increased anti-tumor efficacy or increased lung cancer inhibition. In certain embodiments, the methods provide for increased lung cancer inhibition, e.g., by about 20%, more than 20%, more than 30%, more than 40% more than 50%, more than 60%, more than 70% or more than 80% as compared to a subject administered either antibody as a monotherapy.

[0116] The methods provided herein, according to certain embodiments, comprise administering to a subject with lung cancer a therapeutically effective amount of an anti- PD-1 antibody prior to, concurrent with, or after administering a therapeutically effective amount of anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody may be administered about 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days prior to the anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody and anti-LAG-3 antibody are administered concurrently, or within 30 minutes, or within 60 minutes, or within 2 hours, or within 3 hours, or within a day of each other.

[0117] In certain embodiments, the methods provided herein comprise administering a therapeutically effective amount of an anti-PD-1 antibody or antigen-binding fragment thereof and a therapeutically effective amount of an anti-LAG-3 antibody or antigenbinding fragment thereof to a subject with lung cancer. In specific embodiments, the lung cancer is advanced or metastatic. In specific embodiments, the lung cancer is unresectable. In certain embodiments, the subject is not responsive to prior therapy or has relapsed after prior therapy. Prior therapy can include surgery, radiation, and / or chemotherapy, or treatment with a PD-1 inhibitor, a PD-L1 inhibitor, and / or any other anti-cancer biologic.

[0118] In certain embodiments, the methods of the present disclosure comprise administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject in need thereof as a "first line" treatment (e.g., initial treatment). In other embodiments, an anti-PD-1 antibody in combination with anti-LAG-3 antibody is administered as a "second line" treatment (e.g., after prior therapy). For example, an anti-PD-1 antibody in combination with anti-LAG-3 antibody is administered as a "second line" treatment to a subject that has relapsed after prior therapy with, e.g., chemotherapy or rituximab.

[0119] In certain embodiments, the methods of the present disclosure are used to treat a patient with an MRD-positive disease. Minimum residual disease (MRD) refers to small numbers of cancer cells that remain in the patient during or after treatment, wherein the patient may or may not show symptoms or signs of the disease. Such residual cancer cells, if not eliminated, frequently lead to relapse of the disease. The present disclosure includes methods to inhibit and / or eliminate residual cancer cells in a patient upon MRD testing. MRD may be assayed according to methods known in the art (e.g., MRD flow cytometry). The methods, according to this aspect of the disclosure, comprise administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject in need thereof.

[0120] In certain embodiments, the antibodies may be administered in combination with therapy including a chemotherapeutic agent, radiation or surgery. As used herein, the phrase “in combination with" means that the antibodies are administered to the subject at the same time as, just before, or just after administration of the third therapeutic agent. In a related embodiment, the present disclosure includes methods comprising administering a therapeutically effective amount of an anti-PD-1 antibody incombination with an anti-LAG-3 antibody to a subject who is on a background anticancer therapeutic regimen. The background anti-cancer therapeutic regimen may comprise a course of administration of, e.g., a chemotherapeutic agent, or radiation. The anti-PD-1 antibody in combination with the anti-LAG-3 antibody may be added on top of the background anti-cancer therapeutic regimen. In some embodiments, the antibodies are added as part of a "background step-down" scheme, wherein the background anticancer therapy is gradually withdrawn from the subject over time (e.g., in a stepwise fashion) while the antibodies are administered to the subject at a constant dose, or at an increasing dose, or at a decreasing dose, over time.

[0121] In certain embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of an anti- PD-1 antibody in combination with a therapeutically effective amount of an anti-LAG-3 antibody, wherein administration of the antibodies leads to increased inhibition of lung cancer growth. In certain embodiments, lung cancer growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80% as compared to an untreated subject or a subject administered with either antibody as monotherapy. In certain embodiments, the administration of an anti-PD-1 antibody and / or anti-LAG-3 antibody to a subject leads to increased lung cancer regression, tumor shrinkage and / or disappearance. In certain embodiments, the administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody leads to delay in lung cancer growth and development, e.g., lung cancer growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, at least 10 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years as compared to an untreated subject or a subject treated with either antibody as monotherapy. In certain embodiments, administration of an anti- PD-1 antibody in combination with an anti-LAG-3 antibody prevents lung cancer recurrence and / or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months than an untreated subject or a subject which is administered either antibody as monotherapy. In certain embodiments, administration of the antibodies in combination increases progression-free survival or overall survival. In certain embodiments, administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody increases response and duration of response in a subject, e.g., by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40% or more than 50% over an untreated subject or a subject which has received either antibody as monotherapy. In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with lung cancer leads to complete disappearance of all evidence of lung cancer cells ("complete response"). In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with lung cancer leads to at least 30% or more decrease in lung cancer cells or tumor size ("partial response"). In certain embodiments, administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody to a subject with lung cancer leads to complete or partial disappearance of lung cancer cells / lesions including new measurable lesions, lung cancer tumor reduction can be measured by any of the methods known in the art, e.g., X-rays, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analyses. In some aspects, administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a patient population results in more patients responding to treatment, results in patient responses to treatment that are longer even without more patients responding, and / or the patients that do respond to therapy have deeper responses.

[0122] In certain embodiments, the combination of administered antibodies is safe and well-tolerated by a patient wherein there is no increase or a tolerable increase in an adverse side effect as compared to a patient administered with either antibody as monotherapy.Combination Therapies

[0123] The methods of the present disclosure, according to certain embodiments, comprise administering to the subject an anti-LAG-3 antibody in combination with an anti-PD-1 antibody. In certain embodiments, the methods of the present disclosure comprise administering the antibodies for additive or synergistic activity to treat lung cancer. As used herein, the expression "in combination with" means that the anti-LAG-3 antibody is administered before, after, or concurrent with the anti-PD-1 antibody. The term "in combination with" also includes sequential or concomitant administration of anti- PD-1 antibody and an anti-LAG-3 antibody. For example, when administered "before" the anti-LAG-3 antibody, the anti-PD-1 antibody may be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours,about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the anti-LAG-3 antibody. When administered "after" the anti-LAG-3 antibody, the anti-PD-1 antibody may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after the administration of the anti-LAG-3 antibody. Administration "concurrent" with the anti-LAG-3 antibody means that the anti-PD-1 antibody is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the anti-LAG-3 antibody, e.g. within 5 minutes of completion of anti-LAG-3 antibody infusion, or administered to the subject as a single combined dosage formulation comprising both the anti-PD-1 antibody and the anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody is administered the same day as the anti-LAG-3 antibody. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody are administered as a co-infusion administered over 30 minutes.

[0124] Likewise, when administered in combination with a chemotherapeutic agent, e.g., a platinum-based doublet chemotherapy regimen, the anti-PD-1 antibody, the anti- LAG-3 antibody, and the chemotherapeutic agent(s) can be administered, each, in combination with, before, after, or concurrently with any of the other agents.

[0125] In some embodiments, a combination therapy includes a first therapy, e.g., a neoadjuvant therapy, comprising administration of an anti-PD-1 antibody or antigenbinding fragment thereof, an anti-LAG-3 antibody or antigen-binding fragment thereof, and a platinum-based doublet chemotherapy regimen to a subject in need thereof, followed by an adjuvant therapy, comprising administration of an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-LAG-3 antibody or antigen-binding fragment thereof to a subject in need thereof. In some aspects, surgery to resect the cancer is performed after completion of the neo-adjuvant therapy. In some aspects, surgery is performed within 1 - 10 weeks of completion of the neo-adjuvant therapy. In some aspects, surgery is performed within 1 - 6 weeks of completion of the neoadjuvant therapy. In some aspects, the neoadjuvant therapy is administered once every three weeks, for example, once every three weeks for up to 15 weeks, or 12 weeks, or 9 weeks, or 6 weeks, or three weeks. In some aspects, the adjuvant therapy is administered once every three weeks for up to 51 weeks, for example, up to 48 weeks, or 45 weeks, or 42 weeks, or 39 weeks, or 36 weeks, or 33 weeks, or 30 weeks, or 27weeks, or 24 weeks, or 21 weeks, or 18 weeks, or 15 weeks, or 12 weeks, or 9 weeks, or 6 weeks, or three weeks.

[0126] In certain embodiments, the methods provided herein comprise administration of an additional therapeutic agent wherein the additional therapeutic agent is an anticancer drug. As used herein, "anti-cancer drug" means any agent useful to treat cancer including, but not limited to, cytotoxins and agents such as antimetabolites, alkylating agents, anthracyclines, antibiotics, antimitotic agents, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), biologies (e.g., antibodies and interferons) and radioactive agents. As used herein, "a cytotoxin or cytotoxic agent", also refers to a chemotherapeutic agent and means any agent that is detrimental to cells. Examples include Taxol® (paclitaxel), temozolamide, cytochalasin B, gramicidin D, ethidium bromide, emetine, cisplatin, mitomycin, etoposide, tenoposide, vincristine, vinbiastine, coichicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1 -dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. In certain embodiments, the methods provided herein comprise administration of an additional therapeutic agent selected from the group consisting of radiation, surgery, a cancer vaccine, a PD-L1 inhibitor (e.g., an anti-PD-L1 antibody), a CD3 inhibitor, a CTLA-4 inhibitor (e.g., ipilimumab), a CD38 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, an antagonist of another T-cell co-inhibitor or ligand (e.g., an antibody to CD-28, 2B4, LY108, LAIR1 , ICOS, CD160 or VISTA), an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist [e.g., a "VEGF-Trap" such as aflibercept or other VEGF-inhibiting fusion protein as set forth in U.S. Pat. No. 7,087,411 , or an anti-VEGF antibody or antigen binding fragment thereof (e.g., bevacizumab, or ranibizumab) or a small molecule kinase inhibitor of VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], an Ang2 inhibitor (e.g., nesvacumab), a transforming growth factor beta (TGF|3) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), an agonist to a co-stimulatory receptor (e.g., an agonist to glucocorticoid-induced TNFR-related protein), an antibody to a tumor-specific antigen [e.g., CA9, CA125, melanoma- associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA)], a CD28 agonist, a GITR agonist, a 4-1 BB agonist, vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1 , MART-1 , and CA19-9), a vaccine (e.g., Bacillus Calmette-Guerin, a cancer vaccine), an adjuvant to increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), an oncolytic virus, a cytotoxin, a chemotherapeutic agent(e.g., dacarbazine, temozolomide, cyclophosphamide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), radiotherapy, an IL-6R inhibitor (e.g., sarilumab), an IL-4R inhibitor (e.g., dupilumab), an IL-10 inhibitor, a cytokine such as IL-2, IL-7, IL- 12, IL-21 , and IL-15, an antibody-drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC), chimeric antigen receptor T cells (e.g., CD19-targeted T cells) or other cell therapies, and an anti-inflammatory drug (e.g., corticosteroids, and nonsteroidal anti-inflammatory drugs).

[0127] In certain embodiments, the methods provided herein comprise administration of an anti-LAG-3 antibody in combination with an anti-PD-1 antibody and a platinumbased doublet chemotherapy to generate long-term durable anti-tumor responses and / or enhance survival of patients with lung cancer. Illustratively, platinum-based doublet chemotherapies include, but are not limited to, paclitaxel / carboplatin, pemetrexed / cisplatin, gemcitabine / cisplatin, paclitaxel / cisplatin, and pemetrexed / carboplatin.

[0128] In certain embodiments, the methods provided herein comprise administering an anti-PD-1 antibody and an anti-LAG-3 antibody in combination with radiation therapy / chemotherapy or platinum-based doublet chemotherapy to generate long-term durable anti-tumor responses and / or enhance survival of patients with lung cancer.

[0129] In some embodiments, the methods of the disclosure comprise administering radiation therapy prior to, concomitantly or after administering an anti-PD-1 antibody and an anti-LAG-3 antibody to a lung cancer patient. For example, radiation therapy may be administered in one or more doses after administration of one or more doses of the antibodies. In some embodiments, radiation therapy may be administered locally to a lung cancer lesion to enhance the local immunogenicity of a patient's lung cancer (adjuvinating radiation) and / or to kill tumor cells (ablative radiation) before or after systemic administration of an anti-PD-1 antibody and / or an anti-LAG-3 antibody, i.e., in an adjuvant setting. In certain embodiments, the antibodies may be administered in combination with radiation therapy and a chemotherapeutic agent (e.g., temozolomide or cyclophosphamide) or a VEGF antagonist (e.g., aflibercept). In certain embodiments, theantibodies may be administered in combination with platinum-based doublet chemotherapy.Pharmaceutical Compositions and Administration

[0130] Provided herein are methods which comprise administering an anti-PD-1 antibody in combination with an anti-LAG-3 antibody to a subject wherein the antibodies are contained within separate or combined (single) pharmaceutical composition. The pharmaceutical compositions of the disclosure may be formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0131] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262: 4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.

[0132] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In one embodiment, the syringe is a pre-filled syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical compositionwithin the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0133] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used. In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0134] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.

[0135] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of theactive ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.Administration Regimens

[0136] The present disclosure includes methods comprising administering to a subject an anti-PD-1 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved. In certain embodiments, the present disclosure includes methods comprising administering to a subject an anti-LAG-3 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved. In certain embodiments, the methods involve the administration of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody at a dosing frequency of about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every nine weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved.

[0137] According to certain embodiments of the present disclosure, multiple doses of an anti-PD-1 antibody in combination with an anti-LAG-3 antibody may be administered to a subject over a defined time course. The methods according to this aspect of the disclosure comprise sequentially administering to a subject one or more doses of an anti-PD-1 antibody in combination with one or more doses of an anti-LAG-3 antibody. As used herein, "sequentially administering" means that each dose of the antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequentially administering to the patient a single initial dose of an anti-PD-1 antibody, followed by one or more secondary doses of the anti-PD- 1 antibody, and optionally followed by one or more tertiary doses of the anti-PD-1 antibody. In certain embodiments, the methods further comprise sequentially administering to the patient a single initial dose of an anti-LAG-3 antibody, followed byone or more secondary doses of the anti-LAG-3 antibody, and optionally followed by one or more tertiary doses of the anti-LAG-3 antibody.

[0138] According to certain embodiments of the present disclosure, multiple doses of an anti-PD-1 antibody and an anti-LAG-3 antibody may be administered to a subject over a defined time course. The methods according to this aspect of the disclosure comprise sequentially administering to a subject multiple doses of an anti-PD-1 antibody and an anti-LAG-3 antibody. As used herein, "sequentially administering" means that each dose of the anti-PD-1 antibody in combination with the anti-LAG-3 antibody is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months).

[0139] According to certain embodiments of the present disclosure, multiple doses of an anti-LAG-3 antibody can be administered to a subject for several months or years, once every 3 or 6 weeks, then the subject is administered the anti-PD-1 antibody in combination with the anti-LAG-3 antibody, for several months or years. In some aspects, the anti-LAG-3 antibody dosage is different as a monotherapy versus the combination therapy. In some aspects, the anti-LAG-3 antibody dosage is the same whether administered as a monotherapy or in combination with the anti-PD-1 antibody.

[0140] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the antibody (anti-PD-1 antibody or anti-LAG-3 antibody). In certain embodiments, however, the amount contained in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, one or more (e.g., 1 , 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses"). For example, an anti-PD-1 antibody may be administered to a patient with lung cancer at a loading dose of about 1 -20 mg / kg followed by one or more maintenance doses of about 3 mg / kg of the patient's body weight.

[0141] In one exemplary embodiment of the present disclosure, each secondary and / or tertiary dose is administered1 / 2 to 14 (e.g.,1 / 2, 1 , 11 / 2, 2, 21 / 2, 3, 31 / 2, 4, 41 / 2, 5, 51 / 2, 6, 6 2, 7, 71 / 2, 8, 81 / 2, 9, 91 / 2, 10, 101 / 2, 1 1 , 1 11 / 2, 12, 121 / 2, 13, 131 / 2, 14, 141 / 2, or more)weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of anti-PD-1 antibody (and / or anti-LAG-3 antibody) which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

[0142] The methods according some aspects may comprise administering to a patient any number of secondary and / or tertiary doses of an anti-PD-1 antibody (and / or anti- LAG-3 antibody). For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0143] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks, or 3 weeks, after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks, e.g., 3 weeks, after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

[0144] In certain embodiments, one or more doses of an anti-PD-1 antibody and / or an anti-LAG-3 antibody are administered at the beginning of a treatment regimen as "induction doses" on a more frequent basis (twice a week, once a week or once in 2 weeks) followed by subsequent doses ("consolidation doses" or "maintenance doses") that are administered on a less frequent basis (e.g., once in 4-12 weeks).

[0145] In some embodiments, concomitant administration of anti-PD-1 antibody and the anti-LAG-3 antibody which is administered at a separate dosage at a similar or different frequency relative to the anti-PD-1 antibody is contemplated herein. In some embodiments, the anti-LAG-3 antibody is administered before, after or concurrently withthe anti-PD-1 antibody. In certain embodiments, the anti-LAG-3 antibody is administered as a single dosage formulation (co-infusion) with the anti-PD-1 antibody.

[0146] The present disclosure also includes methods comprising sequential administration of an anti-LAG-3 antibody in combination with an anti-PD-1 antibody, to a patient to treat a lung cancer. In some embodiments, the present methods comprise administering one or more doses of an anti-LAG-3 antibody followed by one or more doses of an anti-PD-1 antibody. In certain embodiments, the present methods comprise administering a single dose of an anti-LAG-3 antibody followed by one or more doses of an anti-PD-1 antibody. In some embodiments, one or more doses of about 0.1 mg / kg to about 50 mg / kg of an anti-LAG-3 antibody may be administered followed by one or more doses of about 0.1 mg / kg to about 20 mg / kg of the anti-PD-1 antibody to inhibit tumor growth and / or to prevent lung cancer recurrence in a subject with lung cancer. In some embodiments, one or more doses of about 50 mg to about 8000 mg of an anti-LAG-3 antibody may be administered followed by one or more doses of about 50 mg to about 1500 mg of the anti-PD-1 antibody to inhibit lung cancer growth and / or to prevent lung cancer recurrence in a subject with lung cancer. In some embodiments, the anti-LAG-3 antibody is administered at one or more doses followed by one or more doses of the anti-PD-1 antibody resulting in increased anti-tumor efficacy (e.g., greater inhibition of lung cancer growth, increased prevention of lung cancer recurrence as compared to an untreated subject or a subject administered with either antibody as monotherapy).Dosage

[0147] The amount of anti-PD-1 antibody and / or anti-LAG-3 antibody administered to a subject according to the methods of the present disclosure is, generally, a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of antibody (anti-PD-1 antibody or anti-LAG-3 antibody) that results in, or has the therapeutic effect of, one or more of: (a) a reduction in the severity or duration of a symptom of lung cancer; (b) inhibition of lung cancer growth, or an increase in lung cancer cell necrosis, lung cancer tumor shrinkage and / or lung cancer tumor disappearance; (c) delay in lung cancer growth and development; (d) inhibit or retard or stop lung cancer metastasis; (e) prevention of recurrence of lung cancer growth; (f) increase in survival of a subject with lung cancer; and / or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use ofchemotherapeutic or cytotoxic agents) as compared to an untreated subject or a subject administered with either antibody as monotherapy.

[0148] In the case of an anti-PD-1 antibody, a therapeutically effective amount can be from about 0.05 mg to about 1500 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1 .5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg, of the anti-PD-1 antibody. In certain embodiments, 350 mg of an anti-PD-1 antibody is administered. In certain embodiments, 1050 mg of an anti-PD-1 antibody is administered.

[0149] In the case of an anti-LAG-3 antibody, a therapeutically effective amount can be from about 10 mg to about 8000 mg, e.g., about 10 mg, about 20 mg, about 50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2200 mg, about 2500 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3200 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, or about 8000 mg of the anti-LAG-3 antibody.

[0150] The amount of either anti-PD-1 antibody or anti-LAG-3 antibody contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of subject body weight (i.e. , mg / kg). In certain embodiments, either anti-PD-1 antibody or anti-LAG-3 antibody used in the methods of the present disclosure may be administered to a subject at a dose of about 1 to about 50 mg / kg of subject body weight. For example, anti-PD-1 antibody may be administered at dose of about 0.1 mg / kg toabout 20 mg / kg of a patient's body weight. The anti-LAG-3 antibody may be administered at a dose of about 0.1 mg / kg to about 50 mg / kg of a patient's body weight.EXAMPLES

[0151] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. Compositions and methods set forth in the Examples form part of the present disclosure.

[0152] Therapeutic monoclonal antibodies (mAbs) that target immune inhibitory receptors (e.g., cytotoxic T lymphocyte-associated protein 4 [CTLA-4], and programmed cell death 1 [PD 1]), have shown impressive clinical activity with an acceptable benefit to risk ratio in several tumor types (Topalian, 2014) (Wolchok, 2013) (Larkin, 2015a) (Baksh, 2015). However, sustained responses were achieved in only a minority of patients, suggesting that combination approaches may be required to overcome tumor immune inhibitory mechanisms (Topalian, 2012).

[0153] Antibodies to the inhibitory receptor lymphocyte-activation gene 3 (LAG-3) represent an appealing potential treatment strategy to invigorate the immune response to cancer, especially in combination with antibodies that block PD-1. LAG-3 binds to major histocompatibility complex class II (MHO II) on antigen-presenting cells and is upregulated on activated CD4+ and CD8+ T cells following T cell receptor engagement. It negatively regulates T-cell proliferation, activation, and proinflammatory cytokine production (Magon-Lemaitre, 2005). Multiple reports demonstrate that a large fraction of PD-1 positive CD8+ and CD4+ tumor infiltrating lymphocytes co-express LAG 3, suggesting the dominant role of PD-1 in modulating anti-tumor T-cell responses, as well as the direct role of LAG-3 in suppressing the activity of a subset of PD-1 expressing T cells (Woo, 2012). Early clinical data indicate that lung cancer patients who received previous anti-PD-1 therapy but progressed can respond to concurrent blockade of LAG 3 and PD 1 (Ascierto, 2017).

[0154] In the Examples below, this antibody (REGN3767 (INN: fianlimab), an antibody to the LAG-3 receptor that blocks LAG-3 / MHC II mediated T-cell inhibition, was tested incombination with cemiplimab (REGN2810), an antibody to the PD-1 receptor that blocks PD 1 / programmed death ligand 1 (PD-L1) mediated T-cell inhibition. LIBTAYO® (cemiplimab known as cemiplimab rwlc in the United States) has been approved by several Health Authorities for the treatment of patients with different tumor types.Example 1 : Phase 2 / 3 Double-Blind Clinical Trial of Anti-LAG3 (REGN3767; Fianlimab) and Anti-PD-1 (REGN2810; Cemiplimab) Versus Cemiplimab Monotherapy in First-Line Treatment of Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with Tumors Expressing PD-L1 >50%

[0155] This present phase 2 / 3 study assesses the combination of fianlimab and cemiplimab versus cemiplimab monotherapy in first-line patients with stage II I B, stage IIIC, or stage IV squamous or non-squamous treatment naive NSCLC whose tumors express PD-L1 >50% of tumor cells, lack actionable mutations with approved targeted therapies, and are not eligible for definitive chemoradiation.Objectives

[0156] The primary objective of the Phase 2 study is to assess the objective response rate (ORR) per blinded independent central review (BICR) of combination of cemiplimab and fianlimab at both 1600 mg and 400 mg compared with cemiplimab monotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors express programmed death cell ligand-1 (PD-L1 ) in >50% of tumor cells.

[0157] Secondary objectives of the Phase 2 study include the following:• To assess the safety and tolerability of combination of cemiplimab and fianlimab compared to cemiplimab monotherapy.• To assess other anti-tumor activities of combination of cemiplimab and fianlimab compared to cemiplimab monotherapy, as assessed by ORR, disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), progression free survival (PFS) by BICR, and overall survival (OS).• To assess the patient-reported outcomes (via European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30], -Lung Cancer 13 [EORTC QLQ-LC13], and 5-Level EQ- 50 Scale [EQ-5D-5L]) of combination of cemiplimab and fianlimab compared with cemiplimab monotherapy.• To assess patient-reported fatigue as measured by the fatigue severity and interference with usual or daily activities items of the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for combination of cemiplimab and fianlimab compared with cemiplimab monotherapy.• To characterize the pharmacokinetics (PK) of fianlimab and cemiplimab.• To assess the immunogenicity of fianlimab and cemiplimab.

[0158] The primary objective of the Phase 3 study is to compare OS of cemiplimab and fianlimab versus cemiplimab monotherapy.

[0159] Secondary objectives of the Phase 3 study include the following:• To assess the safety and tolerability of combination of cemiplimab and fianlimab compared to cemiplimab monotherapy.• To assess other anti-tumor activities of combination of cemiplimab and fianlimab and cemiplimab monotherapy, as measured by ORR, DCR, TTR, DOR, and PFS, and by BICR.• To assess the patient-reported outcomes (via EORTC QLQ-C30, EORTC QLQ-LC13, and EQ-5D-5L) of combination of cemiplimab and fianlimab compared with cemiplimab monotherapy.• To assess patient-reported fatigue as measured by the fatigue severity and interference items of the PRO-CTCAE for combination of cemiplimab and fianlimab compared with cemiplimab.• To characterize the PK of fianlimab and cemiplimab.• To assess the immunogenicity of fianlimab and cemiplimab.Study Design

[0160] This is a randomized, double-blind, multi-center phase 2 / 3 study of cemiplimab in combination with fianlimab, at 2 different doses, versus cemiplimab monotherapy in patients 18 years of age or older with stage HUB, stage IIIC, or stage IV squamous or non-squamous treatment naive NSCLC, whose tumors express PD-L1 >50% of tumor cells, lack actionable mutations with approved targeted therapies, and are not eligible for definitive chemoradiation. Patients with squamous NSCLC are capped at <50% of the total sample size.

[0161] In order to be enrolled in the study, patients must have advanced treatment naive NSCLC along with PD-L1 expressed in >50% of tumor cells (see inclusion criteria below).

[0162] There are 2 phases to the study: phase 2 and phase 3.

[0163] During the phase 2 treatment period, patients are randomized at a 1 :1 :1 ratio into one of 3 treatment arms:• Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) Q3W IV• Arm B: fianlimab (400 mg) + cemiplimab (350 mg) Q3W IV• Arm C: cemiplimab (350 mg) + saline / dextrose placebo Q3W IV

[0164] There may be an accrual “pause” between the phase 2 and phase 3, depending on the timing of the dose selection decision from phase 2 part. The totality of data during phase 2 are monitored to select the optimal dose of fianlimab to be adopted in phase 3 for NSCLC. The decisions are made based upon phase 2 data (including ORR) as to which dose of fianlimab (1600 mg, treatment Arm A, or 400 mg, treatment Arm B) is selected for use in phase 3, in comparison with treatment Arm C (cemiplimab (350 mg) + saline / dextrose placebo Q3W IV).

[0165] In phase 3, patients are randomized at a 1 :1 ratio into one of the 2 treatment arms (either treatment Arm A or Arm B and Arm C).

[0166] The study flow diagram is presented in Error! Reference source not found..

[0167] Approximately 850 patients are enrolled. In phase 2, 150 patients are randomized 1 :1 :1 to Arm A (50 patients), Arm B (50 patients), and Arm C (50 patients). In phase 3, 700 patients are randomized at a 1 :1 ratio into one of the 2 treatment arms.

[0168] In order to be enrolled in the study, patients must have advanced treatment naive NSCLC along with PD-L1 expressed in >50% of tumor cells.

[0169] Patient randomization is stratified by histology (non-squamous versus squamous). Patients with squamous NSCLC are capped at <50% of the total sample size.

[0170] Patients continue treatment for up to 108 weeks or until they experience intolerable adverse events (AEs), disease progression, death, or the patient and / or physician decides to discontinue study therapy. There is a post treatment follow-up period for all patients. After the last follow-up visit, patients are contacted by telephone call every 3 months to survey patient survival.

[0171] Efficacy is assessed by tumor imaging and RECIST 1.1 criteria with the first radiographic tumor assessment occurring after 9 weeks of study treatment and every 9 weeks throughout year 1 and every 12 weeks through year 2 and beyond (if applicable). Radiographic tumor assessment occurs until BICR-assessed RECIST 1.1 -definedprogressive disease, withdrawal of consent, death, or initiation of another anti-cancer treatment.

[0172] Safety is continuously monitored throughout the study. Clinical safety and laboratory monitoring is performed throughout the treatment and follow-up periods. Samples for biomarker assessments are taken throughout the treatment and follow-up periods as well.Inclusion Criteria

[0173] Adult patients >18 years of age (or the legal age of adults to consent to participate in a clinical study per country-specific regulations) with advanced treatment naive NSCLC whose tumors have >50% PD-L1 expression levels as confirmed by immunohistochemistry (IHC) assessment. Given the incidence of lung cancer is higher in patients of African descent, there is an emphasis on patients of African descent.

[0174] Following assessment of phase 2 data, and prior to initiation of the phase 3 part of the study, a protocol amendment is issued to address any phase 3-specific eligibility criteria.

[0175] A patient must meet the following criteria to be eligible for inclusion in the study:1 . Men and women >18 years of age (or the legal age of adults to consent to participate in a clinical study per country-specific regulations).2. Patients with non-squamous or squamous histology NSCLC with stage I II B or stage IHC disease who are not candidates for surgical resection or definitive chemoradiation or stage IV (metastatic disease), who received no prior systemic treatment for recurrent or metastatic NSCLC.3. Availability of an archival or on-study formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample, without intervening therapy between biopsy collection and screening.Guidance on biopsy sites: a. Archival or fresh biopsies are acceptable. b. FFPE tissue block must be <6 months old; however, unstained slides of tumor sample (archival or recent) must be <2 weeks from preparation. A minimum of 10 slides, or equivalent block volume, is required for patients with EGFR, ALK, and ROS1 local results available. A minimum of 19 slides, or equivalent block volume, is required for patients without EGFR, ALK, or ROS1 local results available.c. The biopsy should be from a metastatic or recurrent site which has not previously been irradiated. Bone biopsies are allowed provided that they are not de-calcified. i. Exception: the primary lung tumor can be used if it is still in place and the other metastatic sites are either not accessible (brain) or cannot be used or the biopsy would put the patient at risk.4. For enrollment in the phase 2 part of the study, patients should have PD-L1 levels > 50%, as determined by a College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (CLIA) (or equivalently licensed, according to local regulations) accredited laboratory. If PD-L1 IHC results are not available prior to the time the patient provides informed consent, PD-L1 IHC results are obtained during screening using the VENTANA PD-L1 (SP263) assay. For enrollment in the phase 3 part of the study, patients should have expression of PD-L1 in >50% of tumor cells stained using the VENTANA PD-L1 (SP263) assay as performed by a central laboratory.5. At least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.6. Eastern Cooperative Oncology Group (ECOG) performance status of <1 .7. Adequate organ and bone marrow function.(i) Hemoglobin >9.0 g / dL(ii) Absolute neutrophil count (ANC) >1.5 x 109 / L(iii) Platelet count >100,000 / mm3(iv) Glomerular filtration rate (GFR) >30 mL / min / 1 ,73m2(v) Total bilirubin <1.5 x upper limit of normal (ULN) (if liver metastases <3 x ULN), with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome(vi) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x ULN or <5 x ULN, if liver metastases(vii) Alkaline phosphatase (ALP) <2.5 x ULN (or <5.0 x ULN, if liver or bone metastases)(viii) Not meeting criteria for Hy’s law (ALT >3 x ULN and bilirubin >2 x ULN).8. Willing and able to comply with clinic visits and study-related procedures.9. Provide signed informed consent.10. Able to understand and complete study-related questionnaires.Exclusion Criteria

[0176] A patient who meets any of the following criteria is excluded from the study:1 . Patients who have never smoked, defined as smoking <100 cigarettes in a lifetime.2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. Patients must be off (immunosuppressive doses of) corticosteroid therapy.3. Patients with tumors tested positive for actionable EGFR gene mutations, ALK gene translocations, or ROS1 fusions. For enrollment in the phase 2 part of the study, genetic alteration status, as determined by a CAP / CLIA (or equivalently licensed, according to local regulations) accredited laboratory should be available prior to screening. If genetic alteration status is not available prior to the time the patient provides informed consent, genetic alteration status results is obtained during screening.4. Encephalitis, meningitis, or uncontrolled seizures in the year prior to enrollment.5. History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune- suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved >6 months prior to enrollment.6. Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T- cell-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-cell negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency).7. Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk of immune-mediated treatment-emergent adverse events (imTEAEs). Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are excluded. The following are not exclusionary: vitiligo, childhood asthmathat has resolved, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment.8. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiologic replacement doses are allowed even if they are >10 mg of prednisone / day or equivalent, as long as they are not being administered for immunosuppressive intent. Patients with clinically relevant systemic immune suppression within the last 3 months before trial enrollment are excluded. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.9. Another malignancy that is progressing or requires treatment, with the exception of nonmelanomatous skin cancer that has undergone potentially curative therapy, in situ cervical carcinoma, or any other localized tumor that has been treated, and the patient is deemed to be in complete remission for at least 2 years prior to enrollment, and no additional therapy is required during the study period.10. Known active hepatitis B (known positive result) or known hepatitis C (known positive result) and known quantitative hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or HCV infection; or diagnosis of immunodeficiency (FDA).Exceptions: a. Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. b. Patients with HBV (hepatitis B surface antigen positive) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. c. Patients who are HCV antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.11 . Documented or suspected ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A patient being screened who had documented or suspected SARS-CoV-2 may be enrolled if the patient has: a. Recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that can potentially affect the safety of the patient have resolved), andi. It is advisable that 2 repeat COVID-19 PCR tests, or equivalent test depending on regional recommendations, be conducted to confirm that the patient is negative for SARS-CoV-2. ii. If COVID-19 PCR testing is not feasible, it is advised that at least 3 months have transpired since the initial diagnosis.12. Active infection requiring systemic therapy within 14 days prior to randomization. Patients who have received prior systemic therapies are excluded with the exception of the following: a. Adjuvant or neoadjuvant platinum-based doublet chemotherapy (after surgery and / or radiation therapy) if recurrent or metastatic disease develops more than 6 months after completing therapy as long as toxicities have resolved to CTCAE grade <1 or baseline with the exception of alopecia and peripheral neuropathy. b. Anti-PD-(L)1 with or without LAG-3 as an adjuvant or neoadjuvant therapy as long as the last dose is >12 months prior to enrollment. c. Prior exposure to other immunomodulatory or vaccine therapies as an adjuvant or neoadjuvant therapy such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies as long as the last dose is >6 months prior to enrollment.Note: Immune-mediated AEs must be resolved to CTCAE grade <1 or baseline by the time of enrollment. Endocrine immune-mediated AEs controlled with hormonal or other non-immunosuppressive therapies without resolution prior to enrollment are allowed.14. Hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labeling.15. Receipt of an investigational drug or device within 30 days of enrollment or within 5 half-lives of the investigational drug or therapy being studied (whichever is longer).16. Receipt of a live vaccine within 30 days of planned start of study medication.17. Major surgery or significant traumatic injury within 4 weeks prior to first dose.18. Known psychiatric or substance abuse disorder that would interfere with participation with and / or the requirements of the study, including current use of any illicit drugs.19. Pregnant or breastfeeding women.20. Sexually active men and women of childbearing potential* who are unwilling to practice highly effective contraception prior to the initial dose / start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition ofovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation (occlusion); vasectomized partner; and or sexual abstinence!, t-* Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy. t Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. t Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.Sexually active men and their partners must use highly effective contraception as described above. Contraception is not required for men with documented vasectomy.21 . Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities are excluded from this study.22. Member of the clinical site study team and / or his / her immediate family, unless prior approval granted by the sponsor.23. Active or latent tuberculosis. Latency should be confirmed by purified protein derivative (PPD)ZQuantiFERON testing according to local guidelines in high-risk individuals.24. History of previous organ transplant, including stem cell allograft.25. History or current evidence of significant cardiovascular disease including, myocarditis, congestive heart failure (as defined by New York Heart Association Functional Classification III and IV), unstable angina, serious uncontrolled arrhythmia, and myocardial infarction 6 months prior to study enrollment.26. Patients with a history of myocarditis.27. Troponin T (TnT) or troponin I (Tnl) > 2x institutional ULN at baseline. Patients with TnT or Tnl levels between > 1 to 2x ULN are permitted if repeat levels within 24 hours are < 1x ULN. If TnT or Tnl levels are > 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment. If TnT or Tnl repeat levels beyond 24 hours are < 2x ULN, the subject may undergo a cardiac evaluation and be considered for treatment.Dose / Route / Schedule:

[0177] Study treatment is prepared at the investigative site and is administered in a blinded fashion, in an outpatient setting. Adult and adolescent patients receive study drug co-infusion in a 30 minute (±10 minute) IV infusion Q3W. Similarly, pembrolizumab and placebo are infused in a 30 minute (±10 minute) IV infusion once every three weeks. Fianlimab and Cemiplimab (for Combination Mixed Co-infusion)

[0178] Fianlimab 1600 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30 minute (±10 minutes) IV co-infusion Q3W.

[0179] Fianlimab 400 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30 minute (±10 minutes) IV co-infusion Q3W.

[0180] Cemiplimab 350 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30 minute (±10 minutes) IV co-infusion Q3W.Placebo

[0181] For use in treatment Arm C (cemiplimab 350 mg + placebo), placebo refers to the volume of saline / dextrose in the prepared infusion that remains in the IV bag in place of fianlimab so that it looks identical to the fianlimab + cemiplimab infusion. Placebo (with cemiplimab 350 mg) is administered as a 30-minute (±10 minutes) IV co-infusion.Phase 2

[0182] Fianlimab is investigated at doses of 400 mg and 1600 mg Q3W IV each in combination, as a mixed co-infusion, with cemiplimab 350 mg Q3W IV, to determine the optimal phase 3 dose for fianlimab.

[0183] Treatment Arm A: combination of fianlimab (higher dose) and cemiplimab: patients receive on day 1 of every cycle fianlimab 1600 mg Q3W in combination with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion.

[0184] Treatment Arm B: combination of fianlimab (lower dose) and cemiplimab: patients receive on day 1 of every cycle fianlimab 400 mg Q3W in combination with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion.

[0185] Treatment Arm C: cemiplimab monotherapy and placebo: patients receive on day 1 of every cycle cemiplimab 350 mg Q3W in combination with placebo Q3W as a 30-minute IV co-infusion.Phase 3

[0186] Fianlimab is investigated at the chosen dose level in combination with cemiplimab, versus cemiplimab monotherapy, with the primary endpoint of OS.

[0187] Treatment Arm A or B: combination of fianlimab (chosen dose) and cemiplimab: patients receive on day 1 of every cycle the chosen dose of fianlimab Q3W in combination with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion.

[0188] Treatment Arm C: combination of cemiplimab and placebo: patients receive on day 1 of every cycle cemiplimab 350 mg Q3W in combination with placebo Q3W as a 30-minute IV co-infusion.Endpoints

[0189] For phase 2, the primary endpoint is: ORR as assessed by BICR, using RECIST 1.1 , up to 136 weeks. ORR is defined as proportion of patients with a best overall response of confirmed complete response (CR) or partial response (PR).

[0190] Phase 2 secondary endpoints for efficacy are:• ORR, using RECIST 1 .1 , up to 136 weeks.• Disease control rate (DCR=CR + PR + stable disease [SD]) by BICR, up to 136 weeks.• TTR by BICR, up to 136 weeks. TTR is defined as the time from randomization to the date of the first response of CR or PR (whichever is first recorded) for patients with confirmed CR or PR.• DOR by BICR, up to 5 years. DOR is defined as the time from first response of CR or PR to first radiographic progression or death due to any cause for patients with confirmed CR or PR.• PFS by BICR, up to 5 years. PFS is defined as the time from randomization to the date of the first radiographic progression or death due to any cause, whichever occurred earlier.• OS, up to 5 years, defined as the time from randomization to the date of death due to any cause.

[0191] Phase 2 secondary endpoints for safety are:• The incidence of treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), adverse events of special interest (AESIs), and immune-mediated adverse events (imAEs).• Occurrence of interruption and discontinuation of study drug(s) due to AEs (TEAEs, AESIs, and imAE).• Incidence of deaths due to TEAE.• Incidence of grade 3-4 laboratory abnormalities.

[0192] Phase 2 endpoints include assessment concentrations of cemiplimab and fianlimab in serum, and immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing antibodies (Nab) to fianlimab and cemiplimab.

[0193] Phase 2 Patient Reported Outcomes (PROs) include:• Change from baseline in patient-reported global health status (GHS)Zquality of life (QoL) and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough per EORTC QLQ-LC13.• Time until definitive deterioration in patient-reported GHS / QoL and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough, as well as a composite of these three symptoms, per EORTC QLQ-LC13.• Change from baseline in patient-reported general health status per EQ-5D-5L visual analogue scale (VAS).• Change from baseline in patient-reported severity and interference with usual or daily activities due to fatigue per the PRO-CTCAE.

[0194] For phase 3, the primary endpoint is OS, defined as the time from randomization to the date of death due to any cause.

[0195] The phase 3 secondary endpoint for efficacy is ORR, DCR, TTR, DOR, and PFS by BICR, using RECIST 1.1 , up to 136 weeks.

[0196] The phase 3 secondary endpoints for safety are:• Incidence of TEAEs, treatment-related TEAEs, SAEs, AESIs, and imAEs.• Occurrence of interruption and discontinuation of study drug(s) due to AEs (TEAEs, AESIs, and ImAE).• Incidence of deaths due to TEAE.• Incidence of grade 3-4 laboratory abnormalities.

[0197] Phase 3 endpoints include assessment of concentrations of cemiplimab and fianlimab in serum, and immunogenicity as measured by ADA and Nab to fianlimab and cemiplimab.

[0198] Phase 3 Patient Reported Outcomes include:• Change from baseline in patient-reported GHS / QoL and physical functioning per European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EQRTC-QLQ-C30), and chest pain, dyspnea and cough per EORTC QLQ-LC13.• Time until definitive deterioration in patient-reported GHS / QoL and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough, as well as a composite of these three symptoms, per EORTC QLQ-LC13.• Change from baseline in patient-reported general health status per EQ-5D-5L VAS.• Change from baseline in patient-reported severity and interference with usual or daily activities due to fatigue per the PRO-CTCAE.Procedures and Assessments

[0199] Efficacy endpoints include anti-tumor activity, which is assessed by diagnostic CT or MRI.

[0200] The safety and tolerability of fianlimab in combination with cemiplimab is monitored by clinical assessment of TEAEs / imAEs, SAEs, AESIs and by repeated measurements and clinical evaluation of vital signs (temperature, blood pressure, pulse, and respiration), physical examinations, 12-lead electrocardiograms (ECGs), and laboratory assessments including standard hematology, chemistry, urinalysis, and other lab tests (including blood cortisol and thyroid stimulating hormone [TSH]).

[0201] Blood samples are collected from all patients to measure functional fianlimab and functional cemiplimab in serum and to measure immunogenicity (presence of ADA and Nab to fianlimab and cemiplimab in serum).

[0202] Exploratory pharmacodynamic and / or predictive and prognostic biomarkers related to fianlimab and cemiplimab treatment exposure; clinical activity; and / or underlying disease may be investigated. Serum, plasma, peripheral blood mononuclear cells (PBMCs), genomic DNA (gDNA), soluble LAG-3 and tumor tissue are collected.Results

[0203] It is expected that the combination of fianlimab (REGN3767, anti-LAG-3) and cemiplimab Q3W improves ORR and OS compared to cemiplimab plus placebo in patients with advanced NSCLC whose tumors express PD-L1 in >50% of tumor cells.Example 2: Phase 2 / 3 Randomized, Double-Blind Study of Fianlimab (Anti-LAG-3 antibody), Cemiplimab (Anti-PD-1 antibody), and Chemotherapy versus Cemiplimab and Chemotherapy in First-Line Treatment of Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Irrespective of PD-L1 Expression Levels

[0204] This present phase 2 / 3 study is a randomized, double-blind study of Fianlimab (Anti-LAG-3 antibody), Cemiplimab (Anti-PD-1 antibody), and Chemotherapy versus Cemiplimab and Chemotherapy in first-line treatment of patients with advanced nonsmall cell lung cancer (NSCLC) irrespective of PD-L1 expression levels.Objectives

[0205] The primary objective of the present phase 2 study is to assess the objective response rate (ORR) per blinded independent central review (BICR) of fianlimab + cemiplimab + chemotherapy at both 1600 mg and 400 mg compared with cemiplimab + chemotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) irrespective of PD-L1 expression levels. Chemotherapy typically involves four cycles of platinum-doublet chemotherapy.

[0206] Phase 2 secondary objectives include the following:• To assess the safety and tolerability of fianlimab + cemiplimab + chemotherapy compared to cemiplimab + chemotherapy.• To assess other anti-tumor activities of fianlimab + cemiplimab + chemotherapy compared to cemiplimab + chemotherapy, as assessed by ORR, disease control rate (DCR), time to tumor response (TTR), duration of response (DOR), progression free survival (PFS), by BICR, and overall survival (OS).• To assess the patient-reported outcomes (via European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30], -Lung Cancer 13 [EORTC QLQ-LC13], and 5-Level EQ-5D Scale [EQ-5D-5L]) of fianlimab + cemiplimab + chemotherapy compared with cemiplimab + chemotherapy.• To assess patient-reported fatigue as measured by the fatigue severity and interference with usual or daily activities items of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for fianlimab + cemiplimab + chemotherapy compared with cemiplimab + chemotherapy.• To characterize the pharmacokinetics (PK) of fianlimab and cemiplimab.• To assess the immunogenicity of fianlimab and cemiplimab.

[0207] The primary objective of the present phase 3 study is to compare OS of fianlimab + cemiplimab + chemotherapy versus cemiplimab + chemotherapy.

[0208] Phase 3 secondary objectives include the following:• To assess the safety and tolerability of fianlimab + cemiplimab + chemotherapy compared to cemiplimab + chemotherapy.• To assess other anti-tumor activities for fianlimab + cemiplimab + chemotherapy and cemiplimab + chemotherapy, as measured by ORR, DCR, TTR, DOR, and PFS by BICR.• To assess the patient-reported outcomes (via EORTC QLQ-C30, EORTC QLQ- LC13 and EQ-5D-5L) of fianlimab + cemiplimab + chemotherapy compared to cemiplimab + chemotherapy.• To assess patient-reported fatigue as measured by the fatigue severity and interference items of the PRO-CTCAE for fianlimab + cemiplimab + chemotherapy compared with cemiplimab + chemotherapy.• To characterize the PK of fianlimab and cemiplimab.• To assess the immunogenicity of fianlimab and cemiplimab.Study Design

[0209] This is a randomized, double-blind, multi-center phase 2 / 3 study of fianlimab, at 2 different doses, with cemiplimab + chemotherapy versus cemiplimab + chemotherapy in patients with stage II I B, stage 11 IC, or stage IV squamous or non-squamous treatment naive NSCLC with tumor cells irrespective of PD-L1 levels, lacking actionable mutations with approved therapies, and who are not eligible for definitive chemoradiation. Patients are stratified according to histology (squamous / non squamous) and PD-L1 (<1% vs. 1- 49% vs. >50 to <75% vs. >75%t)

[0210] In phase 2, both investigators and patients are blinded to treatment assignment. The sponsor remains unblinded in phase 2.

[0211] Phase 3 is blinded to the investigators, patients, and the sponsor. Blinding rules for phase 3 are clarified in a subsequent protocol amendment, prior to initiation of the phase 3 part of the study.

[0212] During phase 2, fianlimab is investigated at 400 mg and 1600 mg each in combination with cemiplimab + chemotherapy, to determine the optimal phase 3 dose for fianlimab. The safety and anti-tumor activities of these combinations of fianlimab and cemiplimab + chemotherapy are assessed versus the cemiplimab + chemotherapy to select the optimal dose of fianlimab to be adopted in phase 3 for NSCLC.

[0213] Phase 2: Patients are randomized in a double-blinded 1 :1 :1 ratio to receive one of 3 treatment regimens:• Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) + platinum-doublet chemotherapy every 3 weeks (Q3W) intravenously (IV)• Arm B: fianlimab (400 mg) + cemiplimab (350 mg) + platinum-doublet chemotherapy Q3W IV• Arm C: cemiplimab (350 mg) + platinum-doublet chemotherapy + saline / dextrose placebo (placebo) Q3W IV

[0214] During phase 3, fianlimab is investigated at the chosen dose level in combination with cemiplimab + chemotherapy, with the primary endpoint of OS.• Phase 3: Patients are randomized in a double blinded 1 :1 ratio to receive one of2 treatment regimens:• Arm A or B: fianlimab (chosen dose) + cemiplimab (350 mg) + platinum-doublet chemotherapy Q3W IV• Arm C: cemiplimab (350 mg) + platinum-doublet chemotherapy + placebo Q3W IV

[0215] Patients continue to be treated for up to 108 weeks or until they experience intolerable adverse events (AEs), disease progression, death, or the patient and / or physician decides to discontinue study therapy. There is a post treatment follow-up period for all patients. After the last follow-up visit, patients are contacted by telephone call every 3 months to survey patient survival.

[0216] Approximately 150 patients in phase 2 and approximately 800 patients in phase 3 are enrolled in the study. The patients in the phase 2 and 3 parts of the study are separate and there is no overlap.

[0217] Adult patients >18 years of age (or the legal age of adults to consent to participate in a clinical study per country-specific regulations) with advanced treatment naive NSCLC with tumors of any PD-L1 and LAG-3 expression levels as confirmed by immunohistochemistry (IHC) assessment. Given the incidence of lung cancer is higher in patients of African descent, there is an emphasis on patients of African descent.

[0218] Following assessment of phase 2 data, and prior to initiation of the phase 3 part of the study, a protocol amendment is issued to address any phase 3-specific eligibility criteria.Inclusion Criteria

[0219] A patient must meet the following criteria to be eligible for inclusion in the study:1 . Men and women >18 years of age (or the legal age of adults to consent to participate in a clinical study per country-specific regulations).2. Patients with non-squamous or squamous histology NSCLC with stage III B or stage IIIC disease who are not candidates for surgical resection or definitive chemoradiation, or stage IV (metastatic disease) who received no prior systemic treatment for recurrent or metastatic NSCLC.3. Availability of an archival or on-study obtained formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample, without intervening therapy between biopsy collection and screening.Guidance on biopsy sites:• Archival or fresh biopsies are acceptable.• FFPE tissue block must be <6 months old; however, unstained slides of tumor sample (archival or recent) must be <2 weeks from preparation. A minimum of 10 slides, or equivalent block volume, is required for patients with EGFR, ALK, and ROS1 local results available. A minimum of 19 slides, or equivalent block volume, is required for patients without EGFR, ALK, or ROS1 local results available.• The biopsy should be from a metastatic or recurrent site which has not previously been irradiated. Bone biopsies are allowed provided they are not de-calcified Exception: the primary lung tumor can be used if it is still in place and the other metastatic sites are either not accessible (brain) or the biopsy would put the patient at risk.4. For enrollment in the phase 2 part of the study, patients should have PD-L1 expression results (regardless of expression level) determined by a College of American Pathologists (CAP) / Clinical Laboratory Improvement Amendments (GLIA) (or equivalently licensed, according to local regulations) accredited laboratory. If PD-L1 IHC results are not available prior to the time the patient provides informed consent, PD-L1 IHC results are obtained during screening using the VENTANA PD-L1 (SP263) assay in a central laboratory designated by the sponsor. For enrollment in the phase 3 part of the study, patients should have a valid PD-L1 result, regardless of expression level, using the VENTANA PD-L1 (SP263) assay as performed by a central laboratory.5. At least 1 radiographically measurable lesion by CT or MRI per RECIST 1.1 criteria. Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site.6. Eastern Cooperative Oncology Group (ECOG) performance status of <1 .7. Adequate organ and bone marrow function as defined below:• Hemoglobin >9.0 g / dL• Absolute neutrophil count (ANC) >1 .5 x 109 / L• Platelet count >100,000 / mm3• Glomerular filtration rate (GFR) >45 mL / min / 1 .73m2• Total bilirubin <1.5 x upper limit of normal (ULN) (if liver metastases <3 x ULN), with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 x ULN or <5 x ULN, if liver metastases• Alkaline phosphatase (ALP) <2.5 x ULN (or <5.0 x ULN, if liver or bone metastases)• Not meeting criteria for Hy’s law (ALT >3 x ULN and bilirubin >2 x ULN).8. Willing and able to comply with clinic visits and study-related procedures.9. Provide signed informed consent.10. Able to understand and complete study-related questionnaires.Exclusion Criteria

[0220] A patient who meets any of the following criteria is excluded from the study:1 . Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases are adequately treated and patients have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to enrollment. Patients must be off (immunosuppressive doses of) corticosteroid therapy (see exclusion criterion #7 for details on timing of discontinuation of steroids).2. Patients with tumors tested positive for actionable EGFR gene mutations, ALK gene translocations, or ROS1 fusions. For enrollment in the phase 2 part of the study, genetic alteration status, as determined by a CAP / CLIA (or equivalently licensed, according to local regulations) accredited laboratory, should be available prior to screening. If genetic alteration status is not available prior to the time the patient provides informed consent, genetic alteration status results are obtained during screening in a central laboratory designated by the sponsor.3. Encephalitis, meningitis, or uncontrolled seizures in the year prior to enrollment.4. History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management, or of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is permitted as long as pneumonitis resolved >6 months prior to enrollment.5. Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-cell negative severe combined immunodeficiency [SCID]) or combined T- and B-cellimmunodeficiencies (e.g., T- and B-cell negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency).6. Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk of immune-mediated treatment-emergent adverse events (imTEAEs). Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are excluded. The following are not exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that required only hormone replacement, or psoriasis that does not require systemic treatment.7. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiologic replacement doses are allowed even if they are >10 mg of prednisone / day or equivalent, as long as they are not being administered for immunosuppressive intent. Patients with clinically relevant systemic immune suppression within the last 3 months before trial enrollment are excluded. Inhaled or topical steroids are permitted, provided that they are not for treatment of an autoimmune disorder.8. Another malignancy that is progressing or requires treatment, with the exception of nonmelanomatous skin cancer that has undergone potentially curative therapy, in situ cervical carcinoma, or any other localized tumor that has been treated, and the patient is deemed to be in complete remission for at least 2 years prior to enrollment, and no additional therapy is required during the study period.9. Known active hepatitis B (known positive result) or known hepatitis C (known positive result) and known quantitative hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or HCV infection; or diagnosis of immunodeficiency (FDA).Exceptions:• Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted.• Patients with HBV (hepatitis B surface antigen positive) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted.• Patients who are HCV antibody positive (HCV Ab +) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.10. Documented or suspected ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A patient being screened who had documented or suspected SARS-CoV-2 may be enrolled if the patient has recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that can potentially affect the safety of the patient have resolved), and• It is advisable that 2 repeat COVID-19 PCR tests, or equivalent test depending on regional recommendations, be conducted to confirm that the patient is negative for SARS-CoV-2.• If COVID-19 PCR testing is not feasible, it is advised that at least 3 months have transpired since the initial diagnosis.11 . Active infection requiring systemic therapy within 14 days prior to randomization.12. Patients who have received prior systemic therapies are excluded with the exception of the following:• Adjuvant or neoadjuvant platinum-based doublet chemotherapy (after surgery and / or radiation therapy) if recurrent or metastatic disease develops more than 6 months after completing therapy as long as toxicities have resolved to CTCAE grade <1 or baseline with the exception of alopecia and peripheral neuropathy.• Anti-PD-(L) 1 with or without LAG-3 as an adjuvant or neoadjuvant therapy as long as the last dose is >12 months prior to enrollment.• Prior exposure to other immunomodulatory or vaccine therapies as an adjuvant or neoadjuvant therapy such as anti-CTLA-4 antibodies as long as the last dose is >6 months prior to enrollment.Note: Immune-mediated AEs must be resolved to CTCAE grade <1 or baseline by the time of enrollment. Endocrine immune-mediated AEs controlled with hormonal or other non-immunosuppressive therapies without resolution prior to enrollment are allowed.13. Hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labeling.14. Receipt of an investigational drug or device within 30 days of enrollment or within 5 half-lives of the investigational drug or therapy being studied (whichever is longer).15. Receipt of a live vaccine within 30 days of planned start of study medication.16. Major surgery or significant traumatic injury within 4 weeks prior to first dose.17. Known psychiatric or substance abuse disorder that would interfere with participation with and / or the requirements of the study, including current use of any illicit drugs.18. Pregnant or breastfeeding women.19. Sexually active men and women of childbearing potential* who are unwilling to practice highly effective contraception prior to the initial dose / start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation (occlusion); vasectomized partner; and or sexual abstinence!, t-• * Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy.• f Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.• t Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.• Sexually active men and their partners must use highly effective contraception as described- above. Contraception is not required for men with documented vasectomy.20. Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities is excluded from this study.21 . Member of the clinical site study team and / or his / her immediate family, unless prior approval granted by the sponsor.22. Active or latent tuberculosis. Latency should be confirmed by purified protein derivative (PPD)ZQuantiFERON testing according to local guidelines in high-risk individuals.23. History of previous organ transplant, including stem cell allograft.24. Meeting the comparator products contraindicated criteria as listed in local labeling.25. History or current evidence of significant cardiovascular disease including, myocarditis, congestive heart failure (as defined by New York Heart Association Functional Classification III and IV), unstable angina, serious uncontrolled arrhythmia, and myocardial infarction 6 months prior to study enrollment.26. Patients with a history of myocarditis.27. Troponin T (TnT) or troponin I (Tnl) >2 x institutional ULN at baseline. Patients with TnT or Tnl levels between >1 to 2 x ULN are permitted if repeat levels within 24 hours are <1 x ULN. If TnT or Tnl levels are >1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment. If TnT or Tnl repeat levels beyond 24 hours are <2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment.Dose / Route / Schedule

[0221] Study treatments are prepared by an unblinded pharmacist at the investigative site and are administered in a blinded fashion, in an outpatient setting.

[0222] An unblinded pharmacist or other qualified individual is identified at each site to prepare fianlimab, cemiplimab, and placebo for administration. Detailed preparation and administration instructions are provided to the sites in the pharmacy manual.

[0223] Platinum-based doublet chemotherapy is sourced locally wherever possible. A pharmacist or other qualified individual is identified at each site to prepare platinumbased doublet chemotherapy for administration per local guidelines.

[0224] Placebo (saline / dextrose) is sourced at the site.

[0225] All infusions for adults and adolescents are administered as a 30 minute (±10 minutes) IV infusion in an outpatient setting, every 3 weeks.Fianlimab and Cemiplimab (for combination / co-infusion administration)

[0226] Fianlimab 1600 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30-minute (±10 minutes) IV co-infusion Q3W.

[0227] Fianlimab 400 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30-minute (±10 minutes) IV co-infusion Q3W.

[0228] Cemiplimab 350 mg is supplied as a liquid in sterile, single-use vial and is administered as a 30-minute (±10 minutes) IV co-infusion Q3W.Chemotherapy

[0229] Chemotherapy is administered according to local prescribing information and practice guidelines. Assignment of the chosen chemotherapy from one of the regimens shown in Table 1 is made prior to randomization. The suggested sequence of drugadministration is platinum-based doublet chemotherapy agents followed by cemiplimab and fianlimab or placebo co-infusion.Table 1 : Platinum-Based Doublet Chemotherapy Regimens

[0230] The phase 2 treatment arms are as follows:• Treatment Arm A: combination of fianlimab (higher dose) + cemiplimab + chemotherapyPatients receive on day 1 of every cycle fianlimab 1600 mg Q3W with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion in combination with platinum doublet chemotherapy Q3W for 4 cycles.• Treatment Arm B: combination of fianlimab (lower dose) plus cemiplimab a chemotherapy combinationPatients receive on day 1 of every cycle fianlimab 400 mg Q3W with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion in combination with platinum doublet chemotherapy Q3W for 4 cycles.• Treatment Arm C: cemiplimab + chemotherapy + placeboPatients receive on day 1 of every cycle cemiplimab 350 mg Q3W with placebo Q3W as a 30-minute IV co-infusion in combination with platinum doublet chemotherapy Q3W for 4 cycles.

[0231] The phase 3 treatment arms are as follows:• Treatment Arm A or B: combination of fianlimab + cemiplimab + chemotherapyPatients receive on day 1 of every cycle the chosen dose of fianlimab Q3W with cemiplimab 350 mg Q3W as a 30-minute IV co-infusion in combination with platinum doublet chemotherapy Q3W for 4 cycles.• Treatment Arm C: cemiplimab + chemotherapy + placeboPatients receive on day 1 of every cycle cemiplimab 350 mg Q3W with placebo Q3W as a 30-minute IV co-infusion in combination with platinum doublet chemotherapy Q3W for 4 cycles.Placebo

[0232] For use in treatment Arm C (cemiplimab 350 mg + chemotherapy + placebo), placebo refers to the volume of in the prepared infusion that remains in the IV bag in place of fianlimab so that it looks identical to fianlimab + cemiplimab infusion. Placebo (with cemiplimab 350 mg) is administered as a 30-minute (±10 minutes) IV co-infusion.Endpoints

[0233] The primary phase 2 endpoint is overall response rate (ORR) as assessed by BICR using RECIST 1 .1 , up to 136 weeks. ORR is defined as proportion of patients with a best overall response of confirmed complete response (CR) or partial response (PR).

[0234] The secondary phase 2 endpoints include:Efficacy• ORR using RECIST 1.1 , up to 136 weeks.• DCR (CR + PR + stable disease [SD]) by BICR, up to 136 weeks.• TTR by BICR, up to 136 weeks. TTR is defined as the time from randomization to the date of the first response of CR or PR (whichever is first recorded) for patients with confirmed CR or PR.• DOR by BICR, up to 5 years. DOR is defined as the time from first response of CR or PR to first radiographic progression or death due to any cause for patients with confirmed CR or PR.• PFS by BICR, up to 5 years. PFS is defined as the time from randomization to the date of the first radiographic progression or death due to any cause, whichever occurred earlier.• OS, defined as the time from randomization to the date of death due to any cause.Safety• The incidence of treatment-emergent adverse events (TEAEs), treatment-related TEAEs, serious adverse events (SAEs), adverse events of special interest (AESIs), and immune-mediated adverse events (imAEs).• Occurrence of interruption and discontinuation of study drug(s) due to AEs (TEAEs, AESIs, and imAEs).• Incidence of deaths due to TEAE.• Incidence of grade 3-4 laboratory abnormalities.

[0235] Pharmacokinetic endpoints include assessment of concentrations of cemiplimab and fianlimab in serum.

[0236] Immunogenicity endpoints include immunogenicity, as measured by anti-drug antibodies (ADA) and neutralizing antibodies (NAb) to fianlimab and cemiplimab.

[0237] Patient Reported Outcomes (PRQs)• Change from baseline in patient-reported global health status (GHS) / quality of life (QoL) and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough per EORTC QLQ LC13.• Time until definitive deterioration in patient-reported GHS / QoL and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough, as well as a composite of these three symptoms, per EORTC QLQ-LC13.• Change from baseline in patient-reported general health status per EQ-5D-5L visual analogue scale (VAS).• Change from baseline in patient-reported severity and interference with usual or daily activities due to fatigue per the PRO-CTCAE.

[0238] The primary phase 3 endpoint is overall survival (OS), defined as the time from randomization to the date of death due to any cause.

[0239] The secondary phase 3 endpoints include;Efficacy - ORR, DCR, TTR, DOR, and PFS by BICR using RECIST 1.1.Safety• The incidence of TEAEs, treatment-related TEAEs, SAEs, AESIs, and imAEs.• Occurrence of interruption and discontinuation of study drug(s) due to AEs (TEAEs, AESIs, and imAEs).• Incidence of deaths due to TEAE,• Incidence of grade 3-4 laboratory abnormalities.

[0240] Pharmacokinetic - Concentrations of cemiplimab and fianlimab in serum.

[0241] Immunogenicity - Immunogenicity, as measured by ADA and NAb to fianlimab and cemiplimab.

[0242] Patient Reported Outcomes• Change from baseline in patient-reported GHS / QoL and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough per EORTC QLQ-LC13.• Time until definitive deterioration in patient-reported GHS / QoL and physical functioning per EORTC QLQ-C30, and chest pain, dyspnea and cough, as well as a composite of these three symptoms, per EORTC QLQ-LC13.• Change from baseline in patient-reported general health status per EQ-5D-5L VAS.• Change from baseline in patient-reported severity and interference with usual or daily activities due to fatigue per the PRO-CTCAE.Procedures and Assessments

[0243] Efficacy endpoints include anti-tumor activity. For all patients in the study, antitumor activity is assessed by computed tomography (CT) or magnetic resonance imaging (MRI).

[0244] The safety and tolerability of fianlimab in combination with cemiplimab is monitored by clinical assessment of TEAEs / imAEs, SAEs, AESIs and by repeated measurements and clinical evaluation of vital signs (temperature, blood pressure, pulse, and respiration), physical examinations, 12-lead electrocardiograms (ECGs), and laboratory assessments including standard hematology, chemistry, urinalysis and other lab tests (including blood cortisol and thyroid stimulating hormone [TSH]).

[0245] Blood samples are collected from all patients to measure functional fianlimab and functional cemiplimab in serum and to measure immunogenicity (presence of ADA and NAb to fianlimab and cemiplimab in serum).

[0246] Exploratory pharmacodynamic and / or predictive and prognostic biomarkers related to fianlimab and cemiplimab treatment exposure, clinical activity, and / or underlying disease may be investigated. Serum, plasma, peripheral blood mononuclear cells (PBMCs), genomic DNA (gDNA), soluble LAG-3, and tumor tissue are collected. Additional exploratory endpoints for the Phase 2 and Phase 3 studies include:• Tumor burden reduction by BICR and investigator assessment using RECIST 1.1 up to week 27• Tumor DNA / RNA sequencing and gene expression characterization• Circulating tumor DNA levels pre- and post-treatment• Change from baseline in serum biomarkers in each treatment arm, including but not limited to soluble LAG-3 and PD-L1 by IHC in tumor tissue samples• Correlation of the above parameters and other biomarkers with clinical outcomes and treatment armResults

[0247] It is expected that in the Phase 2 study, Fianlimab + cemiplimab + chemotherapy exhibits clinically meaningful anti-tumor activity, as measured by ORR, compared to cemiplimab + chemotherapy in first-line treatment of patients with advanced NSCLC irrespective of PD-L1 expression levels. In addition, phase 2 data differentiates between the 2 doses of fianlimab (400 mg vs 1600 mg) and guide the selection of the optimal dose for phase 3.

[0248] It is expected that in the Phase 3 study, Fianlimab + cemiplimab + chemotherapy improves OS compared to cemiplimab + chemotherapy in first-line treatment of patients with advanced NSCLC irrespective of PD-L1 expression levels.Example 3: Phase 2 Peri-Operative Study of Fianlimab Plus Cemiplimab Plus Chemotherapy Compared to Cemiplimab Plus Chemotherapy in Resectable Early- Stage NSCLC

[0249] The present study evaluates the efficacy and safety of (I) fianlimab plus cemiplimab plus chemotherapy versus (II) cemiplimab plus chemotherapy as perioperative treatment in patients with resectable stage II to IIIB (N2) NSCLC.

[0250] This Phase 2 peri-operative study provides insights into the clinical activity of (I) fianlimab plus cemiplimab plus chemotherapy in patients with resectable early-stage NSCLC, providing a gateway to broader efforts assessing combination therapies in lung cancer. The study is looking at several other research questions, including:• What side effects may happen from taking the study drugs• How much of each study drug is in the blood at different times• Whether the body makes antibodies against the study drugs (which could make the drugs less effective or could lead to side effects)• How administering the study drugs might affect quality of lifeStudy Design

[0251] A randomized, multi-center, double-blinded Phase 2 peri-operative study (NCT06161441 ) is carried out in patients with early-stage, resectable stage II to stage IIIB (N2) squamous or non-squamous, operable, treatment naive NSCLC, who aretreated with neoadjuvant therapy, followed by surgery and subsequent adjuvant therapy. The study design is shown in Figure 3. Eligible patients are treated in the neoadjuvant therapy period with any one of Arm A, Arm B, or Arm C for 1 , 2, 3, or 4 cycles, then undergo radiologic restaging. Within 6 weeks of completing the neoadjuvant therapy, the patient undergoes post-treatment resection to remove any remaining cancer. The tumor status following treatment and resection is assessed by the residual tumor (R) classification: RO, no residual tumor; R1 , microscopic residual tumor; R2, macroscopic residual tumor. Residual tumor may be found in the area of primary tumor and its regional lymph nodes and / or at distant sites. Patients having RO or R1 status tumors proceed to adjuvant treatment; patients are assigned to any one of Arm A, Arm B, or Arm C, per assignment during the neoadjuvant therapy treatment, and can receive multiple cycles of adjuvant therapy.

[0252] All patients enrolled are stratified based on clinical TNM stage at randomization by stage II versus stage III, histology (non-squamous vs squamous), and PD-L1 expression (<1%, 1—49%, >50%). The study is conducted globally at approximately 130 sites.Treatment

[0253] 180 patients are randomized (1 :1 :1) into the following arms:

[0254] Neoadjuvant period (up to 4 cycles):• Arm A: Placebo + Cemiplimab 350 mg intravenously (IV) every 3 weeks (Q3W) + Platinum doublet chemotherapy IV Q3W• Arm B: Fianlimab high dose (1600mg) + Cemiplimab 350 mg IV Q3W + Platinum-doublet chemotherapy IV Q3W• Arm C: Fianlimab low dose (400mg) + Cemiplimab 350 mg IV Q3W + Platinum-doublet chemotherapy IV Q3W

[0255] Chemotherapeutic agents include pemetrexed (Alimta), paclitaxel (taxol), carboplatin (paraplatin), and cisplatin (platinol).

[0256] Adjuvant period (up to 14 cycles): After surgery, treatment in the adjuvant period continues according to prior randomization as follows:• Arm A: Placebo + Cemiplimab 350 mg IV Q3W• Arm B: Fianlimab high dose (1600mg) + Cemiplimab 350 mg IV Q3W• Arm C: Fianlimab low dose (400mg) + Cemiplimab 350 mg IV Q3W

[0257] Patients are treated for up to approximately 12 months (12 weeks of neoadjuvant therapy + 42 weeks of adjuvant therapy), or until recurrence of disease, unacceptable toxicity, patient’s decision, or investigator’s decision.Endpoints

[0258] The primary endpoint is an assessment of pathological complete response (pCR) by blinded independent pathological review (BIPR) in post-treatment resected tumor samples. Secondary endpoints include event-free survival (by investigator assessment), major pathological response (MPR) by BIPR, MPR (by local pathology review), tumor response to neoadjuvant therapy by investigator assessment, safety and tolerability, pharmacokinetics, immunogenicity, incidence of peri-operative complications associated with surgery (within 90 days of surgery), and patient-reported outcomes. Patient Eligibility

[0259] Eligible patients must be >18 years old (or the legal age of adults to consent to participate in a clinical study per country-specific regulations) who are newly diagnosed with fully resectable, stage II to stage IIIB (N2) NSCLC.Key Inclusion Criteria1 . >18 years old (or the legal age of adults to consent to participate in a clinical study per country-specific regulations)2. Newly diagnosed, histologically confirmed, fully resectable stage II to IIIB (N2) NSCLC3. For patients with evidence of mediastinal adenopathy on imaging, mediastinal lymph node sampling is required4. Disease status showing no evidence of distant metastases documented by a complete physical examination and imaging studies performed within 4 weeks prior to randomization5. An evaluable PD-L1 immunohistochemistry (IHC) result6. An Eastern Cooperative Oncology Group (ECOG) performance status of <17. Adequate hepatic, kidney, and bone marrow functionKey Exclusion Criteria1 . Any evidence of locally advanced unresectable or metastatic disease2. Patients with tumors with known actionable epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene translocations3. Ongoing or recent (within 2 years) evidence of autoimmune disease that required systemic treatment4. Uncontrolled infection with human immunodeficiency virus (HIV), or hepatitis B or C virus5. Systemic immune suppression

[0260] Treatment with anti-cancer therapy including immunotherapy, chemotherapy, radiotherapy, or biological therapy in the 3 years prior to randomization. Adjuvant hormonotherapy used for breast cancer or other hormone-sensitive cancers in long term remission is allowed.• History of myocarditis• Troponin T or troponin I > 2x institutional upper limit of normal• History or current evidence of significant (Common Terminology Criteria for Adverse Events (CTCAE) Grade >2) local or systemic infection requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medicationResults

[0261] It is expected that in the Phase 2, peri-operative study, Fianlimab + cemiplimab + chemotherapy exhibits clinically meaningful anti-tumor activity, as measured by pathological complete response (pCR) in post-treatment resected tumor samples up to 24 months, and event free survival (EFS) up to 3 years, compared to cemiplimab + chemotherapy in patients with resectable early stage (Stage II to II IB [N2]) NSCLC.

[0262] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.Table 2: Informal Sequence Listing

Claims

We claim:1 . A method of treating lung cancer or inhibiting the growth of lung cancer comprising administering to a subject in need thereof:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1); and(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3), wherein the subject suffers from advanced untreated lung cancer and wherein the lung cancer expresses PD-L1 in >50% of cancer cells as determined by immunohistochemistry.

2. The method of claim 1 , wherein the lung cancer is unresectable.

3. The method of any one of claims 1 or 2, wherein the lung cancer is locally advanced lung cancer.

4. The method of any one of claims 1 or 2, wherein the lung cancer is metastatic lung cancer.

5. The method of any one of claims 1 to 4, wherein the subject is further selected as having one or more of the following criteria:(i) at least 18 years of age;(ii) has non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage I II B or stage II IC disease and not a candidate for surgical resection or definitive chemoradiation;(iii) has non-squamous or squamous histology NSCLC stage IV (metastatic disease) and has not received prior systemic treatment for recurrent or metastatic NSCLC;(iv) has at least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria;(v) Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and(vi) Adequate organ and bone marrow function.

6. The method of any one of claims 1 to 5, wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 50 to 1500 mg.

7. The method of any one of claims 1 to 6, wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350mg.

8. The method of any one of claims 1 to 7, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 to 8000 mg.

9. The method of any one of claims 1 to 8, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.

10. The method of any one of claims 1 to 8, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.11 . The method of any one of claims 1 to 10, wherein the lung cancer expresses PD-L1 in >75% of cancer cells as determined by immunohistochemistry.

12. The method of claim 11 , wherein the subject shows > 1% LAG3 in the cancer tissue.

13. The method of any one of claims 1 to 12, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered prior to, concurrent with or after the anti-PD-1 antibody or antigen-binding fragment thereof.

14. The method of any one of claims 1 to 13, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered to the same day as the anti-PD-1 antibody or antigen-binding fragment thereof.

15. The method of any one of claims 1 to 13, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered as a co-infusion with the anti-PD-1 antibody or antigen-binding fragment thereof.

16. The method of any one of claims 1 to 15, wherein two or more doses of the anti- LAG-3 antibody or antigen-binding fragment thereof are administered in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof.

17. The method of claim 16, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 350 mg.

18. The method of either claim 16 or 17, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 and 8000 mg.

19. The method of any one of claims 16 to 18, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

20. The method of any one of claims 16 to 18, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.21 . The method of claim 16, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 200 mg, 250 mg or 350 mg and each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.

22. The method of any one of claims 16 to 21 , wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.

23. The method of any one of claims 16 to 21 , wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.

24. The method of any one of claims 16 to 21 , wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks.

25. The method of any one of claims 16 to 21 , wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks.

26. The method of any one of claims 16 to 21 , wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks.

27. The method of any one of claims 16 to 21 , wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in three weeks.

28. The method of any one of claims 1 to 27, wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally.

29. The method of any one of claims 1 to 28, wherein the treatment produces a therapeutic effect selected from the group consisting of delay in cancer growth, reduction in cancer cell number, cancer regression, increase in survival, partial response, and complete response.

30. The method of claim 29, wherein cancer growth is delayed by at least 10 days as compared to an untreated subject.31 . The method of claim 29, wherein the cancer growth is inhibited by at least 50% as compared to an untreated subject.

32. The method of claim 29, wherein the cancer growth is inhibited by at least 20% as compared to a subject administered with either antibody as monotherapy.

33. The method of any one of claims 1 to 32 further comprising administering to the subject an additional therapeutic agent or therapy, wherein the additional therapeutic agent or therapy is selected from the group consisting of radiation, surgery, a chemotherapeutic agent, a cancer vaccine, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIM3 inhibitor, a BTLA inhibitor, a TIGIT inhibitor, a CD47 inhibitor, a CD28 agonist, a CD38 inhibitor, an indoleamine-2,3-dioxygenase (IDO) inhibitor, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGF|3) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocytemacrophage colony-stimulating factor, an oncolytic virus, a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL- 2, IL-7, IL-21 , IL-12, IL-15, an antibody-drug conjugate, a GITR agonist, a 4-1 BB agonist, and an anti-inflammatory drug.

34. The method of any one of claims 1 to 33, wherein the anti-PD-1 antibody or antigenbinding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

35. The method of claim 34, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2.

36. The method of any one of claims 1 to 35, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

37. The method of any one of claims 1 to 36, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) of a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) of a LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

38. The method of claim 37, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11 and the LCVR comprises the amino acid sequence of SEQ ID NO: 12.

39. The method of any one of claims 1 to 38, wherein the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

40. The method of any one of claims 1 to 39, wherein the inhibition is more efficacious than administration of either antibody as a monotherapy.41 . The method of claim 1 , comprising administering to the subject (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12.

42. The method of claim 41 , wherein the administering occurs once every 3 weeks.

43. The method of claim 41 , wherein the administering occurs once every 6 weeks.

44. A method of treating lung cancer or inhibiting the growth of lung cancer comprising administering to a subject in need thereof:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3); and(c) platinum-based doublet chemotherapy; wherein the subject suffers from advanced untreated lung cancer.

45. The method of claim 44, wherein the lung cancer is unresectable.

46. The method of any one of claims 44 or 45, wherein the lung cancer is locally advanced lung cancer.

47. The method of any one of claims 44 or 45, wherein the lung cancer is metastatic lung cancer.

48. The method of any one of claims 44 to 47, wherein the subject is further selected as having one or more of the following criteria:(i) at least 18 years of age;(ii) has non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage I II B or stage II IC disease and not a candidate for surgical resection or definitive chemoradiation;(iii) has non-squamous or squamous histology NSCLC stage IV (metastatic disease) and has not received prior systemic treatment for recurrent or metastatic NSCLC;(iv) has at least 1 radiographically measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria;(v) Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and(vi) Adequate organ and bone marrow function.

49. A method of treating lung cancer or inhibiting the growth of lung cancer comprising:(i) selecting a subject with resectable lung cancer; and(ii) administering to the subject a neo-adjuvant treatment comprising:(a) an antibody or antigen-binding fragment thereof that specifically binds programmed death 1 (PD-1);(b) an antibody or antigen-binding fragment thereof that specifically binds lymphocyte activation gene-3 (LAG-3); and(c) platinum-based doublet chemotherapy.

50. The method of claim 49, wherein the lung cancer is non-squamous or squamous histology non-small cell lung cancer (NSCLC) with stage II to stage I II B (N2) disease.51 . The method of either claim 49 or 50, wherein the subject is further selected as having one or more of the following criteria:(i) at least 18 years of age;(ii) no evidence of distant metastases;(iii) evaluable PD-L1 IHC result;(iv) Eastern Cooperative Oncology Group (ECOG) performance status of <1 ; and(v) adequate kidney, liver, and bone marrow function.

52. The method of any one of claims 44 to 51 , wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 50 to 1500 mg.

53. The method of any one of claims 44 to 52, wherein one dose of the anti-PD-1 antibody or antigen-binding fragment thereof comprises 350mg.

53. The method of any one of claims 44 to 53, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 to 8000 mg.

55. The method of any one of claims 44 to 54, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.

56. The method of any one of claims 44 to 55, wherein one dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

57. The method of any one of claims 44 to 56, wherein the platinum-based doublet chemotherapy is selected from the group consisting of paclitaxel, carboplatin, cisplatin, gemcitabine and pemetrexed.

58. The method of any one of claims 44 to 57, wherein the subject shows > 1% LAG3 in the cancer tissue.

59. The method of any one of claims 44 to 58, wherein the subject shows <1%, 1% to 49%, >50% to <75%, or >75% PD-L1 in the cancer tissue.

60. The method of any one of claims 44 to 59, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered the same day as the anti-PD-1 antibody or antigen-binding fragment thereof.61 . The method of any one of claims 44 to 59, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered as a co-infusion with the anti-PD-1 antibody or antigen-binding fragment thereof.

62. The method of any one of claims 44 to 59, wherein the chemotherapy is administered after the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof.

63. The method of any one of claims 44 to 59, wherein the chemotherapy is administered prior to the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof.

64. The method of any one of claims 44 to 59, wherein the chemotherapy is administered the same day as the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof.

65. The method of any one of claims 44 to 59, wherein two or more doses of the anti- LAG-3 antibody or antigen-binding fragment thereof are administered in combination with two or more doses of the anti-PD-1 antibody or antigen-binding fragment thereof.

66. The method of claim 65, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 350 mg.

67. The method of either claim 65 or 66, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises between 50 and 8000 mg.

68. The method of any one of claims 65 to 67, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 1600 mg.

69. The method of any one of claims 65 to 67, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg.

70. The method of claim 65, wherein each dose of the anti-PD-1 antibody or antigenbinding fragment thereof comprises 200 mg, 250 mg or 350 mg and each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises 400 mg, 800 mg, 1000 mg, 1400 mg, or 1600 mg.71 . The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.

72. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered 0.5 weeks to 12 weeks after the immediately preceding dose.

73. The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in six weeks.

74. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in six weeks.

75. The method of any one of claims 65 to 70, wherein each dose of the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in three weeks.

76. The method of any one of claims 65 to 70, wherein each dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once in three weeks.

77. The method of any one of claims 44 - 76, comprising administering to the subject the anti-PD-1 antibody or antigen-binding fragment thereof once every three weeks up to 15 weeks.

78. The method of any one of claims 44 - 76, comprising administering to the subject the anti-PD-1 antibody or antigen-binding fragment thereof once every three weeks up to 12 weeks.

79. The method of any one of claims 44 - 78, comprising administering the anti-LAG-3 antibody or antigen-binding fragment thereof once every three weeks up to 15 weeks.

80. The method of any one of claims 44 - 78, comprising administering the anti-LAG-3 antibody or antigen-binding fragment thereof once every three weeks up to 12 weeks.81 . The method of any one of claims 44 - 80, comprising administering chemotherapy once every three weeks up to 15 weeks.

82. The method of any one of claims 44 - 80, comprising administering chemotherapy once every three weeks up to 12 weeks.

83. The method of any one of claims 44 - 82, wherein the cancer is assessed radiologically after treatment.

84. The method of any one of claims 49 - 83, wherein the subject undergoes surgery to resect the cancer.

85. The method of claim 84, wherein the surgery occurs 1 to 10 weeks after administration of the anti-PD-1 antibody or antigen-binding fragment thereof, 1 to 10 weeks after administration of the anti-LAG-3 antibody or antigen-binding fragment thereof, and / or 1 to 10 weeks after administration of the chemotherapy.

86. The method of claim 84, wherein the surgery occurs 1 to 6 weeks after administration of the anti-PD-1 antibody or antigen-binding fragment thereof, 1 to 6 weeks after administration of the anti-LAG-3 antibody or antigen-binding fragment thereof, and / or 1 to 6 weeks after administration of the chemotherapy.

87. The method of claim 85 or claim 86 further comprising administering adjuvant treatment comprising the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigen-binding fragment thereof.

88. The method of any one of claims 84 - 87, comprising administering the anti-PD-1 antibody or antigen-binding fragment thereof and / or the anti-LAG-3 antibody or antigenbinding fragment thereof once every three weeks up to 45 weeks.

89. The method of any one of claims 44 to 88, wherein the antibodies are administered intravenously, subcutaneously, or intraperitoneally.

90. The method of any one of claims 44 to 89, wherein the treatment produces a therapeutic effect selected from the group consisting of delay in cancer growth, reduction in cancer cell number, cancer regression, increase in survival, partial response, and complete response.91 . The method of claim 90, wherein cancer growth is delayed by at least 10 days as compared to an untreated subject.

92. The method of claim 90, wherein the cancer growth is inhibited by at least 50% as compared to an untreated subject.

93. The method of claim 90, wherein the cancer growth is inhibited by at least 20% as compared to a subject administered with either antibody as monotherapy.

94. The method of any one of claims 49 - 93, wherein the subject experiences improvement in pathological complete response (pCR) by blinded independent pathological review (Bl PR) in post-treatment resected tumor samples, event-free survival (by investigator assessment), major pathological response (MPR) by BIPR, MPR (by local pathology review), tumor response to neoadjuvant therapy by investigator assessment, safety and tolerability, pharmacokinetics, immunogenicity, incidence of peri-operative complications associated with surgery (within 90 days of surgery), and patient-reported outcomes.

95. The method of any one of claims 44 to 94, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8.

96. The method of claim 95, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 1 and the LCVR comprises the amino acid sequence of SEQ ID NO: 2.

97. The method of any one of claims 44 to 96, wherein the anti-PD-1 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

98. The method of any one of claims 44 to 97, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain CDRs (HCDR1 , HCDR2 and HCDR3) of a HCVR and three light chain CDRs (LCDR1 , LCDR2 and LCDR3) of a LCVR, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 14; HCDR3 comprises the amino acid sequence of SEQ ID NO: 15; LCDR1 comprises the amino acid sequence of SEQ ID NO: 16; LCDR2 comprises the amino acid sequence of SEQ ID NO: 17; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 18.

99. The method of claim 98, wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 11 and the LCVR comprises the amino acid sequence of SEQ ID NO: 12.

100. The method of any one of claims 44 to 99, wherein the anti-LAG-3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.

101. The method of any one of claims 44 to 100, wherein the inhibition is more efficacious than administration of either antibody as a monotherapy.

102. The method of claim 44 or claim 49, comprising administering to the subject (a) 350 mg anti-PD-1 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 1 / 2; and (b) 400 mg or 1600 mg anti-LAG-3 antibody or antigen-binding fragment thereof comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NOs: 11 / 12.

103. The method of claim 102, wherein the administering occurs once every 3 weeks.

104. The method of claim 102, wherein the administering occurs once every 6 weeks.

105. The method of any one of claims 1 to 104, wherein the anti-PD-1 antibody is cemiplimab.

106. The method of any one of claims 1 -105, wherein the anti-LAG-3 antibody is fianlimab.