Anti-PD-1 antibodies for treatment of lung cancer

Abstract

To provide a pharmaceutical composition for use in a method of treating lung cancer.SOLUTION: Provided is a pharmaceutical composition for use in a method of treating lung cancer or increasing the survival of a patient with lung cancer, the pharmaceutical composition comprising an isolated antibody or an antigen-binding fragment thereof that binds specifically to programmed death 1 (PD-1), the method comprising: (a) selecting a patient having non-small cell lung cancer; (b) measuring expression of programmed death ligand 1 (PD-L1) in lung cancer tumor tissue of the patient; and (c) if the tumor tissue in the patient expresses PD-L1 in ≥50% of tumor cells, administering one or more doses of a therapeutically effective amount of the antibody or the antigen-binding fragment thereof to the patient, thereby treating lung cancer in the patient.SELECTED DRAWING: None

Description

Technical Field

[0001] This application was filed as a PCT international patent application on February 20, 2018, and claims the benefit of priority to U.S. Provisional Application No. 62 / 461,672 (filed February 21, 2017); and No. 62 / 595,190 (filed December 6, 2017) (the disclosures of each are incorporated herein by reference in their entireties).

[0002] Field of the Invention The present invention relates to a method for treating lung cancer, comprising administering to a subject in need thereof a therapeutically effective amount of an antibody that specifically binds to the programmed cell death 1 (PD-1) receptor.

Background Art

[0003] Background Lung cancer is one of the most commonly diagnosed cancers and a leading cause of cancer-related death worldwide (Non-Patent Document 1; Non-Patent Document 2). Non-small cell lung cancer (NSCLC) accounts for 80% - 85% of all lung cancers and is composed of several histopathological subtypes, the most common of which are adenocarcinoma (40% - 60%) and squamous cell carcinoma (30%). Most patients with NSCLC are found to have advanced cancer at the time of diagnosis (Non-Patent Document 3). Using chemotherapy, these patients have a median overall survival (OS) of up to 12 - 18 months and a 5-year survival rate of approximately 18% (Non-Patent Document 3; Non-Patent Document 2).

[0004] Systemic treatment using platinum-based doublet chemotherapy regimens, with or without maintenance therapy, has until recently been the standard first-line treatment for all patients with progressive NSCLC who do not have mutations in the epidermal growth factor receptor (EGFR), rearrangements in anaplastic lymphoma kinase (ALK), or mutations in C-ros oncogene receptor tyrosine kinase (ROS1) (Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6). Despite initial treatment with platinum-based doublet chemotherapy regimens, the disease often progresses, and further treatment options have been limited. Therefore, newer treatment approaches are needed to improve long-term survival and quality of life (QOL) in patients with progressive NSCLC.

[0005] In recent years, immunotherapy has been investigated as a treatment approach that may improve long-term survival and QOL in patients with progressive NSCLC. Tumors modulate and evade the host immune response through multiple mechanisms, including the formation of an immunosuppressive environment within the tumor. Programmed cell death-1 (PD-1) is a co-receptor expressed on the surface of activated T cells that mediates immunosuppression. Binding of PD-1 to one of its ligands, programmed cell death ligand 1 (PD-L1) or programmed cell death ligand 2 (PD-L2), results in inhibition of the cytotoxic T cell response. Increased expression of PD-L1 in the tumor microenvironment promotes evasion from the immune surveillance mechanism (T cell-induced antitumor activity). In contrast, blockade of this interaction results in an enhanced T cell response with antitumor activity.

[0006] Blocking the PD-1 / PD-L1 T cell checkpoint pathway has been shown to be an effective and well-tolerated approach to stimulating the immune response and achieving significant objective responses in patients with NSCLC (Non-Patent Document 7; Non-Patent Document 8; Non-Patent Document 9; Non-Patent Document 10; Non-Patent Document 11; Non-Patent Document 12; Non-Patent Document 13; Non-Patent Document 14; Non-Patent Document 15).

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Summary of the Invention

Means for Solving the Problems

[0008] Gist of the Invention According to certain embodiments, the present invention provides a method for treating or alleviating at least one symptom or sign of lung cancer, inhibiting the growth of lung cancer, and / or increasing survival in a subject. Methods according to this aspect include administering to a subject in need thereof one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed cell death 1 (PD-1). In certain embodiments, the lung cancer is non-small cell lung cancer. In one embodiment, the subject has progressive, recurrent or metastatic lung cancer. In one embodiment, the subject has squamous non-small cell carcinoma. In one embodiment, the subject has non-squamous non-small cell lung cancer. In certain embodiments, the subject has a lung cancer in which the tumor expresses programmed cell death ligand 1 (PD-L1) in <50% of the tumor cells. In certain embodiments, the subject has a lung cancer (e.g., non-small cell lung cancer) in which the tumor expresses PD-L1 in <50%, ≦45%, ≦40%, ≦30%, ≦20%, ≦10%, ≦5%, ≦2%, ≦1% or about 0% of the tumor cells. In certain other embodiments, the subject has a tumor that expresses PD-L1 in ≧50% of the tumor cells Has lung cancer. In certain embodiments, the subject has lung cancer (e.g., non-small cell lung cancer) in which the tumor expresses PD-L1 in ≧50%, ≧60%, ≧70%, ≧80%, or ≧90% of the tumor cells. In certain embodiments, the subject has been treated with a treatment for lung cancer (anti-tumor therapy, e.g., chemotherapy). In certain embodiments, the method comprises administering one or more doses of an anti-PD-1 antibody to a subject in need thereof, wherein each dose comprises from 20 mg to 1500 mg of the anti-PD-1 antibody, and each dose is administered 1 week, 2 weeks, 3 weeks, or 4 weeks after the previous dosing. In certain embodiments, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody, optionally in combination with chemotherapy or a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody such as ipilimumab), to a subject in need thereof. In one embodiment, the chemotherapy comprises a platinum-based chemotherapeutic agent (e.g., pemtrexed, cisplatin, gemcitabine, or combinations thereof). In one embodiment, the anti-PD-1 antibody is REGN2810.

[0009] According to certain embodiments, the present invention includes a method of treating cancer, the method comprising selecting a subject having lung cancer and administering one or more doses of an anti-PD-1 antibody, wherein the administration results in inhibition of tumor growth, an increase in overall survival, and / or an increase in progression-free survival of the subject.

[0010] In certain embodiments of the invention, the method is provided for treating or alleviating at least one symptom or sign of cancer in a subject, or for inhibiting proliferation. In certain embodiments of the invention, the method is provided for delaying tumor growth or preventing tumor recurrence. In certain embodiments of the invention, the method is provided for increasing overall survival or progression-free survival of cancer patients. The method according to this aspect of the invention comprises continuously administering one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds to PD-1. In one embodiment, the anti-PD-1 antibody is administered in combination with chemotherapy. In one embodiment, the anti-PD-1 antibody is administered in combination with a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody such as ipilimumab). In certain embodiments, the cancer or tumor is a solid tumor or a malignant tumor. In certain embodiments, the solid tumor is selected from the group consisting of colorectal cancer, ovarian cancer, prostate cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, anal cancer, uterine cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, endometrial cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and myeloma.

[0011] In certain embodiments, the method comprises administering one or more doses of an anti-PD-1 antibody to a patient having progressive or metastatic cancer (e.g., progressive non-small cell lung cancer), wherein the tumor tissue in the patient expresses PD-L1 in ≦1%, ≦2%, ≦5%, ≦10%, ≦20%, ≦30%, ≦40%, ≦45%, or <50% of the tumor cells. In certain embodiments, the method comprises administering one or more doses of an anti-PD-1 antibody to a patient having cancer (e.g., progressive or metastatic lung cancer), wherein the tumor tissue in the patient expresses PD-L1 in ≧50%, ≧60%, ≧70%, ≧80%, or ≧90% of the tumor cells.

[0012] In certain embodiments, the anti-PD-1 antibody is administered to cancer patients as a "first-line" treatment, where the patient has not previously received systemic treatment for cancer. In certain embodiments, the anti-PD-1 antibody is administered to cancer patients (e.g., metastatic cancer) as a "second-line" treatment, where the patient has previously been treated with a treatment including, but not limited to, an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab), a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), chemotherapy, surgery, and / or radiation.

[0013] In certain embodiments, each dose of the anti-PD-1 antibody comprises from 0.1 to 20 mg / kg of the subject's body weight. In certain embodiments, each dose of the anti-PD-1 antibody comprises 0.3, 1, 3, 5, or 10 mg / kg of the subject's body weight. In certain embodiments, each dose of the anti-PD-1 antibody comprises from 20 to 1500 mg. In one embodiment, each dose of the anti-PD-1 antibody comprises about 200 mg. In one embodiment, each dose of the anti-PD-1 antibody comprises about 250 mg. In one embodiment, each dose of the anti-PD-1 antibody comprises about 350 mg. In one embodiment, each dose of the anti-PD-1 antibody comprises about 1000 mg or about 1050 mg.

[0014] In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of an anti-PD-1 antibody before, concurrently with, or after chemotherapy. In one embodiment, the methods of the invention comprise administering the anti-PD-1 antibody before the administration of chemotherapy.

[0015] In certain embodiments, the methods of the invention comprise administering one or more therapeutic doses of the anti-PD-1 antibody, where each dose is administered 0.5 to 12 weeks after the previous dosing. In one embodiment, each dose is administered 1 week after the previous dosing. In one embodiment, each dose is administered 2 weeks after the previous dosing. In one embodiment, each dose is administered 3 weeks after the previous dosing.

[0016] In certain embodiments, one or more doses of an anti-PD-1 antibody and optionally a second therapeutic agent (e.g., a chemotherapeutic agent) are included in a treatment cycle. Methods according to this aspect of the invention include administering to a subject in need thereof at least one treatment cycle, where at least one treatment cycle includes one or more doses of an anti-PD-1 antibody. In certain embodiments, at least one treatment cycle further includes one or more doses of a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent, such as gemcitabine, pemetrexed, cisplatin).

[0017] In certain embodiments, the anti-PD-1 antibody is administered in combination with a further therapeutic agent or treatment (e.g., an anti-CTLA-4 antibody, or any agent or treatment disclosed herein).

[0018] In certain embodiments, the treatment results in one or more therapeutic effects selected from the group consisting of tumor shrinkage, abscopal effect, inhibition of tumor metastasis, reduction of metastases over time, reduced use of chemotherapeutic or cytotoxic agents, reduction of tumor burden, increased progression-free survival, increased overall survival, complete remission, partial response, and stable disease.

[0019] According to certain embodiments, the anti-PD-1 antibody or antigen-binding protein comprises heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and light chain CDRs of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. One such type of antigen-binding protein that can be used in the context of the methods of the invention is an anti-PD-1 antibody such as REGN2810 (also known as cemiplimab).

[0020] In certain embodiments, the present invention provides the use of an anti-PD-1 antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or inhibiting cancer growth in a subject, including a human. In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer. In certain embodiments, the cancer is colorectal cancer, ovarian cancer, prostate cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, anal cancer, uterine cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, endometrial cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, or myeloma.

[0021] Other embodiments of the invention will become apparent from consideration of the following detailed description.

Brief Description of the Drawings

[0022]

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Mode for Carrying Out the Invention

[0023] Detailed Description Before describing the present invention, it is understood that, of course, methods and conditions can vary, so the present invention is not limited to the specific methods and experimental conditions described. Also, of course, the terms used herein are for the purpose of describing specific embodiments only, and the scope of the present invention is limited only by the appended claims and is not intended to be limiting.

[0024] 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 invention 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, the expression "about 100" as used herein includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0025] Any methods and materials similar or equivalent to those described herein can be used in the practice of the invention, but the preferred methods and materials are described herein. All publications mentioned herein are incorporated herein by reference as if their entireties were set forth herein.

[0026] A method of treating cancer or inhibiting cancer growth The present invention includes methods for treating, alleviating, or reducing the severity of at least one symptom or sign of cancer in a subject, or for inhibiting the growth of cancer in a subject. Methods according to this aspect of the invention include administering to a subject in need thereof a therapeutically effective amount of an antibody that specifically binds to PD-1 or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-1 antibody is administered in combination with an anti-tumor therapy (described elsewhere herein). As used herein, the terms "treat," "treating," or the like mean to alleviate symptoms, either temporarily or permanently, to eliminate the cause of the symptoms, to delay or inhibit tumor growth, to reduce the amount of tumor cells or tumor mass, to promote tumor regression, to cause tumor shrinkage, necrosis, and / or disappearance, to prevent tumor recurrence, to prevent or inhibit metastasis, to inhibit metastatic tumor growth, and / or to increase the survival period of the subject.

[0027] As used herein, the expression "subject in need thereof" means a human or non-human mammal that exhibits one or more symptoms or signs of cancer and / or has been diagnosed with cancer, including a solid tumor, as well as a human or non-human mammal in need of treatment thereof. In many embodiments, the term "subject" may be used interchangeably with the term "patient". For example, a human subject may be diagnosed as having one or more symptoms or signs including, but not limited to, primary or metastatic tumors and / or unexplained weight loss, general malaise, persistent fatigue, anorexia, fever, night sweats, bone pain, shortness of breath, distended abdomen, chest pain / chest pressure, splenomegaly, and elevated levels of cancer-related biomarkers (e.g., CA125). This expression is the original It includes subjects having primary or established tumors. In certain embodiments, this expression includes human subjects having solid tumors, such as colon cancer, breast cancer, lung cancer, prostate cancer, skin cancer, liver cancer, bone cancer, ovarian cancer, cervical cancer, pancreatic cancer, head and neck cancer, and brain cancer, and / or in need of treatment thereof. In certain preferred embodiments, this expression includes human subjects having lung cancer, including small cell lung cancer, and / or in need of treatment thereof. In a preferred embodiment, this expression includes patients having progressive recurrent or metastatic non-small cell lung cancer and / or in need of treatment thereof. In another preferred embodiment, this expression includes patients having squamous or non-squamous non-small cell lung cancer and / or in need of treatment thereof. This term includes subjects having primary or metastatic tumors (progressive malignant tumors). In certain embodiments, the expression "subjects in need thereof" includes patients having solid tumors that are resistant or refractory to previous treatment (e.g., treatment with anti-cancer agents) or are not properly controlled by previous treatment. For example, this expression includes subjects previously treated with one or more courses of treatment, such as treatment with chemotherapy (e.g., carboplatin or docetaxel). In certain embodiments, the expression "subjects in need thereof" includes patients having solid tumors that were previously treated with one or more courses of treatment but then recurred or metastasized. For example, a patient having a solid tumor that may have regressed after treatment with one or more anti-cancer agents but then developed a cancer resistant to one or more anti-cancer agents (e.g., chemotherapy-resistant cancer) is treated by the method of the present invention. This expression also includes subjects having solid tumors for which conventional anti-cancer therapy is not recommended, for example, due to toxic side effects. For example, this expression includes patients who have received one or more cycles of chemotherapy with toxic side effects.

[0028] In certain embodiments, the methods of the invention can be used to treat patients showing elevated levels of one or more cancer-related biomarkers [e.g., programmed cell death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate dehydrogenase, KIT, carcinoembryonic antigen, epidermal growth factor receptor (EGFR), ALK gene rearrangement]. For example, the methods of the invention include administering a therapeutically effective amount of an anti-PD-1 antibody to a patient having an elevated level of PD-L1 in tumor tissue. In certain embodiments, the methods of the invention include administering a therapeutically effective amount of an anti-PD-1 antibody to a patient having lung cancer, wherein the tumor tissue in the patient expresses PD-L1 in <50%, ≦45%, ≦40%, ≦30%, ≦20%, ≦10%, ≦5%, ≦2%, or ≦1% of the tumor cells. In certain embodiments, the methods of the invention include administering a therapeutically effective amount of an anti-PD-1 antibody to a patient having lung cancer, wherein the tumor tissue in the patient expresses PD-L1 in ≧50%, ≧60%, ≧70%, ≧80%, or ≧90% of the tumor cells.

[0029] In certain embodiments, the methods of the invention are used in a subject having a solid tumor. The terms "tumor," "cancer," and "malignant tumor" are used interchangeably herein.

[0030] As used herein, the term "solid tumor" refers to an abnormal tumor of tissue that typically does not contain cysts or liquid regions. Solid tumors can be either benign (non-cancerous) or malignant (cancerous). For the purposes of the present invention, the term "solid tumor" means a malignant solid tumor. This term includes various types of solid tumors named after the cell types that form them, namely, sarcomas, carcinomas, and lymphomas. However, this term does not include leukemia. In various embodiments, the term "solid tumor" includes cancers that arise from connective or supportive tissues (e.g., bone or muscle) (referred to as sarcomas), cancers that arise from glandular cells of the body and epithelial cells that cover the body (referred to as carcinomas), and cancers of lymphoid organs such as lymph nodes, spleen, and thymus (referred to as lymphomas). Lymphoid cells are present in almost all tissues, and thus, lymphomas can occur in a variety of organs. In certain embodiments, the term "solid tumor" includes, but is not limited to, cancers including colorectal cancer, ovarian cancer, prostate cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, anal cancer, uterine cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, endometrial cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and cancers including multiple myeloma. In certain embodiments, the term "solid tumor" includes, but is not limited to, cancers including hepatocellular carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, basal cell carcinoma, breast cancer, cutaneous squamous cell carcinoma, chondrosarcoma, angiosarcoma, cholangiocarcinoma, soft tissue sarcoma, colorectal cancer, melanoma, Merkel cell carcinoma, and glioblastoma multiforme. In certain embodiments, the term "solid tumor" in a subject in need of treatment includes more than one solid tumor lesion located apart from each other, e.g., 2, more than 2, more than 5, more than 10, more than 15, more than 20, or more than 25 lesions. In certain embodiments, more than one lesion are located distally from each other in the same organ. In certain other embodiments, the tumor lesions can be located in different organs.

[0031] In certain embodiments, the invention includes, but is not limited to, methods of treating cancer, including, but not limited to, colorectal cancer, ovarian cancer, prostate cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, anal cancer, uterine cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, endometrial cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and myeloma, or inhibiting cancer growth. In certain embodiments, the invention includes, but is not limited to, methods of treating cancer, including, but not limited to, hepatocellular carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, basal cell carcinoma, cutaneous squamous cell carcinoma, chondrosarcoma, angiosarcoma, cholangiocarcinoma, soft tissue sarcoma, colorectal cancer, melanoma, Merkel cell carcinoma, and glioblastoma multiforme, or inhibiting cancer growth. In certain embodiments, the invention includes methods of treating progressive solid tumors, including, but not limited to, metastatic cutaneous squamous cell carcinoma (CSCC), unresectable locally advanced CSCC, metastatic colorectal cancer, progressive or metastatic hepatocellular carcinoma, progressive non-small cell lung cancer, recurrent glioblastoma multiforme, castration-resistant prostate cancer, and progressive solid tumors refractory to first-line therapy. Methods according to this aspect include administering a therapeutically effective amount of an anti-PD-1 antibody, optionally in combination with an anti-tumor therapy. Anti-tumor therapies include, but are not limited to, chemotherapy, radiation, CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies), and conventional anti-tumor therapies such as surgery. Other anti-tumor therapies are described elsewhere in this specification. In one embodiment, the anti-tumor therapy includes platinum-based chemotherapy. In certain embodiments, one or more doses of the anti-PD-1 antibody are administered to a subject in need thereof, wherein each dose is administered 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the immediately preceding dosing. In certain embodiments, each dose includes 0.1 to 10 mg / kg of subject body weight (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg). In certain other embodiments, each dose includes 20 to 1500 mg of the anti-PD-1 antibody, e.g., 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 550 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1050 mg, 1200 mg, or 1500 mg of the anti-PD-1 antibody.

[0032] In certain embodiments, the present invention includes a method of treating cancer having microsatellite instability (MSI) or inhibiting cancer growth. The term "microsatellite instability," also known as "MSI" as used herein, refers to genetic hypermutability caused by changes or deletions in microsatellite repeats in tumor cells or due to defective DNA mismatch repair. Microsatellites, also known as simple sequence repeats, are repetitive sequences of DNA containing repeating units of 1 to 6 base pairs in length. The length of microsatellites varies highly among humans and contributes to DNA fingerprinting, but each individual has microsatellites of a determined length. MSI results from the inability of mismatch repair (MMR) proteins to repair DNA replication errors. MSI includes DNA polymorphisms where replication errors result in a change in length instead of sequence. MSI includes either insertions or deletions or frameshift mutations due to hypermethylation, resulting in gene silencing. It is known in the art that microsatellite instability can give rise to colon cancer, gastric cancer, endometrial cancer, ovarian cancer, liver cholangiocarcinoma, ureteral cancer, brain cancer, and skin cancer. The present invention includes a method of treating cancer associated with MSI, the method comprising administering to a patient in need thereof a therapeutically effective amount of an anti-PD-1 antibody optionally in combination with a second anti-tumor agent (e.g., chemotherapy, radiation therapy).

[0033] As used herein, the term "chemotherapy" refers to the use of chemotherapeutic agents (chemical compounds used in anti-tumor therapy). This term includes, but is not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / anti-tumor antibodies, topoisomerase inhibitors, photosensitizers, anti-estrogen drugs and selective estrogen receptor modulators (SERMs), anti-progesterone drugs, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, anti-androgen drugs, aromatase inhibitors, EGFR inhibitors, and VEGF inhibitors. Examples of chemotherapeutic agents are disclosed elsewhere in this specification. In one embodiment, this term refers to platinum-based chemotherapeutic agents (e.g., gemcitabine, cisplatin, carboplatin, pemetrexed, or combinations thereof). Chemotherapeutic agents are administered according to dosing regimens known in the art.

[0034] As used herein, the term "radiation therapy" (also referred to as "XRT") generally means the use of ionizing radiation to kill cancer cells, typically as part of an anti-cancer treatment. X-rays, gamma rays, or charged particles (e.g., protons or electrons) are used to generate the ionizing radiation. Radiation therapy may be delivered by a machine placed outside the patient's body (external beam radiation therapy), or by a radiation source placed inside the patient (brachytherapy or sealed source radiotherapy), or may be delivered by systemic radioisotopes administered intravenously or orally (systemic radioisotope therapy). Radiation therapy may be planned and administered in conjunction with imaging-based techniques such as computed tomography (CT), magnetic resonance imaging (MRI), in order to accurately determine the dose and location of the radiation to be administered. In various embodiments, radiation therapy is selected from the group consisting of total body irradiation therapy, conventional external beam radiation therapy, stereotactic radiosurgery, body trunk stereotactic radiotherapy, three-dimensional conformal radiation therapy, intensity modulated radiation therapy, image-guided radiation therapy, tomotherapy, brachytherapy, and total body irradiation therapy. Depending on the purpose, in certain embodiments, radiation therapy is therapeutic, adjuvinating, or palliative. In certain embodiments, the term "radiation therapy" refers to hypofractionated radiation therapy. Hypofractionated radiation therapy refers to radiation therapy in which the radiation dose is composed of two or more fractional doses. In various embodiments, each fractional dose includes from 2 to 20 Gy. For example, a radiation dose of 50 Gy can be divided into 10 fractional doses each including 5 Gy. In certain embodiments, two or more fractional doses are administered on consecutive days, or on sequential days. In certain other embodiments, two or more fractional doses are administered once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, or combinations thereof.

[0035] According to certain embodiments, the present invention includes a method for treating a tumor or delaying or inhibiting the growth of a tumor. In certain embodiments, the present invention includes a method for promoting tumor regression. In certain embodiments, the present invention includes a method for reducing the amount of tumor cells or the amount of tumor. In certain embodiments, the present invention includes a method for preventing tumor recurrence. The method according to this aspect of the present invention comprises continuously administering a therapeutically effective amount of an anti-PD-1 antibody in combination with a second anti-tumor therapy to a subject in need thereof, wherein the antibody is administered to the subject in multiple doses, for example as part of a specific treatment dosing regimen. For example, the treatment dosing regimen may include administering one or more doses of the anti-PD-1 antibody to the subject approximately 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 two months, once every three months, once every four months, or at a frequency less than that. In certain embodiments, one or more doses of the anti-PD-1 antibody are administered in combination with one or more doses of the second anti-tumor therapy, where one or more doses of the second anti-tumor therapy are administered to the subject at a frequency of approximately once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every two months, once every three months, once every four months, or at a frequency less than that.

[0036] In certain embodiments, one or more doses are included in a treatment cycle. The method according to this aspect comprises administering at least one treatment cycle to a subject in need thereof, where at least one treatment cycle includes 1 to 10 doses of the anti-PD-1 antibody and optionally one or more doses of chemotherapy. In certain embodiments, 2 to 12 or more treatment cycles are administered to a subject in need thereof.

[0037] In certain embodiments, the present invention provides a method for increased antitumor efficacy or increased tumor inhibition. Methods according to this aspect of the invention include administering to a subject having a solid tumor a therapeutically effective amount of an anti-PD-1 antibody, followed by administering a dose of a second antitumor therapy (e.g., chemotherapy or an anti-CTLA-4 antibody), wherein the anti-PD-1 antibody can be administered approximately 1 day before, more than 1 day before, more than 2 days before, more than 3 days before, more than 4 days before, more than 5 days before, more than 6 days before, more than 7 days before, or more than 8 days before the second antitumor therapy. In certain embodiments, this method provides, for example, about 20%, more than 20%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, or more than 80% increased tumor inhibition compared to a subject administered an antitumor therapy (e.g., chemotherapy) prior to the anti-PD-1 antibody. In certain embodiments, the chemotherapy includes platinum-based chemotherapy. In certain embodiments, the second antitumor therapy includes a CTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody).

[0038] In certain embodiments, the present invention provides a method for treating cancer, the method comprising selecting a subject having a first tumor lesion and at least a second tumor lesion, and administering one or more doses of an anti-PD-1 antibody in combination with radiotherapy such that the lesions of the therapy are treated. In certain embodiments, the method includes administering radiotherapy to the first tumor lesion but not to the second tumor lesion, wherein the administration results in tumor regression in both tumor lesions (abscopal effect). In certain embodiments, the method includes selecting a subject having a first tumor lesion and at least a second tumor lesion, and administering one or more doses of an anti-PD-1 antibody in combination with a hypofractionated irradiation method, wherein the hypofractionated irradiation method is administered to the first lesion but not to the second lesion, and both lesions are treated upon said administration. In certain embodiments, the anti-PD-1 antibody is administered prior to radiotherapy.

[0039] In certain embodiments, the invention includes a method of treating cancer, the method comprising administering to a subject in need thereof a sub-therapeutic dose of an anti-PD-1 antibody in combination with one or more anti-tumor therapies, such as radiation therapy. As defined elsewhere herein, the term "sub-therapeutic dose" refers to a dose lower than a therapeutic dose and can be used to reduce the toxicity of the administered treatment. In certain embodiments, administration of a sub-therapeutic dose of an anti-PD-1 antibody in combination with radiation therapy results in therapeutic anti-tumor efficacy as compared to administration of a sub-therapeutic dose of the anti-PD-1 antibody alone. In certain other embodiments, the method of the invention comprises administering a therapeutically effective amount of an anti-PD-1 antibody in combination with a sub-therapeutic dose of an anti-tumor therapy such as chemotherapy or radiation. For example, a therapeutically effective amount of an anti-PD-1 antibody can be administered in combination with a sub-therapeutic dose of cyclophosphamide for increased efficacy as compared to either monotherapy.

[0040] In certain embodiments, the invention includes a method for inhibiting, delaying, or arresting tumor metastasis or tumor infiltration into an ablated organ. Methods according to this aspect comprise administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 anti- body. In certain embodiments, the anti-PD-1 antibody is administered in combination with chemotherapy. In one embodiment, the chemotherapy is platinum-based chemotherapy. In one embodiment, the chemotherapy is administered before, concurrently with, or after administration of one or more doses of the anti-PD-1 antibody.

[0041] In certain embodiments, the method of the invention comprises administering a therapeutically effective amount of an anti-PD-1 antibody to a subject having a progressive solid tumor. In certain embodiments, the progressive solid tumor is metastatic lung cancer, head and neck cancer, hepatocellular carcinoma, or breast cancer. In certain other embodiments, the progressive solid tumor is cutaneous squamous cell carcinoma. In certain embodiments, the progressive solid tumor is of low or high grade. In certain embodiments, the subject is not responsive to previous treatment or has relapsed after previous treatment (e.g., using carboplatin). In certain embodiments, the subject has a progressive solid tumor that is refractory to first-line chemotherapy. In certain further embodiments, the method of the invention further comprises administering a further anti-cancer therapy (e.g., a CTLA-4 inhibitor) to a subject having a progressive solid tumor.

[0042] In certain embodiments, the invention includes methods of treating or inhibiting the growth of cancers including, but not limited to, colorectal cancer, ovarian cancer, prostate cancer, breast cancer, brain cancer, cervical cancer, bladder cancer, anal cancer, uterine cancer, colon cancer, liver cancer, pancreatic cancer, lung cancer, endometrial cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, gastric cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and myeloma. In certain embodiments, the invention includes methods of treating or inhibiting the growth of cancers including, but not limited to, hepatocellular carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, basal cell carcinoma, cutaneous squamous cell carcinoma, chondrosarcoma, angiosarcoma, cholangiocarcinoma, soft tissue sarcoma, colorectal cancer, melanoma, Merkel cell carcinoma, and glioblastoma multiforme. In certain embodiments, the invention includes methods of treating progressive solid tumors including, but not limited to, metastatic cutaneous squamous cell carcinoma (CSCC), locally advanced inoperable CSCC, metastatic colorectal cancer, progressive or metastatic hepatocellular carcinoma, progressive non-small cell lung cancer, recurrent glioblastoma multiforme, newly diagnosed glioblastoma multiforme, castration-recurrent prostate cancer, and progressive solid tumors refractory to first-line treatment.

[0043] In one aspect, the present invention includes a method of treating a tumor or inhibiting the growth of a tumor, the method comprising: (a) selecting a patient having cutaneous squamous cell carcinoma (CSCC), where the patient is selected based on a characteristic selected from the group consisting of: (i) the patient has locally advanced CSCC; (ii) the patient has metastatic CSCC; (iii) the tumor is inoperable; (iv) the patient has been previously treated with at least one anti-tumor therapy; (v) the patient has a disease considered inoperable; (vi) surgery and / or radiation is contraindicated; (vii) the patient has been previously treated with radiation and the tumor is resistant or refractory to radiation; and (viii) the tumor contains UV-induced DNA damage; and (b) administering to the patient in need thereof a therapeutically effective amount of an anti-PD-1 antibody. In certain embodiments, one or more doses of the anti-PD-1 antibody are administered 1 to 12 weeks after the previous dosing, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the previous dosing. In certain embodiments, each dose of the anti-PD-1 antibody comprises 0.1, 1, 0.3, 3, 4, 5, 6, 7, 8, 9, or 10 mg per kg of the patient's body weight. In certain embodiments, each dose comprises 50 to 500 mg of the anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is REGN2810.

[0044] In one aspect, the present invention includes a method of treating a tumor or increasing the survival of a cancer patient, the method comprising: (a) selecting a patient having lung cancer, where the patient is selected from the group consisting of: (i) the patient has non-small cell lung cancer; (ii) the tumor tissue in the patient expresses PD-L1 in <50% of the tumor cells; (iii) the patient has non-squamous stage III or IV lung cancer; (iv) the patient has not previously received systemic treatment for recurrent lung cancer; and (v) the patient has previously received treatment with an anti-tumor therapy. selected based on such characteristics; and (b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1. In one embodiment, the patient has progressive or recurrent non-small cell lung cancer, the tumor tissue in the patient expresses PD-L1 in <50% of tumor cells, and the patient has not been previously treated with a systemic treatment for lung cancer. In one embodiment, the patient has progressive or recurrent non-small cell lung cancer, the tumor tissue in the patient expresses PD-L1 in <50% of tumor cells, and the patient has been previously treated with a systemic treatment (e.g., chemotherapy) for lung cancer. In certain embodiments, the patient has progressive or recurrent non-small cell lung cancer, and the tumor tissue in the patient expresses PD-L1 in <50%, ≦45%, ≦40%, ≦30%, ≦20%, ≦10%, ≦5%, ≦2%, or ≦1% of tumor cells.

[0045] In certain embodiments, the invention includes a method of treating cancer or increasing the survival of a cancer patient, the method comprising: (a) selecting a patient having lung cancer, [wherein the tumor tissue in the patient expresses PD-L1 in ≧50% of tumor cells]; and (b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1. In one embodiment, the tumor tissue in the patient expresses PD-L1 in ≧60%, ≧70%, ≧80%, or ≧90% of tumor cells. In one embodiment, the patient has progressive or metastatic non-small cell lung cancer. In one embodiment, the patient has squamous or non-squamous stage III or IV non-small cell lung cancer. In one embodiment, the patient has not been previously treated with a systemic treatment for lung cancer.

[0046] According to one aspect, the present invention includes a method for treating cancer or increasing the survival of a cancer patient, the method comprising: (a) selecting a patient having lung cancer, [wherein the patient has at least one of the following characteristics: (i) the patient has progressive or metastatic non-small cell lung cancer; (ii) the patient has squamous or non-squamous stage III or IV lung cancer; (iii) the patient has not been previously treated with a systemic treatment for lung cancer; and (iv) the patient has been previously treated with an anti-tumor therapy (e.g., platinum-based chemotherapy, surgery and / or radiation)]; (b) determining the expression of PD-L1 in the tumor tissue; and (c) when the tumor tissue expresses PD-L1 in <50% of the tumor cells, administering to the patient a therapeutically effective amount of one or more doses of an antibody that specifically binds to PD-1 or an antigen-binding fragment thereof. In one embodiment, the tumor tissue expresses PD-L1 in <50%, ≦45%, ≦40%, ≦30%, ≦20%, ≦10%, ≦5%, ≦2%, ≦1% or 0% of the tumor cells.

[0047] According to one aspect, the present invention includes a method for treating cancer or increasing the survival of a cancer patient, the method comprising: (a) selecting a patient having lung cancer, [wherein the patient has at least one of the following characteristics: (i) the patient has progressive or metastatic non-small cell lung cancer; (ii) the patient has squamous or non-squamous stage III or IV lung cancer; (iii) the patient has not been previously treated with a systemic treatment for lung cancer; and (iv) the patient has been previously treated with an anti-tumor therapy (e.g., platinum-based chemotherapy, surgery and / or radiation)]; (b) determining the expression of PD-L1 in the tumor tissue; and (c) when the tumor tissue expresses PD-L1 in ≧50% of the tumor cells, administering to the patient a therapeutically effective amount of one or more doses of an antibody that specifically binds to PD-1 or an antigen-binding fragment thereof. In one embodiment, the tumor tissue expresses PD-L1 in ≧60%, ≧70%, ≧80%, or ≧90% of the tumor cells.

[0048] In certain embodiments, each dose of the anti-PD-1 antibody is administered 1, 2, 3, or 4 weeks after the immediately preceding dose, where each dose comprises 20 to 1500 mg of the anti-PD-1 antibody. In one embodiment, each dose comprises 200, 250, 300, 350, 500, 600, 700, 800, 900, 1000, or 1050 mg of the anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is REGN2810 (cemiplimab).

[0049] In certain embodiments, the method comprises administering to a cancer patient one or more doses of a therapeutically effective amount of an anti-PD-1 antibody, where the patient is selected based on PD-L1 expression in less than 1% of tumor cells. In certain embodiments, the tumor tissue in the patient expresses PD-L1 in less than 2%, 5%, 10%, 20%, 30%, 40%, or 50% of tumor cells. In certain embodiments, the method comprises selecting a cancer patient based on PD-L1 expression in ≧50% of tumor cells and administering to the patient one or more doses of a therapeutically effective amount of an anti-PD-1 antibody. In certain embodiments, the expression of PD-L1 in the tumor tissue is determined by any assay known in the art, such as by ELISA assay or immunohistochemistry (IHC) assay, as described in PCT Publication WO2016124558 or WO2016191751 or U.S. Patent Application Publication US20160305947. In certain embodiments, the expression of PD-L1 is determined, for example, by in situ hybridization or by quantifying RNA expression by RT-PCR. In certain embodiments, the expression of PD-L1 is determined using a labeled anti-PD-L1 antibody, for example, by imaging by immuno-positron emission tomography or iPET [see, for example, The Oncologist, 12:1379 (2007); Journal of Nuclear Medicine, 52(8):1171 (2011); U.S. Provisional Patent Application No. 62 / 428,672 (filed December 1, 2016)].

[0050] In certain embodiments, administration of at least one dose of the anti-PD-1 antibody results in an increase in progression-free survival (PFS) or overall survival (OS) of the patient as compared to a patient administered platinum-based chemotherapy as a monotherapy. In certain embodiments, the PFS is increased by at least 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years or more as compared to a patient administered platinum-based chemotherapy. In certain embodiments, the OS is increased by at least 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years or more as compared to a patient administered platinum-based chemotherapy.

[0051] According to one aspect, the present invention includes a method of treating a tumor or inhibiting the growth of a tumor, the method comprising selecting a subject having brain cancer and administering to the subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, the brain cancer is glioblastoma multiforme. In one embodiment, the subject is newly diagnosed with glioblastoma multiforme. In one embodiment, the subject is ≧65 years old. In one embodiment, the anti-PD-1 antibody is administered as one or more doses, where each dose is administered 0.5 to 4 weeks after the previous dosing. In one embodiment, each dose of the anti-PD-1 antibody comprises 1, 3, or 10 mg / kg of the subject's body weight. In certain embodiments, the anti-PD-1 antibody is administered in combination with radiation therapy. In one embodiment, the radiation therapy is a hypofractionated irradiation method. In one embodiment, the subject is administered 20 to 60 Gy in 2 to 20 fractionated doses. In certain embodiments, one or more doses of the anti-PD-1 antibody are included in one or more treatment cycles, where each treatment cycle comprises 1 to 6 doses of the anti-PD-1 antibody. In one embodiment, at least one cycle of treatment further comprises radiation therapy. In a further embodiment, the radiation therapy is a hypofractionated irradiation method. In a specific embodiment, the subject is administered a hypofractionated irradiation method in the first cycle of treatment, where the hypofractionated irradiation method comprises 20 to 60 Gy in 2 to 20 fractionated doses. In one embodiment, the subject is administered the hypofractionated irradiation method 1 week after administration of the anti-PD-1 antibody in the first cycle of treatment. In certain embodiments, the method of the present invention is such that the subject has intracranial If edema occurs, it further includes administering an anti-angiogenic agent to the subject. In one embodiment, the anti-angiogenic agent is a vascular endothelial growth factor (VEGF) inhibitor. In one embodiment, the anti-angiogenic agent is an angiopoietin-2 (Ang-2) inhibitor (e.g., an anti-Ang-2 antibody such as nesvacumab). In certain embodiments, the VEGF inhibitor is selected from the group consisting of a VEGF inhibitory fusion protein (e.g., a "VEGF-trap" such as aflibercept or other VEGF inhibitory fusion proteins as described in US 7,087,411), an anti-VEGF antibody (e.g., bevacizumab), and a small molecule kinase inhibitor of the VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib).

[0052] The method of the invention according to a particular embodiment comprises administering to a subject a therapeutically effective amount of an anti-PD-1 antibody in combination with a further therapeutic agent or treatment regimen or procedure. The further therapeutic agent or treatment regimen or procedure can be administered to increase the anti-tumor efficacy, to reduce the toxic effects of one or more treatments, and / or to reduce the dosage of one or more treatments.In various embodiments, additional therapeutic agents or treatment regimens or procedures include, for example, chemotherapy, cyclophosphamide, surgery, radiation, cancer vaccines, programmed cell death ligand 1 (PD-L1) inhibitors (e.g., anti-PD-L1 antibodies), lymphocyte activation gene 3 (LAG3) inhibitors (e.g., anti-LAG3 antibodies), cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitors (e.g., anti-CTLa-4 antibodies such as ipilimumab), glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitors (e.g., anti-GITR antibodies), T cell immunoglobulin and mucin-containing-3 (TIM3) inhibitors, B- and T-lymphocyte attenuator (BTLA) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, CD47 inhibitors, indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists [selected from the group consisting of VEGF inhibitory fusion proteins (e.g., “VEGF-traps” such as aflibercept or other VEGF inhibitory fusion proteins as described in US 7,087,411), anti-VEGF antibodies (e.g., bevacizumab), and small molecule kinase inhibitors of VEGF receptors (e.g., sunitinib, sorafenib, or pazopanib)], angiopoietin-2 (Ang2) inhibitors, transforming growth factor beta (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, antibodies against tumor-specific antigens [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9], anti-CD3 / anti-CD20 bispecific antibodies, vaccines (e.g., Bacillus Calmette-Guerin), granulocyte macrophage colony-stimulating factor, cytotoxins, chemotherapeutic agents, IL-6R inhibitors, IL-4R inhibitors, IL-10 inhibitors, cytokines such as IL-2, IL-7, IL-21, and IL-15, T cell therapy, anti-inflammatory drugs such as corticosteroids, and non-steroidal anti-inflammatory drugs, and dietary supplements such as antioxidants, selected from the group consisting of.In certain embodiments, the anti-PD-1 antibody can be administered in combination with a treatment comprising a chemotherapeutic agent and surgery. As used herein, the phrase "in combination with" means that the anti-PD-1 antibody is administered to a subject at the same time as, immediately prior to, or immediately following the administration of radiotherapy and the administration of additional therapeutic agents. In certain embodiments, the additional therapeutic agent is administered as a co-formulation with the anti-PD-1 antibody.

[0053] In certain embodiments, the invention includes a method for treating a large tumor or a progressive malignant tumor, the method comprising administering to a subject in need thereof an anti-PD-1 antibody in combination with radiotherapy and an additional therapeutic agent, wherein the additional therapeutic agent is administered to overcome regulatory T cell (Treg)-mediated immunosuppression. In certain embodiments, the additional therapeutic agent is selected from the group consisting of an anti-GITR antibody, an anti-LAG3 antibody, cyclophosphamide, and GM -CSF.

[0054] As used herein, the term "large tumor" refers to the size of the tumor. This typically correlates with a higher tumor burden or tumor mass. In certain embodiments, this correlates with the stage of the disease, such as a progressive malignant tumor. In certain embodiments, this correlates with an increased likelihood of metastasis.

[0055] In certain embodiments, the invention includes a method comprising administering one or more doses of an anti-PD-1 antibody in combination with radiotherapy and a dose of cyclophosphamide below the therapeutic amount. As used herein, a dose of cyclophosphamide below the therapeutic amount (also referred to herein as "low-dose cyclophosphamide") means an amount of cyclophosphamide that does not confer a therapeutic effect on its own and preferably does not cause toxicity. Examples of doses of cyclophosphamide that may be considered "below the therapeutic amount" in the context of the present invention include 100 mg / m2, 90 mg / m2, 80 mg / m2 or less.

[0056] In certain embodiments, radiation therapy is administered to a first tumor lesion but not to a second tumor lesion, where administration in combination with an anti-PD-1 antibody results in tumor regression (abscopal effect) in both the first and second tumor lesions. In certain embodiments, the methods of the invention include administering an anti-PD-1 antibody in combination with radiation therapy to produce a long-term abscopal effect.

[0057] In certain embodiments, the method of the invention comprises administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody, optionally in combination with a second anti-tumor therapy, wherein administration of this combination results in increased inhibition of tumor growth. In certain embodiments, tumor growth is inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% compared to an untreated subject or a subject administered either the antibody or the second anti-tumor therapy as a monotherapy. In certain embodiments, administration of the anti-PD-1 antibody and / or the second anti-tumor therapy results in increased tumor regression, tumor shrinkage, and / or disappearance. In certain embodiments, administration of the anti-PD-1 antibody and / or chemotherapy results in a delay in tumor growth and development, e.g., tumor growth is delayed by about 3 days, longer than 3 days, about 7 days, longer than 7 days, longer than 15 days, longer than 1 month, longer than 3 months, longer than 6 months, longer than 1 year, longer than 2 years, or longer than 3 years compared to an untreated subject or a subject treated with the antibody or chemotherapy as a monotherapy. In certain embodiments, administration of an anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) prevents tumor recurrence and / or increases the survival period of the subject, e.g., increasing the survival period by 15 days, longer than 1 month, longer than 3 months, longer than 6 months, longer than 12 months, longer than 18 months, longer than 24 months, longer than 36 months, or longer than 48 months compared to an untreated subject or a subject administered either the antibody or the second anti-tumor therapy as a monotherapy. In certain embodiments, administration of an anti-PD-1 antibody in combination with an additional anti-tumor therapy increases progression-free survival or overall survival. In certain embodiments, administration of an anti-PD-1 antibody in combination with chemotherapy increases the response and response duration in the subject by, e.g., more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40%, or more than 50% compared to an untreated subject or a subject administered the antibody or chemotherapy as a monotherapy.In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject having cancer results in complete disappearance of all evidence of tumor cells (“complete remission”). In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject having cancer results in at least a 30% or greater decrease in tumor cells or tumor size (“partial response”). In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject having cancer results in complete or partial disappearance of tumor cells / lesions, including new measurable lesions. Tumor reduction can be measured by any of the methods known in the art, e.g., by x-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analysis. In certain embodiments, the methods of the invention include administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody, wherein administration of the anti-PD-1 antibody results in increased overall survival (OS) or progression-free survival (PFS) of the patient as compared to patients who have received “standard of care” (e.g., chemotherapy, surgery or radiation). In certain embodiments, PFS is increased by at least 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years or more as compared to patients who have received platinum-based chemotherapy. In certain embodiments, OS is increased by at least 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years or more as compared to patients who have received platinum-based chemotherapy.

[0058]

[0059] Method for suppressing regulatory T cells According to certain aspects, the present invention provides a method for suppressing or inhibiting the activation and / or proliferation of T regulatory (Treg) cells. In certain embodiments, the present invention provides a method for suppressing the activation of Treg cells. Methods according to these aspects include selecting a subject having a solid tumor, and administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the subject in combination with at least one of (i) radiotherapy, and (ii) a glucocorticoid-induced tumor necrosis factor receptor (GITR) antagonist. In certain embodiments, the method includes administering an anti-PD-1 antibody or an antigen-binding fragment thereof to a subject in need thereof in combination with radiotherapy and a GITR antagonist.

[0060] In certain embodiments, the GITR antagonist is an anti-GITR antibody or an antigen-binding fragment thereof. According to certain exemplary embodiments of the present invention, the anti-GITR antibody or an antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any amino acid sequence of an anti-GITR antibody as shown in USSN 62 / 256,922 (filed Nov. 18, 2015) (the contents of which are incorporated herein by reference in their entirety). Other anti-GITR antibodies that can be used in the context of the methods of the present invention include, for example, any of the anti-GITR antibodies shown in U.S. Pat. Nos. 9,228,016; 8,709,424; 8,591,886; 7,812,135; or U.S. Patent Publication No. 2015 / 0368349.

[0061] In certain embodiments, the present invention provides a method for suppressing or eliminating Treg activity, the method comprising administering an anti-PD-1 antibody or an antigen-binding fragment thereof to a subject in need thereof in combination with one or more doses of radiation and a cytotoxic T lymphocyte antigen-4 (CTLA) antagonist. In certain embodiments, the CTLA antagonist is an anti-CTLA antibody (e.g., ipilimumab).

[0062] In certain embodiments, the present invention provides a method for suppressing or eliminating Treg activity, the method comprising administering to a subject in need thereof an anti-PD-1 antibody or antigen-binding fragment thereof in combination with one or more doses of radiation and lymphocyte activation gene 3 (LAG-3) antagonist. In certain embodiments, the LAG-3 antagonist is an anti-LAG-3 antibody. Anti-LAG-3 antibodies that can be used in the context of the methods of the present invention are disclosed in USSN 62 / 239,524 (filed Oct. 9, 2015), the contents of which are incorporated herein in their entirety.

[0063] In certain embodiments, the present invention provides a method for suppressing or eliminating Treg activity, the method comprising administering to a subject in need thereof an anti-PD-1 antibody or antigen-binding fragment thereof in combination with one or more doses of radiation and cyclophosphamide.

[0064] In one aspect, the methods of the present invention comprise administering an anti-PD-1 antibody to a subject having a solid tumor in combination with radiation therapy and a further therapeutic agent selected from the group consisting of a GITR antagonist, an anti-LAG-3 antibody, and cyclophosphamide, wherein the administration results in an effect selected from the group consisting of inhibition of tumor growth, reduction of tumor size, delay of tumor growth, inhibition of tumor metastasis, reduction of metastatic lesions over time, reduced use of chemotherapeutic or cytotoxic agents, increased survival, complete remission, partial response, and stable disease. In certain embodiments, the administration results in a reduction of tumor burden in the subject. In certain embodiments, the subject has a large tumor. As defined elsewhere herein, the term "large tumor" refers to the size of the tumor and correlates with increased tumor burden and an increased likelihood of the occurrence of metastases. In certain embodiments, the term refers to a progressive malignant tumor.

[0065] Anti-PD-1 antibodies and antigen-binding fragments thereof According to certain exemplary embodiments of the present invention, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof. As used herein, the term "antibody" includes an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, two heavy (H) chains and two light (L) chains, and multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or V H for short) and a heavy chain constant region. The heavy chain constant region comprises three domains, C H 1, C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L for short) and a light chain constant region. The light chain constant region comprises one domain (C L 1). The V H and V L regions can be further subdivided into hypervariable regions named complementarity-determining regions (CDRs) incorporated into more conserved regions named framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present invention, the FRs of the anti-IL-4R antibody (or antigen-binding portion thereof) may be the same as the human germline sequences, or may be naturally or artificially modified. Amino acid consensus sequences can be defined based on side-by-side analysis of two or more CDRs.

[0066] As used herein, the term "antibody" also includes antigen-binding fragments of whole antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody and the like include naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from whole antibody molecules using any suitable standard techniques, such as proteolytic digestion, or recombinant genetic engineering techniques including manipulation and expression of DNA encoding antibody variable domains and optionally constant domains. Such DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and manipulated, for example, to arrange one or more variable domains and / or constant domains in appropriate configurations, or to introduce codons, generate cysteine residues, modify, add or delete amino acids, using chemical or molecular biological techniques.

[0067] 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 amino acid residues mimicking the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, bispecific antibodies, trispecific antibodies, tetravalent antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also included within the "antigen-binding fragment" as used herein.

[0068] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain can be of any size or amino acid composition and generally contains at least one CDR adjacent to or in-frame with one or more framework sequences. V L domain and the related V H domain in an antigen-binding fragment having a V H and V L domain can be positioned relative to each other in an appropriate arrangement. For example, the variable region can be a dimer, and V H -V H 、V H -V L or V L -V L dimers can be contained. Alternatively, the antigen-binding fragment of an antibody can contain a monomeric V H or V L domain.

[0069] In certain embodiments, the antigen-binding fragment of an antibody can contain at least one variable domain covalently linked to at least one constant domain. Non-limiting examples of configurations of variable and constant domains that can be found within the antigen-binding fragments of the antibodies of the present invention are: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ; (viii) V L -C H 1; (ix) V L -C H2; (x) V L -C H 3; (xi) V L -C H 1 - C H 2; (xii) V L -C H 1 - C H 2 - C H 3; (xiii) V L -C H 2 - C H 3; and (xiv) V L -C L are included. In any of the variable domain and constant domain configurations including any of the configurations listed above as examples, the variable domain and the constant domain may be directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region can consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that give rise to a mobile or semi-mobile linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragments of the antibodies of the present invention can include any of the variable domain and constant domain configurations listed above that are non-covalently bound to each other and / or a homodimer or heterodimer (or other multimer) with one or more monomeric V H or V L domains (e.g., by disulfide bonds).

[0070] As used herein, the term "antibody" also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically include at least two different variable domains, where each variable domain can specifically bind to a distinct antigen or to different epitopes on the same antigen. Any form of multispecific antibody can be adapted for use in the context of the antibodies or antigen-binding fragments of the invention using conventional techniques available in the art. For example, the invention includes methods that include the use of bispecific antibodies in which one arm of the immunoglobulin is specific for PD-1 or a fragment 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 invention include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain immunoglobulins (DVD)-Ig, quadromas, knob-into-hole, common light chain (e.g., common light chain having knob-into-hole, etc.), CrossMab, CrossFab, (SEED)body, leucine zipper, Duobody, IgG1 / IgG2, dual action Fab (DAF)-IgG, and Mab 2 bispecific formats (e.g., see Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein for a discussion of the foregoing formats). Bispecific antibodies can also be constructed, for example, using peptide / nucleic acid conjugates in which non-natural amino acids having orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates, which then self-assemble into multimeric complexes having defined composition, valency, and arrangement (e.g., see Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0071] The antibodies used in the method of the present invention may be human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies of the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or somatic mutations in vivo), for example, in the CDRs and particularly in 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, are grafted onto human framework sequences.

[0072] The antibodies used in the method of the present invention may be recombinant human antibodies. As used herein, the term "recombinant human antibody" includes all human antibodies produced, expressed, generated or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (further described below), antibodies isolated from a recombinant human antibody library (further described below), antibodies isolated from an animal that is transgenic for a human immunoglobulin gene (e.g., a mouse) [see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295] or antibodies produced, expressed, generated or isolated by any other means including 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. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, in the case of using an animal transgenic for a human Ig sequence, in vivo somatic mutagenesis), and thus the amino acid sequences of the V H and V L regions of the recombinant antibody are different from the human germline V H and V LDerived from and related to arrays, but may not be present in the human antibody germline repertoire in vivo.

[0073] According to certain embodiments, the antibodies used in the methods of the invention specifically bind to PD-1. The term "specifically binds" or similar means that an antibody or an antigen-binding fragment thereof forms a relatively stable complex with an antigen under physiological 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, etc. For example, an antibody that "specifically binds" to PD-1 as used in the context of the present invention binds to PD-1 or a portion thereof with a K D in a surface plasmon resonance assay 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. However, an isolated antibody that specifically binds to human PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from other (non-human) species.

[0074] According to certain exemplary embodiments of the present invention, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any amino acid sequence of an anti-PD-1 antibody as shown in U.S. Patent Publication No. 20150203579 (incorporated herein by reference in its entirety). 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 present invention comprises the heavy chain complementarity determining regions (HCDRs) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of the 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 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. 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 invention 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 comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10 is the fully human anti-PD-1 antibody known as REGN2810 (also known as cemiplimab). According to certain exemplary embodiments of the present invention, the methods of the present invention comprise the use of REGN2810, or a bioequivalent thereof.As used herein, the term "biological equivalent" refers to a pharmaceutical equivalent or pharmaceutical alternative of an anti-PD-1 antibody or PD-1 binding protein or a fragment thereof that, when administered at the same molar dose under the same experimental conditions, either as a single dose or multiple doses, does not show a significant difference in the rate and / or extent of absorption from that of REGN2810. In the context of the present invention, this term refers to an antigen-binding protein that binds to PD-1 and does not have a clinically meaningful difference from REGN2810 in terms of their safety, purity and / or efficacy.

[0075] Other anti-PD-1 antibodies that can be used in the context of the methods of the present invention include, for example, nivolumab (U.S. Patent No. 8,008,449), pembrolizumab (U.S. Patent No. 8,354,509), MEDI0608 (U.S. Patent No. 8,609,089), pidilizumab (U.S. Patent No. 8,686,119), or any of the antibodies known as and disclosed in U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, 8,354,509, 8,779,105, or 8,900,587.

[0076] The anti-PD-1 antibodies used in the context of the methods of the present invention can have pH-dependent binding characteristics. For example, an anti-PD-1 antibody for use in the methods of the present invention can show decreased binding to PD-1 at acidic pH compared to neutral pH. Alternatively, the anti-PD-1 antibodies of the present invention can show enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values of less than about 6.2, for example, about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0 or lower. The expression "neutral pH" as used herein includes pH values from about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.2 5, 7.3, 7.35, and 7.4.

[0077] In certain instances, "decreased binding to PD-1 at acidic pH compared to neutral pH" refers to the K D K values ​​for antibody binding to PD-1 at acidic pH D For example, an antibody or antigen-binding fragment thereof may be expressed in terms of a ratio of values ​​(or the inverse of the ratio). D When a ratio is presented, it may be considered for purposes of the present invention to indicate "decreased binding to PD-1 at acidic pH compared to neutral pH." In certain exemplary embodiments, the acidic / neutral K D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0078] Antibodies with pH-dependent binding characteristics can be obtained, for example, by screening a population of antibodies for decreased (or enhanced) binding to a particular antigen at acidic pH compared to neutral pH. Furthermore, antibodies with pH-dependent characteristics can be obtained by modifying the antigen-binding domain at the amino acid level. For example, by replacing one or more amino acids in the antigen-binding domain (e.g., within the CDRs) with histidine residues, an antibody with decreased antigen binding at acidic pH compared to neutral pH can be obtained. As used herein, the phrase "acidic pH" refers to a pH of 6.0 or lower.

[0079] Combination Therapy According to certain embodiments, the method of the invention comprises administering to a subject a further anti-tumor therapy in combination with an anti-PD-1 antibody. In certain embodiments, the method of the invention comprises administering radiotherapy or chemotherapy in combination with an anti-PD-1 antibody for additional or synergistic activity in treating cancer. As used herein, the phrase "in combination with" means that the further anti-tumor therapy is administered before, after, or simultaneously with the anti-PD-1 antibody. The term "in combination with" also includes sequential or concurrent administration of the anti-PD-1 antibody and the further anti-tumor therapy. For example, when administered "before" the further anti-tumor therapy, the anti-PD-1 antibody may be administered more than 150 hours before, about 150 hours before, about 100 hours before, about 72 hours before, about 60 hours before, about 48 hours before, about 36 hours before, about 24 hours before, about 12 hours before, about 10 hours before, about 8 hours before, about 6 hours before, about 4 hours before, about 2 hours before, about 1 hour before, or about 30 minutes before, about 15 minutes before, or about 10 minutes before the administration of the further therapy. When administered "after" the further anti-tumor therapy, the anti-PD-1 antibody may be administered about 10 minutes after, about 15 minutes after, about 30 minutes after, about 1 hour after, about 2 hours after, about 4 hours after, about 6 hours after, about 8 hours after, about 10 hours after, about 12 hours after, about 24 hours after, about 36 hours after, about 48 hours after, about 60 hours after, about 72 hours after, or more than 72 hours after the administration of the further anti-tumor therapy. "Concurrent" administration with the further anti-tumor therapy means that the anti-PD-1 antibody is administered to the subject within less than 10 minutes (before, after, or simultaneously) of the administration of the further anti-tumor therapy.

[0080] In certain embodiments, the methods of the invention include administration of additional therapeutic agents that are anti-cancer drugs. As used herein, "anti-cancer drug" means a drug useful for treating cancer, including but not limited to drugs such as cytotoxic and antimetabolic agents, alkylating agents, anthracycline agents, antibiotics, mitotic inhibitors, procarbazine, hydroxyurea, asparaginase, corticosteroids, mitotane (O,P’-(DDD)), biological agents (e.g., antibodies and interferons), and radiopharmaceuticals. As used herein, "cytotoxic or cytopathic agent" also refers to a chemotherapeutic agent and means an agent that is harmful to cells. Examples include but are not limited to Taxol (R) ( paclitaxel), temozolamide, cytochalasin B, gramicidin D, ethidium bromide, emetine, cisplatin, mitomycin, etoposide, tenoposide, vincristine, vinbiastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin, as well as analogs or homologs thereof.

[0081] In certain embodiments, the methods of the invention include surgery, radiation, a programmed cell death ligand 1 (PD-L1) inhibitor (e.g., an anti-PD-L1 antibody or atezolizumab as disclosed in U.S. Patent Publication No. 2015 / 0203580), a lymphocyte activation gene 3 (LAG-3) inhibitor (e.g., an anti-LAG-3 antibody), a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor (e.g., an anti-CTLA-4 antibody such as ipilimumab), a glucocorticoid-induced tumor necrosis factor (GITR) inhibitor, a T cell immunoglobulin and mucin-containing-3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (BTLA) inhibitor, a T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, a CD47 inhibitor, another T cell co-inhibitor or antagonist of a ligand (e.g., an antibody against CD-28, 2B4, LY108, LAIR1, ICOS, CD160 or VISTA), a CD20 inhibitor (e.g., an anti-CD20 antibody, or a bispecific CD3 / CD20 antibody), 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 inhibitory fusion proteins as described in US 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 a VEGF receptor (e.g., sunitinib, sorafenib, or pazopanib)], an angiopoietin 2 (Ang2) inhibitor (e.g., nesvacumab), a transforming growth factor beta (TGFβ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor (e.g., erlotinib, cetuximab), an agonist for a co-stimulatory receptor (e.g., an agonist for a glucocorticoid-induced TNFR-related protein), an antibody against a tumor-specific antigen [e.g., CA9, CA125, melanoma-associated antigen 3 (MAGE3), carcinoembryonic antigen (CEA), vimentin, tumor-M2-PK, prostate-specific antigen (PSA), mucin-1, MART-1, and CA19-9], a vaccine (e.g., Bacillus Calmette-Guerin Bacillus Calmette-Guerin), cancer vaccine), cyclophosphamide, an adjuvant that increases antigen presentation (e.g., granulocyte macrophage colony-stimulating factor), cytotoxic agent, chemotherapeutic agent (e.g., dacarbazine, temozolomide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), interleukin-6 receptor (IL-6R) inhibitor (e.g., sarilumab), IL-4R inhibitor (e.g., dupilumab), IL-10 inhibitor, cytokines such as IL-2, IL-7, IL-21, and IL-15, antibody-drug conjugate (ADC) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC), chimeric antigen receptor T cell (e.g., CD19-targeted T cell), anti-inflammatory drug (e.g., corticosteroid, and non-steroidal anti-inflammatory drug), and nutritional supplement such as antioxidant.

[0082] In certain embodiments, the method of the invention comprises administering an anti-PD-1 antibody in combination with radiation therapy and optionally an anti-GITR antibody to produce a long-lasting anti-tumor response and / or enhance the survival of cancer patients. In some embodiments, the method of the invention administers an anti-PD-1 antibody and an anti-GITR antibody to a cancer patient before, simultaneously with, or after the administration of comprising administering radiotherapy. For example, radiotherapy can be administered at one or more doses to a tumor lesion after administration of one or more doses of an antibody. In some embodiments, radiotherapy can be locally administered to a tumor lesion to enhance the local immunogenicity of a patient's tumor (adjuvinating radiotherapy) and / or to kill tumor cells (ablative radiotherapy) after systemic administration of an anti-PD-1 antibody and / or an anti-GITR antibody. In certain embodiments, radiotherapy is administered to a first tumor lesion but not to a second tumor lesion, where administration in combination with an anti-PD-1 antibody results in tumor regression in both the first and second tumor lesions (abscopal effect). In certain embodiments, the methods of the invention comprise administering an anti-PD-1 antibody in combination with radiotherapy and optionally an anti-GITR antibody to produce a long-term abscopal effect.

[0083] In certain embodiments, the anti-PD-1 antibody can be administered in combination with radiotherapy and a chemotherapeutic agent (e.g., temozolomide or cyclophosphamide), a VEGF antagonist (e.g., aflibercept), or granulocyte macrophage colony-stimulating factor.

[0084] Pharmaceutical Compositions and Administration The invention includes methods comprising administering an anti-PD-1 antibody to a subject in combination with radiation, wherein the anti-PD-1 antibody is contained within a pharmaceutical composition. The pharmaceutical compositions of the invention can be formulated using suitable carriers, excipients, and other agents that provide for appropriate delivery, transport, resistance, etc. Numerous suitable formulations can be found in formularies known to all pharmacists: 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 (e.g., LIPOFECTIN TM) DNA conjugates, anhydrous absorption pastes, water-in-oil and oil-in-water emulsions, carbowax emulsions (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0085] A variety of delivery systems are known and can be used to administer the pharmaceutical compositions of the present invention, for example, encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, receptor-mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by absorption through epithelial or mucosal linings (e.g., oral mucosa, rectal and intestinal mucosa) by any convenient route, for example, by injection or bolus injection, and can be administered together with other biologically active agents.

[0086] The pharmaceutical compositions of the present invention can be delivered subcutaneously or intravenously using standard needles and syringes. Further, with respect to subcutaneous delivery, pen-type delivery devices are readily useful in the delivery of the pharmaceutical compositions of the present invention. Such pen-type delivery devices can be reusable or disposable. Reusable pen delivery devices generally utilize replaceable cartridges containing the pharmaceutical composition. When all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen-type delivery device can then be reused. Disposable pen-type delivery devices do not have replaceable cartridges. Rather, The disposable pen-type delivery device is pre-filled with a pharmaceutical composition held in a reservoir within the device. When the pharmaceutical composition is emptied from the reservoir, the entire device is discarded.

[0087] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump can be used. In another embodiment, a polymeric material can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed in the vicinity of the target of the composition and thus requires 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.

[0088] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, infusions, etc. These injectable preparations can be manufactured by known methods. For example, an injectable preparation can be manufactured by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous medium or an oily medium conventionally used for injection. Examples of the aqueous medium for injection include isotonic solutions containing physiological saline, glucose, and other adjuvants, and these can be used in combination with appropriate solubilizing agents such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of the oily medium include sesame oil, soybean oil, etc., and these can be used in combination with solubilizing agents such as benzyl benzoate, benzyl alcohol. Therefore, the injection is preferably filled into appropriate ampoules.

[0089] Advantageously, the pharmaceutical compositions for the above oral or parenteral use are manufactured in dosage forms with unit doses adapted to the dose of the active ingredient. Examples of such dosage forms with unit doses include tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0090] In certain embodiments, the present invention provides a pharmaceutical preparation comprising a therapeutically effective amount of an anti-PD-1 antibody and a pharmaceutical carrier. In certain embodiments, the present invention provides an anti-PD-1 antibody formulated in a pharmaceutical composition for use in intravenous administration.

[0091] Dosing regimen The present invention includes a method comprising administering an anti-PD-1 antibody to a subject at a dosing frequency of about 4 times per week, 2 times per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, or at a frequency below that as long as a therapeutic response is achieved. In certain embodiments, the method comprises administering the anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) at a dosing frequency of about 2 times per week, once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 8 weeks, once every 9 weeks, once every 12 weeks, or at a frequency below that as long as a therapeutic response is achieved.

[0092] In certain embodiments, the method of the present invention comprises administering radiation therapy, wherein the radiation therapy is a hypofractionated irradiation method. In certain embodiments, the hypofractionated irradiation method comprises 2 to 12 fractional doses. In certain embodiments, the 2 to 12 fractional doses are administered on consecutive days. In certain embodiments, the radiation therapy is administered after administering 1 or more doses of the anti-PD-1 antibody. In certain embodiments, the anti-PD-1 antibody is administered 0.5 to 2 weeks before the administration of 1 or more fractional doses of the radiation therapy. In certain embodiments, the anti-PD-1 antibody is administered 0.5 to 2 weeks before the administration of 1 or more fractional doses of the radiation therapy.

[0093] According to certain embodiments of the present invention, multiple doses of an anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) can be administered to a subject over a defined period of time. Methods according to this aspect of the invention include continuously administering to a subject one or more doses of an anti-PD-1 antibody in combination with one or more doses of a second anti-tumor therapy. As used herein, "continuously administering" means that each dose of the antibody is administered to the subject at different times, e.g., on different days separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). In certain embodiments, the method of the invention includes continuously administering one or more doses of an anti-PD-1 antibody, where each dose is administered 0.5 to 12 weeks after the previous dosing. In certain further embodiments, the method further includes administering a second anti-tumor therapy (e.g., chemotherapy). In certain embodiments, the chemotherapy can be platinum-based chemotherapy. In certain embodiments, the method further includes administering one or more doses of chemotherapy, where each dose is administered 1 to 6 weeks after the previous dosing.

[0094] In certain embodiments, the present invention includes a method comprising continuously administering to a 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 one or more tertiary doses of the anti-PD-1 antibody thereafter. In certain embodiments, the method further comprises continuously administering to the patient a single initial dose of chemotherapy, followed by one or more secondary doses of chemotherapy, and optionally one or more tertiary doses of chemotherapy thereafter. The terms "initial dose," "secondary dose," and "tertiary dose" refer to the chronological order of administration. Thus, an "initial dose" is the dose administered at the start of the treatment regimen (also referred to as the "baseline dose"); a "secondary dose" is the dose administered after the initial dose; and a "tertiary dose" is the dose administered after the secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of antibody (anti-PD-1 antibody). However, in certain embodiments, the amounts contained in the initial, secondary, and / or tertiary doses are different from each other during the course of the treatment (e.g., adjusted up or down as needed). In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5) doses are administered as a "loading dose" at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., a "maintenance dose"). For example, the anti-PD-1 antibody can be administered to a cancer patient at a loading dose of about 1-3 mg / kg of the patient's body weight, followed by one or more maintenance doses of about 0.1-about 20 mg / kg of the patient's body weight.

[0095] In one exemplary embodiment of the invention, each secondary and / or tertiary dose is 1 / 2 to 14 (e.g., 1 / 2, 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1 It is administered after 1 (alternatively 2, 3, 4, 5, 6, 7, 8, or more) week(s) after the immediately preceding dose. As used herein, the phrase "immediately preceding dose" means the dose of the anti-PD-1 antibody (and optionally, the second anti-tumor therapy) administered to a patient immediately prior to the administration of the very next dose without intervening doses in a series of multiple administrations.

[0096] The method according to this aspect of the invention may include administering to the patient any number of secondary and / or tertiary doses of either the anti-PD-1 antibody (and / or the second anti-tumor therapy). For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, 2 or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Similarly, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, 2 or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0097] In embodiments comprising 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 after the immediately preceding dose. Similarly, in embodiments comprising 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 after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to the patient may vary over the course of the treatment regimen. The dosing frequency may also be adjusted by the physician depending on the needs of the individual patient after clinical examination during the course of the treatment.

[0098] In certain embodiments, one or more doses of the anti-PD-1 antibody and / or the second anti-tumor therapy are administered more frequently (twice a week, once a week, or once every two weeks) as a "loading dose" at the start of treatment, followed by subsequent doses (the "consolidation doses" or "maintenance doses") being administered less frequently (e.g., once every 2 to 12 weeks). In certain embodiments, one or more doses of the anti-PD-1 antibody and / or radiation are administered more frequently (twice a week, once a week, or once every two weeks) as a "loading dose" at the start of the treatment regimen, followed by subsequent doses of the anti-PD-1 antibody being administered.

[0099] The present invention includes methods comprising continuously administering one or more doses of an anti-PD-1 antibody in combination with one or more doses of a further anti-tumor therapy, wherein the one or more doses are included in one or more treatment cycles.

[0100] According to certain embodiments of the present invention, the method comprises administering in at least one treatment cycle, wherein the at least one treatment cycle comprises administering one or more doses of an anti-PD-1 antibody and optionally one or more doses of a second anti-tumor therapy (e.g., chemotherapy, radiation). In certain embodiments, the treatment cycle comprises 1 to 10 doses of the anti-PD-1 antibody, wherein each dose of the anti-PD-1 antibody is administered 0.5 to 8 weeks after the previous dosing. In certain embodiments, the method of the present invention comprises administering up to 6 or 8 treatment cycles. In certain other embodiments, the method of the present invention comprises up to 100 treatment cycles, or more administrations as needed for a therapeutic effect. In certain embodiments, the at least one treatment cycle further comprises a second anti-tumor therapy (e.g., chemotherapy). In some embodiments, the chemotherapy is platinum-based chemotherapy. In certain embodiments, the doses of chemotherapy are administered once a week, once every two weeks, once every three weeks, once every four weeks or more.

[0101] The present invention includes methods comprising the sequential administration of an anti-PD-1 antibody in combination with chemotherapy to treat cancer (e.g., lung cancer) to produce increased antitumor efficacy (e.g., higher inhibition of tumor growth, increased prevention of tumor recurrence as compared to an untreated subject or a subject administered either an antibody or chemotherapy as monotherapy). In some embodiments, the chemotherapy is administered before, after, or simultaneously with the anti-PD-1 antibody.

[0102] Dosage The amount of anti-PD-1 antibody administered to a subject according to the methods of the invention is generally a therapeutically effective amount. As used herein, the term "therapeutically effective amount" means an amount of an antibody (anti-PD-1 antibody) that produces one or more of: (a) a decrease in the severity or duration of symptoms or signs of cancer, e.g., solid tumors; (b) inhibition of tumor growth, or an increase in tumor necrosis, tumor shrinkage and / or tumor disappearance; (c) delay in tumor growth and development; (d) inhibition of tumor metastasis; (e) prevention of recurrence of tumor growth; (f) an increase in the survival of a subject having cancer; and / or (g) a decrease in the use or need for conventional anti-cancer therapies (e.g., a decreased or eliminated use of chemotherapy or cytotoxic agents) as compared to an untreated subject or a subject administered an antibody as monotherapy. Means.

[0103] In the case of an anti-PD-1 antibody, a therapeutically effective amount can be from about 0.05 mg to about 1500 mg, from about 1 mg to about 1500 mg, from about 10 mg to about 1400 mg, from about 50 mg to about 1400 mg, from about 75 mg to about 1400 mg, or from about 100 mg to about 1300 mg of the antibody. For example, in various embodiments, the amount of the anti-PD-1 antibody is about 0.05 mg, about 0.1 mg, about 1.0 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 150 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1400 mg, or about 1500 mg of the anti-PD-1 antibody. In one embodiment, 250 mg of the anti-PD-1 antibody is administered according to the method of the present invention. In one embodiment, 200 mg of the anti-PD-1 antibody is administered according to the method of the present invention. In one embodiment, 350 mg of the anti-PD-1 antibody is administered according to the method of the present invention. In one embodiment, 1050 mg of the anti-PD-1 antibody is administered according to the method of the present invention.

[0104] The amount of the anti-PD-1 antibody contained within an individual dose can be expressed as milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). In certain embodiments, the anti-PD-1 antibody used in the method of the present invention can be administered to a subject at a dose of about 0.0001 to about 100 mg / kg of the subject's body weight. In certain embodiments, the anti-PD-1 antibody can be administered at a dose of about 0.1 mg / kg of the patient's body weight to about 20 mg / kg of the patient's body weight. In certain embodiments, the method of the present invention includes administration of the anti-PD-1 antibody at a dose of about 1 mg / kg of the patient's body weight, 3 mg / kg of the patient's body weight, 5 mg / kg of the patient's body weight, or 10 mg / kg of the patient's body weight.

[0105] In certain embodiments, the amount of anti-PD-1 antibody administered to a patient may be less than a therapeutically effective amount, i.e., a sub-therapeutic dose. For example, if the therapeutically effective amount of the anti-PD-1 antibody includes 3 mg / kg, a sub-therapeutic dose includes an amount less than 3 mg / kg, such as, for example, 2 mg / kg, 1.5 mg / kg, 1 mg / kg, 0.5 mg / kg, or 0.3 mg / kg. As defined herein, a "sub-therapeutic dose" refers to an amount of anti-PD-1 antibody that does not, by itself, produce a therapeutic effect. However, in certain embodiments, a sub-therapeutic dose of the anti-PD-1 antibody is administered in combination with a second and optionally a third therapeutic agent to promote a therapeutic effect.

Example

[0106] The following examples are presented in order to provide a complete disclosure and description of how to make and use the methods and compositions of the invention to those skilled in the art and are not intended to limit the scope that the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental error and deviation should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0107] Example 1: In Vivo Efficacy of Anti-PD-1 Antibody in Combination with Radiation Therapy against MC38 Tumors In this example, the effect of PD-1 blockade in combination with radiation therapy was tested against established MC38 tumors in mice.

[0108] 5x10 5 MC38 colon cancer cells were subcutaneously implanted into the right flank of female C57BL / 6 mice (Jackson Laboratory). When the average tumor volume reached approximately 100 mm 3Treatment was initiated 9 days after transplantation when the tumor reached a certain size. For a total of 5 intraperitoneal injections, mice were randomly assigned to receive either an isotype control (2A3, BioXcell) or a PD-1 blocking antibody (RMP1-14, BioXCell) at 5 mg / kg, twice a week. One day after the start of antibody treatment, mice assigned to the radiotherapy group received 12 Gy of irradiation to the right flank tumor. Radiotherapy was delivered using an RS 2000 Biological Research Irradiator (Rad Source) to anesthetized mice (ketamine / xylazine) shielded with a partial body irradiation fixture (Precision X-ray) and a lead sheet (Images Scientific Instruments). Tumor growth was evaluated three times a week until day 70 - 80 when all mice were euthanized. Figure 1 shows the study design of the experiment, which includes the administration of anti-PD-1 antibody and radiation.

[0109] Figures 2 and Table 1 show the mean tumor volumes in mice administered anti-PD-1 antibody alone or in combination with radiation.

[0110]

Table 1

[0111] PD-1 (RMP1-14) blockade synergized with local irradiation (XRT) and significantly induced tumor regression in MC38 tumor-bearing mice (4 / 6 mice) compared to XRT + isotype control-treated mice (2 / 6 mice). Tumor growth was inhibited or delayed in mice treated with anti-PD-1 antibody in combination with radiation. It took less than 20 days to reach a tumor volume of 500 mm 3 Compared to mice receiving monotherapy that took less than 20 days to reach a tumor volume of 500 mm, mice treated with anti-PD-1 antibody and radiation 3It took more than 40 days to reach the tumor volume. For the XRT + isotype treatment group (1 out of 2 mice was excluded, tumor recurrence), tumor regression persisted until 4 weeks for the combination (XRT + anti-PD-1 antibody) treatment group (1 out of 4 mice had tumor recurrence at this time point and was excluded) for 1.5 weeks. In this tumor model, PD-1 blockade as a monotherapy had no effect on primary tumor growth.

[0112]

Table 2

[0113] The therapeutic efficacy of the combination treatment (XRT + anti-PD-1 antibody) was demonstrated by the statistically increased overall survival of this group compared to all other treatment groups (50% survival 70 days after tumor transplantation): isotype control (0% survival on day 70), anti-PD-1 antibody treatment (0% survival on day 70), and XRT + isotype treatment mice (17% survival on day 70) (Figure 3; Table 2).

[0114] Example 2: In Vivo Efficacy of Anti-PD-1 Antibody and Radiation Against B16 Tumors In this example, the antitumor effect of an anti-mouse PD-1 antibody in combination with radiotherapy was examined against established B16 tumors in mice.

[0115] 2x10 5 B16F10.9 melanoma cells were subcutaneously transplanted into the right flank of female C57BL / 6 mice (Jackson Laboratory). The average tumor volume was approximately 150 mm 3Treatment was initiated when [the relevant condition] was reached. Mice were randomly assigned to receive either isotype control (2A3, BioXcell) or PD-1 blocking antibody (RMP1-14, BioXCell) at 5 mg / kg twice a week for a total of 5 intraperitoneal injections. One day after the start of antibody treatment, mice assigned to the radiotherapy group received 8 Gy of irradiation to their right flank tumors. Radiotherapy was delivered using an RS 2000 Biological Research Irradiator (Rad Source) to anesthetized (ketamine / xylazine) mice shielded with a partial body irradiation fixture (Precision X-ray) and a lead sheet (Images Scientific Instruments). Tumor growth was evaluated three times a week until day 70 - 80 when all mice were euthanized. Figure 4 shows the study design of the experiment including the dosing of anti-PD-1 antibody and radiation.

[0116] Treatment with a PD-1 (RMP1-14) blocking antibody in combination with local irradiation (XRT) delayed B16 primary tumor growth compared to XRT or anti-PD-1 antibody monotherapy (Figure 5; Table 3).

[0117]

Table 3

[0118]

Table 4

[0119] The combination treatment of XRT and anti-PD-1 antibody increased overall survival (50% survival 50 days after transplantation) compared to XRT alone (0% survival by day 50), anti-PD-1 antibody alone (0% survival by day 40), and isotype alone (0% survival by day 30) (Figure 6; Table 4).

[0120] Example 3: In Vivo Efficacy of Anti-PD-1 Antibody in Combination with Radiotherapy against Metastatic Lung Tumors In this example, the effect of PD-1 blockade in combination with radiotherapy was examined against established metastatic tumors in mice.

[0121] 1.5x10 5 4T1 breast cancer cells were subcutaneously implanted into the right flank of female Balb / c mice (Jackson La boratory). Treatment was initiated 12 days after implantation when the average tumor volume reached approximately 100 mm 3 . Mice were randomly assigned to a total of 5 intraperitoneal injections at 5 mg / kg twice a week with either an isotype control (2A3, BioXcell) or a PD-1 blocking antibody (RMP1-14, BioXCell). One day after the start of antibody treatment, mice assigned to the radiotherapy group received 8 Gy of irradiation to their right flank tumors. Radiotherapy was delivered using an RS 2000 Biological Research Irradiator (Rad Source) to anesthetized mice (ketamine / xylazine) shielded with a partial body irradiation fixture (Precision X-ray) and lead sheets (Images Scientific Instruments). Tumor growth was evaluated three times a week until day 28 when all mice were euthanized to assess the lung metastasis burden using a colony formation assay. Briefly, lung tissue was isolated using DNAse / Ribonuclease TL (Roche) and cultured in medium supplemented with 60 uM 6-thioguanine. After 2 weeks of culture, plates were counterstained with methylene blue and the number of colonies was counted (one colony represents one metastatic 4T1 cell).

[0122] Treatment with an anti-PD-1 antibody in combination with radiation is expected to promote tumor regression and further mediate the suppression of metastatic growth.

[0123] Example 4: The in vivo efficacy of an anti-human PD-1 antibody in combination with radiotherapy promotes the abscopal effect on distal tumors In this example, the effect of PD-1 blockade in combination with radiation therapy was examined in humanized mice for PD-1 using an anti-human PD-1 antibody against primary distal MC38 tumors.

[0124] The exemplary anti-PD-1 antibody used in this example is REGN2810 (also called H4H7798N as disclosed in US20150203579), a full human monoclonal anti-PD-1 antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[0125] Mice humanized for PD-1 were engineered using VelociGene (R) technology (Valenzuela et al 2003, Nat. Biotechnol. 21:652-659; US Patent Application Publication No. 2015 / 0366174).

[0126] 5x10 5 MC38 colon cancer cells were subcutaneously implanted into female humanized PD-1 / C57BL / 6 mice on day 0 (primary tumor in the right flank) and day 3 (tumor in the left flank; distal tumor). The average primary tumor volume was approximately 150 mm 3Treatment was initiated when [the relevant condition] was reached. For a total of 8 intraperitoneal injections, mice were randomly assigned to receive either an isotype control or the PD-1 blocking antibody (REGN2810) at 5 mg / kg, twice a week. One day after antibody treatment, mice assigned to the radiation group received 8 Gy of irradiation to their right flank tumors. Radiation therapy was delivered using an RS 2000 Biological Research Irradiator (Rad Source) to anesthetized mice (ketamine / xylazine) shielded with a partial body irradiation fixture (Precision X-ray) and a lead sheet (Images Scientific Instruments). Primary and metastatic tumor growth was evaluated three times a week until days 70 - 80 when all mice were euthanized. Figure 7 shows the study design of the experiment including administration of the anti-PD-1 antibody and radiation.

[0127] Results Primary tumor: PD-1 blockade (REGN2810) treatment provided a synergistic effect with local irradiation (XRT) in the rejection of the primary MC38 tumor compared to XRT + isotype control-treated mice (1 / 6 tumor-free mice) (4 out of 6 tumor-free mice). Tumor regression persisted for 8 weeks until the end of the experiment in the combination treatment group compared to 3 weeks for the XRT + isotype treatment group (at which point the rejected tumors recurred) (Figure 8; Table 5).

[0128] [Table 5]

[0129] PD-1 blockade as monotherapy mediated rejection in 2 out of 5 mice; however, 1 out of the mice that rejected the primary tumor died of metastatic tumor growth and only 1 mouse survived until the end of the experiment. The potential therapeutic efficacy of the combination treatment (XRT+REGN2810) was demonstrated by significantly increased overall survival (approximately 67% survival 70 days after implantation), compared to all other groups: isotype control or XRT alone (0% survival at day 70), and REGN2810 as monotherapy (20% survival at day 70) (Figure 9; Table 6).

[0130]

Table 6

[0131] Distal tumor: REGN2810 in combination with XRT significantly promoted the abscopal effect in 5 out of 6 tumor-free mice (rejection of tumors implanted at distal sites), compared to XRT alone (2 / 6 without distal tumors), REGN2810 alone (1 / 6 without distal tumors), and isotype control-treated mice (1 / 6 without distal tumors) (Figure 10; Table 7).

[0132]

Table 7

[0133] Example 5: In Vivo Efficacy of Anti-PD-1 Antibody in Combination with Radiation and GITR Antagonist Against MC38 Tumors In this example, the effect of PD-1 blockade in combination with radiotherapy and glucocorticoid-induced tumor necrosis factor receptor (GITR) antagonist (anti-GITR antibody) was investigated against large established MC38 tumors in mice.

[0134] 5x10 5 MC38 colon cancer cells were subcutaneously implanted into the right flank of female C57BL / 6 mice (Jackson Laboratory). When the average tumor volume was approximately 150 - 200 mm 3Treatment was initiated when tumors reached those classified as "large tumors." For a total of five intraperitoneal injections, mice were randomly assigned to receive either an isotype control antibody (2A3 or LTF-2; BioXcell), an anti-PD-1 antibody (RMP1-14; BioXcell), an anti-GITR antibody (DTA-1; BioXcell), or a combination of both the anti-PD-1 and anti-GITR antibodies, at 5 mg / kg twice a week. One day after the start of antibody treatment, mice assigned to the radiotherapy group received 8 Gy of irradiation to the right flank tumor. Radiotherapy was delivered to anesthetized mice (ketamine / xylazine) shielded with a partial body irradiation fixture (P recision X-ray) and lead sheets (Images Scientific Instruments) using an RS 2000 Biological Research Irradiator (Rad Source). Tumor growth was evaluated three times a week until day 70 - 80, when all mice were euthanized. Figure 11 shows the study design of an experiment involving the administration of an anti-PD-1 antibody, an anti-GITR antibody, and radiation.

[0135] Treatment with the anti-PD-1 antibody (RMP1-14) provided a synergistic effect with local irradiation (XRT) and the anti-GITR antibody in the rejection of large MC38 tumors (4 out of 6 tumor-free mice) compared to XRT + anti-GITR antibody (2 / 6 tumor-free), XRT + anti-PD-1 antibody (2 / 6 rejection), or XRT alone (0 / 6 tumor-free) treated mice. Monotherapy (using either the anti-PD-1 or anti-GITR antibody) or combination treatment (anti-PD-1 antibody + anti-GITR antibody) had a minimal effect mediating rejection in 1 / 5 mice against tumor growth using the anti-PD-1 or anti-GITR antibody, and the combination of the two antibodies mediated rejection in 2 / 5 mice. Tumor regression persisted for two weeks for XRT + anti-GITR antibody treated mice and up to 6.5 weeks after the start of treatment for triple combination treated mice (Figure 12).

[0136]

Table 8

[0137] Table 8 and Figure 13 show the survival of mice administered an anti-PD-1 antibody in combination with radiotherapy and an anti-GITR antibody. Furthermore, administration of the anti-PD-1 antibody + XRT resulted in tumor regression of very large tumors (about 300 mm 3 ).

[0138] Example 6: In Vivo Efficacy of an Anti-PD-1 Antibody in Combination with Radiotherapy and a GITR Antagonist against B16 Tumors In this example, the effect of PD-1 blockade in combination with radiotherapy and a GITR antagonist (anti-GITR antibody) was examined against established B16 tumors in mice.

[0139] 2.5x10 5 B16F10.9 melanoma cells were subcutaneously implanted into the right flank of female C57BL / 6 mice (Jackson Laboratory). Treatment was initiated when the average tumor volume reached approximately 100 mm 3 . For five intraperitoneal injections, mice were randomly assigned to receive either an isotype control (2A3, LTF-2; BioXcell), an anti-PD-1 antibody (RMP1-14, BioXcell), an anti-GITR antibody (DTA-1; BioXcell), or a combination of both the anti-PD-1 antibody and the anti-GITR antibody at 5 mg / kg twice a week. One day after the start of antibody treatment, mice assigned to the radiotherapy group received 8 Gy of irradiation to the right flank tumor. Radiotherapy was delivered to anesthetized mice (ketamine / xylazine) shielded with a partial body irradiation fixture (Precision X-ray) and a lead sheet (Images Scientific Instruments) using an RS 2000 Biological Research Irradiator (Rad Source). Tumor growth was evaluated three times a week until days 70 - 80 when all mice were euthanized.

[0140] Anti-GITR antibody and anti-PD-1 antibody in combination with radiotherapy are expected to promote more tumor regression and delay tumor growth than anti-PD-1 antibody alone or in combination with radiotherapy.

[0141] Example 7: Clinical Trial of Anti-PD-1 Antibody and Radiotherapy in Patients with Progressive Solid Tumors This study is an open-label, multi-center, dose-escalation trial using multiple-dose escalation and expansion arms to investigate the efficacy, safety, and tolerability of anti-PD-1 antibody alone and in combination with other anti-cancer therapies (including radiotherapy) in adult patients with progressive solid tumors.

[0142] The anti-PD-1 antibody used as an example in this study is REGN2810 (also known as H4H7798N disclosed in US20150203579), a fully human monoclonal anti-PD-1 antibody containing a heavy chain with the amino acid sequence of SEQ ID NO: 9 and a light chain with the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair containing SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences containing SEQ ID NOs: 3-8.

[0143] Study Objectives The primary objective of the study is to characterize the safety, tolerability, and dose-limiting toxicity (DLT) of REGN2810 administered intravenously (IV) as a single agent or in combination with targeted radiotherapy (intended mainly as immune activation rather than tumor resection therapy), low-dose cyclophosphamide (a therapy shown to inhibit regulatory T cell responses), granulocyte macrophage colony-stimulating factor, carboplatin, docetaxel, or combinations thereof in patients with progressive malignancies.

[0144] The secondary objectives of the study are: (1) to determine the recommended Phase 2 dose (RP2D) of REGN2810 as monotherapy and in combination with other anti-cancer therapies (targeted radiation, low-dose cyclophosphamide, or both); (2) to characterize the preliminary anti-tumor activity of REGN2810 alone and with each combination partner; (3) to characterize the PK of REGN2810 as monotherapy and in combination with other anti-cancer therapies (targeted radiation, low-dose cyclophosphamide, or both); and (4) to evaluate the immunogenicity of REGN2810.

[0145] Rationale for Study Design The 3+3 model for the dose escalation phase of this study is designed to allow assessment of the safety of REGN2810 as monotherapy at various dose levels and in combination with immune-boosting treatments: cyclophosphamide; limited targeted radiation delivered in one of two dosing regimens; or a combination of radiation and cyclophosphamide.

[0146] Once the tolerability of REGN2810 is established alone and in combination with radiation and / or cyclophosphamide, multiple expansion cohorts using various combinations or monotherapy in selected indications [NSCLC, BC, HNSCC, CSCC, tumors with MSI (colorectal, endometrial, prostate, or other tumor types), HCC, and other progressive solid tumors] are added to further confirm safety and to evaluate increased anti-tumor activity. Granulocyte macrophage colony-stimulating factor (GM-CSF), carboplatin and / or docetaxel are added to some of these combinations.

[0147] Table 9 lists some of the cohorts using REGN2810 as monotherapy and in combination with other treatment modalities.

[0148] [Table 9] [Table 10]

[0149] The initially planned treatment for REGN2810 is every 14 days until 48 weeks and a 24-week follow-up observation. Radiation is administered 1 week after the first dose of REGN2810. Low-dose cyclophosphamide is administered to patients assigned to cyclophosphamide 1 day prior to each of the first 4 doses of REGN2810.

[0150] Study period Patients receive treatment until 48 weeks, followed by a 24-week follow-up observation period. Patients receive treatment until the 48-week treatment period is completed or until disease progression, unacceptable toxicity, withdrawal of consent, or another study discontinuation criterion is met. Patients who have achieved a complete remission (CR) confirmed after at least 24 weeks of treatment may choose to discontinue treatment and continue all related study evaluations (e.g., efficacy evaluations). Patients with a stable disease (SD) or partial response (PR) tumor burden assessment that has not changed between three consecutive tumor evaluations after at least 24 weeks of treatment may also choose to discontinue treatment and continue all related study evaluations (e.g., efficacy evaluations).

[0151] Study population The target population for this study includes patients with progressive malignancies who are not candidates for standard treatment, do not wish to receive standard treatment, or for whom no available treatment is expected to provide clinical benefit; and patients with malignancies that are refractory and have not been able to respond or have shown tumor progression despite standard treatment.

[0152] Inclusion criteria:Patients must meet the following criteria to be eligible for inclusion in the study: (1) Proven progression of solid tumors for which no alternative standard treatment options are available; (2) At least one lesion for response assessment. Patients assigned to radiation therapy require at least one additional lesion that can be safely irradiated while sparing the index lesion and for which radiation at a limited symptomatic dose considered for it is thought to be medically appropriate; (3) Patients must have relapsed or been refractory after first-line treatment (and up to two prior lines of treatment) in a recurrent or metastatic disease setting and must not have a disease for which conventional radiation therapy is supported; (4) Patients with metastatic cancer having microsatellite instability (MSI) that was refractory up to two prior lines of treatment; (5) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1; (6) Age ≥ 18 years; (7) Liver function: a. Total bilirubin ≤ 1.5 x upper limit of normal (ULN; ≤ 3 x ULN in case of liver metastases), b. Transaminases ≤ 3 x ULN (or ≤ 5.0 x ULN in case of liver metastases), c. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (or 5.0 x ULN in case of liver metastases); (8) Renal function: Serum creatinine ≤ 1.5 x ULN; (9) Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L, c. Platelet count ≥ 75 x 10 9 / L; (10) Ability to provide signed informed consent; and (11) Ability and willingness to comply with scheduled clinic visits, treatment plans, laboratory tests, and other study-related procedures.

[0153] Study Treatment REGN2810 is supplied as a liquid in a sterile single-use vial. Each vial contains a volume sufficient to withdraw 10 mL of REGN2810 at a concentration of 25 mg / mL. REGN2810 is administered in an outpatient setting as a 30-minute intravenous (IV) infusion. The dose for each patient depends on the individual body weight. The dose of REGN2810 is adjusted for each cycle for a body weight change of ≥ 10%. REGN2810 is administered alone or in combination with radiation and / or cyclophosphamide. Cyclophosphamide is administered at 200 mg / m2 or as a low dose (100 mg / m2).

[0154] Monotherapy REGN2810 is administered every 14 days for 48 weeks over 30 minutes by IV infusion in an outpatient setting (i.e., a 56-day cycle on days 1, 15 ± 3, 29 ± 3, and 43 ± 3). The planned monotherapy regimens to be assigned are: (i) 1 mg / kg IV infusion over 30 minutes every 14 days for 48 weeks; (ii) 3 mg / kg infusion over 30 minutes every 14 days for 48 weeks; (iii) 10 mg / kg infusion over 30 minutes every 14 days for 48 weeks; (iv) 0.3 mg / kg infusion over 30 minutes every 14 days for 48 weeks (if the MTD is determined to be less than 1 mg / kg); and (v) may include a fixed dose of 200 mg IV infusion over 30 minutes every 14 days for 48 weeks.

[0155] Combination therapy Concurrent radiation therapy, cyclophosphamide, GM-CSF, carboplatin, and docetaxel are supplied through the prescription, and their utilization, dose, dose modification, reduction, or delay, and further AEs that may result from their use are tracked together with REGN2810.

[0156] Co-administration of REGN2810 and radiation : REGN2810 is administered by IV infusion over 30 minutes every 14 days for 48 weeks in combination with radiation treatment on days 8 to 12. The planned combination REGN2810 and radiation therapy regimens are: · Administration of 1 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks, and 30 Gy radiotherapy (6 Gy × 5 times / week; administered preferably on consecutive days, 1 week after the first dose of REGN2810) · Administration of 1 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks, and 27 Gy radiotherapy (9 Gy × 3 times / week; administered preferably on consecutive days, 1 week after the first dose of REGN2810) · Administration of 3 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks, and 30 Gy radiotherapy (6 Gy × 5 times / week; administered preferably on consecutive days, 1 week after the first dose of REGN2810) · Administration of 3 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks, and 27 Gy radiotherapy (9 Gy × 3 times / week; administered preferably on consecutive days, 1 week after the first dose of REGN2810) may be included.

[0157] Patients receive either 30 Gy given as a 5 - fraction dose of 6 Gy administered daily starting 1 week after the first dose of REGN2810, or 27 Gy given as a 3 - fraction dose of 9 Gy administered every other day starting 1 week after the first dose of REGN2810. The lesions selected for radiation should be lesions that can be safely irradiated by focal irradiation while sparing the target lesion and for which radiation at the limited symptomatic dose considered for them is considered medically appropriate.

[0158] Co-administration of REGN2810 and cyclophosphamide : REGN2810 is administered by intravenous infusion over 30 minutes every 14 days (2 weeks) in combination with low - dose cyclophosphamide 100 mg / m2 IV infusion every 14 days for 4 doses. Each of the 4 cyclophosphamide doses is administered 1 day before each of the first 4 REGN2810 doses (days - 1, 14, 28, and 42 of the first 56 - day cycle).

[0159] The planned combination of REGN2810 and cyclophosphamide regimen is: · Cyclophosphamide 100 mg / m2 or 200 mg / m2 IV every 14 days for a total of 4 doses (on days -1, 14, 28, and 42 of the first 56-day cycle); and · REGN2810 infusion at 3 mg / kg over 30 minutes every 14 days for 48 weeks (however, if the single-agent dose 3 mg / kg < MTD; 3 mg / kg > MTD, the dose is 1 mg / kg is).

[0160] Co-administration of REGN2810, radiation and cyclophosphamide : The planned combination of REGN2810, radiation, and cyclophosphamide regimen is: · Cyclophosphamide 100 mg / m2 (low dose) IV every 14 days for a total of 4 doses (on days -1, 14, 28, and 42 of the first 56-day cycle); and · 27 Gy radiotherapy (9 Gy × 3 times / week; 7 or 8 days after the first dose of REGN2810, preferably on non-consecutive days) or 30 Gy radiotherapy (6 Gy × 5 times / week; 7 or 8 days after the first dose of REGN2810, preferably on consecutive days); and · REGN2810 infusion at 3 mg / kg over 30 minutes every 14 days for 48 weeks (however, if the single-agent dose 3 mg / kg < MTD; 3 mg / kg > MTD, the dose is 1 mg / kg is included.

[0161] Co-administration of REGN2810, radiation and GM-CSF : The planned combination of REGN2810, radiation, and GM-CSF regimen is: · GM-CSF 250 mcg SC daily for 7 days for 4 cycles (on days 1 - 7, 15 - 21, 29 - 35, and 43 - 49 of the first 56-day cycle); and · 27 Gy radiotherapy (9 Gy × 3 times / week; given 1 week after the first dose of REGN2810, preferably on non-consecutive days); and · Infusion of 3 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks (however, if the monotherapy dose of 3 mg / kg < MTD; 3 mg / kg > MTD, the dose is 1 mg / kg) including

[0162] Co-administration of REGN2810, radiation, GM-CSF and cyclophosphamide : The planned combination REGN2810, radiation, GM-CSF, and cyclophosphamide regimen is as follows: · For 4 seven-day intervals (days 1 - 7, 15 - 21, 29 - 35, and 43 - 49 of the first 56-day cycle), GM-CSF 250 mcg SC daily for 7 days ; and · 27 Gy radiotherapy (9 Gy × 3 times / week; given 1 week after the first dose of REGN2810, preferably on non-consecutive days); and · Cyclophosphamide 100 mg / m2 or 200 mg / m2 IV every 14 days for a total of 4 doses (days - 1, 14, 28, and 42 of the first 56-day cycle); and · Infusion of 3 mg / kg REGN2810 over 30 minutes every 14 days for 48 weeks (however, if the monotherapy dose of 3 mg / kg < MTD; 3 mg / kg > MTD, the dose is 1 mg / kg) including

[0163] Co-administration of REGN2810 and docetaxel with or without carboplatin : The proposed order of drug administration is docetaxel, followed by carboplatin (if enrolled in the carboplatin-containing cohort), followed by REGN2810. · Docetaxel 30 mg / m2 IV over approximately 1 hour on days 1, 8, 29, and 36 of the first 56-day cycle. Dexamethasone 8 mg IV is administered prior to the first dose of docetaxel. For subsequent docetaxel treatments, the dose of dexamethasone premedication may be 8 mg or 4 mg at the discretion of the principal investigator of the clinical trial. · On days 1, 8, 29, and 36 of the initial 56-day cycle, administer carboplatin AUC 2 IV over approximately 30 minutes. Carboplatin dosing should use the Calvert formula relative to the carboplatin label. Creatinine clearance should be calculated using the Cockcroft-Gault formula. · Infuse 3 mg / kg REGN2810 over approximately 30 minutes every 14 days for 48 weeks.

[0164] Procedures and Assessments The screening procedures to be performed include serum beta-HCG, brain MRI, and chest X-ray.

[0165] The safety procedures include medical history, physical examination, vital signs, electrocardiogram (ECG), coagulation, immune safety assay (for patients treated with REGN2810), assessment of B symptoms and performance status, clinical laboratory tests, AEs, and concomitant medications.

[0166] The efficacy procedures to be performed for tumor evaluation include CT or MRI scans, 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scans, and / or tumor biopsies. CT or MRI for tumor evaluation is performed at screening visit (within 28 days before infusion) and on days 56 ± 3 of each cycle (approximately every 8 weeks) during the entire cycle, and when disease progression is suspected. Additionally, for patients who do not progress to the study, tumor evaluation is performed at follow-up visits 3, 5, and 7. When the choice is made to use a CT scan or MRI, subsequent evaluations are performed using the same procedure. Tumor response evaluation is performed according to the Response Evaluation Criteria in Solid Tumors ) RECIST version 1.1 (Eisenhauer et al 2009, Eur.J.Cancer 45:228-247). Measurable lesions selected as target lesions for RECIST measurement are used as index lesions for immune-related response criteria (irRC; Nishino et al 2013, Clin.Cancer It is also included in (Res.19:3936 - 3943). The RECIST response is prioritized as a statistical evaluation of the response rate. For individual patients, the irRC can provide information for the decision of whether to continue treatment at the discretion of the principal investigator of the clinical trial due to the possibility of a negative response.

[0167] Collect blood samples for PK and anti - drug antibody (ADA) evaluation.

[0168] Research variables The primary variables in the study are the DLT incidence rate during 48 weeks of treatment, as well as the incidence rate and severity of TEAE and abnormal test findings.

[0169] Secondary variables are: · Antitumor activity evaluated using appropriate criteria for the indication (described elsewhere in this specification): ∨ Response Evaluation Criteria in Solid Tumors (RECIST; Eisenhauer et al 2009, Eur.J.Cancer 45:228 - 247) criteria measured by CT or MRI ∨ Other evaluation criteria are also used for certain main ones where the RECIST scale is not the standard ∨ Immune - related response criteria (irRC; Nishino et al 2013, Clin.Cancer Res.19:3936 - 3943) applied to the RECIST scale. In all cases, RECIST (or other tumor - specific criteria) is the dominant tool for determining PD, SD, CR, or PR. The irRC is collected for clinical decision - making and information purposes. · Incidence rate of anti - REGN2810 antibody · Antitumor activity measured by PFS and overall survival are.

[0170] For the purpose of this trial, patients are re - evaluated for response every 8 weeks. A confirmatory scan is also obtained 4 weeks after the first documentation of an objective response or progressive disease. Response and progression are determined in this study according to the new guidelines for the evaluation of the treatment effect of solid tumors (revised Evaluated using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1; Eisenhauer et al 2009, Eur. J. Cancer 45:228-247). Changes in the maximum diameter of tumor lesions (one-dimensional measurement) and, in the case of malignant lymph nodes, the shortest diameter are used in the RECIST criteria.

[0171] Lesion selection Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or ≥10 mm (≥1 cm) with calipers by CT scan, MRI, or clinical examination. All tumor measurements must be recorded in millimeters (or decimals of a centimeter). Note: See below for the evaluation of radially extending lesions.

[0172] Malignant lymph nodes: For lymph nodes to be considered pathologically enlarged and measurable, they must be ≥15 mm (≥1.5 cm) in short axis when evaluated by CT scan (recommended CT scan slice thickness is greater than 5 mm [0.5 cm]). At baseline and during follow-up, only the short axis is measured and followed.

[0173] Non-measurable disease:All other lesions (or affected areas), including small lesions (pathological lymph nodes with a short axis of longest diameter < 10 mm [< 1 cm] or ≥ 10 to < 15 mm [≥ 1 to < 1.5 cm]), are considered non-measurable diseases. Bone lesions, leptomeningeal diseases, ascites, pleural / pericardial fluid collections, lymphangitis cutis / pneumonia, inflammatory breast diseases, and abdominal tumors (not followed by CT or MRI) are considered non-measurable. Note: Cystic lesions that meet the criteria for simple cysts as defined by X-ray examination are not to be considered malignant diseases by definition (neither measurable nor non-measurable) as they are simple cysts by definition. "Cystic lesions" considered to represent cystic metastases may be considered measurable lesions if they meet the above-mentioned measurability criteria. However, if non-cystic lesions are present in the same patient, they are preferably selected as target lesions.

[0174] Target lesion: All measurable lesions up to 2 lesions per organ, representing all included organs, and a total of 5 lesions are identified as target lesions and should be measured at baseline. Target lesions are selected based on their size (lesions with the longest diameter), representing all included organs, and further including those useful for reproducible repeated measurements. Sometimes, the largest lesion may not be useful for reproducible measurements, and in this situation, the next largest lesion that can be measured reproducibly is selected. Calculate the sum of the diameters (longest for non-nodular lesions, short axis for nodular lesions) for all target lesions and report it as the baseline total diameter. When including lymph nodes in the sum, only the short axis is added to the sum. The baseline total diameter is used as a reference to further characterize objective tumor regression in the measurable dimension of the disease.

[0175] Non-target lesion: All other lesions (or affected areas) that include any measurable lesions in addition to the 5 target lesions are identified as non-target lesions and recorded at baseline. Measurement of these lesions is not required, but their presence, absence, or, in rare cases, obvious progression is noted during follow-up.

[0176] Evaluation methods for measurable diseases All measurements were made and recorded in metric notation using a ruler or calipers. All baseline evaluations were performed as close as possible to the start of treatment, and not more than 4 weeks prior to the start of treatment. The same methods and techniques of evaluation should be used to characterize each identified and reported lesion at baseline and during follow-up. If the lesions being followed are not unable to be evaluated by clinical examination, an imaging-based evaluation is preferred for evaluation by clinical trials.

[0177] Clinical lesions: Clinical lesions are considered measurable only if they are superficial (e.g., skin nodules and palpable lymph nodes) and have a diameter of ≥ 10 mm (≥ 1 cm) as measured with calipers (e.g., skin nodules). For skin lesions, documentation with color photographs including a scale for estimating the size of the lesion is recommended.

[0178] Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions if they are clearly defined and surrounded by aerated lung. However, CT is preferred.

[0179] Conventional CT and MRI: This guideline defines the measurability of lesions on CT scans based on the assumption that the CT slice thickness is 5 mm (0.5 cm) or less. If the CT scan has a slice thickness greater than 5 mm (0.5 cm), the minimum size of a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations.

[0180] PET-CT: If the CT performed as part of a PET-CT is of the same diagnostic quality as diagnostic CT (using IV and oral contrast), the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT when accurately measuring cancer lesions over time.

[0181] Ultrasound:Ultrasound is not useful for the assessment of lesion size and should not be used as a measurement method. If a new lesion is identified by ultrasound during the course of a trial, confirmation by CT or MRI is recommended. If there are concerns about radiation exposure with CT, MRI can be used in place of CT if it is selected.

[0182] Endoscopy, laparoscopy: The use of these techniques for the purpose of tumor evaluation of interest is not recommended. However, such techniques may be useful for confirming a complete pathologic response if a biopsy is obtained, or for determining recurrence in a trial where complete remission (CR) or recurrence after surgical resection is the endpoint.

[0183] Tumor markers: Tumor markers alone cannot be used to assess response. If the markers are initially higher than the normal upper limit, they must normalize in order for the patient to be considered a complete clinical response.

[0184] Cytology, histology: These techniques can be used to distinguish between partial response (PR) and complete remission (CR) in rare cases (e.g., residual lesions in tumor types such as germ cell tumors where known residual benign tumors may remain). When a measurable tumor meets the criteria for response or stable disease, a cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment is mandatory to distinguish between response or stable disease (the effusion may be a treatment side effect) and progressive disease.

[0185] FDG-PET:FDG-PET response assessment requires further testing, but it may be appropriate to incorporate the use of FDG-PET scanning to complement CT scanning in the assessment of progression (especially in potentially "new" diseases). New lesions based on FDG-PET imaging can be identified according to the following algorithm: a. A negative FDG-PET at baseline and a positive FDG-PET on follow-up are signs of PD based on new lesions. b. No FDG-PET at baseline and a positive FDG-PET on follow-up: If the positive FDG-PET on follow-up corresponds to a site confirmed by CT, this is PD. If the positive FDG-PET on follow-up is not confirmed as a new site of disease by CT, further follow-up CT scans are needed to determine whether progression is truly occurring at that site (in which case the PD data is the date of the first abnormal FDG-PET scan). If the positive FDG-PET on follow-up corresponds to an existing disease site on CT that is not progressing based on anatomical imaging, this is not PD. c. FDG-PET can be used to upstage the response to CR in a manner similar to biopsy when residual radiographic abnormalities represent fibrosis or scarring. The use of FDG-PET in this situation should be pre-specified in the clinical trial protocol and supported by disease-specific medical literature for the indication. However, it must be recognized that both approaches may produce false-positive CRs due to the limitations in the resolution / sensitivity of FDG-PET and biopsy. Note: A "positive" FDG-PET scan lesion means an FDG avid with uptake higher than twice that of the surrounding tissue in the attenuation-corrected image.

[0186] Response criteria for the evaluation of target lesions · Complete remission (CR): Disappearance of all target lesions. Any pathologic lymph nodes (target or non-target) must have a short-axis reduction to < 10 mm (< 1 cm). · Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, with reference to the baseline total diameter. · Progressive Disease (PD): An increase of at least 20% in the sum of the diameters of target lesions, considering as reference the smallest sum (which includes the baseline sum if it is the smallest in the trial). In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm (0.5 cm). (Note: The appearance of one or more new lesions is also considered progression). · Stable Disease (SD): Considering the smallest sum of diameters during the trial as reference, there is neither a reduction sufficient to confer PR eligibility nor an increase sufficient to confer PD eligibility.

[0187] Response criteria for the evaluation of non-target lesions · Complete Remission (CR): Disappearance of all target lesions and normalization of tumor marker levels. All lymph nodes must be of non-pathological size (<10 mm [<1 cm] short axis). Note: If tumor markers are initially above the normal upper limit, they must normalize for the patient to be considered in complete clinical response. · Non-CR / Non-PD: Persistence of one or more non-target lesions and / or maintenance of tumor marker levels above the normal limits. · Progressive Disease (PD): Appearance of one or more new lesions and / or clear progression of existing non-target lesions. Clear progression should generally not exceed the target lesion status. It should not be an increase in a single lesion, but rather representative of an overall change in the disease state.

[0188] Immune-related response criteria The immune-related response criteria differ from RECIST (version 1.1) in that the sum of the longest diameters of all target and, if any, new lesions is used to determine the response. The mere presence of new lesions does not determine progression; the total tumor burden is considered.

[0189] Evaluation of Target Lesions · Complete Remission (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have a reduction in short axis to <10 mm (<1 cm). · Partial Response (PR): A decrease of at least 30% in the sum of the diameters of the target lesions, including new lesions, considering the baseline total diameter as a reference. · Progressive Disease (PD): An increase of at least 20% in the sum of the diameters of the target lesions, including new lesions, considering the minimum sum in the study (including the baseline sum if it is the minimum in the study) as a reference. In addition to the 20% relative increase, the sum must also show an absolute increase of at least 5 mm (0.5 cm). · Stable Disease (SD): Considering the minimum total diameter during the study as a reference, and including the measurement of new lesions, there is neither a reduction sufficient to qualify for PR nor an increase sufficient to qualify for PD.

[0190] Evaluation of Non-Target Lesions · Complete Remission (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be of non-pathological size (<10 mm [<1 cm] short axis). Note: If the tumor markers are initially higher than the normal upper limit, they must normalize for the patient to be considered in complete clinical remission. · Non-CR / Non-PD: Persistence of one or more non-target lesions and / or maintenance of tumor marker levels higher than the normal limit. · Progressive Disease (PD): Definite progression of existing non-target lesions. Definite progression should usually not exceed the target lesion status. It should not be an increase in a single lesion but representative of an overall change in the disease state. Definite progression of only "non-target" lesions is exceptional, and the treating physician's options should take precedence in such situations, and the progression status should be confirmed subsequently.

[0191] Evaluation of overall response criteria The best overall response is the best response recorded from the start of treatment to disease progression / recurrence (consider the smallest measurement recorded since treatment started as the reference for progressive disease). Assignment of the patient's best response depends on achievement of both measurement and confirmation criteria. The new guidelines (RECIST) version 1.1 for the assessment of treatment effect in solid tumors (Eisenhauer et al 2009, Eur.J.Cancer 45:228-247) and immune-related response criteria (irRC; Nishino et al 2013, Clin.Cancer Res.19:3936-3943) are summarized in Tables 10 and 11 below.

[0192]

Table 11

[0193]

Table 12

[0194] Evaluation of radial target lesions Radial target lesions were evaluated using a modified version of the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1. Additional definitions beyond the specific RECIST 1.1 guidelines are incorporated to define local management in this study protocol.

[0195] Response criteria for radial lesions are as follows: Local expansion (LE): At least a 20% increase in the LD of target lesions, considering the smallest LD recorded since treatment started as the reference. Ideally, this determination is made based on CT image evaluation.

[0196] Local failure (LF): Refer to the primary treated tumor after treatment in the study protocol and correspond to the fulfillment of both of the following two criteria: (1) local expansion ( An increase of 20% in the tumor dimensions as defined above for LE; (2) Measurable tumors that meet the criteria for LE should be accumulations on positron emission tomography (PET) imaging having an uptake intensity similar to that of the pretreatment staging diagnostic PET, or the measurable tumors should be confirmed as viable carcinomas by biopsy.

[0197] Local control (LC): The absence of local insufficiency.

[0198] Using appropriate tissue-specific windowing techniques, the longest diameter (LD) of the radial target lesion calculated from the treatment planning CT scan is reported as the baseline LD. The baseline LD is used as a reference for characterizing the target tumor. For follow-up evaluation, diagnostic CT scans performed using lung windowing with a 5-mm contiguous reconstruction algorithm, taken as part of the planned study protocol follow-up, are preferred as a method for evaluating response. If CT scans are not available, MRI or x-ray determination is permitted as long as the target lesion is clearly visible.

[0199] Results REGN2810 is safe and well tolerated by patients, alone and in combination. Administration of REGN2810, alone or in combination with other treatment modalities, inhibits tumor growth and / or promotes tumor regression in patients with progressive solid tumors. The overall response rate is better for combination therapy with radiation compared to monotherapy.

[0200] Sixty patients with progressive solid malignancies (47% with four or more previous treatments) have been treated to date. Progressive solid malignancies include colorectal cancer, head and neck cancer, breast cancer, soft tissue sarcoma, adrenal cancer, anal cancer, appendiceal cancer, bladder cancer, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, non-small cell lung adenocarcinoma, ovarian cancer, pancreatic cancer, prostate cancer, renal sarcomatoid, salivary gland cancer, non-melanoma skin cancer, Merkel cell carcinoma, squamous cell carcinoma, basal cell carcinoma, small intestine cancer, thyroid cancer, and uterine cancer.

[0201] Forty-two patients (70%) experienced one or more treatment-related adverse events (AEs). The most common treatment-related AEs were fatigue (28.3%), arthralgia (11.7%), and nausea (11.7%). Of the 60 patients evaluated for tumor response, 11 (18.3%) had a target response (PR / CR), while 31 patients (51.7%) demonstrated disease control (CR / PR / SD). Among the 36 patients who received combination therapy including radiotherapy, the target response was seen in 6 patients (16.7%), and disease control was seen in 19 patients (52.8%). Among the 24 patients who did not receive radiotherapy, the target response was seen in 5 patients (20.8%), and disease control was seen in 12 patients (50%). Table 12 shows a summary of the responders.

[0202]

Table 13

[0203] Among the responders, the median response time to monotherapy was 113 days (ranging from 52 to 226), and for patients using radiotherapy it was 59 days (ranging from 56 to 113).

[0204] Example 8: Metastatic non-melanoma skin cancer: Case report of PD-1 blockade with monoclonal antibody REGN2810 achieving durable objective response in basal cell carcinoma and cutaneous squamous cell carcinoma Introduction Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share UV light exposure as a major risk factor, and thus these tumors are hypermutated (Chalmers et al 2016, AACR Ann. Meeting, Abs 3576). In other malignancies, high mutational burden has been associated with clinical benefit from treatment with antibodies specific to the PD-1 immune checkpoint [Le et al 2015, New Engl. J. Med. May 30 (Epub ahead of print)]. Highly mutated tumors are more likely to express immunogenic tumor neoantigens that attract effector T cells that cannot be liberated by blockade of the PD-1 immune checkpoint (Mandal and Chan 2016, Cancer Discov. 6:1-12). This example describes patients with metastatic BCC and metastatic CSCC treated with REGN2810, a fully human anti-PD-1 monoclonal antibody, in an ongoing phase 1 trial (NCT02383212; described in Example 7 herein).

[0205] Case report 1 The patient was a 66-year-old female diagnosed with stage 1 BCC arising on the left lateral aspect of the ear, which was excised by Mohs surgery. A local recurrence at the same site was identified 2 years later, and wide local excision revealed invasion into the left mandibular bone and involvement of 1 out of 18 lymph nodes. The patient received adjuvant radiation and remained disease-free for 4 years, at which time an enlarged pulmonary nodule observed on surveillance chest imaging was biopsied, and the presence of metastatic BCC was confirmed. The patient was then treated with the hedgehog pathway inhibitor (HHI) vismodegib for 5 months. She initially responded but discontinued due to progressive disease.

[0206] Six months after bisphosphonate therapy, if progression continued slowly, the patient entered the cohort of the phase 1 trial of REGN2810, receiving 10 mg / kg IV every two weeks, and received the first dose. Two lung metastases were followed as target lesions. Response evaluations at the end of week 8 (3% increase) and week 16 (10% decrease) showed stable disease according to the RECIST criteria. The response evaluation at the end of week 24 showed a 37% decrease in tumor measurement (Figure 14A), and this was confirmed at week 32. The patient tolerated the treatment well and continued REGN2810 for more than 10 months of treatment.

[0207] Case report 2 The patient was a 52-year-old man diagnosed with cutaneous squamous cell carcinoma of the left cheek. He underwent Mohs surgery, and the margins were clear. He experienced multiple recurrences and underwent at least nine additional Mohs surgeries. He underwent wide local excision of the left mandible four years later and left parotidectomy 20 months later. Adjuvant radiotherapy was also administered to the left cheek, left mandible, left neck (with cetuximab), and both necks (with carboplatin). Other systemic therapies were capecitabine and cisplatin + docetaxel. Ten years after the initial diagnosis, he underwent excision for an in-scar recurrence of 2.2 cm in the left neck, and the margins were clear. Subsequently, invasive CSCC in the C4-C5 vertebral body required emergency decompression of the cervical spinal cord using anterior corpectomy of C4-C5 and posterior laminectomy of C4-C6. He also developed lower limb muscle weakness thought to be due to perineural involvement and required the use of a walker for ambulation.

[0208] He participated in a Phase 1 trial in the first cohort receiving 1 mg / kg REGN2810 every two weeks. Within weeks of starting treatment, his lower extremity strength recovered modestly and he no longer required the use of a walker. The response at week 16 is shown in Figure 14B. Radiologic complete remission of the left neck lesion was achieved at week 40. The patient completed the planned 48-week treatment protocol with REGN2810. He is continuing close and active follow-up with his oncologist without evidence of clinical or radiologic disease recurrence.

[0209] Discussion This example discloses the first confirmed partial response in a patient with metastatic BCC treated with a PD-1 inhibitor (REGN2810), and furthermore, a durable complete remission ongoing in a patient with metastatic CSCC. The deep and durable responses to anti-PD-1 monotherapy in this Phase 1 trial in these highly pre-treated patients are consistent with the hypothesis that the high mutational burden in BCC and CSCC will elicit anti-tumor cell immunity that can be unleashed by blockade of the PD-1 / PD-L1 checkpoint pathway.

[0210] This example supports the general principle that UV-related skin cancers other than melanoma are sensitive to PD-1 blockade. A reductionist model would predict that UV-related tumors with a higher burden of non-synonymous mutations would be more responsive to PD-1 blockade than those with a lower mutational burden. blockade.

[0211] Example 9: Safety and Efficacy of Anti-PD-1 Antibody in Patients with Inoperable Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma (CSCC) Background There is no established standard of care for inoperable locally advanced or metastatic CSCC. Due to UV-induced DNA damage, most CSCCs are hypermutated. Thus, these tumors may be responsive to PD-1 checkpoint blockade. This example is a ongoing Phase 1 trial (NCT02383212; described in Example 7 herein) treated with REGN2810, a fully human anti-PD-1 monoclonal antibody.

[0212] Method In the expansion cohort (EC) of the Phase 1 trial of REGN2810, patients with distant metastatic CSCC (EC7) and locally advanced CSCC (EC8) participated (Table 9). All patients were administered 3 mg / kg REGN2810 intravenously every 2 weeks for up to 48 weeks. Serial biopsies were performed at baseline and day 29 (and at progression if possible). Tumor measurements were performed every 8 weeks according to RECIST 1.1 to determine overall response rate.

[0213] Results Twenty-five patients participated (10 in EC7 and 15 in EC8): median age, 72.5 years (y) (range, 56 - 88 y); median PS 1 (range, 0 - 1); 20 males (M): 5 females (F); median number of previous systemic treatment regimens, 1 (range, 0 - 3). Median exposure to REGN2810 was 6 doses (range, 1 - 22). The most commonly seen treatment-related adverse events of any grade were fatigue (16.7%), nausea, arthralgia, and rash (8.3% each). Each of the following grade ≥ 3 related adverse events (AEs) occurred once: elevated AST, elevated ALT, arthralgia, and rash.

[0214] The overall response rate (uPR+PR+CR) and disease control rate (ORR+SD) were 48% (11 / 23; 3 uPR, 5 PR, 2 CR, 1 uCR) and 70% (16 / 23, including 5 SD), respectively. Two patients were not yet evaluable. The median PFS and median OS were calculated, and only one patient experienced PD during REGN2810 treatment after the initial response. Correlative science studies are ongoing, which include whole exome tumor DNA sequencing.

[0215] Conclusion REGN2810 demonstrates strong antitumor activity in patients with progressive CSCC.

[0216] Example 10: Clinical trial of an anti-PD-1 antibody in combination with hypofractionated radiotherapy compared to standard therapy in patients aged ≥65 years with newly diagnosed glioblastoma Introduction Glioblastoma is a fatal disease with a median survival of approximately 16 months (nGBM) in newly diagnosed patients and approximately 9 months (rGBM) in the recurrent setting (Friedman et al, 2009, J. Clin. Oncol. 27:4733-4740). The current standard of treatment for patients with newly diagnosed glioblastoma is radiotherapy (60 Gy over 6 weeks) together with concomitant temozolomide (TMZ), followed by adjuvant temozolomide (Stupp et al, 2005, N. Engl. J. Med. 352:987-996), but subgroup analysis suggests that the addition of temozolomide may not improve efficacy in older individuals (Laperriere et al, 2013, Cancer Treat. Rev. 39:350-357).

[0217] This example describes a phase 3 trial to evaluate the efficacy of an anti-PD-1 antibody in combination with hypofractionated radiotherapy (hfRT) compared to standard of care (SoC) with respect to overall survival in patients aged ≥65 years with nGBM.

[0218] The exemplary anti-PD-1 antibody used in this study is REGN2810 (also known as H4H7798N disclosed in US20150203579), a fully human monoclonal anti-PD-1 antibody comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10; an HCVR / LCVR amino acid sequence pair comprising SEQ ID NO: 1 / 2; and heavy and light chain CDR sequences comprising SEQ ID NOs: 3-8.

[0219] Research Objectives The primary objective of this study is to evaluate the efficacy of REGN2810 administered in combination with hfRT on overall survival (OS) against standard therapy for patients aged ≥ 65 years with nGBM.

[0220] The secondary objective of the study is to determine improvement in progression-free survival (PFS).

[0221] Other objectives of the study are: (i) improvement in objective response rate (ORR), response duration, and duration of disease control; (ii) clinical evaluation using neuroassessment on the Neuro-Oncology (NANO) scale; (iii) safety; (iv) improvement in quality of life (QoL) and mental state; (v) changes in edema and steroid use; (vi) serum REGN2810 concentration and anti-REGN2810 antibodies; and (vii) to investigate possible pharmacodynamic, predictive, or prognostic biomarkers.

[0222] Study Design This is a randomized, phase 3 trial of 2:1 of REGN2810, a fully human antibody against PD-1 in combination with a hypofractionated irradiation regimen, against standard therapy in patients aged ≥ 65 years with newly diagnosed glioblastoma. Patients are randomly selected in a 2:1 ratio to REGN2810 in combination with hypofractionated irradiation regimen vs. standard therapy using methylation status (methylated vs. non-methylated vs. undetermined) and extent of resection (partial vs. gross resection) as stratification factors. Efficacy is evaluated by overall survival.

[0223] nGBM patients who are candidates for radiotherapy are randomly selected in a 2:1 ratio to receive one of the following treatments: · Investigational treatment: 3 mg / kg REGN2810 intravenously (IV) (every 2 weeks) and hypofractionated RT (6 Gy x 5, only in the second week). Radiotherapy is provided in the second week of cycle 1 but not in subsequent cycles. · Comparative treatment: Standard treatment TMZ (oral, 75 mg / m 2 per day) for 6 weeks in combination with standard RT (5 daily radiation fractions / week 2 Gy), followed by adjuvant TMZ (oral, 150 mg / m2 - 200 mg / m 2 5 days / 28 days) for 6 cycles. Radiotherapy is provided only in the first 6-week cycle.

[0224] Study period The study consists of a 28-day screening period, after which eligible patients may have up to 12 treatment cycles of 56 days (8 weeks) for a total of up to 96 weeks of treatment. During the screening period (-28 days to -1 day), all eligible patients must have available pre-treatment tumor resection (partial or total) or biopsy for central pathology confirmation and MGMT methylation determination and confirmation.

[0225] After day 1 / baseline, patients return to the hospital on days 8 ± 3, 15 ± 3, 29 ± 3, 43 ± 3, and 56 ± 3 during cycle 1. During subsequent 8-week cycles (cycles 2 - 12), patients return to the hospital on days 1, 15 ± 3, 29 ± 3, 43 ± 3, and 56 ± 3. Tumor evaluations (brain MRI, iRANO and NANO evaluations, MMSE, and EORTC QLQ-C30 / BN20 questionnaires) are performed on day 1 / baseline and at the end of each treatment cycle. Extended safety evaluations are performed on day 1 of each cycle; conventional safety evaluations are performed at each visit. Samples (cells and molecules, as described herein) are also collected for the evaluation of REGN2810 treatment exposure, clinical activity, or biomarkers associated with underlying diseases.

[0226] During the 24-week follow-up observation period, patients return to the hospital 21 to 42 days after the last test for the first follow-up visit. Subsequent follow-up visits (Follow-up Visit 2 to Follow-up Visit 7) are every 28 days ± 7 days. Tumor evaluations (brain MRI, iRANO and NANO evaluations, MMSE, and EORTC QLQ-C30 / BN20 questionnaires) are performed at Follow-up Visit 3, Follow-up Visit 5, and Follow-up Visit 7. Extended safety evaluations are performed during the first follow-up visit; routine safety evaluations are performed at subsequent follow-up visits. Samples are collected for the evaluation of REGN2810 treatment exposure, clinical activity, or biomarkers (cells and molecules, described herein) related to underlying diseases.

[0227] Target population The target population includes patients aged ≥ 65 years with nGBM.

[0228] Inclusion criteria : Patients must meet the following criteria to be eligible for inclusion in the study: (1) newly diagnosed with histologically confirmed primary glioblastoma with a maximum diameter ≤ 5 cm, and the patient had a partial or complete surgical resection; (2) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2; (3) ≥ 65 years old; (4) liver function: (a) total bilirubin ≤ 1.5 x upper limit of normal; (b) ALT and AST ≤ 3 x ULN; (c) alkaline phosphatase (ALP) ≤ 2.5 x ULN; (5) renal function: serum creatinine ≤ 1.5 × ULN; (6) bone marrow function: hemoglobin ≥ 9.0 g / dL; absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L; platelet count ≥ 75 × 10 9 / L; (7) able to read, understand, and sign the ICF; and (8) ability and willingness to comply with scheduled visits, treatment plans, laboratory tests, and other study-related procedures.

[0229] Exclusion criteriaPatients who meet any of the following criteria are excluded from the study: (1) previous treatment (other than surgery) for GBM; (2) had a known contraindication to Gd-MRI; (3) evidence of an ongoing or recent (within 5 years) significant autoimmune disease requiring treatment with immunosuppressive therapy, which may suggest a risk for immune-related adverse events (irAE). The following are not exclusions: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormonal replacement, or psoriasis not requiring systemic treatment. (4) Ongoing systemic corticosteroid treatment, excluding the use of corticosteroids for other (non-tumor and non-immunosuppressive) indications up to a maximum of 10 mg / day of prednisone or equivalent. (5) A primary tumor located in the brainstem, spinal cord, or any secondary brain tumor active infection requiring treatment including a known infection with the human immunodeficiency virus or an active infection with hepatitis B or C virus. (6) A history of interstitial pneumonia within the past 5 years. (7) Any trial or anti-tumor treatment within 30 days prior to the first dose of REGN2810. (8) A history of documented allergic reaction or acute hypersensitivity reaction caused by treatment with a general antibody treatment or the agent specifically used in this study. (9) Poorly controlled hypertension (defined as systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg) (10) Known allergy to doxycycline or tetracycline. (Caution due to the presence of trace components in REGN2810) (11) A previous history of hypertensive crisis or hypertension or hypertensive encephalopathy (12) A history within the past 5 years of invasive malignant tumors other than those treated in this study, excluding in-situ resected / cured basal or squamous cell carcinomas of the neck or other local tumors considered curable by local treatment, (13) Acute or chronic psychiatric problems that, in the opinion of the study responsible physician, would disqualify the patient from participation, (14) Use of Tumor Treating Fields (Optune NovoTTF-100A device) at the time of screening for tumor treatment. Planned or anticipated use of Novocure tumor treatment fields during the study, (15) Previous treatment with carmustine wafers, (16) Continued sexual activity in men who do not desire appropriate contraception during the study. A history within the past 5 years of invasive malignant tumors other than those treated in this study, excluding in-situ resected / cured basal or squamous cell carcinomas of the neck or other local tumors considered curable by local treatment, (13) Acute or chronic psychiatric problems that, in the opinion of the study responsible physician, would disqualify the patient from participation, (14) Use of Tumor Treating Fields (Optune NovoTTF-100A device) at the time of screening for tumor treatment. Planned or anticipated use of Novocure tumor treatment fields during the study, (15) Previous treatment with carmustine wafers, (16) Continued sexual activity in men who do not desire appropriate contraception during the study.

[0230] Research treatment Patients receive one of the following treatment regimens:

[0231] Trial treatment : 3 mg / kg REGN2810 (IV infusion administered over 30 minutes every 2 weeks up to 96 weeks) and hfRT in the second week of cycle 1

[0232] Control drug: Standard treatment 6 weeks of standard RT (5 daily radiation fractions of 2 Gy / week), followed by 6 weeks of adjuvant TMZ (oral, 150 mg / m2 - 200 mg / m 2 5 days / 28 days) and TMZ (oral, 75 mg / m2, daily) in combination. Radiation therapy is provided only in the first cycle.

[0233] REGN2810 is supplied as a liquid in sterile single-use vials. Each vial contains a volume sufficient to withdraw 10 mL of REGN2810 at a concentration of 25 mg / mL. REGN2810 is administered as a 30-minute intravenous (IV) infusion. The dose for each patient depends on the individual body weight. The dose of REGN2810 can be adjusted in each cycle for a weight change of ≧10%.

[0234] Radiation therapy : Patients in the control arm receive standard radiotherapy (60 Gy over 6 weeks). Patients in the experimental treatment group receive hfRT (6 Gy X 5 daily fractions) administered 1 week after the first dose of REGN2810.

[0235] REGN2810 and radiation (trial procedure) : REGN2810 is administered by IV infusion over 30 minutes every 14 weeks for 96 weeks in combination with hfRT from day 8 to day 12.

[0236] Planned combination REGN2810 and hfRT regimen : In addition to the 3 mg / kg REGN2810 infusion over 30 minutes every 14 weeks for 96 weeks, radiotherapy (hfRT at 6 Gy × 5 daily fractions; preferably administered on consecutive days 1 week after the first dose of REGN2810).

[0237] Specification for radiotherapy: The patient receives 30 Gy given as a 5 - fraction dose of 6 Gy administered daily starting 1 week after the first dose of REGN2810.

[0238] Comparison arm: Standard treatment : TMZ (oral, 75 mg / m 2 , daily) in combination with 6 - week standard RT (5 daily fractions of 2 Gy / week), followed by adjuvant oral TMZ. The dose of TMZ is 150 mg / m 2 for the first 5 days of the first adjuvant cycle, and if there is no unacceptable hematological toxicity in the first adjuvant cycle, it is increased to 200 mg / m 2 for 5 days / 28 days to start the second cycle.

[0239] During the first adjuvant cycle, if all observed non - hematological toxicities are grade ≤ 2 (excluding alopecia, nausea, and vomiting), and platelets are ≥ 100 x 109 / L, and ANC >= 1.5 x 109 / L, the TMZ dose should be increased to dose level 1 (20 0 mg / m 2 ), and this dose should be used as the starting dose in subsequent cycles. After cycle 1, if TMZ has to be withheld due to ongoing grade ≥ 2 non - hematological toxicity, an increase is not possible. If the dose was not increased in the second cycle, the dose should not be increased in subsequent cycles.

[0240] Treatment of CNS edema : Patients who develop symptomatic cerebral edema during the study have REGN2810 dosing and radiotherapy stopped until the edema resolves.

[0241] For patients who develop cerebral edema, bevacizumab is administered IV at a reduced dose (up to 3 doses of 5 mg / kg Q2W, not exceeding 10 mg / kg Q2W per dose) if not contraindicated (e.g., if the patient has not had surgery within the past 28 days).

[0242] If bevacizumab does not dissipate cerebral edema, systemic corticosteroids may be administered at the minimum dose deeded for symptom management, in addition to or instead of bevacizumab. For patients with bevacizumab intolerance, it is used at the dose deeded for appropriateness for symptom management.

[0243] Research variables The primary efficacy evaluation item is overall survival (OS), which is defined as the time interval from randomization to the date of death from any cause.

[0244] The main secondary evaluation item is progression-free survival (PFS), which is defined as the time interval from the date of randomization to the date of the first disease progression or the date of death (from any cause). Disease progression is determined according to the iRANO criteria.

[0245] Other secondary efficacy evaluation items are as follows: Objective response rate (ORR): For the total number of patients in the analysis population, the ratio of patients with confirmed complete remission (CR) or confirmed partial response (PR) defined according to the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria. in Neuro-Oncology)(iRANO) criteria.

[0246] Response duration: Determined for patients with the best overall response of CR or PR. The response duration is measured from the time when the measurement criteria first meet CR / PR (whichever is recorded first) to the first date of recurrence or progressive disease (radiographic image) or death from any cause.

[0247] Disease control period: Determined for patients with the best overall response of SD, CR, or PR. The disease control period is measured from the start of treatment to the first date of recurrence or progressive disease (radiographic image) or death due to any cause.

[0248] Quality of life and symptom control variables : Quality of life and symptom control variables are as follows: · Single-item scales for symptom assessment using the EORTC QLQ-C30 questionnaire among five functional scales, three symptom scales, one overall scale of health status, and six studies · Four scales and seven single items using the EORTC QLQ-BN20 questionnaire during the study · Clinical evaluation using NANO; · Total MMSE score during the study · Use of corticosteroids at baseline, cumulative corticosteroid use during the study, and periods of steroid non-use or low-dose steroid use during the progression-free period of the study · Use of bevacizumab PRN at baseline, cumulative bevacizumab PRN during the study, and periods of bevacizumab non-use during the progression-free period of the study

[0249] Exploratory biomarker variables : Other evaluation items include pharmacodynamic, prognostic, and predictive biomarkers related to clinical response, mechanism of action, and AEs potentially related to REGN2810 after treatment. Biomarker variables include the following: · Expression levels of immune checkpoint receptors PD-L1, GITR, and LAG3, and other potential biomarkers (e.g., EGFRvIII, Ki67, etc.) in tumor samples; · Number and distribution of TILs in tumor samples; · IDH1 mutation status, microsatellite instability (MSI), and amount of mutations in tumor samples; · Circulating biomarkers including cytokines and angiogenic factors; · Cellular subsets and expression levels of the biomarker of interest in PBMCs; · MGMT promoter methylation status (also used for stratification) Other variables include the concentration of REGN2810 in serum (pharmacokinetic variable) and the occurrence of anti-REGN2810 antibodies.

[0250] Procedures and evaluations After the screening period up to Day 28, patients receive treatment for up to 96 weeks in a treatment cycle of up to 56 days for up to 12 cycles, followed by a 24-week follow-up period. Efficacy, safety, PK, ADA, and exploratory biomarker analysis are conducted.

[0251] Efficacy procedure MRI : For tumor evaluation, MRI is performed 72 hours after surgery, at screening visit (within 28 days before injection), on Day 56 ± 3 of all cycles (every approximately 8 weeks), and when PD is suspected. Patients in whom the disease did not progress had additional tumor evaluations at follow-up visits 3, 5, and 7. Note: If PD is confirmed, further scans are not necessary during follow-up visits. If pre- and post-surgery MRIs were performed before study participation, these scans must also be submitted to the study to assist in determining tumor volume and tumor progression.

[0252] Tumor response evaluation is performed according to iRANO; and clinical neurological evaluation is performed by NANO. Evaluation according to RANO is also performed as a supportive investigation; however, the main determination of disease progression for individual patients is made according to iRANO.

[0253] The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC Brain Cancer Module (EORTC QLQ-BN20) Questionnaire : The EORTC QLQ-C30 is a 30-item questionnaire that evaluates health-related quality of life (HRQoL) in cancer patients on 15 scales (single-item or multi-item), each with a possible score ranging from 0 to 100. Twenty-four of the 30 items are grouped into 9 multi-items representing various HRQoL aspects: 5 functional scales (physical, role, emotional, cognitive, and social), 3 symptom scales (fatigue, pain, and nausea / vomiting), and 1 general scale of health status. The remaining 6 single-item scales evaluate symptoms: dyspnea, loss of appetite, sleep disturbance, constipation and diarrhea, and the perceived economic impact of disease treatment. Higher scores indicate better HRQoL for the general scale of health status and functional scales, and worse HRQoL for symptom scales.

[0254] The EORTC QLQ-BN20 is a 20-item QoL assessment specific to brain neoplasms and is intended to complement the EORTC QLQ-C30 when assessing health-related quality of life. The EORTC QLQ-BN20 questionnaire assesses disease symptoms, treatment side effects, and several specific psychosocial issues important to patients with brain cancer using four scales (assessing anxiety about the future, visual impairment, motor function, and speech function) and seven single items (other disease symptoms [e.g., headache and epilepsy] and treatment toxic effects [e.g., hair loss]). The possible score range is 0 - 100; a higher score indicates worse HRQoL.

[0255] Mini-Mental Status Assessment : Mini-Mental State Examination (MMSE (C) ) is a short quantitative scale of cognitive status in adults. It can be used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, and to track the course of an individual's cognitive changes over time. In this study, the MMSE score is part of the neurological examination conducted in the context of disease evaluation.

[0256] The MMSE is performed on Day 1 / baseline, at the end of the pretreatment cycle, and every 8 weeks during the follow-up observation period. MMSE evaluations coincide with the disease evaluation schedule, but they must be completed before the radiological results are communicated to the patient. The MMSE can then be completed at the start of the next scheduled treatment administration. During the survival follow-up observation period, the MMSE should be continued to be completed every 8 weeks (once per survival visit) if the patient has not yet progressed.

[0257] The total score of the MMSE has a possible range from 0 (worst) to 30 (best).

[0258] Safety procedure On the first day of Cycle 1 and all subsequent treatment days, vital signs including body temperature, resting blood pressure, pulse, and respiration are collected, along with weight, before infusion and approximately 15 minutes after completion of the infusion. A complete physical examination and a 12-lead ECG are performed at the start of the entire cycle.

[0259] Exploratory tumor biomarker procedure Biomarkers to be analyzed by immunohistochemistry (IHC) include, but are not limited to, EGFRvIII and biomarkers of cell proliferation (e.g., Ki67). The expression levels (mRNA and / or protein) of PD-L1, GITR, and LAG-3, as well as cell lineage markers of tumor-infiltrating lymphocytes (CD4, CD8, CD25, FoxP3) are analyzed in tumor biopsy samples to investigate the potential effects of REGN2810.

[0260] Tumor tissue samples can be used for extraction of tumor DNA and RNA and subsequent analysis of test treatment and putative gene biomarkers associated with glioblastoma. Blood samples are collected for isolation of germline DNA on the first day / baseline (before dosing), or at any test visit if collection at the first day / baseline is not possible. Analysis of tumor DNA includes, but is not limited to, methylation status of the MGMT promoter, IDH1 mutation status, microsatellite instability (MSI), and tumor mutational burden (both of which can predict response to REGN2810 and other immunotherapy agents). Analysis of gene variants in tumor (somatic) DNA and germline DNA is performed, which can affect disease progression, drug response, and possible toxicity. Germline DNA is also used for comparison to tumor DNA to search for potential novel gene variants underlying the malignant process.

[0261] Results REGN2810 in combination with hfRT was safe and well tolerated by patients with nGBM. Administration of REGN2810 in combination with hfRT inhibited tumor growth and / or promoted tumor regression in patients with nGBM as compared to standard therapy. Patients with nGBM treated with REGN2810 and hfRT demonstrated longer OS as compared to standard therapy.

[0262] Example 11: Tolerability and Antitumor Activity of REGN2810 in Patients with Non-Small Cell Lung Cancer: Interim Data from Phase 1 In a dose escalation (DE) study in Phase 1 (described in Example 7 herein), monotherapy with REGN2810 (semiplimab) was evaluated in non-small cell lung cancer (NSCLC) at 1 mg / kg intravenous (IV) over 30 minutes every 2 weeks (Q2W). The NSCLC expansion cohort (EC 1) enrolled patients who had relapsed after at least first-line therapy or were refractory to first-line therapy in a recurrent or metastatic disease setting; patients were administered semiplimab 200 mg IV over 30 minutes Q2W up to week 48. Laboratory tests were performed at baseline and day 29 (and at progression if possible). Tumor measurements were performed every 8 weeks according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1.

[0263] Intermediate Results: Twenty-one patients with NSCLC were enrolled (1 in DE; 20 in EC1); the median age was 65.0 years (range, 50 - 82; 14 males (M) / 7 females (F)); 81.0% had an Eastern Cooperative Oncology Group Performance Status median of 1. Most (61.9%) had a history of adenocarcinoma at baseline. Overall, the most common treatment-related adverse events (TRAEs) were asthenia, interstitial pneumonia, and rash (n = 3 each, 14.3%). The following ≥ grade 3 TRAEs occurred once: interstitial pneumonia, diabetic ketoacidosis, and nephritis. Of the patients in EC1, 6 had a partial response (PR) and 4 had stable disease (SD). The overall response rate (ORR = complete remission [CR] + PR) by central independent review (data cutoff: August 31, 2017) was 28.6% (n = 6 / 21). The disease control rate (ORR + SD) was 57.1% (n = 12 / 21; 1 of whom was non-CR / non-progressive disease [PD]). Overall, 9 patients (all from EC1) had PD during treatment with semiprimab.

[0264] Semiprimab was generally well tolerated and demonstrated antitumor activity in NSCLC patients from this study.

[0265] Example 12: Clinical Trial of REGN2810 in the First-Line Treatment of Patients with Progressive or Metastatic PD-L1+ Non-Small Cell Lung Cancer The current study is a randomized, global, open-label, phase 3 trial of REGN2810 monotherapy versus standard-of-care, platinum-based, doublet chemotherapy in patients with progressive or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥ 50% of tumor cells and who have not previously received systemic treatment for their progressive disease.

[0266] Study Objectives The primary objective of the study is to determine whether REGN2810 improves progression-free survival (PFS) compared to standard-of-care platinum doublet chemotherapy in patients with progressive or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥ 50% of tumor cells. The primary secondary objective of the study is to compare REGN2810 to platinum-based chemotherapy with respect to: · Overall survival (OS) · Objective response rate (ORR) Other secondary objectives of the study are as follows: · Compare the duration of response (DPR) of REGN2810 to platinum-based chemotherapy · Evaluate the quality of life (QOL) of patients treated with REGN2810 compared to patients receiving platinum-based chemotherapy, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13) · Evaluate the safety and tolerability of REGN2810 compared to platinum-based chemotherapy · Measure the concentration of REGN2810 in serum and characterize the pharmacokinetics (PK) of REGN2810 Exploratory objectives include: · Evaluate immunogenicity as measured by immunogenicity assessment of REGN2810 · Evaluate the correlation between baseline PD-L1 expression levels and the efficacy of study treatment · Evaluate the time to new anti-tumor therapy are included.

[0267] Study Design This is a randomized, multi-center, open-label, pivotal Phase 3 trial of REGN2810 versus platinum-based doublet chemotherapy in patients with Stage IIIB or IV squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥ 50% of tumor cells and who have not previously received systemic treatment for their progressive disease.

[0268] The study consists of the following three periods: screening, treatment, and follow-up. Patients undergo screening evaluations to determine their eligibility within 28 days prior to randomization. Eligible patients are randomly assigned to one of the following two treatment groups: REGN2810 350 mg monotherapy or standard-of-care chemotherapy. Randomization is stratified by histology (non-squamous vs. squamous) and geographic region (EU or ROW). Patients with NSCLC randomly assigned to chemotherapy may receive one of the following regimens: · Paclitaxel + cisplatin or carboplatin · Gemcitabine + cisplatin or carboplatin · Pemetrexed + cisplatin or carboplatin, followed by optional pemetrexed maintenance (patients with squamous NSCLC are recommended not to be given pemetrexed-containing regimens).

[0269] Patients assigned to the REGN2810 treatment group receive REGN2810 350 mg as an intravenous (IV) infusion on Day 1 of each treatment cycle (every 3 weeks [Q3W]) until Week 108 or until progressive disease, unacceptable toxicity, death, or withdrawal of consent, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. REGN2810 patients who experience progressive disease as defined by RECIST 1.1 during treatment may continue REGN2810 treatment if the patient is determined to have experienced clinical benefit and the patient has not completed the 108-week treatment period. If further progressive disease (defined as a further 10% increase in tumor volume from the time of the first progressive disease) is confirmed, REGN2810 must be discontinued and, if appropriate, other anticancer therapies are considered.

[0270] Patients assigned to chemotherapy receive one of the options provided in the study protocol for platinum doublet chemotherapy treatment for up to 4 - 6 cycles or until progressive disease, unacceptable toxicity, death, or withdrawal of consent, as defined by RECIST 1.1. Patients who experience disease progression during chemotherapy may, provided they meet certain criteria, Patients are offered the option to switch to REGN2810 350 mg Q3W for up to 108 weeks. Patients are seen for follow-up every 6 weeks for 6 months, and then at 9 months and 12 months after the last dose of treatment. The study duration for each patient is approximately 40 months.

[0271] Study population Patients included in this study are males and females ≥ 18 years of age diagnosed with stage IIIB or IV non-squamous or squamous NSCLC whose tumors express PD-L1 in ≥ 50% of tumor cells (using the diagnostic assay) and who have not previously received systemic treatment for their progressive disease.

[0272] Inclusion criteria: Patients must meet the following criteria to be eligible for inclusion in the study: 1. Males and females ≥ 18 years of age 2. Patients with histologically or cytologically documented squamous or non-squamous NSCLC with stage IIIB or IV disease who have not previously received systemic treatment for recurrent or metastatic NSCLC. a. Patients who have received adjuvant or neoadjuvant platinum doublet chemotherapy (after surgery and / or radiotherapy) and developed recurrent or metastatic disease more than 6 months after completion of treatment are eligible. 3. Archived or newly obtained formalin-fixed tumor tissue from the metastasis / recurrence site, which has not been previously irradiated 4. Tumor cells expressing PD-L1 in ≥ 50% of tumor cells by IHC 5. At least one lesion measurable by radiographic examination by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1 criteria. Target lesions may be located in previously irradiated areas if there is documented (radiographic) disease progression at that site. 6. ECOG performance status ≤ 1 7. A predicted life expectancy of at least 3 months 8. Appropriate organ and bone marrow functions as defined below: a. Hemoglobin ≥ 9.0 g / dL, b. Absolute neutrophil count ≥ 1.5 × 109 / L, c. Platelet count ≥ 100,000 / mm3, d. Glomerular filtration rate (GFR) > 30 mL / min / 1.73 m2, e. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (in case of liver metastasis, ≤ 3 × ULN), excluding patients diagnosed with clinically confirmed Dubin-Johnson syndrome, f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN in case of liver metastasis, g. Alkaline phosphatase ≤ 2.5 × ULN (or ≤ 5.0 × ULN in case of liver or bone metastasis), h. Does not meet the criteria for Hy's law (ALT > 3 × ULN and bilirubin > 2 × ULN). 9. Willing and able to comply with study visit and research-related procedures 10. Submit a signed informed consent 11. Understand the study-related questionnaire and be able to complete all items.

[0273] Exclusion criteria: Patients who meet any of the following criteria are excluded from the study: 1. Patients who have never smoked, defined as ≤ 100 cigarettes smoked in a lifetime, 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if CNS metastases have been appropriately treated and the patient has returned neurologically to baseline at least 2 weeks prior to enrollment (excluding residual signs or symptoms related to CNS treatment). Patients must have discontinued corticosteroid treatment (at immunosuppressive doses). 3. Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions, 4. Encephalitis, meningitis, or uncontrolled epilepsy within 1 year prior to informed consent, 5. History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia requiring immunosuppressive doses of glucocorticoids to assist management. Radiation in the irradiated field A history of radiation pneumonia is acceptable. 6. Patients with active, known, or suspected autoimmune diseases that required systemic treatment in the past two years. Patients with vitiligo, type I true diabetes mellitus, and hypothyroidism that only requires hormonal replacement (including hypofunction due to autoimmune thyroiditis) are permitted to enroll. 7. Patients with a condition that requires corticosteroid treatment (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiological replacement doses are acceptable even if prednisone / day >10 mg or equivalent, as long as they are not administered with immunosuppressive intent. Inhaled or topical steroids are acceptable, provided that they are not for the treatment of autoimmune disorders. 8. Another malignancy that is ongoing or requires treatment. Excluding non-melanoma skin cancer that may have received definitive treatment, or in situ cervical cancer that has been treated and the patient is considered to be in complete remission at least two years prior to trial enrollment and does not require further treatment during the trial period. 9. Known active hepatitis B (positive result) or hepatitis C (known positive result) and known quantitative HCV RNA results higher than the assay's detection limit. 10. Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome indicating uncontrolled active infection. Patients on highly active antiretroviral therapy with undetectable RNA levels and CD4 counts higher than 350 are acceptable. 11. Active infections that require systemic treatment within 14 days prior to randomization. 12. Previous treatment with anti-PD-1 or anti-PD-L1. Previous exposure to other immunomodulatory or vaccine therapies such as anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies is acceptable, but the last dosing of such antibodies should be at least 3 months prior to the first dosing of the investigational drug. 13. Treatment-related immune-mediated adverse events (AEs) from immunomodulators (including but not limited to anti-PD1 / PD-L1 Mab, anti-CTLA4 monoclonal antibodies, and PI3K-δ inhibitors) that had not recovered to baseline at least 3 months prior to the start of treatment with the investigational drug.Patients who have experienced immune-mediated AEs related to previous treatment with PD-1 / PD-L1 pathway blockers, regardless of the timing of onset, with a severity of grade 3 or 4 and / or requiring drug discontinuation, are excluded from treatment with REGN2810. 14. Received investigational drug or device within 30 days of screening or within 5 half-lives (whichever is longer) of the investigational drug or treatment being tested. 15. Received live vaccine within 30 days of the planned start of investigational drug application. 16. Major surgery or severe trauma within 4 weeks prior to the first dose. 17. Documented allergic or acute hypersensitivity reaction due to antibody treatment. 18. Known allergy to doxycycline or other tetracycline antibiotics. 19. Known psychiatric or substance use disorders that would interfere with trial participation requirements, including current use of any illegal drugs. 20. Women who are pregnant or breastfeeding. 21. Women of childbearing potential who do not wish to implement highly effective contraception before the first dose, during the trial, and for at least 6 months after the last dose. 22. Patients who are institutionalized by order of any judicial or administrative authority.

[0274] Study treatment Investigational drug: REGN2810 is administered at 350 mg by IV infusion Q3W up to week 108.

[0275] Reference drug: Standard treatment chemotherapy (one of the options shown in the study implementation protocol for platinum doublet chemotherapy treatment, Table 13) is administered up to 4 - 6 cycles or until progressive disease as defined by RECIST 1.1, unacceptable toxicity, death, or withdrawal of consent.

[0276]

Table 14

[0277] Study evaluation items The primary endpoint is PFS evaluated using RECIST 1.1. The important secondary endpoints in the study are OS and ORR. Other secondary endpoints include DOR and QOL, and further the safety and tolerability of REGN2810.

[0278] Procedures and Assessments Procedures performed at screening include informed consent; recording of medical, oncology, and concomitant medication histories; recording of demographics; collection of tumor tissue for PD-L1 assessment; examination of tumor tissue for epithelial growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations and the human homolog of the transforming gene v-ros (ROS1) fusion of the avian sarcoma virus UR2; radiographic tumor assessment; tumor burden assessment; chest X-ray; serum pregnancy test; 12-lead electrocardiogram (ECG); thorough physical examination including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; and laboratory tests. Samples for any genomic sub-studies may also be obtained. During treatment and follow-up, the following procedures are performed to assess safety: physical examination; ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for women of childbearing potential; ECG and chest X-ray (at the discretion of the study physician); and recording of adverse events (AEs) and concomitant medications. Computed tomography (CT) or magnetic resonance imaging (MRI) for tumor assessment is performed at time points throughout the study. Quality of life is measured using validated patient self-administered questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13). Other assessments include samples for biomarker assessment, samples for REGN2810 concentration measurement, and samples for REGN2810 immunogenicity assessment.

[0279] Results In patients with progressive non-small cell carcinoma whose tumors express ≥50% PD-L1 in tumor tissue, REGN2810 treatment is expected to result in increased progression-free survival and overall survival compared to treatment with chemotherapy.

[0280] Example 13: Standard and High-Dose REGN2810 (cemiplimab) and Ipilimumab (Anti-CTLA-4 Antibody) in Second-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with Tumors Expressing <50% PD-L1 This example describes a clinical study of the combination of standard and high-dose REGN2810 (cemiplimab; anti-PD-1 antibody) and ipilimumab (anti-CTLA-4 antibody) in second-line treatment of patients with metastatic non-small cell lung cancer with tumors expressing <50% PD-L1.

[0281] The primary objective of this study is to compare the objective response rate (ORR) of high-dose REGN2810 ("HDREGN2810") and combination therapy of standard-dose REGN2810 ("SDREGN2810 / ipi") and ipilimumab with standard-dose REGN2810 ("SDREGN2810") in patients with progressive or metastatic squamous or non-squamous non-small cell lung cancer (NSCLC) in second-line treatment, in patients whose tumors express programmed cell death ligand 1 (PD-L1) in <50% of tumor cells.

[0282] The secondary objectives of the study are as follows: (1) To compare the overall survival (OS) of SDREGN2810, HDREGN2810, and the SDREGN2810 / ipi combination therapy in the second-line treatment of patients with progressive squamous or non-squamous NSCLC whose tumors express PD-L1 in <50% of tumor cells; (2) To compare the progression-free survival (PFS) of HDREGN2810 and SDREGN2810 / ipi against SDREGN2810 in the second-line treatment of patients with progressive squamous or non-squamous NSCLC who have tumors that express PD-L1 in <50% of tumor cells. (3) To evaluate the safety and tolerability of HDREGN2810 and SDREGN2810 / ipi compared to SDREGN2810 treatment; (4) To evaluate the OS at 12 and 18 months of HDREGN2810 and SDREGN2810 / ipi against SDREGN2810 treatment in the second-line treatment of patients with progressive squamous or non-squamous NSCLC who have tumors that express PD-L1 in <50% of tumor cells; (5) To evaluate the quality of life (QOL) in patients with progressive squamous or non-squamous NSCLC receiving HDREGN2810 and SDREGN2810 / ipi compared to SDREGN2810 treatment; (6) To evaluate the immunogenicity measured by anti-drug antibodies (ADA) against REGN2810; (7) To characterize the pharmacokinetics (PK) of REGN2810 when administered in combination with ipilimumab or as HDREGN2810.

[0283] Study Design This is a clinical study of HDREGN2810 and SDREGN2810 / ipi compared to SDREGN2810 treatment in the second-line treatment of patients with progressive or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 in <50%. This study consists of the following three periods: screening, treatment, and follow-up. Patients receive a screening evaluation within 28 days prior to randomization to determine their eligibility. Eligible patients are randomly selected 1:1:1 to receive one of the following treatment regimens: · Treatment Arm A: REGN2810 350 mg every 3 weeks (Q3W) for 108 weeks (hereinafter referred to as "SDREGN2810" in this specification) · Treatment Arm B: REGN2810 350 mg Q3W for 108 weeks and ipilimumab 50 mg every 6 weeks (Q6W) up to 4 doses (hereinafter referred to as "SDREGN2810 / ipi" in this specification) · Treatment Arm C: REGN2810 1050 mg Q3W for 108 weeks (hereinafter referred to as "HDREGN2810" in this specification) At randomization, patients are stratified by histology (squamous vs. non-squamous) and PD-L1 expression level (<1% vs. 1% to <50%). Patients receive the treatment to which they are assigned (as shown above) during the treatment period. Treatment may be discontinued early due to progressive disease as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anti-cancer treatment, or confirmed complete response (CR), partial response (PR) or stable disease (SD) in certain situations. Patients who experience progressive disease as defined by RECIST 1.1 during treatment may continue study treatment if the study physician in charge determines that the patient is experiencing clinical benefit and the patient has not completed the 108-week treatment period. If further progressive disease (defined as a further 10% increase in tumor volume from the time of initial progressive disease) is confirmed, REGN2810 (and ipilimumab if applicable) must be discontinued and other anti-cancer treatments are considered if appropriate. After discontinuation of the study treatment, patients enter the follow-up period. Each patient has the first follow-up visit 14 to 30 days (±7 days) after the last study treatment if the treatment was discontinued early due to progressive disease, toxicity or for another reason. Otherwise, each patient has the first follow-up visit 14 to 30 days (±7 days) after the last cycle visit. Follow-up visits 2 to 7 are conducted 28 days (±7 days) after the previous visit. Subsequently, survival data are collected by telephone or at the hospital every 3 months until death, loss to follow-up, or withdrawal of study consent.

[0284] Study Population Patients in this study include male and female patients aged ≥ 18 years who are diagnosed with progressive or metastatic non-squamous or squamous NSCLC, have received only first-line treatment for progressive or metastatic NSCLC, and whose tumors express < 50% PD-L1.

[0285] Inclusion criteria : 1. Male and female patients aged ≥ 18 years; 2. Patients with histologically or cytologically documented stage IIIB squamous or non-squamous NSCLC who are not candidates for definitive concurrent chemoradiation treatment, or who have stage IV disease if they have previously received systemic treatment for progressive or metastatic NSCLC and have previously received first-line treatment for progressive NSCLC; 3. Availability of formalin-fixed paraffin-embedded tumor tissue biopsy samples obtained during record-keeping or the study. Guidance for biopsy sites: a. Record-keeping or fresh biopsies are acceptable; b. If record-keeping biopsies are used, they must be less than 5 months old; c. Biopsies should be from metastatic or recurrent sites that have not been previously irradiated. Exception: The primary tumor is still in place and other metastatic sites are inaccessible (brain) or unusable (bone) or the biopsy would put the patient at risk. 4. Expression of PD-L1 in < 50% of tumor cells as determined by the PD-L1 IHC 22C3 pharmDx assay performed by a central laboratory; 5. Lesions measurable by radiography by computed tomography (CT) according to at least one RECIST 1.1 criterion. Target lesions may be located in previously irradiated areas if there is documented (radiographic) disease progression at that site. 6. ECOG performance status ≤ 1; 7. Predicted lifespan of at least 3 months.

[0286] Exclusion criteria : 1. Patients with no history of smoking defined as ≤ 100 lifetime pack-years of tobacco smoking; 2. Active or untreated brain metastases or spinal cord compression. Central nervous system (CNS) metastases have been appropriately treated and the patient has returned neurologically to baseline at least 2 weeks prior to enrollment. If so (excluding residual signs or symptoms related to CNS treatment), the patient is eligible. The patient must have discontinued corticosteroid treatment (at immunosuppressive doses) (see exclusion criterion 7 for details regarding the timing of steroid discontinuation), and be a patient with a tumor that has been tested positive for 3. EGFR gene mutation, ALK gene translocation, or ROS1 fusion. All patients will have their tumors evaluated for EGFR mutation, ALK rearrangement, and ROS1 fusion. 4. Encephalitis, meningitis, or uncontrolled epilepsy within 1 year prior to informed consent. 5. Interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia that required immunosuppressive doses of glucocorticoids to assist in management, or a history of pneumonitis within the last 5 years. A history of radiation pneumonitis in the irradiated field is acceptable as long as the pneumonia has resolved for ≥6 months prior to enrollment. 6. Evidence of ongoing or recent (within 5 years) major autoimmune disease that required treatment with immunosuppressive regimens, which may suggest a risk for immune-related treatment-emergent adverse events (irTEAE). The following are not excluded: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormonal replacement, or psoriasis not requiring systemic treatment. 7. Patients who have a condition that requires corticosteroid treatment (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiological replacement doses are acceptable even if prednisone / day >10 mg or equivalent as long as they are not administered with immunosuppressive intent. Inhaled or topical steroids are acceptable, provided they are not for the treatment of autoimmune disorders.

[0287] Study treatment · REGN2810 (「SDREGN2810」) administered at 350 mg as an intravenous (IV) infusion Q3W for 108 weeks · REGN2810 (「SDREGN2810 / ipi」) administered at 350 mg as an IV infusion Q3W for 108 weeks in combination with ipilimumab administered IV at 50 mg Q6W for up to 4 doses · REGN2810 (「HDREGN2810」) administered at 1050 mg as an IV infusion Q3W for 108 weeks Research evaluation items The primary evaluation item is the objective response rate (ORR), which is defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) based on RECIST 1.1, evaluated by a blinded independent review committee (IRC).

[0288] The secondary evaluation items in the study are: (1) overall survival (OS), defined as the time from randomization to the date of death. For patients who have not died, the follow-up is censored at the last known date when the patient was alive. (2) Progression-free survival (PFS), defined as the time from randomization to the date of the first documented tumor progression as determined by RECIST 1.1 and evaluated by the blinded IRC, or the date of death from any cause. (3) Overall survival at 12 months, 18 months, and at the end of treatment. (4) The safety and tolerability of SDREGN2810, HDREGN2810, and the SDREGN2810 / ipi combination treatment, measured by the incidence of adverse events, dose-limiting toxicities, serious adverse events, deaths, and laboratory abnormalities occurring during treatment. (5) Quality of life, measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13). (6) Characterization of the pharmacokinetic (PK) properties of REGN2810 when administered in combination with ipilimumab or as HDREGN2810. (7) Assessment of immunogenicity, measured by anti-drug antibody (ADA) titers against REGN2810. (8) Assessment of hair depigmentation by the principal investigator of the clinical trial. (9) Tumor mutational burden, evaluated by the Foundation Medicine "FoundationOne (R) " panel. (10) Assessment of tumor volume. (11) Evaluation of ICOS+CD4 T cell frequency and other markers of T cell activation.

[0289] Procedures and evaluations Procedures to be performed at screening include informed consent; assessment of inclusion / exclusion criteria; recording of medical, oncology, and concomitant medication history; recording of demographics; collection and testing of tumor tissue samples for PD-L1 assessment and for epithelial growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations and C-ros oncogene receptor tyrosine kinase (ROS1) fusions; radiographic tumor assessment; tumor burden assessment; chest x-ray; serum pregnancy test; 12-lead electrocardiogram; recording of adverse events (AE); physical examination including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; and laboratory tests. Samples for any genomic sub-studies may also be obtained. During the treatment period, the following procedures are performed to evaluate efficacy and safety: QOL measurement using a validated patient questionnaire; physical examination; ECOG performance status assessment; vital signs; laboratory tests including pregnancy test for women of childbearing potential; recording of AE and concomitant medications. Computed tomography for radiographic tumor burden assessment and tumor burden assessment based on RECIST 1.1 criteria are performed at pre-specified time points during the study. Other evaluations include investigator assessment of hair pigmentation, REGN2810 concentration measurement, REGN2810 ADA assessment, and biomarker assessment. The biomarker procedures include the use of tumor tissue samples for further validation of the PD-L1 assay. Survival data are then collected by telephone or at clinic visits every 3 months until death, loss to follow-up, or withdrawal of study consent.

[0290] Results SDREGN2810 / ipi or HDREGN2810 is expected to have a higher response rate than SDREGN2810 in patients whose tumors express PD-L1 in <50% of tumor cells. Assuming a 10% overall response rate in patients with 1% - <50% PD-L1 expression treated with SDREGN2810, HDREGN2810 or SDREGN2810 / ipi is expected to achieve an ORR of 30%; a 20% absolute increase compared to SDREGN2810.

[0291] Example 14: Clinical Study of the Combination of REGN2810 (an anti-PD-1 antibody), Ipilimumab (an anti-CTLA4 antibody), and Platinum Doublet Chemotherapy in the First-Line Treatment of Patients with Progressive or Metastatic Non-Small Cell Lung Cancer Whose Tumors Express <50% PD-L1 This example describes a clinical study of the combination of REGN2810 (an anti-PD-1 antibody), ipilimumab (an anti-CTLA-4 antibody), and platinum-based doublet chemotherapy in the first-line treatment of patients with progressive or metastatic non-small cell lung cancer having tumors that express <50% PD-L1 and who have not previously received systemic treatment for their progressive disease.

[0292] The primary objective of this study is to compare the progression-free survival (PFS) of combination therapies of REGN2810 with 4 - 6 cycles of standard-of-care platinum-based doublet chemotherapy (REGN2810 / chemo-f) and REGN2810 with 2 cycles only of standard-of-care platinum-based doublet chemotherapy and ipilimumab (REGN2810 / chemo-l / ipi) to standard-of-care platinum-based doublet chemotherapy in the first-line treatment of patients with progressive squamous or non-squamous non-small cell lung cancer (NSCLC) in a subgroup of patients whose tumors express programmed cell death ligand 1 (PD-L1) in 1% - <50% of tumor cells and in the overall population of study patients whose tumors express PD-L1 in <50% of tumor cells.

[0293] The secondary objectives are: (1) to compare the overall survival (OS) of REGN2810 / chemo-f and REGN2810 / chemo-l / ipi to standard-of-care platinum-based doublet chemotherapy in the first-line treatment of patients with progressive squamous or non-squamous NSCLC in a subgroup of patients whose tumors express PD-L1 in 1% - <50% of tumor cells and in the overall population of study patients whose tumors express PD-L1 in <50% of tumor cells. Compare with the study therapy. (2) Compare the objective response rate (ORR) of REGN2810 / chemo-f and REGN2810 / chemo-l / ipi against platinum-based doublet chemotherapy as the standard treatment in the subgroup of patients whose tumors express PD-L1 in 1% to <50% of tumor cells and in the overall population of study patients whose tumors express PD-L1 in <50% of tumor cells, in the first-line treatment of patients with progressive squamous or non-squamous NSCLC. (3) Evaluate the safety and tolerability of REGN2810 and 4 to 6 cycles of platinum doublet chemotherapy and REGN2810 and ipilimumab. (4) Characterize the pharmacokinetics of REGN2810 and 4 to 6 cycles of platinum doublet chemotherapy and REGN2810 and ipilimumab. (5) Compare the OS at 12 and 18 months of REGN2810 / chemo-f or REGN2810 / chemo-l / ipi against platinum-based doublet chemotherapy as the standard treatment in the subgroup of patients whose tumors express PD-L1 in 1% to <50% of tumor cells and in the overall population of study patients whose tumors express PD-L1 in <50% of tumor cells, in the first-line treatment of patients with progressive squamous or non-squamous NSCLC. (6) Evaluate the immunogenicity as measured by anti-drug antibodies against REGN2810, including.

[0294] Study population The target population includes males and females aged ≥18 years with <50% PD-L1+ tumor cells, stage IIIB or IV, squamous or non-squamous NSCLC who have not previously received treatment for their progressive disease.

[0295] Inclusion criteria : 1) Males and females aged ≥18 years 2) Patients with histologically or cytologically documented squamous or non-squamous NSCLC having stage IIIB or IV disease who have not previously received systemic treatment for recurrent or metastatic NSCLC 3) Patients who have received adjuvant or neoadjuvant platinum-doublet chemotherapy (after surgery and / or radiotherapy) and develop recurrent or metastatic disease more than 6 months after completion of treatment are eligible. 4) Patients who have received adjuvant or neoadjuvant PD-1 or PD-L1 blockade and develop recurrent or metastatic disease more than 12 months after completion of treatment are eligible. 5) Archived or newly obtained formalin-fixed tumor tissue from the metastasis / recurrence site that has not been previously irradiated. 6) Tumor cells expressing PD-L1 in <50% of tumor cells by IHC performed by a central laboratory. 7) At least one lesion measurable by computerized tomography (CT) or magnetic resonance imaging (MRI) by X-ray examination according to RECIST 1.1 criteria. Target lesions may be located in previously irradiated areas if there is documented (X-ray examination) disease progression at that site. 8) ECOG performance status ≤1 9) Predicted lifespan of at least 3 months 10) Appropriate organ and bone marrow function as defined below: 11) Hemoglobin ≥10.0 g / dL 12) Absolute neutrophil count ≥1.5 × 10 9 / L 13) Platelet count ≥100,000 / mm 3 14) Glomerular filtration rate (GFR) >30 mL / min / 1.73 m 2 15) Total bilirubin ≤1.5 × upper limit of normal (ULN) (≤3 × ULN in case of liver metastasis), excluding patients clinically diagnosed with Gilbert's syndrome. 16) Aspartate aminotransferase (AST) and alanine aminotransferase (A LT) ≤3 × ULN or ≤5 × ULN in case of liver metastasis 17) Alkaline phosphatase ≤2.5 × ULN (or ≤5.0 × ULN in case of liver or bone metastasis) 18) Does not meet the criteria for Hy's law (ALT > 3×ULN and bilirubin > 2×ULN) 19) Is willing and able to follow the visit and research-related procedures 20) Submit a signed informed consent 21) Can understand the research-related questionnaire and fill in all items.

[0296] Exclusion criteria: 1. Defined as smoking ≤100 cigarettes in a lifetime, patients who have never smoked; 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if CNS metastases have been appropriately treated and the patient has returned to neurological baseline for at least 2 weeks prior to registration (excluding residual signs or symptoms related to CNS treatment). Patients must have discontinued corticosteroid treatment (at immunosuppressive doses) (see exclusion criterion 7 for details regarding the timing of steroid discontinuation), 3. Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions. All patients will have their tumors evaluated for EGFR mutations, ALK rearrangements, and ROS1 fusions. 4. Encephalitis, meningitis, or uncontrolled epilepsy within 1 year prior to informed consent. 5. Interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia requiring immunosuppressive doses of glucocorticoids to assist management, or a history of pneumonia within the last 5 years. A history of radiation pneumonitis in the radiation field is acceptable as long as the pneumonia has resolved ≥6 months prior to registration. 6. Evidence of ongoing or recent major autoimmune diseases requiring treatment with systemic immunosuppressive agents, which may suggest a risk for immune-related treatment-emergent adverse events (irTEAE). The following are not exclusions: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormonal replacement, or psoriasis not requiring systemic treatment. 7. Patients with a condition requiring corticosteroid treatment (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiological replacement doses are acceptable even if prednisone / day >10 mg or equivalent as long as they are not administered with immunosuppressive intent. Inhaled or topical steroids are acceptable, provided they are not for the treatment of autoimmune disorders.

[0297] Study Design This clinical trial is a study of REGN2810 / chemo-f vs REGN2810 / chemo-l / ipi vs standard-of-care platinum-based doublet chemotherapy in the first-line treatment of patients with stage IIIB or IV squamous or non-squamous NSCLC whose tumors express PD-L1 in <50% of tumor cells and who have not previously received systemic treatment for their progressive disease. Tumor tissue (tumor blocks or at least 12 unstained slides) is provided for PD-L1 assessment using a validated PD-L1 assay.

[0298] Patients with progressive untreated NSCLC were randomly assigned 1:1:1 to one of the following treatment arms: Treatment Arm A: Standard-of-care platinum-based doublet chemotherapy every 3 weeks (Q3W) for 4 - 6 cycles (followed by optional pemetrexed maintenance for patients initially assigned to receive a pemetrexed-containing regimen) Treatment Arm B: REGN2810 350 mg Q3W for 108 weeks and standard-of-care platinum-based doublet chemotherapy for 4 - 6 cycles (hereinafter referred to as "REGN2810 / chemo-f" in this specification) Treatment Arm C: REGN2810 350 mg Q3W for 108 weeks and standard-of-care platinum-based doublet chemotherapy for 2 cycles and ipilimumab 50 mg every 6 weeks (Q6W ) for up to 4 doses (hereinafter referred to as "REGN2810 / chemo-l / ipi" in this specification) Randomization was stratified by histology (non-squamous vs squamous) and level of PD-L1 expression (<1% vs 1% - 24% vs 25% - <50%).

[0299] Patients receive the treatment assigned to them during the treatment period (as shown above). Treatment may be discontinued early due to progressive disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anti-cancer treatment, or in specific situations of complete remission (CR) or partial response (PR) for patients in treatment arms B and C.

[0300] Test treatment Treatment arm (A) : Standard treatment platinum-based doublet chemotherapy administered IV Q3W for 4 - 6 cycles (subsequently, optional pemetrexed maintenance for patients initially assigned to receive a pemetrexed-containing regimen) Treatment arm (B) : REGN2810 administered IV at 350 mg as an IV infusion Q3W for 108 weeks, in combination with standard treatment platinum-based doublet chemotherapy administered IV Q3W for 4 - 6 cycles Treatment arm (C) : REGN2810 administered IV at 350 mg as an IV infusion Q3W for 108 weeks, in combination with standard treatment platinum-based doublet chemotherapy administered IV Q3W for 2 cycles and ipilimumab administered IV at 50 mg over approximately 90 minutes Q6W for up to 4 doses The 4 - 6 cycles of standard treatment platinum doublet chemotherapy are administered according to one of the following regimens: (i) Paclitaxel + cisplatin: Participants receive paclitaxel 200 mg / m administered IV on day 1 every 21 days for 4 - 6 cycles or until documented disease progression 2 , followed by cisplatin 75 mg / m administered IV 2 . (ii) Paclitaxel + carboplatin: Participants receive paclitaxel 200 mg / m administered IV on day 1 every 21 days for 4 - 6 cycles or until documented disease progression 2 , followed by carboplatin AUC of 5 or 6 mg / ml / min administered IV 2 . (iii) Gemcitabine + cisplatin: Participants receive gemcitabine 1250 mg / m administered IV on days 1 and 8 of each 21 - day cycle for 4 - 6 cycles or until disease progression, and cisplatin 75 mg / m administered IV on day 1 every 21 days 2 . (iv) Gemcitabine + carboplatin: Participants receive gemcitabine 1250 mg / m administered IV on days 1 and 8 of each 21 - day cycle for 4 - 6 cycles or until disease progression 2And receive carboplatin AUC 5 or 6 mg / ml / min administered IV on day 1 every 21 days. (v) Pemetrexed + cisplatin (for non-squamous histology only): Participants receive pemetrexed 500 mg / m 2 iv on day 1 every 21 days for 4 - 6 cycles, followed by cisplatin 75 mg / m 2 administered IV, followed by maintenance pemetrexed 500 mg / m 2 for the remainder of the study or until documented disease progression. (vi) Pemetrexed + carboplatin (for non-squamous histology only): Participants receive IV-administered pemetrexed 500 mg / m 2 on day 1 every 21 days for 4 - 6 cycles, followed by carboplatin AUC 5 or 6 mg / ml / min administered IV, followed by maintenance pemetrexed 500 mg / m 2 for the remainder of the study or until documented disease progression.

[0301] Procedures and Assessments Procedures to be performed at screening are informed consent; assessment of inclusion / exclusion criteria; recording of medical, histological, and concomitant medication history; recording of demographics; collection and testing of tumor tissue samples for PD-L1 assessment and for epidermal growth factor receptor and anaplastic lymphoma kinase mutations and C-ros oncogene receptor tyrosine kinase fusions; radiographic tumor assessment ; tumor burden assessment; chest x-ray; serum pregnancy test; 12-lead electrocardiogram; recording of adverse events (AE); physical examination including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; and laboratory tests. Samples for any genomic sub-studies may also be obtained.

[0302] During the treatment period, the following procedures are carried out to evaluate efficacy and safety: QOL measurement using a valid patient questionnaire, physical examination, ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for women of childbearing potential; recording of AEs and concomitant medications. Computed tomography or magnetic resonance imaging (or positron emission tomography) for X-ray tumor volume assessment and tumor volume assessment based on RECIST 1.1 criteria is performed at pre-specified time points during the study.

[0303] Survival data are collected by telephone or at clinic visits every 3 months until death, loss to follow-up, or withdrawal of informed consent from the study.

[0304] Results The R2810 combination regimen is expected to increase the median PFS to 4 months in patients with tumors expressing PD-L1 between 1% and <50%, and in the overall study population (from 6 months for standard-of-care platinum doublet chemotherapy to 10 months for any R2810 combination regimen). REGN2810 and 4 - 6 cycles of platinum doublet chemotherapy or REGN2810 or REGN2810 and ipilimumab extend OS and improve ORR compared to platinum doublet chemotherapy.

[0305] Example 15: Clinical study of the combination of REGN2810 (anti-PD-1 antibody), platinum-based doublet chemotherapy, and ipilimumab (anti-CTLA-4 antibody) versus pembrolizumab monotherapy as first-line treatment in patients with progressive or metastatic non-small cell lung cancer whose tumors express PD-L1 ≥50% This example describes a clinical study of the combination of REGN2810 monotherapy, platinum-based doublet chemotherapy, and ipilimumab (administered up to 4 doses) versus pembrolizumab monotherapy in patients with progressive or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 in ≥50% of tumor cells and who have not previously received systemic treatment for their progressive disease.

[0306] The primary objective of the study is to compare the progression-free survival (PFS) of combination therapy with REGN2810 (semiplimab) and ipilimumab (hereinafter referred to as REGN2810 / ipi in this specification) and combination therapy with REGN2810, platinum-based doublet chemotherapy for only 2 cycles, and ipilimumab (hereinafter referred to as "REGN2810 / chemo / ipi" in this specification) with standard treatment pembrolizumab monotherapy in the first-line treatment of patients with progressive squamous or non-squamous non-small cell lung cancer (NSCLC) whose tumors express programmed cell death ligand 1 (PD-L1) in ≥50% of tumor cells. Further objectives include further characterization of overall survival, tumor response, patient-reported outcomes, safety, and pharmacokinetics (PK).

[0307] Study population The target population includes male and female patients ≥18 years of age with ≥50% PD-L1+ tumor cells, stage IIIB or IV, squamous or non-squamous NSCLC who have not previously received treatment for their progressive disease.

[0308] Inclusion criteria : 1) Male and female patients ≥18 years of age 2) Have histologically or cytologically documented squamous or non-squamous NSCLC of stage IIIB or IV disease and have not previously received systemic treatment for recurrent or metastatic NSCLC 3) Have received adjuvant or neoadjuvant platinum doublet chemotherapy (after surgery and / or radiotherapy) and developed recurrent or metastatic disease more than 6 months after completion of treatment 4) Patients who have received adjuvant or neoadjuvant PD-1 or PD-L1 blockade and developed recurrent or metastatic disease more than 12 months after completion of treatment are eligible 5) Archived or newly obtained formalin-fixed tumor tissue from metastatic / recurrent sites that have not been previously irradiated 6) Tumor cells expressing PD-L1 in ≥50% of tumor cells by IHC performed by a central laboratory 7) At least one lesion measurable by X-ray examination by computed tomography (CT) or magnetic resonance imaging (MRI) according to the RECIST 1.1 criteria. If there is documented disease progression (by X-ray examination) at that site, the target lesion may be located in a previously irradiated area. 8) ECOG performance status ≤ 1 9) Predicted lifespan of at least 3 months 10) Appropriate organ and bone marrow function as defined below: 11) Hemoglobin ≥ 8.0 g / dL 12) Absolute neutrophil count ≥ 1.0 × 10 9 / L 13) Platelet count ≥ 75,000 / mm 3 14) Glomerular filtration rate (GFR) > 30 mL / min / 1.73 m 2 15) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (≤ 3 × ULN in case of liver metastases), excluding patients diagnosed with clinically confirmed Gilbert's syndrome 16) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN in case of liver metastases 17) Alkaline phosphatase ≤ 2.5 × ULN (or ≤ 5.0 × ULN in case of liver or bone metastases) 18) Does not meet the criteria for Hy's law (ALT > 3 × ULN and bilirubin > 2 × ULN) 19) Is willing and able to comply with study visits and study-related procedures 20) Submits a signed informed consent 21) Can understand the study-related questionnaire and complete all items.

[0309] Exclusion criteria: 1. Defined as ≤ 100 cigarettes smoked in a lifetime, patients who have never smoked; 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if CNS metastases have been appropriately treated and the patient has returned to neurologic baseline for at least 2 weeks prior to registration (excluding residual signs or symptoms related to CNS treatment). Patients must have discontinued corticosteroid treatment (at immunosuppressive doses) (see exclusion criterion 7 for details regarding the timing of steroid discontinuation), 3. Patients with tumors tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions. All patients will have their tumors evaluated for EGFR mutations, ALK rearrangements, and ROS1 fusions. 4. Encephalitis, meningitis, or uncontrolled epilepsy within 1 year prior to informed consent. 5. Interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia requiring immunosuppressive doses of glucocorticoids to assist in management, or a history of pneumonia within the last 5 years. A history of radiation pneumonitis in the radiation field is acceptable as long as the pneumonia had resolved ≥ 6 months prior to registration. 6. Evidence of ongoing or recent significant autoimmune disease requiring treatment with systemic immunosuppressive therapy, which may suggest a risk for immune-related treatment-emergent adverse events (irTEAE). The following are not excluded: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormonal replacement, or psoriasis not requiring systemic treatment. 7. Patients with a condition requiring corticosteroid treatment (> 10 mg prednisone / day or equivalent) within 14 days of randomization. Physiologic replacement doses are acceptable even if prednisone / day > 10 mg or equivalent as long as they are not administered with immunosuppressive intent. Inhaled or topical steroids are acceptable, provided they are not for the treatment of autoimmune disorders.

[0310] Study Design This clinical trial is a study of the efficacy and safety of REGN2810 / ipi versus REGN2810 / chemo / ipi versus pembrolizumab monotherapy in patients with stage IIIB or IV squamous or non-squamous NSCLC, whose tumors express PD-L1 in ≥50% of tumor cells and who have not previously received systemic treatment for their progressive disease.

[0311] The study consists of the following three periods: screening, treatment, and follow-up. Patients receive a screening evaluation to determine their eligibility within 28 days prior to randomization. Eligible patients are randomly assigned 1:1:1 to one of the following treatment arms: · Treatment arm A : Pembrolizumab monotherapy 200 mg every 3 weeks (Q3W) for 108 weeks · Treatment arm B : REGN2810 350 mg Q3W for 108 weeks and ipilimumab 50 mg up to 4 doses every 6 weeks (Q6W) · Treatment arm C : REGN2810 350 mg Q3W for 108 weeks and platinum-based doublet chemotherapy Q3W for 2 cycles and ipilimumab 50 mg up to 4 doses every 6 weeks (Q6W) Patients will receive their assigned treatment for a treatment period of 108 weeks. Treatment may be discontinued early due to progressive disease as defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anti-cancer treatment, or in specific circumstances of complete remission (CR) or partial response (PR) for treatment arms B and C, for patients. Patients who experience progressive disease as defined by RECIST 1.1 during treatment may continue on study treatment if the study responsible physician determines that the patient is experiencing clinical benefit and the patient has not completed the 108-week treatment period. If further progressive disease (defined as a further 10% increase in tumor volume from the time of initial progressive disease) is confirmed, REGN2810 (and ipilimumab if applicable) must be discontinued and other anti-cancer treatments considered if appropriate. A similar approach to treatment beyond the first evidence of progression is offered to patients receiving pembrolizumab in treatment arm A.

[0312] Study treatment Treatment arm A : Pembrolizumab administered at 200 mg as an IV infusion Q3W for 108 weeks Treatment arm B : REGN2810 administered at 350 mg as an intravenous (IV) infusion Q3W for 108 weeks, in combination with ipilimumab administered IV at 50 mg Q6W for up to 4 doses over approximately 90 minutes. Treatment arm C : REGN2810 administered at 350 mg as an IV infusion Q3W for 108 weeks, in combination with platinum-based doublet chemotherapy administered IV Q3W for 2 cycles and ipilimumab administered IV at 50 mg Q6W for up to 4 doses over approximately 90 minutes.

[0313] Procedures and Assessments Procedures to be performed at screening are informed consent; inclusion / exclusion criteria Standard evaluation; recording of medical, oncology, and combination drug history; recording of demographics; collection and examination of tumor tissue samples for PD-L1 evaluation and for epithelial growth factor receptor and anaplastic lymphoma kinase mutations and C-ros oncogene receptor tyrosine kinase fusions; baseline X-ray tumor evaluation and tumor burden evaluation; chest X-ray; serum pregnancy test; 12-lead electrocardiogram; a full physical examination including vital signs, height, and weight evaluation; Eastern Cooperative Oncology Group (ECOG) performance status evaluation; recording of adverse events (AE); and including laboratory tests. Samples may also be obtained for any genomic sub-studies.

[0314] During the treatment period, the following procedures are conducted to evaluate efficacy and safety: QOL measurement using a validated patient questionnaire examination, physical examination, ECOG performance status evaluation; vital signs; laboratory tests including pregnancy tests for women who may be pregnant; recording of AE and concomitant medications. Computed tomography or magnetic resonance imaging (or positron emission tomography) for X-ray tumor burden evaluation and tumor burden evaluation based on RECIST 1.1 criteria are conducted at pre-specified time points during the study.

[0315] Survival data are collected by telephone or at clinic visits every three months until death, loss to follow-up, or withdrawal of informed consent from the study.

[0316] Results Any REGN2810 combination is expected to extend PFS by 1 - 5 months compared to pembrolizumab monotherapy. REGN2810 in combination with chemotherapy and / or anti-CTLA-4 antibody extends OS and improves ORR compared to pembrolizumab monotherapy.

[0317] The invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to be within the scope of the appended claims.

Claims

1. 16. A method of treating cancer or increasing survival of a cancer patient, comprising: (a) selecting a patient having lung cancer based on characteristics selected from the group consisting of: (i) the patient has non-small cell lung cancer, (ii) tumor tissue in the patient expresses programmed cell death-ligand 1 (PD-L1) in <50% of the tumor cells; (iii) tumor tissue in the patient expresses PD-L1 in >= 50% of the tumor cells; (iv) the patient has squamous or non-squamous stage III or stage IV lung cancer; (v) the patient has not previously undergone systemic treatment for lung cancer; and (vi) the patient has previously undergone treatment with an anti-tumor therapy; and (b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to programmed cell death 1 (PD-1), thereby treating the lung cancer in the patient.

2. 2. The method of claim 1, wherein the patient has progressive or recurrent non-small cell lung cancer, tumor tissue in the patient expresses PD-L1 in >= 50% of the tumor cells, and the patient has not been previously treated with a systemic treatment for lung cancer.

3. 2. The method of claim 1, wherein the patient has progressive or recurrent non-small cell lung cancer, tumor tissue in the patient expresses PD-L1 in >= 50% of tumor cells, and the patient has been previously treated with chemotherapy.

4. 2. The method of claim 1, wherein the patient has progressive or recurrent non-small cell lung cancer, tumor tissue in the patient expresses PD-L1 in <50%, <= 40%, <= 30%, <= 20%, <= 10%, <= 5%, <= 25, or <= 1% of the tumor cells, and has been previously treated with an anti-tumor therapy.

5. 2. The method of claim 1, wherein the patient has progressive or recurrent non-small cell lung cancer, and tumor tissue in the patient expresses PD-L1 in <50%, <= 40%, <= 30%, <= 20%, <= 10%, <= 5%, <= 25, or <= 1% of the tumor cells, and has not been previously treated with an anti-tumor therapy.

6. 1. A method of treating cancer or increasing survival of a cancer patient, comprising: (a) selecting a patient with lung cancer, wherein tumor tissue in the patient expresses PD-L1 in >= 50% of tumor cells; and (b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1, thereby treating the lung cancer in the patient.

7. 1. A method of treating cancer or increasing survival of a cancer patient, comprising: (a) selecting a patient with lung cancer, wherein tumor tissue in the patient expresses PD-L1 in <50% of tumor cells; and (b) administering to the patient one or more doses of a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to PD-1, thereby treating the lung cancer in the patient.

8. 8. The method of claim 6 or 7, wherein the patient has advanced or metastatic non-small cell lung cancer.

9. The method of any one of claims 6 to 8, wherein the patient has squamous or non-squamous stage III or stage IV non-small cell lung cancer.

10. The method of any one of claims 6 to 9, wherein the patient has not been previously treated with a systemic treatment for lung cancer.

11. The method of any one of claims 6 to 9, wherein the patient has been previously treated with an anti-tumor therapy comprising platinum-based chemotherapy.

12. 1. A method for treating cancer or increasing survival of a cancer patient, comprising: (a) selecting a patient having lung cancer based on at least one characteristic selected from the group consisting of: (i) the patient has advanced or metastatic non-small cell lung cancer; (ii) the patient has squamous or non-squamous stage III or stage IV lung cancer; (iii) the patient has not been previously treated with a systemic treatment for lung cancer; and (iv) the patient has been previously treated with an anti-tumor therapy; (b) determining the expression of PD-L1 in the tumor tissue; and (c) if the tumor tissue expresses PD-L1 in >= 50% of the tumor cells, administering to the patient a therapeutically effective amount of one or more doses of an antibody or antigen-binding fragment thereof that specifically binds to PD-1, thereby treating the lung cancer in the patient. The above method.

13. 1. A method for treating cancer or increasing survival of a cancer patient, comprising: (a) selecting a patient having lung cancer based on at least one characteristic selected from the group consisting of: (i) the patient has advanced or metastatic non-small cell lung cancer; (ii) the patient has squamous or non-squamous stage III or stage IV lung cancer; (iii) the patient has not been previously treated with a systemic treatment for lung cancer; and (iv) the patient has been previously treated with an anti-tumor therapy; (b) determining the expression of PD-L1 in the tumor tissue; and (c) if the tumor tissue expresses PD-L1 in <50% of the tumor cells, administering to the patient a therapeutically effective amount of one or more doses of an antibody or antigen-binding fragment thereof that specifically binds to PD-1, thereby treating the lung cancer in the patient. The above method.

14. 14. The method of claim 13, wherein the tumor tissue expresses PD-L1 in < 45%, < 40%, < 30%, < 20%, < 10%, < 5%, < 2%, or < 1% of the tumor cells.

15. 15. The method of any one of claims 1-14, wherein each dose of anti-PD-1 antibody is administered 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose.

16. 16. The method of any one of claims 1-15, wherein each dose comprises 20-1500 mg of anti-PD-1 antibody.

17. 17. The method of claim 16, wherein each dose comprises 200, 250, 300, 350, 450, 600, 750, 800, 1000, or 1050 mg of the anti-PD-1 antibody.

18. 18. The method of claim 16 or 17, wherein each dose comprises 350 mg of the anti-PD-1 antibody and is administered 3 weeks after the immediately preceding dose.

19. The method of any one of claims 1 to 14, wherein each dose of the anti-PD-1 antibody comprises 0.1 to 10 mg / kg of the patient's body weight.

20. 20. The method of claim 19, wherein each dose of the anti-PD-1 antibody comprises 1, 3, 4, 5, 6, or 10 mg / kg of the patient's body weight.

21. 21. The method of claim 20, wherein each dose is administered 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose.

22. The method of any one of claims 1 to 21, wherein the anti-PD-1 antibody is administered as an intravenous infusion to the patient.

23. 23. The method of any one of claims 1 to 22, wherein the anti-PD-1 antibody is administered in combination with a second therapeutic agent selected from the group consisting of chemotherapy, a cytotoxic T-lymphocyte protein 4 (CTLA-4) inhibitor (e.g., an anti-CTLA-4 antibody), radiation, surgery, a lymphocyte-activation gene 3 (LAG-3) inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, and a PD-L1 inhibitor.

24. The method of claim 23, wherein the anti-PD-1 antibody is administered in combination with platinum-based chemotherapy.

25. The method of claim 23 or 24, wherein the anti-PD-1 antibody is administered in combination with an anti-CTLA-4 antibody.

26. 26. The method of any one of claims 1 to 25, wherein administration of at least one dose of the anti-PD-1 antibody results in an increase in progression-free survival (PFS) or overall survival (OS) of the patient compared to patients administered platinum-based chemotherapy as monotherapy.

27. 27. The method of claim 26, wherein PFS is increased by at least 1 month compared to patients administered platinum-based chemotherapy.

28. 28. The method of claim 26 or 27, wherein OS is increased by at least 1 month compared to patients administered platinum-based chemotherapy.

29. The method of any one of claims 1 to 28, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1, and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

2.

30. The method of any one of claims 1-28, wherein 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 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.

31. 31. The method of claim 30, 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.

32. The method of any one of claims 1 to 31, 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.

33. The method of any one of claims 1 to 31, wherein the anti-PD-1 antibody is REGN2810 (cemiplimab).

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