Anti-PD-1 Antibodies for the Treatment of Lung Cancer

Abstract

To provide methods for treating, reducing the severity, or inhibiting the growth of cancer (e.g., lung cancer).SOLUTION: Methods of the present invention comprise administering a therapeutically effective amount of a programmed death 1 (PD-1) antagonist (e.g., an anti-PD-1 antibody), to a subject with lung cancer wherein the cancer tissue expresses PD-L1.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 Nos. 62 / 461,672 (filed February 21, 2017); and 62 / 595,190 (filed December 6, 2017), the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THEINVENTION 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 technology]

[0003] background Lung cancer is one of the most commonly diagnosed cancers and the leading cause of cancer-related deaths 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 include adenocarcinoma (40%-60%) and squamous cell carcinoma (30%). The majority of patients with NSCLC are known to have aggressive cancer at the time of diagnosis (Non-Patent Document 3). With chemotherapy, these patients have a median overall survival (OS) of 12-18 months and a 5-year survival rate of approximately 18% (Non-Patent Document 3; Non-Patent Document 2).

[0004] Until recently, systemic treatment with platinum-based doublet chemotherapy regimens, with or without maintenance therapy, was the standard first-line treatment for all patients with advanced NSCLC whose tumors did not have epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, or C-ros oncogene receptor tyrosine kinase (ROS1) mutations (Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6). Despite initial treatment with platinum-based doublet chemotherapy regimens, the disease often progressed, and further treatment options were limited. Therefore, newer therapeutic approaches are needed to improve long-term survival and quality of life (QOL) in patients with advanced NSCLC.

[0005] In recent years, immunotherapy has been investigated as a potential therapeutic approach to improve long-term survival and quality of life in patients with advanced NSCLC. Tumors modulate and evade host immune responses by numerous mechanisms, including the creation 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 cytotoxic T cell responses. Increased expression of PD-L1 in the tumor microenvironment promotes evasion from immune surveillance (T cell-induced antitumor activity). In contrast, blocking this interaction results in enhanced T cell responses with antitumor activity.

[0006] Blockade of the PD-1 / PD-L1 T cell checkpoint pathway has been shown to be an effective and well-tolerated approach to stimulating immune responses and achieved 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 literature]

[0007]

Non-licensed literature 1

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

Non-licensed Document 12

Non-licensed Document 13

[0008] Summary of the Invention According to certain embodiments, the present invention provides a method for treating or ameliorating at least one symptom or sign of lung cancer, inhibiting the growth of lung cancer, and / or increasing survival in a subject. The method according to this aspect comprises 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 advanced, recurrent or metastatic lung cancer. In one embodiment, the subject has squamous non-small cell lung cancer. In one embodiment, the subject has non-squamous non-small cell lung cancer. In certain embodiments, the subject has 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 lung cancer (e.g., non-small cell lung cancer) whose tumors express PD-L1 on <50%, <45%, <40%, <30%, <20%, <10%, <5%, <2%, <1%, or about 0% of the tumor cells. In certain other embodiments, the subject has lung cancer (e.g., non-small cell lung cancer) whose tumors express PD-L1 on >50% of the tumor cells. Having 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 to a subject in need thereof one or more doses of an anti-PD-1 antibody, wherein each dose comprises 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 immediately preceding dose. In certain embodiments, the method comprises administering to a subject in need thereof 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). In one embodiment, the chemotherapy comprises a platinum-based chemotherapy agent (e.g., pemetrexed, cisplatin, gemcitabine, or a combination thereof). In one embodiment, the anti-PD-1 antibody is REGN2810.

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

[0010] In certain embodiments of the invention, a method is provided for treating or ameliorating at least one symptom or sign, or inhibiting the growth of cancer in a subject. In certain embodiments of the invention, a method is provided for slowing tumor growth or preventing tumor recurrence. In certain embodiments of the invention, a method is provided for increasing overall survival or progression-free survival of a cancer patient. The method according to this aspect of the invention comprises sequentially administering a therapeutically effective amount of one or more doses 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 methods comprise administering one or more doses of an anti-PD-1 antibody to a patient with advanced or metastatic cancer (e.g., advanced non-small cell lung cancer), where tumor tissue in the patient expresses PD-L1 on ≦1%, ≦2%, ≦5%, ≦10%, ≦20%, ≦30%, ≦40%, ≦45%, or <50% of tumor cells. In certain embodiments, the methods comprise administering one or more doses of an anti-PD-1 antibody to a patient with cancer (e.g., advanced or metastatic lung cancer), where tumor tissue in the patient expresses PD-L1 on ≧50%, ≧60%, ≧70%, ≧80%, or ≧90% of tumor cells.

[0012] In certain embodiments, the anti-PD-1 antibody is administered to a cancer patient as a "first line" treatment, where the patient has not previously received systemic treatment for the cancer. In certain embodiments, the anti-PD-1 antibody is administered to a cancer patient (e.g., metastatic cancer) as a "second line" treatment, where the patient has previously been treated with therapies 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 is between 0.1 and 20 mg / body weight of the subject. In certain embodiments, each dose of the anti-PD-1 antibody comprises 0.3, 1, 3, 5, or 10 mg / kg of body weight of the subject. In certain embodiments, each dose of the anti-PD-1 antibody comprises 20-1500 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 prior to, concurrently with, or following chemotherapy, hi one embodiment, the methods of the invention comprise administering an anti-PD-1 antibody prior to chemotherapy.

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

[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. The method according to this aspect of the invention comprises administering to a subject in need thereof at least one treatment cycle, wherein at least one treatment cycle comprises one or more doses of an anti-PD-1 antibody. In certain embodiments, at least one treatment cycle further comprises 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 an additional therapeutic agent or therapy (e.g., an anti-CTLA-4 antibody, or any agent or therapy 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 in metastatic foci over time, reduced use of chemotherapeutic or cytotoxic agents, reduction in 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 a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain CDR of the 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 in the manufacture of a medicament for treating or inhibiting the growth of cancer 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 present invention will become apparent from consideration of the following detailed description. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the study design involving administration of anti-PD-1 antibody and radiation (XRT) in mice implanted with MC38 tumors (study described in Example 1 herein). [Diagram 2] Figure 2 shows the mean tumor growth in mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control + radiation (XRT) (▲), or anti-PD-1 antibody + XRT (▼) in the study described in Example 1 herein. [Diagram 3] Figure 3 shows overall survival of mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control plus radiation (XRT) (▲), or anti-PD-1 antibody plus XRT (▼) in the study described in Example 1 herein. [Figure 4] FIG. 4 shows the study design involving administration of anti-PD-1 antibody and radiation (XRT) in mice implanted with B16F10.9 tumors (study described in Example 2 herein). [Diagram 5]Figure 5 shows the average tumor growth in mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control + radiation (XRT) (◆), or anti-PD-1 antibody + XRT (○) in the study described in Example 2 herein. [Figure 6] Figure 6 shows overall survival of mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control + radiation (XRT) (◆), or anti-PD-1 antibody + XRT (○) in the study described in Example 2 herein. [Figure 7] FIG. 7 shows the study design involving administration of anti-PD-1 antibody and radiation (XRT) in mice implanted with MC38 tumors (study described in Example 4 herein). [Figure 8] Figure 8 shows the mean primary tumor growth in mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control + radiation (XRT) (▲), or anti-PD-1 antibody + XRT (▼) in the study described in Example 4 herein. [Figure 9] Figure 9 shows overall survival of mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control plus radiation (XRT) (▲), or anti-PD-1 antibody plus XRT (▼) in the study described in Example 4 herein. [Figure 10] Figure 10 shows secondary tumor growth in mice treated with isotype control antibody (●), anti-PD-1 antibody (■), isotype control + radiation (XRT) (▲), or anti-PD-1 antibody + XRT (▼) in the study described in Example 4 herein. [Figure 11] FIG. 11 shows the study design involving dosing of anti-PD-1 antibody, anti-GITR antibody, and radiation (XRT) in mice implanted with MC38 tumors (study described in Example 5 herein). [Figure 12]Figure 12 shows the average tumor growth in mice treated with an isotype control antibody (●), anti-PD-1 antibody (■), anti-GITR antibody (▲), a combination of anti-PD-1 and anti-GITR antibodies (▼), isotype control + radiation (XRT) (◆), anti-PD-1 antibody + XRT (○), anti-GITR antibody + XRT (□), or a combination of anti-PD-1 antibody, anti-GITR antibody + XRT (r) in the study described in Example 5 herein. [Figure 13] Figure 13 shows overall survival of mice treated with isotype control antibody (●), anti-PD-1 antibody (■), anti-GITR antibody (▲), a combination of anti-PD-1 antibody and anti-GITR antibody (▼), isotype control + radiation (XRT) (◆), anti-PD-1 antibody + XRT (○), anti-GITR antibody + XRT (□), or a combination of anti-PD-1 antibody, anti-GITR antibody + XRT (r) in the study described in Example 5 herein. [Figure 14A] FIG. 14A shows radiographic images of lung metastases in a patient with basal cell carcinoma (BCC) indicated by arrows at baseline (left) and week 24 (right). [Figure 14B] FIG. 14B shows X-ray images of a neck mass in a patient with cutaneous squamous cell carcinoma (CSCC) at baseline (left) and week 16 (right). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description Before describing the present invention, it is to be understood that the present invention is not limited to the particular methods and experimental conditions described, since the methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.The term "about" used herein, when used in relation to a specific recited numerical value, means that the value may vary by 1% or less from the recited value.For example, the expression "about 100" used herein includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

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

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

[0027] As used herein, the phrase "subject in need thereof" refers to a human or non-human mammal that exhibits one or more symptoms or signs of cancer and / or has been diagnosed with cancer, including solid tumors, and 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 with a primary or metastatic tumor and / or one or more symptoms or signs, including, but not limited to, unexplained weight loss, general weakness, persistent fatigue, loss of appetite, fever, night sweats, bone pain, shortness of breath, distended abdomen, chest pain / tightness, splenomegaly, and elevated levels of cancer-related biomarkers (e.g., CA125). This phrase is intended to be used interchangeably with the term "subject." The term includes subjects with emerging or established tumors. In certain embodiments, the term includes human subjects with and / or in need of treatment for 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. In certain preferred embodiments, the term includes human subjects with and / or in need of treatment for lung cancer, including small cell lung cancer. In preferred embodiments, the term includes patients with and / or in need of treatment for progressive recurrent or metastatic non-small cell lung cancer. In another preferred embodiment, the term includes patients with and / or in need of treatment for squamous or non-squamous non-small cell lung cancer. The term includes subjects with primary or metastatic tumors (advanced malignancies). In certain embodiments, the term "subject in need thereof" includes patients with solid tumors that are resistant or refractory to previous treatments (e.g., treatments with anticancer drugs) or that are not adequately controlled by previous treatments. For example, the phrase includes subjects who have been previously treated with one or more treatments, such as treatment with chemotherapy (e.g., carboplatin or docetaxel). In certain embodiments, the phrase "subject in need thereof" includes patients with solid tumors who have been previously treated with one or more treatments, but have subsequently recurred or metastasized. For example, patients with solid tumors who may have been treated with one or more anti-cancer drugs, leading to tumor regression; but who subsequently recur with cancer resistant to the one or more anti-cancer drugs (e.g., chemotherapy-resistant cancer) are treated with the methods of the present invention. The phrase also includes subjects with solid tumors for whom conventional anti-cancer therapy is not advisable, for example, due to toxic side effects. For example, the phrase includes patients who have been treated with one or more cycles of chemotherapy with toxic side effects.

[0028] In certain embodiments, the methods of the present invention can be used to treat patients who exhibit elevated levels of one or more cancer-associated 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 present invention include administering a therapeutically effective amount of an anti-PD-1 antibody to a patient who has elevated levels of PD-L1 in tumor tissue. In certain embodiments, the methods of the present invention include administering a therapeutically effective amount of an anti-PD-1 antibody to a patient who has lung cancer, wherein the tumor tissue in the patient expresses PD-L1 in <50%, ≦45%, ≦40%, ≦30%, ≦20%, ≦10%, ≦5%, ≦2%, or ≦1% of tumor cells. In certain embodiments, the methods of the invention comprise administering a therapeutically effective amount of an anti-PD-1 antibody to a patient with lung cancer, wherein tumor tissue in the patient expresses PD-L1 in ≧50%, ≧60%, ≧70%, ≧80%, or ≧90% of tumor cells.

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

[0030] The term "solid tumor" as used herein refers to an abnormal mass of tissue that does not usually contain cysts or liquid areas. Solid tumors can be benign (not cancerous) or malignant (cancer). For the purposes of the present invention, the term "solid tumor" refers to malignant solid tumors. This term includes various types of solid tumors named for the cell type that forms them, i.e., sarcomas, carcinomas, and lymphomas. However, this term does not include leukemias. In various embodiments, the term "solid tumor" includes cancers arising from connective or supporting tissues (e.g., bone or muscle) (called sarcomas), cancers arising from the glandular cells and epithelial cells that cover the body (called carcinomas), and cancers of lymphatic organs such as lymph nodes, spleen, and thymus (called lymphomas). Lymphatic cells are present in almost all tissues, and therefore lymphomas can occur in a variety of organs. In certain embodiments, the term "solid tumor" refers to, but is 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, stomach cancer, esophageal cancer, head and neck cancer, In certain embodiments, the term "solid tumor" includes cancers including, but not limited to, hepatocellular carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, basal cell carcinoma, breast cancer, cutaneous squamous cell carcinoma, chondrosarcoma, hemangiosarcoma, cholangiocarcinoma, soft tissue sarcoma, colorectal cancer, melanoma, Merkel cell carcinoma, and glioblastoma multiforme. In certain embodiments, the term "solid tumor" includes more than one solid tumor lesion located away from each other in a subject in need of treatment, for example, 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 is located away 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 present invention includes methods for treating or inhibiting the growth of 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, stomach cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and myeloma.In certain embodiments, the present invention includes methods for treating or inhibiting the growth of 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. In certain embodiments, the present invention includes a method for treating advanced solid tumors, including but not limited to metastatic cutaneous squamous cell carcinoma (CSCC), unresectable locally advanced CSCC, metastatic colorectal cancer, advanced or metastatic hepatocellular carcinoma, advanced non-small cell lung cancer, recurrent glioblastoma multiforme, castration-recurrent prostate cancer, and advanced solid tumors refractory to first-line treatment. The method according to this aspect includes administering a therapeutically effective amount of an anti-PD-1 antibody, optionally in combination with an anti-tumor therapy. Anti-tumor therapy includes conventional anti-tumor therapy, such as but not limited to chemotherapy, radiation, CTLA-4 inhibitors (e.g., anti-CTLA-4 antibodies), and surgery. Other anti-tumor therapies are described elsewhere herein. In one embodiment, the anti-tumor therapy includes platinum-based chemotherapy. In certain embodiments, one or more doses of anti-PD-1 antibody are administered to a subject in need thereof, where each dose is administered 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks after the immediately preceding dose. In certain embodiments, each dose comprises 0.1-10 mg / kg of the subject's body weight (e.g., 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg). In certain other embodiments, each dose comprises 20-1500 mg of 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 anti-PD-1 antibody.

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

[0033] The term "chemotherapy" as used herein refers to the use of chemotherapeutic agents (chemical compounds used in antitumor therapy). This term includes, but is not limited to, alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic / antitumor antibodies, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogesterone agents, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, luteinizing hormone releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, and VEGF inhibitors. Examples of chemotherapeutic agents are disclosed elsewhere herein. 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] The term "radiotherapy" (also referred to as "XRT") as used herein refers to the use of ionizing radiation to kill cancer cells, generally as part of anti-cancer therapy. X-rays, gamma rays, or charged particles (e.g., protons or electrons) are used to generate ionizing radiation. Radiation therapy may be delivered by a machine placed outside the patient's body (external beam radiation therapy), by a source placed inside the patient's body (internal beam radiation therapy or brachytherapy), or by whole-body radioisotopes delivered intravenously or orally (total body radioisotope therapy). Radiation therapy may be planned and administered in conjunction with imaging-based techniques such as computed tomography (CT), magnetic resonance imaging (MRI), to precisely determine the dose and location of the radiation to be administered. In various embodiments, the radiation therapy is selected from the group consisting of total body radiation therapy, conventional external beam radiation therapy, stereotactic radiosurgery, stereotactic body radiation therapy, 3-D conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, tomotherapy, brachytherapy, and total body radiation therapy. Depending on the purpose, in certain embodiments, radiation therapy is therapeutic, adjuvanting, or palliative. In certain embodiments, the term "radiation therapy" refers to hypofractionation. Hypofractionation refers to radiation therapy in which the radiation dose is composed of two or more fractionated doses. In various embodiments, each fractionated dose contains 2-20 Gy. For example, a radiation dose of 50 Gy can be divided into 10 fractionated doses each containing 5 Gy. In certain embodiments, two or more fractionated doses are administered on consecutive days or on sequential days. In certain other embodiments, two or more fractionated doses are administered every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, or a combination thereof.

[0035] In certain embodiments, the invention includes a method for treating a tumor or slowing or inhibiting tumor growth. In certain embodiments, the invention includes a method for promoting tumor regression. In certain embodiments, the invention includes a method for reducing tumor cell burden or reducing tumor volume. In certain embodiments, the invention includes a method for preventing tumor recurrence. The method according to this aspect of the invention includes sequentially 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, where the antibody is administered to the subject in multiple doses, for example as part of a particular therapeutic dosing regimen. For example, the therapeutic dosing regimen may include administering one or more doses of an anti-PD-1 antibody to a subject approximately once a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once a month, once every 2 months, once every 3 months, once every 4 months, or less frequently. In certain embodiments, one or more doses of the anti-PD-1 antibody are administered in combination with one or more doses of a second anti-tumor therapy, The one or more doses of the second anti-tumor therapy are administered to the subject 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 less frequently.

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

[0037] In certain embodiments, the present invention provides a method for increased anti-tumor efficacy or increased tumor inhibition. The method according to this aspect of the present invention comprises administering a therapeutically effective amount of an anti-PD-1 antibody to a subject having a solid tumor, followed by a dose of a second anti-tumor therapy (e.g., chemotherapy or anti-CTLA-4 antibody), where the anti-PD-1 antibody can be administered about 1 day, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, more than 7 days, or more than 8 days before the second anti-tumor therapy. In certain embodiments, the method provides increased tumor inhibition, 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%, compared to a subject administered an anti-tumor therapy (e.g., chemotherapy) prior to the anti-PD-1 antibody. In certain embodiments, the chemotherapy comprises a platinum-based chemotherapy. In certain embodiments, the second anti-tumor therapy comprises a CTLA-4 inhibitor (eg, an anti-CTLA-4 antibody).

[0038] In certain embodiments, the present invention provides a method for treating cancer, 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 radiation therapy such that the lesions of the therapy are treated. In certain embodiments, the method comprises administering radiation therapy 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 comprises 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 hypofractionation, wherein hypofractionation is administered to the first lesion but not to the second lesion, and both lesions are treated during the administration. In certain embodiments, the anti-PD-1 antibody is administered prior to radiation therapy.

[0039] In certain embodiments, the present invention includes a method of treating cancer, comprising administering to a subject in need thereof one or more sub-therapeutic doses 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 that is lower than the therapeutic dose and may be used to reduce the toxicity of the administered therapy. In certain embodiments, administering a sub-therapeutic dose of an anti-PD-1 antibody in combination with radiation therapy results in a therapeutic anti-tumor efficacy compared to administering a sub-therapeutic dose of an anti-PD-1 antibody alone. In certain other embodiments, the method of the present 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 may be administered in combination with a sub-therapeutic dose of cyclophosphamide for increased efficacy compared to either monotherapy.

[0040] In certain embodiments, the invention includes a method for inhibiting, slowing, or stopping tumor metastasis or tumor invasion into peripheral organs. The method according to this aspect comprises administering a therapeutically effective amount of an anti-PD-1 antibody to a patient. The method includes administering to a subject in need thereof a therapeutically effective amount of an anti-PD-1 antibody. In certain embodiments, the anti-PD-1 antibody is administered in combination with chemotherapy. In one embodiment, the chemotherapy is a platinum-based chemotherapy. In one embodiment, the chemotherapy is administered before, simultaneously with, or after administration of one or more doses of the anti-PD-1 antibody.

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

[0042] In certain embodiments, the present invention includes methods for treating or inhibiting the growth of 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, stomach cancer, esophageal cancer, head and neck cancer, salivary gland cancer, and myeloma.In certain embodiments, the present invention includes methods for treating or inhibiting the growth of 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. In certain embodiments, the present invention comprises a method of treating advanced solid tumors, including, but not limited to, metastatic cutaneous squamous cell carcinoma (CSCC), unresectable locally advanced CSCC, metastatic colorectal cancer, advanced or metastatic hepatocellular carcinoma, advanced non-small cell lung cancer, recurrent glioblastoma multiforme, newly diagnosed glioblastoma multiforme, castration-recurrent prostate cancer, and advanced solid tumors refractory to first line therapy.

[0043] According to one aspect, the invention includes a method of treating or inhibiting the growth of a tumor, the method comprising: (a) selecting a patient having cutaneous squamous cell carcinoma (CSCC), wherein 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 unresectable; (iv) the patient has been previously treated with at least one anti-tumor therapy; (v) the patient has disease considered inoperable; (vi) surgery and / or radiation are 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 a therapeutically effective amount of an anti-PD-1 antibody to a patient in need thereof. In certain embodiments, one or more doses of anti-PD-1 antibody are administered 1-12 weeks after the immediately preceding dose, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks after the immediately preceding dose. In certain embodiments, each dose of anti-PD-1 antibody comprises 0.1, 1, 0.3, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg of patient body weight. In certain embodiments, each dose comprises 50-500 mg of anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is REGN2810.

[0044] According to one aspect, the invention includes a method of treating a tumor or increasing survival of a cancer patient, the method comprising: (a) selecting a patient having lung cancer, wherein the patient is selected from the group consisting of: (i) the patient has non-small cell lung cancer; (ii) tumor tissue in the patient expresses PD-L1 in <50% of the tumor cells; (iii) the patient has non-squamous stage III or stage 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. and (b) 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. In one embodiment, the patient has progressive or recurrent non-small cell lung cancer, the tumor tissue in the patient expresses PD-L1 on <50% of the tumor cells, and 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 on <50% of the tumor cells, and has not been previously treated with a systemic treatment for lung cancer (e.g., chemotherapy). In certain embodiments, the patient has progressive or recurrent non-small cell lung cancer, and the tumor tissue in the patient expresses PD-L1 on <50%, <45%, <40%, <30%, <20%, <10%, <5%, <2%, or <1% of the tumor cells.

[0045] In certain embodiments, the present invention includes a method of treating cancer or increasing survival of a cancer patient, the method comprising: (a) selecting a patient with lung cancer, wherein the tumor tissue in the patient expresses PD-L1 on >50% of the 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 on >60%, >70%, >80%, or >90% of the tumor cells. In one embodiment, the patient has advanced or metastatic non-small cell lung cancer. In one embodiment, the patient has squamous or non-squamous stage III or stage 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 invention includes a method for treating cancer or increasing 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 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 (e.g., platinum-based chemotherapy, surgery and / or radiation); (b) determining expression of PD-L1 in tumor tissue; and (c) if the tumor tissue expresses PD-1 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. In one embodiment, the tumor tissue expresses PD-L1 in <50%, <45%, <40%, <30%, <20%, <10%, <5%, <2%, <1%, or 0% of tumor cells.

[0047] According to one aspect, the invention includes a method for treating cancer or increasing survival of a cancer patient, the method comprising: (a) selecting a patient with lung cancer, wherein the patient has at least one of the following characteristics: (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 (e.g., platinum-based chemotherapy, surgery and / or radiation); (b) determining expression of PD-L1 in tumor tissue; and (c) 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 if the tumor tissue expresses PD-L1 in ≧50% of the tumor cells. 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 anti-PD-1 antibody is administered 1 week, 2 weeks, 3 weeks, or 4 weeks after the immediately preceding dose, and wherein each dose contains 20-1500 mg of anti-PD-1 antibody. In one embodiment, each dose contains 200, 250, 300, 350, 500, 600, 700, 800, 900, 1000, or 1050 mg of 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, wherein 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%, less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, or less than 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, expression of PD-L1 in tumor tissue is determined by any assay known in the art, e.g., by ELISA assay or by immunohistochemistry (IHC) assay, as described in PCT Publication WO2016124558 or WO2016191751 or U.S. Patent Application Publication US20160305947. In certain embodiments, expression of PD-L1 is determined by quantifying RNA expression, e.g., by in situ hybridization or RT-PCR. In certain embodiments, expression of PD-L1 is determined by imaging, e.g., by immuno-positron emission tomography or iPET, using a labeled anti-PD-L1 antibody (see, e.g., 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 an anti-PD-1 antibody results in an increase in progression-free survival (PFS) or overall survival (OS) of a patient compared to patients administered platinum-based chemotherapy as monotherapy. 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 compared to patients administered 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 compared to patients administered platinum-based chemotherapy.

[0051] According to one aspect, the present invention includes a method of treating or inhibiting tumor growth, comprising selecting a subject with brain cancer and administering a therapeutically effective amount of an anti-PD-1 antibody or an antigen-binding fragment thereof to a subject in need thereof. In certain embodiments, the brain cancer is glioblastoma multiforme. In one embodiment, the subject has been newly diagnosed with glioblastoma multiforme. In one embodiment, the subject is >65 years old. In one embodiment, the anti-PD-1 antibody is administered in one or more doses, wherein each dose is administered 0.5-4 weeks after the immediately preceding dose. 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 hypofractionated. In one embodiment, the subject is administered 20-60 Gy in 2-20 fractionated doses. In certain embodiments, one or more doses of the anti-PD-1 antibody are included in one or more treatment cycles, wherein each cycle of treatment comprises 1-6 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 hypofractionated radiation therapy. In a specific embodiment, the subject is administered hypofractionated radiation therapy in the first cycle of treatment, wherein the hypofractionated radiation therapy comprises 20-60 Gy in 2-20 fraction doses. In one embodiment, the subject is administered hypofractionated radiation therapy one week after administration of the anti-PD-1 antibody in the first cycle of treatment. In certain embodiments, the methods of the invention comprise administering intracranial radiation therapy to the subject following administration of the anti-PD-1 antibody. If edema occurs, it further comprises administering an antiangiogenic agent to the subject. In one embodiment, the antiangiogenic agent is a vascular endothelial growth factor (VEGF) inhibitor. In one embodiment, the antiangiogenic 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 VEGF inhibitor fusion proteins (e.g., "VEGF-traps" such as aflibercept or other VEGF inhibitor 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).

[0052] The methods of the invention, according to certain embodiments, comprise administering to a subject a therapeutically effective amount of an anti-PD-1 antibody in combination with an additional therapeutic agent or therapeutic regimen or procedure, which may be administered to increase anti-tumor efficacy, to reduce toxic effects of one or more therapies, and / or to reduce the dosage of one or more therapies.In various embodiments, the additional therapeutic agent or treatment regimen or procedure is, for example, chemotherapy, cyclophosphamide, surgery, radiation, a cancer vaccine, a programmed death-ligand 1 (PD-L1) inhibitor (e.g., an anti-PD-L1 antibody), a lymphocyte-activation gene 3 (LAG3) inhibitor (e.g., an anti-LAG3 antibody), a cytotoxic T-lymphocyte protein 4 (CTLA-4) inhibitor (e.g., an anti-CTLa-4 antibody such as ipilimumab), a glucocorticoid-inducible tumor necrosis factor receptor (GITR) inhibitor (e.g., an anti-GITR antibody), a T-cell immunoglobulin and mucin-containing-3 (TIM3) inhibitor, a B- and T-lymphocyte attenuator (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 [VEGF inhibitor fusion proteins (e.g., "VEGF-traps" such as aflibercept or 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 (Bacillus Calmette-Guerin), granulocyte macrophage colony stimulating factor, cytotoxins, chemotherapeutic agents, cytokines such as IL-6R inhibitors, IL-4R inhibitors, IL-10 inhibitors, IL-2, IL-7, IL-21, and IL-15, T cell therapy, anti-inflammatory drugs such as corticosteroids, and nonsteroidal anti-inflammatory drugs, and nutritional supplements such as antioxidants.In certain embodiments, the anti-PD-1 antibody may be administered in combination with treatments including chemotherapy and surgery. As used herein, the phrase "in combination with" means that the anti-PD-1 antibody is administered to the subject at the same time as, immediately before, or immediately after the administration of radiation therapy and the additional therapeutic agent. In certain embodiments, the additional therapeutic agent is administered as a co-formulation with the anti-PD-1 antibody.

[0053] In certain embodiments, the present invention includes a method for treating large tumors or aggressive malignant tumors, comprising administering to a subject in need thereof an anti-PD-1 antibody in combination with radiation therapy and an additional therapeutic agent, wherein the additional therapeutic agent is administered to overcome regulatory T cell (Treg)-mediated immune suppression. In certain embodiments, the additional therapeutic agent is an anti-GITR antibody, an anti-LAG3 antibody, cyclophosphamide, and GM - CSF.

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

[0055] In certain embodiments, the invention includes methods comprising administering one or more doses of an anti-PD-1 antibody in combination with radiation therapy and a subtherapeutic dose of cyclophosphamide. As used herein, a subtherapeutic dose of cyclophosphamide (also referred to herein as "low-dose cyclophosphamide") refers to an amount of cyclophosphamide that does not impart a therapeutic effect by itself and preferably does not cause toxicity. Exemplary doses of cyclophosphamide that are considered "subtherapeutic" 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 in both the first and second tumor lesions (the abscopal effect). 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 methods of the invention comprise 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 the 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 untreated subjects or subjects administered either the antibody as monotherapy or the second anti-tumor therapy. 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 elimination. 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 may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years, compared to untreated subjects or subjects treated with the antibody or chemotherapy as monotherapy. In certain embodiments, administration of the anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) prevents tumor recurrence and / or increases the survival time of the subject, e.g., increasing survival time by 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months, compared to untreated subjects or subjects administered either the antibody or the second anti-tumor therapy as monotherapy. In certain embodiments, administration of an anti-PD-1 antibody in combination with an additional anti-tumor therapy increases survival-free or overall survival. In certain embodiments, administration of an anti-PD-1 antibody in combination with chemotherapy increases response and duration of response in a subject by, for example, 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% over untreated subjects or subjects administered the antibody or chemotherapy as monotherapy.In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject with cancer results in the complete disappearance of all evidence of tumor cells (a "complete response"). In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject with cancer results in at least a 30% or greater reduction in tumor cells or tumor size (a "partial response"). In certain embodiments, administration of an anti-PD-1 antibody and / or a second anti-tumor therapy to a subject with cancer results in a new. The therapeutic agent results in the complete or partial disappearance of tumor cells / lesions, including new measurable lesions. Tumor reduction can be measured by any method known in the art, for example, by X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analysis.

[0058] In certain embodiments, the methods of the invention comprise 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 compared to patients administered "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 compared to patients administered 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 compared to patients administered platinum-based chemotherapy.

[0059] Methods for suppressing regulatory T cells According to certain aspects, the present invention provides methods for suppressing or inhibiting activation and / or proliferation of T regulatory (Treg) cells. In certain embodiments, the present invention provides methods for suppressing activation of Treg cells. The methods according to these aspects include selecting a subject having a solid tumor and administering to the subject an anti-PD-1 antibody or antigen-binding fragment thereof in combination with at least one of: (i) radiation therapy, and (ii) a glucocorticoid-induced tumor necrosis factor receptor (GITR) antagonist. In certain embodiments, the method includes administering to a subject in need thereof an anti-PD-1 antibody or antigen-binding fragment thereof in combination with radiation therapy 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 of the amino acid sequences of the anti-GITR antibodies set forth in USSN 62 / 256,922 (filed November 18, 2015), the contents of which are incorporated herein 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 set forth in U.S. Patent Nos. 9228016, 8709424, 8591886, 7812135, or U.S. Patent Publication No. 20150368349.

[0061] In certain embodiments, the invention provides a method for suppressing or eliminating Treg activity, comprising administering to a subject in need thereof an anti-PD-1 antibody or antigen-binding fragment thereof in combination with radiation and one or more doses of 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, comprising administering to a subject in need thereof an anti-PD-1 antibody or antigen-binding fragment thereof in combination with radiation and one or more doses of a 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 October 9, 2015, the contents of which are incorporated herein in their entirety.

[0063] In certain embodiments, the 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 method of the present invention comprises administering an anti-PD-1 antibody to a subject having a solid tumor in combination with radiation therapy and an additional 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 in tumor size, slowing of tumor growth, inhibition of tumor metastasis, reduction in 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 in 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 increased likelihood of developing metastases. In certain embodiments, the term refers to an aggressive 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 immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain comprises a heavy chain variable region (referred to herein as HCVR or VL). H The heavy chain constant region is made up of three domains: H 1. C H 2 and C H Each light chain comprises a light chain variable region (herein referred to as LCVR or V L The light chain constant region comprises one domain (C L 1) is included. H and V L The regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L is composed of three CDRs and four FRs arranged in the following order from amino terminus to 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 sequence or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0066] The term "antibody" as used herein also includes antigen-binding fragments of a complete antibody molecule. 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 a complete antibody molecule using any suitable standard technique, such as, for example, proteolytic digestion, or recombinant genetic engineering techniques, including the manipulation and expression of DNA encoding antibody variable domains and optionally constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and engineered chemically or by using molecular biology techniques, for example, to place one or more variable and / or constant domains in the appropriate configuration, or to introduce codons, to generate cysteine ​​residues, to modify, add or delete amino acids, etc.

[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, tetraspecific antibodies, minibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the term "antigen-binding fragment" as used herein.

[0068] An antigen-binding fragment of an antibody typically contains at least one variable domain. The variable domain may 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. L Domain and associated V H In an antigen-binding fragment having a domain, H and V L The domains can be positioned relative to each other in any suitable configuration. For example, the variable region can be a dimer, and the V H -V H , V H -V L Or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a dimer of monomer V H Or V L It may contain domains.

[0069] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) a 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 In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that create a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies of the invention may comprise any of the variable and constant domain configurations listed above non-covalently linked to each other, and / or one or more monomeric V H Or V L It may include homodimers or heterodimers (or other multimers) with the domains (eg, via disulfide bonds).

[0070] The term "antibody" as used herein also includes multispecific (e.g., bispecific) antibodies. Multispecific antibodies or antigen-binding fragments of antibodies typically contain at least two different variable domains, where each variable domain can specifically bind to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format can be adapted for use in the context of the antibodies or antigen-binding fragments of antibodies of the present invention using conventional techniques available in the art. For example, the present invention includes methods involving the use of bispecific antibodies, where 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 linked to a therapeutic moiety. Exemplary bispecific formats that can be used in the context of the present invention include, but are not limited to, for example, scFv-based or bispecific antibody bispecific formats, IgG-scFv fusions, dual variable domains, and the like. (DVD)-Ig, Quadroma, Knob-into-hole, Common Light Chain (e.g., Common Light Chain with Knob-into-hole), CrossMab, CrossFab, (SEED) body, Leucine zipper, Duobody, IgG1 / IgG2, Dual-acting Fab (DAF)-IgG, and Mab 2 Bispecific formats include those described herein (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a review of such formats). Bispecific antibodies can also be constructed using peptide / nucleic acid conjugates, for example, in which unnatural amino acids with orthogonal chemical reactivity are used to generate site-specific antibody-oligonucleotide conjugates that then self-assemble into multimeric complexes with defined composition, valency and configuration (see, e.g., Kazane et al., J. Am. Chem. Soc. [Epub: Dec. 4, 2012]).

[0071] The antibody used in the method of the present invention may be a human antibody. 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 include amino acid residues (e.g., mutations introduced by in vitro random or site-specific mutagenesis or in vivo somatic mutation), e.g., in the CDRs and particularly in CDR3, that are not encoded by human germline immunoglobulin sequences. 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, e.g., mouse, have been grafted onto human framework sequences.

[0072] The antibody used in the method of the present invention may be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to include all human antibodies that are produced, expressed, generated or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes [see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295], or antibodies 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 vivo somatic mutation, when animals transgenic for human Ig sequences are used), thus modifying the V and V regions of the recombinant antibody. H and V L The amino acid sequence of the region is H and V LThese sequences are derived from and related to, but may not be present within the human antibody germline repertoire in vivo.

[0073] According to certain embodiments, the antibody used in the methods of the invention specifically binds to PD-1. The term "specifically binds" or the like means that the antibody or antigen-binding fragment thereof forms a relatively stable complex with the 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, and the like. For example, an antibody that "specifically binds" to PD-1 as used in the context of the present invention has a K of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM, or less than about 0.5 nM as measured in a surface plasmon resonance assay. D However, antibodies that bind to human PD-1 or parts thereof are not specific for human PD-1. An isolated antibody that specifically binds may have cross-reactivity to other antigens, such as PD-1 molecules from other (non-human) species.

[0074] According to certain exemplary embodiments of the present invention, an 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 the amino acid sequence of any of the anti-PD-1 antibodies as set forth in U.S. Patent Publication No. 20150203579, which is incorporated herein in its entirety. In certain exemplary embodiments, an anti-PD-1 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present invention comprises a heavy chain complementarity determining region (HCDR) of the heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:1, and a light chain complementarity determining region (LCDR) 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), where 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 a HCVR comprising SEQ ID NO:1 and a LCVR comprising SEQ ID NO:2. In certain embodiments, the methods of the 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, the methods of the invention include the use of REGN2810, or a bioequivalent thereof.The term "bioequivalent" as used herein refers to an anti-PD-1 antibody or PD-1 binding protein or fragment thereof that is a pharmaceutical equivalent or substitute whose rate and / or extent of absorption does not differ significantly from that of REGN2810 when administered at the same molar dose under similar experimental conditions, either in single or multiple doses. In the context of the present invention, the term refers to antigen binding proteins that bind to PD-1 that do not have clinically meaningful differences from REGN2810 in their safety, purity and / or potency.

[0075] Other anti-PD-1 antibodies that can be used in the context of the methods of the invention include, for example, antibodies known and referred to as 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 anti-PD-1 antibodies set forth 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] Anti-PD-1 antibodies used in the context of the methods of the invention may have pH-dependent binding characteristics. For example, anti-PD-1 antibodies for use in the methods of the invention may exhibit decreased binding to PD-1 at acidic pH compared to neutral pH. Alternatively, anti-PD-1 antibodies of the invention may exhibit enhanced binding to their antigen at acidic pH compared to neutral pH. The expression "acidic pH" includes pH values ​​less than about 6.2, e.g., 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 less. As used herein, the expression "neutral pH" includes pH values ​​from about 7.0 to about 7.4. The expression "neutral pH" refers to approximately 7.0, 7.05, 7.1, 7.15, 7.2, 7.2 Includes pH values ​​of 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 present invention includes administering an additional anti-tumor therapy to the subject in combination with the anti-PD-1 antibody. In certain embodiments, the method of the present invention includes administering radiation therapy or chemotherapy in combination with the anti-PD-1 antibody for additive or synergistic activity to treat cancer. As used herein, the phrase "in combination with" means that the additional anti-tumor therapy is administered before, after, or simultaneously with the anti-PD-1 antibody. The term "in combination with" also includes sequential or simultaneous administration of the anti-PD-1 antibody and the additional anti-tumor therapy. For example, when administered "prior to" an additional anti-tumor therapy, the anti-PD-1 antibody can be administered more than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes, about 15 minutes, or about 10 minutes before administration of the additional therapy. When administered "after" an additional anti-tumor therapy, the anti-PD-1 antibody can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours after administration of the additional anti-tumor therapy. Administration "concurrently" with an additional 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 administration of the additional anti-tumor therapy.

[0080] In certain embodiments, the method of the present invention includes the administration of an additional therapeutic agent that is an anti-cancer drug. As used herein, "anti-cancer drug" refers to a drug useful for treating cancer, including, but not limited to, drugs such as cytotoxins and antimetabolites, alkylating agents, anthracyclines, antibiotics, mitotic inhibitors, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (O,P'-(DDD)), biologics (e.g., antibodies and interferons), and radioactive drugs. As used herein, "cytotoxins or cytotoxic drugs" also refers to chemotherapeutic agents and means drugs that are 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 and analogs or homologs thereof.

[0081] In certain embodiments, the methods of the invention include any combination of treatments that include surgery, radiation, a programmed death-ligand 1 (PD-L1) inhibitor (e.g., an anti-PD-L1 antibody disclosed in U.S. Patent Publication No. 2015 / 0203580 or atezolizumab), 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 (B-ILA) inhibitor, or a combination of these. TLA) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, CD47 inhibitors, antagonists of another T cell co-inhibitor or ligand (e.g., antibodies against CD-28, 2B4, LY108, LAIR1, ICOS, CD160, or VISTA), CD20 inhibitors (e.g., anti-CD20 antibodies, or bispecific CD3 / CD20 antibodies), indoleamine-2,3-dioxygenase (IDO) inhibitors, vascular endothelial growth factor (VEGF) antagonists [e.g., “VEGF-traps” such as aflibercept or US other VEGF inhibitory fusion proteins as described in US Pat. No. 7,087,411, or anti-VEGF antibodies or antigen-binding fragments thereof (e.g., bevacizumab, or ranibizumab), or small molecule kinase inhibitors of VEGF receptors (e.g., sunitinib, sorafenib, or pazopanib), angiopoietin 2 (Ang2) inhibitors (e.g., nesvacumab), transforming growth factor beta (TGFβ) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, These include inhibitors (e.g., erlotinib, cetuximab), agonists for costimulatory receptors (e.g., agonists for glucocorticoid-inducible TNFR-associated protein), 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], vaccines (e.g., Bacillus Calmette-Guerin), and vasculitis (e.g., vasculitis). Calmette-Guerin), cancer vaccines), cyclophosphamide, adjuvants that increase antigen presentation (e.g., granulocyte-macrophage colony-stimulating factor), cytotoxins, chemotherapeutic agents (e.g., dacarbazine, temozolomide, docetaxel, doxorubicin, daunorubicin, cisplatin, carboplatin, gemcitabine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, and vincristine), interleukin-6 receptor (IL-6R) inhibitors (e.g., sarilumab), IL-4R inhibitors (e.g., dupilumab), IL-10 inhibitors, cytokines such as IL-2, IL-7, IL-21, and IL-15, antibody-drug conjugates (ADCs) (e.g., anti-CD19-DM4 ADC, and anti-DS6-DM4 ADC). ADC), chimeric antigen receptor T cells (e.g., CD19-targeted T cells), anti-inflammatory drugs (e.g., corticosteroids and nonsteroidal anti-inflammatory drugs), and nutritional supplements such as antioxidants.

[0082] In certain embodiments, the methods of the invention comprise 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 survival of a cancer patient. In some embodiments, the methods of the invention are administered to a cancer patient prior to, concurrently with, or after administration of an anti-PD-1 antibody and an anti-GITR antibody. The present invention also includes administering radiation therapy to the tumor lesion. For example, radiation therapy can be administered in one or more doses to the tumor lesion after administration of one or more doses of the antibody. In some embodiments, radiation therapy can be administered locally to the tumor lesion after systemic administration of the anti-PD-1 antibody and / or anti-GITR antibody to enhance the local immunogenicity of the patient's tumor (adjuvinating radiation) and / or to kill tumor cells (ablative radiation). In certain embodiments, radiation therapy is administered to a first tumor lesion but not to a second tumor lesion, where administration in combination with the anti-PD-1 antibody results in tumor regression in both the first tumor lesion and the second tumor lesion (abscopal effect). In certain embodiments, the methods of the invention include administering an anti-PD-1 antibody in combination with radiation therapy and optionally an anti-GITR antibody to produce a long-term abscopal effect.

[0083] In certain embodiments, the anti-PD-1 antibody may be administered in combination with radiation therapy 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 present invention includes methods comprising administering to a subject an anti-PD-1 antibody in combination with radiation, wherein the anti-PD-1 antibody is contained within a pharmaceutical composition. The pharmaceutical compositions of the present invention may be formulated using suitable carriers, excipients, and other agents that provide for suitable transport, delivery, tolerance, and the like. A large number of suitable formulations can be found in the formulary known to any pharmacist: 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, 1997), and the like. TM"Compendium of excipients for parenteral formulations" PDA See also (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, for example, Wu et al., 1987, J.Biol.Chem.262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucosal skin linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered together with other biologically active agents.

[0086] The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously using a standard needle and syringe. Moreover, for subcutaneous delivery, a pen delivery device has ready utility in delivering the pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. Reusable pen delivery devices generally utilize a replaceable cartridge containing the pharmaceutical composition. Once all the pharmaceutical composition in the cartridge has been administered and the cartridge is emptied, the empty cartridge can be easily discarded and replaced with a new cartridge containing the pharmaceutical composition. The pen delivery device can then be reused. Disposable pen delivery devices do not have a replaceable cartridge; rather, they are used to administer the pharmaceutical composition to the patient. Disposable pen delivery devices come pre-filled with a pharmaceutical composition held in a reservoir within the device Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0087] In certain circumstances, pharmaceutical compositions can be delivered in controlled release systems. In one embodiment, pumps can be used. In another embodiment, polymeric materials can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, controlled release systems can be placed in the vicinity of the target of the composition, thus requiring only a fraction of the systemic dose (see, for example, 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] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injections, drip infusions, and the like. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or its salt in a sterile aqueous or oily medium conventionally used for injections. Aqueous media for injection include, for example, isotonic solutions containing physiological saline, glucose, and other auxiliary agents, and the like, which may be used in combination with suitable solubilizers such as alcohol (e.g., ethanol), polyalcohol (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. As oily media, for example, sesame oil, soybean oil, and the like may be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, and the like. Therefore, the injectable preparation is preferably filled into a suitable ampoule.

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

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

[0091] Dosing regimen The invention includes methods comprising administering an anti-PD-1 antibody to a subject at a dosing frequency of about 4 times per week, twice 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 less frequently as long as a therapeutic response is achieved. In certain embodiments, the methods comprise administering an anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) at a dosing frequency of about twice per week, once per week, once per 2 weeks, once per 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 less frequently as long as a therapeutic response is achieved.

[0092] In certain embodiments, the methods of the invention comprise administering radiation therapy, wherein the radiation therapy is hypofractionated radiation therapy. In certain embodiments, the hypofractionated radiation therapy comprises 2-12 fractionated doses. In certain embodiments, the 2-12 fractionated doses are administered on consecutive days. In certain embodiments, the radiation therapy comprises administering one or more doses of an anti-PD-1 antibody. In certain embodiments, the anti-PD-1 antibody is administered 0.5 to 2 weeks prior to the administration of one or more fractionated doses of radiation therapy.

[0093] According to certain embodiments of the invention, multiple doses of an anti-PD-1 antibody in combination with a second anti-tumor therapy (e.g., chemotherapy) may be administered to a subject over a defined time course. The method according to this aspect of the invention comprises sequentially 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, "sequentially administering" means that each dose of the antibody is administered to a subject at different time points, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). In certain embodiments, the method of the invention comprises sequentially administering one or more doses of an anti-PD-1 antibody, where each dose is administered 0.5-12 weeks after the immediately preceding dose. In certain further embodiments, the method further comprises administering a second anti-tumor therapy (e.g., chemotherapy). In certain embodiments, the chemotherapy can be a platinum-based chemotherapy. In certain embodiments, the method further comprises administering one or more doses of chemotherapy, where each dose is administered 1-6 weeks after the immediately preceding dose.

[0094] In certain embodiments, the present invention includes a method comprising sequentially 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 thereafter one or more tertiary doses of the anti-PD-1 antibody. In certain embodiments, the method further comprises sequentially administering to the patient a single initial dose of chemotherapy, followed by one or more secondary doses of chemotherapy, and optionally thereafter one or more tertiary doses of chemotherapy. The terms "initial dose", "secondary dose", and "tertiary dose" refer to the temporal order of administration. Thus, an "initial dose" is a dose administered at the beginning of a treatment regimen (also called a "baseline dose"); a "secondary dose" is a dose administered after the initial dose; and a "tertiary dose" is a 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 differ from each other during the course of 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 at the beginning of a treatment regimen as a "loading dose," followed by subsequent doses administered less frequently (e.g., "maintenance doses"). For example, an anti-PD-1 antibody may be administered to a cancer patient at a loading dose of about 1-3 mg / kg of patient body weight, followed by one or more maintenance doses of about 0.1 to about 20 mg / kg of patient body weight.

[0095] In one exemplary embodiment of the invention, each secondary and / or tertiary dose is administered at a dose equal to or greater than the dose administered immediately prior. 1 / 2~14 (for example, 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 As used herein, the phrase "immediately preceding" refers to a dose of anti-PD-1 antibody (and optionally a second anti-tumor therapy) administered to a patient prior to administration of the immediately subsequent dose, without any intervening doses, in a series of multiple doses.

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

[0097] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1-2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2-4 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 frequency of administration may also be adjusted by the physician depending on the needs of the individual patient following clinical testing during the course of 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 weekly, once weekly, or once every two weeks) as an "induction dose" at the start of treatment, followed by subsequent doses ("consolidation doses" or "maintenance doses") administered less frequently (e.g., once every 2-12 weeks). In certain embodiments, one or more doses of the anti-PD-1 antibody and / or radiation are administered more frequently (twice weekly, once weekly, or once every two weeks) as an "induction dose" at the start of the treatment regimen, followed by subsequent doses of the anti-PD-1 antibody.

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

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

[0101] The invention includes methods that involve sequential administration of an anti-PD-1 antibody in combination with chemotherapy to treat cancer (e.g., lung cancer) resulting in increased anti-tumor efficacy (e.g., greater inhibition of tumor growth, increased prevention of tumor recurrence compared to untreated subjects or subjects administered either the antibody or chemotherapy as monotherapy). In some embodiments, 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 phrase "therapeutically effective amount" refers to an amount of antibody (anti-PD-1 antibody) that results in one or more of: (a) a reduction in the severity or duration of symptoms or signs of cancer, e.g., a solid tumor; (b) inhibition of tumor growth or an increase in tumor necrosis, tumor shrinkage, and / or tumor disappearance; (c) a delay in tumor growth and development; (d) inhibition of tumor metastasis; (e) prevention of recurrence of tumor growth; (f) an increase in survival of a subject with cancer; and / or (g) a reduction in the use or need for conventional anti-cancer therapy (e.g., reduced or eliminated use of chemotherapy or cytotoxic agents) compared to untreated subjects or subjects administered the antibody as monotherapy. It means.

[0103] In the case of an anti-PD-1 antibody, a therapeutically effective amount can be about 0.05 mg to about 1500 mg, about 1 mg to about 1500 mg, about 10 mg to about 1400 mg, about 50 mg to about 1400 mg, about 75 mg to about 1400 mg, or about 100 mg to about 1300 mg of the antibody. For example, in various embodiments, the amount of anti-PD-1 antibody can be 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, or about 350 mg of the antibody. 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. In one embodiment, 250 mg of an anti-PD-1 antibody is administered according to the methods of the invention. In one embodiment, 200 mg of an anti-PD-1 antibody is administered according to the methods of the invention. In one embodiment, 350 mg of an anti-PD-1 antibody is administered according to the methods of the invention. In one embodiment, 1050 mg of an anti-PD-1 antibody is administered according to the methods of the invention.

[0104] The amount of anti-PD-1 antibody contained within an individual dose may be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). In certain embodiments, the anti-PD-1 antibody used in the methods of the invention may be administered to the subject at a dose of about 0.0001 to about 100 mg / kg of subject body weight. In certain embodiments, the anti-PD-1 antibody may be administered at a dose of about 0.1 mg / kg of patient body weight to about 20 mg / kg of patient body weight. In certain embodiments, the methods of the invention include administration of the anti-PD-1 antibody at a dose of about 1 mg / kg of patient body weight, 3 mg / kg of patient body weight, 5 mg / kg of patient body weight, or 10 mg / kg of patient 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 subtherapeutic dose. For example, if a therapeutically effective amount of an anti-PD-1 antibody comprises 3 mg / kg, a subtherapeutic dose comprises an amount less than 3 mg / kg, such as 2 mg / kg, 1.5 mg / kg, 1 mg / kg, 0.5 mg / kg, or 0.3 mg / kg. As defined herein, a "subtherapeutic dose" refers to an amount of anti-PD-1 antibody that does not provide a therapeutic effect by itself. However, in certain embodiments, a subtherapeutic dose of anti-PD-1 antibody is administered together with a second and optionally a third therapeutic agent to promote a therapeutic effect. EXAMPLES

[0106] The following examples are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, 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 antibodies in combination with radiation therapy against MC38 tumors In this example, the effect of PD-1 blockade in combination with radiation therapy was tested on established MC38 tumors in mice.

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

[0109] FIG. 2 and Table 1 show the mean tumor volume in mice administered anti-PD-1 antibodies alone or in combination with radiation.

[0110] [Table 1]

[0111] PD-1 (RMP1-14) blockade synergized with localized radiation (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 antibodies in combination with radiation. 3 Compared to mice receiving monotherapy, which took less than 20 days to reach a tumor volume of 500 mm 3It took more than 40 days for tumor volume to be reached. Tumor regression lasted for up to 4 weeks for the combination (XRT + anti-PD-1 antibody) treated group (1 of 4 mice had tumor recurrence at this time point and were not accepted) versus 1.5 weeks for the XRT + isotype treated group (1 of 2 mice were not accepted, tumor recurrence). PD-1 blockade as a monotherapy had no effect on primary tumor growth in this tumor model.

[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% alive 70 days after tumor implantation): isotype control (0% alive at day 70), anti-PD-1 antibody treated (0% alive at day 70), and XRT + isotype treated mice (17% alive at day 70) (Figure 3; Table 2).

[0114] Example 2: In vivo efficacy of anti-PD-1 antibodies and radiation against B16 tumors In this example, the anti-tumor effect of an anti-mouse PD-1 antibody in combination with radiation therapy was examined against established B16 tumors in mice.

[0115] 2x10 5 B16F10.9 melanoma cells were implanted subcutaneously into the right flank of female C57BL / 6 mice (Jackson Laboratory). The mean tumor volume was approximately 150 mm 3Treatment began when tumor size reached 100%. Mice were randomly assigned to receive either isotype control (2A3, BioXcell) or PD-1 blocking antibody (RMP1-14, BioXCell) at 5 mg / kg twice weekly for a total of five intraperitoneal injections. One day after the initiation of antibody treatment, mice assigned to the radiation therapy group received 8 Gy of radiation to their right flank tumors. Radiation therapy was delivered to anesthetized (ketamine / xylazine) mice shielded with a partial body radiation fixture (Precision X-ray) and lead sheets (Images Scientific Instruments) using an RS 2000 Biological Research Irradiator (Rad Source). Tumor growth was assessed three times a week until day 70–80, when all mice were euthanized. Figure 4 shows the study design of the experiment including dosing of anti-PD-1 antibody and radiation.

[0116] PD-1 (RMP1-14) blocking antibody treatment in combination with localized radiation therapy (XRT) delayed B16 primary tumor growth compared with XRT or anti-PD-1 antibody monotherapy (Figure 5; Table 3).

[0117] [Table 3]

[0118] [Table 4]

[0119] The combination of XRT and anti-PD-1 antibody treatment increased overall survival (50% survival 50 days after transplant) 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 antibodies in combination with radiation therapy against metastatic lung tumors In this example, the effect of PD-1 blockade in combination with radiation therapy was examined on established metastatic tumors in mice.

[0121] 1.5x10 5 4T1 breast cancer cells were cultured in female Balb / c mice (Jackson La The tumors were subcutaneously implanted in the right flank of the boratory. The average tumor volume was approximately 100 mm. 3 Treatment began 12 days after implantation, when tumor size reached 100%. Mice were randomly assigned to receive either isotype control (2A3, BioXcell) or PD-1 blocking antibody (RMP1-14, BioXCell) at 5 mg / kg twice weekly for a total of five intraperitoneal injections. One day after the start of antibody treatment, mice assigned to the radiotherapy group received 8 Gy of radiation to their right flank tumors. Radiotherapy was delivered to anesthetized mice (ketamine / xylazine) using a RS 2000 Biological Research Irradiator (Rad Source) shielded with a partial body radiation fixture (Precision X-ray) and lead sheet (Images Scientific Instruments). Tumor growth was assessed three times weekly until day 28, when all mice were euthanized, to assess lung metastatic burden using a clonogenicity assay. Briefly, lung tissue was dissociated using DNAse / Liberase 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 anti-PD-1 antibodies in combination with radiation is expected to promote tumor regression and also mediate inhibition of metastatic growth.

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

[0124] The exemplary anti-PD-1 antibody used in this example is REGN2810 (also referred to as H4H7798N as disclosed in US20150203579), a fully human monoclonal anti-PD-1 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; a 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 developed by VelociGene (R) The plasmid p53 was engineered using technology (Valenzuela et al 2003, Nat. Biotechnol. 21:652-659; U.S. Patent Application Publication No. 2015 / 0366174).

[0126] 5x10 5 MC38 colon cancer cells were implanted subcutaneously into female humanized PD-1 / C57BL / 6 mice on days 0 (right flank primary tumors) and 3 (left flank tumors; distant tumors). The mean primary tumor volume was approximately 150 mm 3Treatment began when tumor size reached 100%. Mice were randomly assigned to receive either isotype control or PD-1 blocking antibody (REGN2810) at 5 mg / kg twice weekly for a total of eight intraperitoneal injections. One day after antibody treatment, mice assigned to the radiation group received 8 Gy of radiation to their right flank tumors. Radiotherapy was delivered to anesthetized mice (ketamine / xylazine) using a RS 2000 Biological Research Irradiator (Rad Source) shielded with a partial body radiation fixture (Precision X-ray) and lead sheet (Images Scientific Instruments). Primary and secondary tumor growth was assessed three times weekly until day 70-80, when all mice were euthanized. Figure 7 shows the study design of the experiment including administration of anti-PD-1 antibody and radiation.

[0127] result Primary tumor: PD-1 blockade (REGN2810) treatment synergized with localized radiation (XRT) in rejecting primary MC38 tumors (4 of 6 tumor-free mice) compared to XRT+isotype control treated mice (1 / 6 tumor-free mice). Tumor regression persisted for 8 weeks in the combination treatment group until the end of the experiment, versus 3 weeks for the XRT+isotype treatment group (at which point rejected tumors recurred) (Figure 8; Table 5).

[0128] [Table 5]

[0129] PD-1 blockade as monotherapy mediated rejection in 2 of 5 mice; however, one of the mice that rejected the primary tumor died of secondary tumor growth, resulting in only one mouse surviving to the end of the experiment. The potential therapeutic efficacy of the combination treatment (XRT+REGN2810) was demonstrated by the statistically increased overall survival (approximately 67% survival 70 days after transplantation) 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 tumors: REGN2810 in combination with XRT significantly promoted the abscopal effect (rejection of tumors implanted at distant sites) in 5 of 6 tumor-free mice compared to XRT alone (2 / 6 no distant tumors), REGN2810 alone (1 / 6 no distant tumors), and isotype control-treated mice (1 / 6 no distant tumors) (FIG. 10; Table 7).

[0132] [Table 7]

[0133] Example 5: In vivo efficacy of anti-PD-1 antibodies in combination with radiation and GITR antagonists against MC38 tumors In this example, the effects of PD-1 blockade in combination with radiation therapy and a glucocorticoid-induced tumor necrosis factor receptor (GITR) antagonist (anti-GITR antibody) were examined on large, established MC38 tumors in mice.

[0134] 5x10 5 MC38 colon cancer cells were implanted subcutaneously into the right flank of female C57BL / 6 mice (Jackson Laboratory). The mean tumor volume was approximately 150–200 mm. 3Treatment was initiated when tumors reached a size of 100 mm (classified as "large tumors"). 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 anti-PD-1 and anti-GITR antibodies at 5 mg / kg twice weekly for a total of five intraperitoneal injections. One day after the initiation of antibody treatment, mice assigned to the radiation therapy group received 8 Gy of radiation to the right flank tumor. Radiation therapy was performed by RS 2000 Biological Research Using an Irradiator (Rad Source), a partial body irradiation fixture (P Tumors were delivered to anesthetized mice (ketamine / xylazine) shielded with a resection X-ray and lead sheet (Images Scientific Instruments). Tumor growth was assessed three times a week until days 70-80, when all mice were euthanized. Figure 11 shows the study design of the experiment, including administration of anti-PD-1 antibody, anti-GITR antibody, and radiation.

[0135] Anti-PD-1 antibody (RMP1-14) treatment synergized with local radiation (XRT) and anti-GITR antibody in rejecting large MC38 tumors (4 of 6 tumor-free mice) compared to mice treated with XRT + anti-GITR antibody (2 / 6 tumor-free), XRT + anti-PD-1 antibody (2 / 6 rejected), or XRT alone (0 / 6 tumor-free). Monotherapy (with anti-PD-1 antibody or anti-GITR antibody) or combination treatment (anti-PD-1 antibody + anti-GITR antibody) had minimal effect on tumor growth with anti-PD-1 antibody or anti-GITR antibody, which mediated rejection in 1 / 5 mice, and the combination of the two antibodies mediated rejection in 2 / 5 mice. Tumor regression lasted up to 6.5 weeks after the start of treatment for the triple combination treated mice, versus 2 weeks for XRT + anti-GITR antibody treated mice (Figure 12).

[0136] [Table 8]

[0137] Table 8 and Figure 13 show the survival of mice receiving anti-PD-1 antibody in combination with radiation therapy and anti-GITR antibody. Furthermore, administration of anti-PD-1 antibody + XRT reduced the survival of very large tumors (approximately 300 mm 3 ) resulting in tumor regression.

[0138] Example 6: In vivo efficacy of anti-PD-1 antibodies in combination with radiation therapy and GITR antagonists against B16 tumors In this example, the effects of PD-1 blockade in combination with radiation therapy and a GITR antagonist (anti-GITR antibody) were examined on established B16 tumors in mice.

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

[0140] Anti-PD-1 antibody in combination with anti-GITR antibody and radiation therapy is expected to promote more tumor regression and slow tumor growth than anti-PD-1 antibody alone or in combination with radiation therapy.

[0141] Example 7: Clinical Trial of Anti-PD-1 Antibody and Radiation Therapy in Patients with Advanced Solid Tumors This study is an open-label, multicenter, dose-escalation study with multiple dose-escalation and expansion arms to investigate the efficacy, safety, and tolerability of an anti-PD-1 antibody, alone and in combination with other anti-cancer therapies (including radiation therapy), in adult patients with advanced solid tumors.

[0142] The exemplary anti-PD-1 antibody used in this study is REGN2810 (also known as H4H7798N, as disclosed in US20150203579), a fully human monoclonal anti-PD-1 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; a 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.

[0143] Research purpose The primary objective of the study is to characterize the safety, tolerability, and dose-limiting toxicities (DLTs) of REGN2810 administered intravenously (IV) as monotherapy or in combination with targeted radiation (intended to serve primarily as an immunostimulatory rather than tumor-ablative therapy), low-dose cyclophosphamide (a treatment shown to inhibit regulatory T-cell responses), granulocyte-macrophage colony-stimulating factor, carboplatin, docetaxel, or combinations thereof in patients with advanced malignancies.

[0144] 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 describe 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] Study design rationale The 3+3 model for the dose escalation phase of this study is designed to allow evaluation of the safety of REGN2810 both as a monotherapy at various dose levels and in combination with immune enhancing treatments: cyclophosphamide; localized targeted radiation delivered in one of two dosing regimens; or a combination of radiation and cyclophosphamide.

[0146] Once the tolerability of REGN2810 is established, both alone and in combination with radiation and / or cyclophosphamide, multiple expansion cohorts using various combinations or both as single agents in select indications (NSCLC, BC, HNSCC, CSCC, tumors with MSI (colorectal, endometrial, prostate, or other tumor types), HCC, and other advanced solid tumors) will be added to further confirm safety and evaluate increased antitumor activity. Granulocyte-macrophage colony-stimulating factor (GM-CSF), carboplatin, and / or docetaxel will be 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] Initial planned treatment with REGN2810 is every 14 days until 48 weeks, followed by 24 weeks of follow-up. Radiation will be administered 1 week after the first dose of REGN2810. Low-dose cyclophosphamide will be administered to patients assigned to cyclophosphamide 1 day prior to each of the first 4 doses of REGN2810.

[0150] Research period Patients will receive treatment for up to 48 weeks, followed by a 24-week follow-up period. Patients will receive treatment until the 48-week treatment period is completed or until disease progression, unacceptable toxicity, withdrawal of consent, or another study withdrawal criterion is met. After a minimum of 24 weeks of treatment, patients with a confirmed complete response (CR) may choose to discontinue treatment and continue with all relevant study evaluations (e.g., efficacy evaluations). After a minimum of 24 weeks of treatment, patients with a tumor burden assessment of stable disease (SD) or partial response (PR) that has not changed for three consecutive tumor evaluations may also choose to discontinue treatment and continue with all relevant study evaluations (e.g., efficacy evaluations).

[0151] Study population The target population for this study includes patients with advanced malignancies who are not candidates for standard therapy, are unwilling to undergo standard therapy, or for whom there is no available treatment expected to provide clinical benefit; and patients with malignancies that are incurable and have failed to respond or have shown tumor progression despite standard therapy.

[0152] Inclusion Criteria:Patients must meet the following criteria to be eligible for inclusion in the study: (1) documented progression of a solid tumor for which no alternative standard treatment options are available; (2) at least one lesion for response assessment. Patients assigned to radiation therapy will need at least one additional lesion that can be safely irradiated while sparing the index lesion and for which radiation at a limited symptomatic dose is considered medically appropriate; (3) patients must have relapsed after or be refractory to first-line treatment (and up to two prior lines of treatment) in the recurrent or metastatic disease setting and have disease for which contrast radiation therapy is supported; (4) patients with metastatic cancer with microsatellite instability (MSI) that is refractory to two prior lines of treatment; (5) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (6) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (7) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (8) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (9) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (10) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (11) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (12) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (13) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (14) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines of treatment; (15) patients with metastatic cancer with microsatellite instability that is refractory to two prior lines (6) Age >18 years; (7) Liver function: a. Total bilirubin ≤1.5x upper limit of normal (ULN; ≤3xULN if liver metastases), b. Transaminases ≤3xULN (or ≤5.0xULN if liver metastases), c. Alkaline phosphatase (ALP) ≤2.5xULN (or 5.0xULN if liver metastases); (8) Renal function: Serum creatinine ≤1.5xULN; (9) Neutrophil count (ANC) ≥1.5x10 9 / L, c. Platelet count ≥75x10 9 (10) Ability to provide signed informed consent; and (11) Ability and willingness to comply with scheduled visits, treatment plans, laboratory tests, and other study-related procedures.

[0153] Test procedure REGN2810 is supplied as a liquid in sterile single-use vials. Each vial contains sufficient volume 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. Each patient's dose depends on their individual body weight. The dose of REGN2810 is adjusted each cycle for weight changes 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 will be administered in an outpatient setting by IV infusion over 30 minutes every 14 days for 48 weeks (i.e., 56-day cycles on days 1, 15±3, 29±3, and 43±3). Planned monotherapy regimens to be assigned may include: (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 MTD determined to be less than 1 mg / kg); and (v) 200 mg flat-dose IV infusion over 30 minutes every 14 days for 48 weeks.

[0155] Combination therapy Concomitant radiation therapy, cyclophosphamide, GM-CSF, carboplatin, and docetaxel will be provided via prescription, and their utilization, dosage, dose modifications, reductions, or delays, as well as any AEs that may result from their use will be tracked along with REGN2810.

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

[0157] Patients will receive either 30 Gy given as 5 fractions of 6 Gy administered daily starting 1 week after the first dose of REGN2810, or 27 Gy given as 3 fractions of 9 Gy administered every other day starting 1 week after the first dose of REGN2810. Lesions selected for radiation should be those that can be safely irradiated with focal radiation while sparing the index lesion, and for which radiation with limited symptomatic doses taken into consideration is deemed medically appropriate.

[0158] Coadministration of REGN2810 and cyclophosphamide : REGN2810 is administered by IV 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 prior to each of the first 4 REGN2810 doses (days -1, 14, 28, and 42 of the first 56-day cycle).

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

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

[0161] Concurrent administration of REGN2810, radiation and GM-CSF The planned combination REGN2810, radiation, and GM-CSF regimen is: GM-CSF 250 mcg SC daily for 7 days on 4 7-day intervals (days 1-7, 15-21, 29-35, and 43-49 of the first 56-day cycle); and 27 Gy radiation therapy (9 Gy x 3 fractions / week; given 1 week after the first dose of REGN2810, preferably on non-consecutive days); and REGN2810 3mg / kg infusion over 30 minutes every 14 days for 48 weeks (monotherapy dose 3mg / kg<MTD;3mg / kg> If it is at the MTD, the dose is 1mg / kg) Includes.

[0162] Concomitant administration of REGN2810, radiation, GM-CSF, and cyclophosphamide The planned combination REGN2810, radiation, GM-CSF, and cyclophosphamide regimen is: GM-CSF 250mcg SC daily for 7 days on 4 7-day intervals (days 1-7, 15-21, 29-35, and 43-49 of the first 56-day cycle) and 27 Gy radiation therapy (9 Gy x 3 fractions / 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 (days -1, 14, 28, and 42 of the first 56-day cycle) for a total of 4 doses; and REGN2810 3mg / kg infusion over 30 minutes every 14 days for 48 weeks, monotherapy dose 3mg / kg<MTD;3mg / kg> If it is at the MTD, the dose is 1mg / kg) Includes.

[0163] Concomitant 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 dexamethasone premedication dose may be 8 mg or 4 mg at the investigator's discretion. Carboplatin AUC 2 IV over approximately 30 minutes on days 1, 8, 29, and 36 of an initial 56-day cycle. Carboplatin dosing should use the Calvert formula for the carboplatin label. Creatinine clearance should be calculated using the Cockcroft-Gault formula. · 3mg / kg REGN2810 infusion over approximately 30 minutes every 14 days for 48 weeks.

[0164] Procedures and Evaluation Screening procedures to be performed include serum beta-HCG, brain MRI, and chest x-ray.

[0165] Safety procedures include medical history, physical examination, vital signs, electrocardiogram (ECG), coagulation, immune safety assays (for patients treated with REGN2810), B symptom assessments and behavioral status assessments, clinical laboratory tests, AEs, and concomitant medications.

[0166] 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 will be performed at the screening visit (within 28 days prior to infusion) and on days 56±3 during all cycles (approximately every 8 weeks), and if disease progression is suspected. In addition, for patients who do not progress to the study, tumor evaluations will be performed at follow-up visits 3, 5, and 7. If the choice is made to use CT scans or MRIs, subsequent evaluations will be performed using the same procedures. Tumor response evaluation will be performed according to the Response Evaluation Criteria in Solid Tumors (SCT) and / or MRI. RECIST version 1.1 (Eisenhauer et al. 2009, Eur. J. Cancer 45:228-247). Measurable lesions selected as target lesions for RECIST measurements were selected as index lesions according to immune-related response criteria (irRC; Nishino et al. 2013, Clin. Cancer 45:228-247). Res. 19:3936-3943). RECIST response is preferred as the statistical assessment of response rate. For individual patients, the irRC can inform decisions regarding whether to continue treatment at the investigator's discretion due to the possibility of a negative response.

[0167] Blood samples for PK and anti-drug antibody (ADA) evaluation are collected.

[0168] Study variables The primary variables in the study are the incidence of DLTs and the incidence and severity of TEAEs and abnormal laboratory findings during 48 weeks of treatment.

[0169] The secondary variables are: Antitumor activity assessed using appropriate criteria for the indication (as described elsewhere herein): ∨ 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 may be used for specific objectives for which RECIST 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 governing tool for determining PD, SD, CR, or PR. The irRC is collected for clinical decision and information purposes. Incidence of anti-REGN2810 antibodies Antitumor activity measured by PFS and overall survival It is.

[0170] For the purposes of this study, patients will be re-evaluated every 8 weeks for response. Confirmatory scans will also be obtained 4 weeks after the first documentation of objective response or progressive disease. Response and progression will be assessed in this study according to the revised Guidelines for Response Assessment in Solid Tumors. Responses are assessed 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 (unidimensional measurement) and in the case of malignant lymph nodes, the shortest diameter are used in the RECIST criteria.

[0171] Lesion Selection Measurable disease: A measurable lesion is defined as one that can be accurately measured in at least one dimension (longest diameter attempted to be recorded) as ≥ 20 mm (≥ 2 cm) by chest x-ray or ≥ 10 mm (≥ 1 cm) by caliper by CT scan, MRI, or clinical examination. All tumor measurements must be recorded in millimeters (or decimals of centimeters). Note: See below for evaluation of radially elongated lesions.

[0172] Malignant lymph nodes: To be considered pathologically enlarged and measurable, lymph nodes must be ≥ 15 mm (≥ 1.5 cm) in the short axis when assessed by CT scan (recommended CT scan slice thickness is greater than 5 mm [0.5 cm]). Only the short axis will be measured and tracked at baseline and follow-up.

[0173] Unmeasurable disease:All other lesions (or areas of disease), including small lesions (pathologic lymph nodes with a short axis of <10 mm [<1 cm] or ≥10 to <15 mm [≥1 to <1.5 cm] in longest diameter), are considered nonmeasurable disease. Bone lesions, leptomeningeal disease, ascites, pleural / pericardial effusion, lymphangitis cutis / pneumonia, inflammatory breast disease, and abdominal masses (not tracked by CT or MRI) are considered nonmeasurable. Note: Cystic lesions that meet the criteria for a radiographically defined solitary cyst should not be considered malignant lesions (neither measurable nor nonmeasurable) since they are solitary cysts by definition. "Cystic lesions" thought to represent cystic metastases may be considered measurable lesions if they meet the measurability criteria above. However, if noncystic lesions are present in the same patient, they should be considered measurable lesions. These are preferably selected as target lesions.

[0174] Target Lesions: All measurable lesions, up to two per organ and five total, representative of all included organs, should be identified as target lesions and measured at baseline. Target lesions are selected based on their size (lesions with the longest diameter), including those that are representative of all included organs, but also lend themselves to reproducible repeated measurements. Sometimes, it may be the case that the largest lesion does not lend itself to reproducible measurements, and in this situation, the next largest lesion that can be reproducibly measured is selected. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions is calculated and reported as the baseline sum diameter. If lymph nodes are to be included in the sum, only the short axis is added to the sum. The baseline sum diameter is used as a reference to further characterize objective tumor regression in the measurable dimensions of the disease.

[0175] Non-target lesions: All other lesions (or areas of involvement), including any measurable lesions in addition to the five target lesions, will be identified as non-target lesions and recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or, in rare cases, frank progression of each will be noted during follow-up.

[0176] How to assess measurable disease 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, but no earlier than 4 weeks before the start of treatment. The same method of evaluation and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to assess by clinical examination, unless the lesion being followed cannot be assessed by clinical examination.

[0177] Clinical manifestations: Clinical lesions are considered measurable only if they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm (≥ 1 cm) in diameter (e.g., skin nodules) as measured with a caliper. In the case of skin lesions, color photographic documentation including a scale to estimate the size of the lesion is recommended.

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

[0179] Conventional CT and MRI: This guideline defined 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 may also be acceptable in certain circumstances.

[0180] PET-CT: If the CT performed as part of the PET-CT is of the same diagnostic quality as a 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 in accurately measuring cancerous lesions over time.

[0181] Ultrasound:Ultrasound is not useful for assessing lesion size and should not be used as a method of measurement. If new lesions are identified by ultrasound during the course of the study, confirmation by CT or MRI is recommended. If there are concerns about radiation exposure with CT, MRI may be used instead of CT in the case of choice.

[0182] Endoscopy, Laparoscopy: Use of these techniques for objective tumor evaluation is not recommended, however, such techniques may be useful to confirm complete pathologic response when biopsies are obtained, or to determine recurrence in studies where complete response (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 above the upper limit of normal, they must normalize in order for the patient to be considered as having a complete clinical response.

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

[0185] FDG-PET:Although FDG-PET response assessment requires further testing, it may be reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in the assessment of progression (especially possible "new" disease). New lesions based on FDG-PET imaging can be identified according to the following algorithm: a. Negative FDG-PET at baseline and positive FDG-PET at follow-up is indicative of PD based on new lesions. b. No FDG-PET at baseline and positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a site confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, a further follow-up CT scan is needed to determine if progression is indeed occurring at that site (in which case the PD date is the date of the first abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a site of existing disease on CT that has not progressed based on anatomic imaging, this is not PD. c.FDG-PET may be used to elevate a 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 indications. However, it must be acknowledged that both approaches may produce false-positive CRs due to the limitations of resolution / sensitivity of FDG-PET and biopsy. Note: A "positive" FDG-PET scan lesion is one that has FDG avid with uptake higher than twice that of surrounding tissue in attenuation-corrected images.

[0186] Response criteria for evaluation of target lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have a short-axis reduction to <10mm (<1cm). Partial response (PR): At least a 30% reduction in the sum of the diameters of the target lesions, taking the baseline sum diameter as reference. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of the target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). 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 as progression). · Stable Disease (SD): Taking as reference the smallest total diameter during the study, there is neither a sufficient reduction to qualify for PR nor a sufficient increase to qualify for PD.

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

[0188] Immune-Related Response Criteria Immune-related response criteria differ from RECIST (version 1.1) in that the sum of the longest diameters of all targets and new lesions, if any, is used to determine response. The presence of new lesions by itself does not determine progression; total tumor burden is taken into account.

[0189] Target Lesion Evaluation Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) must have a short axis reduction to <10mm (<1cm). Partial response (PR): At least a 30% reduction in the sum of the diameters of the target lesions, including new lesions, taking the baseline sum diameter as reference. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of the target lesions, including new lesions, taking as reference the smallest sum in the study (this includes the baseline sum if it is the smallest in the study). 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): The smallest total diameter during the study is taken as the reference and includes measurements of new lesions, and has not shrinked sufficiently to qualify for PR, nor increased sufficiently to qualify for PD.

[0190] Evaluation of non-target lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be nonpathologic in size (<10 mm [<1 cm] short axis). Note: If tumor markers are initially higher than the upper limit of normal, 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 normal limits. Progressive Disease (PD): Definite progression of existing non-target lesions. Definite progression should not normally exceed target lesion status. It should be representative of the overall disease status change, not an increase in a single lesion. Definite progression of only "non-target" lesions is exceptional and the physician's choice of treatment should prevail in this situation, and progression status should be subsequently confirmed.

[0191] Evaluation of overall response criteria Best overall response is the best response recorded from the start of treatment until disease progression / recurrence (the smallest measurement recorded since treatment was started is considered as the reference for progressive disease). Best response assignment of patients depends on the achievement of both measurement and confirmation criteria. The new guidelines for evaluation of response in solid tumors (RECIST) version 1.1 (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 assessed 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 RECIST 1.1 guidelines specific to this protocol are incorporated to define local control.

[0195] Response criteria for radial lesions were as follows: Local Expansion (LE): At least a 20% increase in the LD of the target lesion, taking as reference the smallest LD recorded since treatment began. Ideally, this determination is made based on CT imaging evaluation.

[0196] Local failure (LF): Refers to the primary treated tumor after treatment in the clinical trial protocol and corresponds to meeting both of the following two criteria: (1) local spread ( (1) a 20% increase in tumor size as defined above for LE; (2) a measurable tumor meeting the criteria for LE should have accretion on positron emission tomography (PET) imaging with similar intensity of uptake as the pretreatment staging PET, or a measurable tumor should have biopsy-confirmed viable carcinoma.

[0197] Local Management (LC): Absence of focal failure.

[0198] The longest radial diameter (LD) of the target lesion calculated from the treatment planning CT scan using the appropriate tissue-specific fenestration technique is reported as the baseline LD. The baseline LD is used as a reference to characterize the target tumor. For follow-up evaluations, diagnostic CT scans performed using a pulmonary fenestration technique using a 5 mm continuous reconstruction algorithm, taken as part of the scheduled protocol follow-up, are the preferred method of response assessment. If a CT scan is not available, MRI or x-ray determinations are acceptable as long as the target lesion is clearly visible.

[0199] result REGN2810 is safe and well tolerated by patients, both 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 advanced solid tumors. Overall response rates are better for combination therapy with radiation compared to monotherapy.

[0200] Sixty patients (47% had had four or more prior lines of therapy) with advanced solid malignancies had been treated to date, including colorectal, head and neck, breast, soft tissue sarcoma, adrenal, anal, appendix, bladder, cervical, endometrial, esophageal, hepatic, non-small cell lung adenocarcinoma, ovarian, pancreatic, prostate, renal sarcomatoid, salivary gland, non-melanoma skin, Merkel cell, squamous cell, basal cell, small intestine, thyroid, 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 an objective response (PR / CR), while 31 patients (51.7%) showed disease control (CR / PR / SD). In the 36 patients who received combination therapy including radiotherapy, an objective response was seen in 6 patients (16.7%), and disease control was seen in 19 patients (52.8%). In the 24 patients who did not receive radiotherapy, an objective 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 responders, the median response time to monotherapy was 113 days (range 52-226) and for patients using radiation therapy it was 59 days (range 56-113).

[0204] Example 8: Metastatic Non-Melanoma Skin Cancer: Case Reports of PD-1 Blockade with Monoclonal Antibody REGN2810 Achieving Durable Objective Responses in Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma introduction Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to UV light as a major risk factor, and therefore 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 for 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 released 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 patients with metastatic CSCC who were 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 woman diagnosed with stage 1 BCC arising on the left aspect of the chin, which was resected by Mohs surgery. A localized recurrence in the same location was identified 2 years later, and wide local excision revealed involvement of the left mandible and 1 of 18 lymph nodes. The patient underwent adjuvant radiation and remained in remission for 4 years, when an enlarging pulmonary nodule seen 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 responded initially but discontinued due to progressive disease.

[0206] After 6 months of vismodegib treatment, with continued slow progression, the patient was entered into a cohort of a Phase 1 study of REGN2810 administered 10 mg / kg IV every 2 weeks and received the first dose. The two lung metastases were followed as target lesions. Response assessments at the end of week 8 (3% increase) and week 16 (10% decrease) showed stable disease by RECIST criteria. Response assessments at the end of week 24 showed a 37% decrease in tumor measurement (Figure 14A), which was confirmed at week 32. The patient tolerated the treatment well and continued REGN2810 for 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 with clear margins. He experienced multiple recurrences and underwent at least nine additional Mohs surgeries. He underwent wide local excision of the left mandible 4 years later and left parotidectomy 20 months thereafter. Adjuvant radiation therapy was also administered to the left cheek, left mandible, left neck (with cetuximab), and bilateral neck (with carboplatin). Other systemic therapy was capecitabine, and cisplatin plus docetaxel. Ten years after the initial diagnosis, he underwent resection for a 2.2 cm in-scar recurrence in the left neck with clear margins. Invasive CSCC in the C4-C5 vertebral body subsequently necessitated emergency decompression of the cervical spinal cord with a C4-C5 anterior corpectomy and a C4-C6 posterior laminectomy. He also developed lower extremity weakness thought to be due to perineural involvement and required the use of a walker for ambulation.

[0208] He was enrolled in the first cohort of the Phase 1 study receiving 1 mg / kg REGN2810 every 2 weeks. Within weeks of initiating treatment, his lower extremity strength slowly recovered and he no longer required the use of a walker. Responses at week 16 are shown in Figure 14B. Complete radiographic response of the left cervical lesion was achieved at week 40. The patient completed the planned 48 weeks of protocol treatment with REGN2810. He continues to receive close, active follow-up with his oncologist with no evidence of disease recurrence, either clinically or radiologically.

[0209] Consideration This example discloses the first confirmed partial response in a patient with metastatic BCC treated with a PD-1 inhibitor (REGN2810), as well as an ongoing durable complete response in a patient with metastatic CSCC. The profound and durable response of these heavily pretreated patients to anti-PD-1 monotherapy in this Phase 1 study is consistent with the hypothesis that high mutational burden in BCC and CSCC may 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-associated skin cancers other than melanoma are more sensitive to PD-1 blockade. Reductionist models suggest that UV-associated tumors with a higher burden of nonsynonymous mutations are more susceptible to PD-1 blockade than those with a lower mutation burden. One would predict that the IL-10 receptor agonist is more responsive to IL-10 inhibition than the IL-10 receptor agonist.

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

[0212] method The expansion cohort (EC) in the phase 1 study of REGN2810 included patients with distant metastatic CSCC (EC7) and locally advanced CSCC (EC8) (Table 9). All patients received REGN2810 at 3 mg / kg intravenously every 2 weeks for up to 48 weeks. Study 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] result Twenty-five patients were enrolled (10 in EC7 and 15 in EC8): median age, 72.5 years (y) (range, 56-88y); median PS 1 (range, 0-1); 20 men (M): 5 women (F); median number of prior systemic treatment regimens, 1 (range, 0-3). Median exposure to REGN2810 was 6 doses (range, 1-22). The most common 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: AST elevated, ALT elevated, arthralgia, and rash.

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

[0215] conclusion REGN2810 demonstrates robust antitumor activity in patients with advanced CSCC.

[0216] Example 10: Clinical Trial of Anti-PD-1 Antibody Combined with Hypofractionated Radiation Versus Standard of Care in Patients ≧65 Years Old with Newly Diagnosed Glioblastoma introduction Glioblastoma is a fatal disease with a median survival of approximately 16 months in newly diagnosed patients (nGBM) and approximately 9 months in the recurrent setting (rGBM) (Friedman et al., 2009, J. Clin. Oncol. 27:4733-4740). The current standard of care for patients with newly diagnosed glioblastoma is radiation (60 Gy over 6 weeks) with concomitant temozolomide (TMZ), followed by adjuvant temozolomide (Stupp et al., 2005, N. Engl. J. Med. 352:987-996), although subgroup analyses suggest 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 study to evaluate the efficacy of an anti-PD-1 antibody in combination with hypofractionated radiation therapy (hfRT) versus standard of care (SoC) on overall survival in patients ≥ 65 years old with nGBM.

[0218] An exemplary anti-PD-1 antibody used in this study is REGN2810 (also known as H4H7798N, as disclosed in US20150203579), a fully human monoclonal anti-PD-1 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; a 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 purpose The primary objective of this study is to evaluate the efficacy in terms of overall survival (OS) of REGN2810 given in combination with hfRT versus standard of care for patients ≥ 65 years of age with nGBM.

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

[0221] Other objectives of the study are to investigate: (i) improvement in objective response rate (ORR), duration of response, and duration of disease control; (ii) clinical assessment using the Neuroassessment with Neurological Demand (NANO) scale; (iii) safety; (iv) improvement in quality of life (QoL) and mental status; (v) changes in edema and steroid usage; (vi) serum REGN2810 concentrations and anti-REGN2810 antibodies; and (vii) potential pharmacodynamic, predictive or prognostic biomarkers.

[0222] research design This is a 2:1 randomized Phase 3 trial of REGN2810, a fully human antibody against PD-1, in combination with hypofractionated radiation therapy versus standard of care in patients ≥65 years of age with newly diagnosed glioblastoma. Patients will be randomized in a 2:1 ratio to REGN2810 in combination with hypofractionated radiation therapy versus standard of care, using methylation status (methylated vs. unmethylated vs. undetermined) and extent of resection (partial vs. total resection) as stratification factors. Efficacy will be assessed by overall survival.

[0223] nGBM patients who are candidates for radiation therapy will be randomized 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, week 2 only). Radiation therapy is provided in week 2 of cycle 1, but not in subsequent cycles. Comparator treatment: Standard RT (5 daily fractions / weekly dose of 2 Gy) combined with standard TMZ (oral, 75 mg / m 2 , daily) for 6 weeks, followed by adjuvant TMZ (oral, 150 mg / m2–200 mg / m 2 5 days / 28 days) for 6 cycles. Radiation therapy is provided only in the first 6-week cycle.

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

[0225] After Day 1 / baseline, patients will return to the clinic on days 8±3, 15±3, 29±3, 43±3, and 56±3 for Cycle 1. During subsequent 8-week cycles (Cycles 2-12), patients will return to the clinic on days 1, 15±3, 29±3, 43±3, and 56±3. Tumor assessments (brain MRI, iRANO and NANO assessments, MMSE, and EORTC QLQ-C30 / BN20 questionnaires) will be performed on Day 1 / baseline and at the end of each treatment cycle. Expanded safety assessments will be performed on Day 1 of each cycle; conventional safety assessments will be performed at each visit. Samples (cellular and molecular, as described herein) for evaluation of biomarkers related to REGN2810 treatment exposure, clinical activity, or underlying disease will also be collected.

[0226] During the 24-week follow-up phase, patients return to the clinic 21-42 days after the last study for their first follow-up visit. Subsequent follow-up visits (Follow-up Visit 2-Follow-up Visit 7) are every 28 days ± 7 days. Tumor assessments (brain MRI, iRANO and NANO assessments, MMSE, and EORTC QLQ-C30 / BN20 questionnaires) will be performed at Follow-up Visit 3, Follow-up Visit 5, and Follow-up Visit 7. Expanded safety assessments will be performed during the first follow-up visit; routine safety assessments will be performed at subsequent follow-up visits. Samples will be collected for evaluation of biomarkers (cellular and molecular, as described herein) related to REGN2810 treatment exposure, clinical activity, or underlying disease.

[0227] Target population The target population includes patients ≥ 65 years of age 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 of ≤5 cm, and patients had a partial or complete surgical resection; (2) Eastern Cooperative Oncology Group (ECOG) performance status 0-2; (3) age ≥65 years; (4) liver function: (a) total bilirubin ≤1.5x upper limit of normal; (b) ALT and AST ≤3xULN; (c) alkaline phosphatase (ALP) ≤2.5xULN; (5) renal function: serum creatinine ≤1.5xULN; (6) bone marrow function: hemoglobin ≥9.0g / dL; absolute neutrophil count (ANC) ≥1.5x10 9 / L; Platelet count ≧75×10 9 (7) able to read, understand, and willingly sign the ICF; and (8) able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study-related procedures.

[0229] Exclusion criteriaPatients who meet any of the following criteria will be excluded from the study: (1) previous treatment for GBM (other than surgery); (2) had a known contraindication to Gd-MRI; (3) ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with immunosuppressive treatment, which may indicate risk for immune-related adverse events (irAEs). The following are not exclusions: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormone replacement, or psoriasis not requiring systemic treatment. (4) Ongoing systemic corticosteroid treatment, excluding use of corticosteroids for other (non-oncology and non-immunosuppressive) indications up to a maximum of 10 mg / day prednisone or equivalent. (5) Any secondary brain tumor active infection requiring treatment, including a primary tumor located in the brainstem, spinal cord, or known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C virus. (6) History of interstitial pneumonia within the last 5 years. (7) Any investigational or antitumor treatment within 30 days prior to the first dose of REGN2810. (8) History of documented allergic or acute hypersensitivity reactions due to treatment with antibody therapy in general or to drugs used specifically in this study. (9) Inadequately controlled hypertension (defined as systolic blood pressure >150 mm Hg and / or diastolic blood pressure >100 mm Hg). (10) Known allergy to doxycycline or tetracycline (precaution due to the presence of trace components in REGN2810). (11) Previous history of hypertensive crisis or hypertension or hypertensive encephalopathy. (12) In situ resected / sectioned basal or squamous cell carcinoma of the neck or other lesions thought to be cured by local treatment. (13) any acute or chronic psychiatric problem that would disqualify the patient from participating in the study, as assessed by the investigator; (14) use of Tumor Treating Fields (Optune NovoTTF-100A device) at screening; planned or anticipated use of Novocure Tumor Treating Fields during study participation; (15) previous treatment with carmustine wafers; (16) continued sexual activity in men unwilling to practice adequate contraception during the study.

[0230] Study Procedures Patients will receive one of the following treatment regimens:

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

[0232] Comparator: Standard of Care Six weeks of standard RT (five daily radiation fractions of 2 Gy / week) followed by six weeks of adjuvant TMZ (oral, 150 mg / m2–200 mg / m 2 TMZ (oral, 75 mg / m2, daily) in combination with 5 d / 28 d. Radiotherapy is provided only in the first cycle.

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

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

[0235] REGN2810 and Radiation (Investigational Treatment) :REGN2810 will be administered by IV infusion over 30 minutes every 14 days for 96 weeks in combination with hfRT from days 8 to 12.

[0236] Planned combination REGN2810 and hfRT regimen : 3 mg / kg REGN2810 infusion over 30 minutes every 14 days for 96 weeks plus radiation therapy (hfRT at 6 Gy x 5 daily fractionated doses; given 1 week after the first dose of REGN2810, preferably on consecutive days).

[0237] Specification for radiation therapy: Patients will receive 30 Gy given as 5 fractionated doses of 6 Gy administered daily starting 1 week after the first dose of REGN2810.

[0238] Comparison arm: standard of care TMZ (oral, 75 mg / m) combined with standard RT (2 Gy in 5 daily fractions / week) for 6 weeks. 2 , daily), followed by adjuvant oral TMZ. The dose of TMZ was 150 mg / m for the first 5 days of the first adjuvant administration. 2 and 200 mg / m for 5 days / 28 days in the absence of unacceptable hematologic toxicity in the first adjuvant cycle. 2 to start the second cycle.

[0239] During the first adjuvant cycle, if all observed non-hematological toxicities were grade ≦2 (except for alopecia, nausea, and vomiting), and platelets were ≧100×109 / L, and ANC>=1.5×109 / L, the TMZ dose was reduced to dose level 1 (20 0 mg / m 2 ), and this dose should be used as the starting dose in subsequent cycles. If after cycle 1 TMZ must be withdrawn due to ongoing grade ≥ 2 non-hematological toxicity, escalation is not possible. If the dose was not escalated in the second cycle, it should not be escalated in subsequent cycles.

[0240] Treatment of CNS Edema Patients who develop symptomatic cerebral edema during the study will have REGN2810 and radiation therapy discontinued until the edema subsides.

[0241] For patients who develop intracerebral edema, bevacizumab is given IV at a reduced standard dose (suggested dose 5 mg / kg Q2W for up to 3 doses, not to exceed 10 mg / kg Q2W per dose) unless contraindicated (e.g., the patient has not had surgery within the past 28 days).

[0242] If bevacizumab does not resolve intracerebral edema, systemic corticosteroids may be administered in addition to or instead of bevacizumab at the lowest dose required to adequately manage symptoms. For patients with bevacizumab intolerance, they are used at the dose required to adequately manage symptoms.

[0243] Study variables The primary efficacy outcome was overall survival (OS), defined as the time interval from randomization to the date of death from any cause.

[0244] The key secondary endpoint was progression-free survival (PFS), defined as the time interval from the date of randomization to the date of first disease progression or death (from any cause), as determined by iRANO criteria.

[0245] Other secondary efficacy outcomes included: Objective Response Rate (ORR): The ORR was calculated based on the total number of patients in the analysis population and the Immunotherapy Response Assessment in Neuro-Oncology (IMRA) score. The proportion of patients with confirmed complete response (CR) or confirmed partial response (PR) as defined by the International Randomized Clinical Oncology (IRANO) criteria is defined as the proportion of patients with confirmed complete response (CR) or confirmed partial response (PR) as defined by the International Randomized Clinical Oncology (IRANO) criteria.

[0246] Duration of Response: Determined for patients with a best overall response of CR or PR. Duration of response is measured from the first time the metric met CR / PR (whichever was documented first) to the first date of recurrence or progressive disease (radiographic), or death from any cause.

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

[0248] Quality of life and symptom control variables Quality of life and symptom control variables were: Five functioning scales, three symptom scales, one global health status scale and six single-item scales assessing symptoms using the EORTC QLQ-C30 questionnaire during the study. Four scales and seven single items of the EORTC QLQ-BN20 questionnaire were used during the study. · Clinical evaluation using NANO; MMSE total score during the study Corticosteroid use at baseline, cumulative corticosteroid use during the study, and duration of steroid-free 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 duration of bevacizumab-free progression-free time in the study

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

[0250] Procedures and Evaluation Following a screening period of up to day 28, patients will receive up to twelve 56-day treatment cycles for up to 96 weeks total treatment, followed by a 24-week follow-up period. Efficacy, safety, PK, ADA, and exploratory biomarker analyses will be performed.

[0251] Efficacy Procedures MRI : MRIs for tumor evaluation will be performed 72 hours after surgery, at the screening visit (within 28 days prior to infusion), on day 56 ± 3 of every cycle (approximately every 8 weeks), and if PD is suspected. Patients whose disease did not progress had further tumor evaluations at follow-up visits 3, 5, and 7. NOTE: If PD is confirmed, further scans are not required between follow-up visits. If pre- and post-operative MRIs were performed prior to study entry, these scans must also be submitted to the study to assist in determining tumor volume and tumor progression.

[0252] Tumor response assessments will be performed according to iRANO; and clinical neurological assessments will be performed according to NANO. Evaluations according to RANO will also be performed as supportive investigations; however, the primary determination of disease progression for individual patients will be performed according to iRANO.

[0253] The European Organization for Cancer Research and Treatment EORTC Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and EORTC Brain Cancer Module (EORTC QLQ-BN20) questionnaires The EORTC QLQ-C30 is a 30-item questionnaire assessing health-related quality of life (HRQoL) in cancer patients on 15 scales (single or multi-item), each with a possible score ranging from 0 to 100. Twenty-four of the 30 items are collected into nine multi-item scales representing different HRQoL aspects: five functional scales (physical, role, emotional, cognitive, and social), three symptom scales (fatigue, pain, and nausea / vomiting), and one global scale of health status. The remaining six single-item scales assess symptoms: dyspnea, loss of appetite, sleep disorders, constipation and diarrhea, and perceived economic impact of disease treatment. Higher scores indicate better HRQoL for the global scale of health status and the functional scales, and worse HRQoL for the 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 in 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 disturbances, motor function, and language function) and seven single items (other disease symptoms [e.g., headache and epilepsy] and treatment toxic effects [e.g., hair loss]). Possible score range 0-100; higher scores indicate worse HRQoL.

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

[0256] MMSE will be performed at Day 1 / baseline, at the end of the conditioning cycle, and every 8 weeks during the follow-up period. MMSE assessments will coincide with the disease assessment schedule, but they must be completed before patients are informed of their radiological results. MMSE may be completed at the start of the next scheduled treatment administration. During the survival follow-up period, MMSE should continue to be completed every other survival visit (every 8 weeks) if the patient has not yet progressed.

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

[0258] Safety Procedures On Day 1 of Cycle 1 and all subsequent treatment days, vital signs including temperature, resting blood pressure, pulse, and respiration, along with body weight, will be collected prior to infusion and approximately 15 minutes after completion of the infusion. A complete physical examination and 12-lead ECG will be performed at the start of every cycle.

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

[0260] Tumor tissue samples may be used for extraction of tumor DNA and RNA and subsequent analysis of putative genetic biomarkers associated with the test treatment and glioblastoma. Blood samples are collected for isolation of germline DNA at Day 1 / baseline (pre-dose), or at any study visit if Day 1 / baseline collection is not possible. Analysis of tumor DNA includes (but is not limited to) MGMT promoter methylation status, IDH1 mutation status, microsatellite instability (MSI), and tumor mutation burden, both of which may predict response to REGN2810 and other immunotherapeutic agents. Analysis of genetic variants in tumor (somatic) DNA and germline DNA that may affect disease progression, drug response, and possible toxicity is performed. Germline DNA is also used for comparison to tumor DNA to explore potential novel genetic variants underlying the malignant process.

[0261] result 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 compared to standard therapy. Patients with nGBM treated with REGN2810 and hfRT showed longer OS 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 Phase 1 dose escalation (DE) study (described in Example 7 herein), REGN2810 (cemiplimab) monotherapy was evaluated in non-small cell lung cancer (NSCLC) at 1 mg / kg intravenously (IV) over 30 minutes every 2 weeks (Q2W). The NSCLC expansion cohort (EC 1) enrolled patients who had relapsed after at least first-line treatment or were refractory to first-line treatment in the recurrent or metastatic disease setting; patients received cemiplimab 200 mg IV over 30 minutes Q2W up to week 48. Study biopsies were performed at baseline and on 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] Interim Results: Twenty-one patients with NSCLC (1 in DE; 20 in EC 1) were enrolled; median age was 65.0 years (range, 50-82; 14 male (M) / 7 female (F)); 81.0% had a median Eastern Cooperative Oncology Group performance status of 1. The majority (61.9%) had a history of adenocarcinoma at baseline. Overall, the most common treatment-related adverse events (TRAEs) were asthenia, pneumonitis, and rash (n=3, 14.3%, respectively). The following ≥ grade 3 TRAEs occurred once: pneumonitis, diabetic ketoacidosis, and nephritis. Of patients in EC 1, 6 had a partial response (PR), and 4 had stable disease (SD). The overall response rate (ORR = complete response [CR] + PR) was 28.6% (n = 6 / 21) by central independent review (data transfer: August 31, 2017). The disease control rate (ORR + SD) was 57.1% (n = 12 / 21; one of whom had non-CR / non-progressive disease [PD]). Overall, nine patients (all from EC 1) had PD during treatment with cemiplimab.

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

[0265] Example 12: Clinical Trial of REGN2810 in the First-Line Treatment of Patients with Advanced 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 advanced 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] Research purpose The primary objective of the study is to determine whether REGN2810 improves progression-free survival (PFS) over standard of care platinum doublet chemotherapy in patients with advanced or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 on ≥ 50% of tumor cells. Key secondary objectives of the study are to compare REGN2810 to platinum-based chemotherapy with respect to: · Overall survival (OS) Objective response rate (ORR) Other secondary objectives of the study are: To compare the duration of response (DPR) of REGN2810 versus platinum-based chemotherapy To assess the quality of life (QOL) of patients treated with REGN2810 versus those receiving platinum-based chemotherapy, as measured by the European Organisation 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) To evaluate the safety and tolerability of REGN2810 versus platinum-based chemotherapy To measure the concentration of REGN2810 in serum and characterize the pharmacokinetics (PK) of REGN2810 Exploratory objectives include: To assess immunogenicity as measured by immunogenicity assessment for REGN2810 To assess the correlation between baseline PD-L1 expression levels and efficacy of study treatment - To evaluate the time to new anti-tumor therapies Examples include:

[0267] research design This is a randomized, multicenter, open-label, pivotal Phase 3 study 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 received prior systemic treatment for their advanced disease.

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

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

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

[0271] Study population Patients included in this study were men and women aged ≧18 years diagnosed with stage IIIB or IV non-squamous or squamous NSCLC whose tumors express PD-L1 in ≧50% of tumor cells (using a diagnostic assay) and who had 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 aged 18 and over 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 received adjuvant or neoadjuvant platinum doublet chemotherapy (following surgery and / or radiation therapy) and who develop recurrent or metastatic disease more than 6 months after completion of treatment are eligible. 3. Archival or freshly obtained formalin-fixed tumor tissue from metastatic / recurrent sites, which has not been previously irradiated 4. Tumor cells expressing PD-L1 in ≥ 50% of tumor cells by IHC 5. At least one lesion radiographically measurable 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. Projected life span of at least 3 months 8. Adequate organ and bone marrow function as defined below: a. Hemoglobin ≥ 9.0 g / dL, b. Absolute neutrophil count ≥ 1.5 x 109 / L, c. Platelet count ≥ 100,000 / mm3, d. Glomerular filtration rate (GFR) > 30 mL / min / 1.73 m2, e. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (≤ 3 x ULN if liver metastases), excluding patients with a diagnosis of clinically confirmed Gilbert's syndrome, f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN or ≤ 5 x ULN if liver metastases, g. Alkaline phosphatase ≤ 2.5 x ULN (or ≤ 5.0 x ULN if liver or bone metastases), h. Criteria not met for Hy's rule (ALT > 3 x ULN and bilirubin > 2 x ULN). 9. Willing and able to comply with clinic and study-related procedures 10. Provide signed informed consent 11. Able to understand and complete all study-related questionnaires.

[0273] Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study: 1. Patients who have never smoked, defined as smoking ≦100 cigarettes in their lifetime; 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases have been adequately treated and the patient has returned to baseline neurologically (excluding residual signs or symptoms related to CNS treatment) at least 2 weeks prior to enrollment. Patients must have discontinued corticosteroid treatment (in immunosuppressive doses); 3. Patients with tumors that have tested positive for EGFR gene mutations, ALK gene translocations, or ROS1 fusions; 4. Encephalitis, meningitis, or uncontrolled epilepsy in the year prior to informed consent; 5. History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious interstitial pneumonia that has required immunosuppressive doses of glucocorticoids to aid in management. Radiation in the radiation field A history of radiopneumonitis is acceptable. 6. Patients with active, known, or suspected autoimmune disease that has required systemic treatment within the past 2 years. Patients with vitiligo, type I diabetes mellitus, and hypothyroidism requiring only hormone replacement (including hypothyroidism due to autoimmune thyroiditis) are permitted to enroll. 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 they are >10 mg prednisone / day 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 an autoimmune disorder. 8. Another malignancy that is ongoing or requires treatment. Except for non-melanoma skin cancer that has undergone potentially curative therapy, or in situ cervical cancer, or any other tumor that has been treated and the patient is considered to be in complete remission at least 2 years prior to study enrollment and will not require further treatment during the study period. 9. Known active hepatitis B (positive result) or hepatitis C (known positive result) and known quantitative HCV RNA result higher than the detection limit of the assay), 10. Known history of human immunodeficiency virus (HIV) or known acquired immune deficiency syndrome indicating uncontrolled active infection. Patients on highly active antiretroviral therapy with undetectable RNA levels and CD4 counts higher than 350 are permitted. 11. Active infection requiring 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 permitted, but the last dose of such antibodies should be at least 3 months prior to the first dose of study drug. 13. Treatment-related immune-mediated adverse events (AEs) from immunomodulators (including but not limited to anti-PD1 / PD-L1 Mabs, anti-CTLA4 monoclonal antibodies, and PI3K-δ inhibitors) that were not resolved to baseline at least 3 months prior to initiation of treatment with study treatment.Patients will be excluded from treatment with REGN2810 if they have experienced an immune-mediated AE associated with prior treatment with a PD-1 / PD-L1 pathway blocker that was Grade 3 or 4 in severity and / or required discontinuation of the drug, regardless of time of onset. 14. Receipt of an investigational drug or device within 30 days of screening or within 5 half-lives of the investigational drug or treatment being studied (whichever is longer). 15. Receipt of a live vaccine within 30 days of planned initiation of study drug administration, 16. Major surgery or severe trauma within 4 weeks prior to first dose, 17. Documented allergic or acute hypersensitivity reaction attributable to antibody treatment, 18. Known allergy to doxycycline or other tetracycline antibiotics, 19. Known psychiatric or substance abuse disorder that would interfere with the study participation requirements, including current use of any illicit drugs, 20. Pregnant or lactating women. 21. Females of childbearing potential who are unwilling to practice highly effective contraception prior to the first dose, during the study, and for at least 6 months after the last dose. 22. Patients who are institutionalized pursuant to an order issued by either a judicial or administrative authority.

[0274] Study Procedures Study Medication: REGN2810 will be administered as an IV infusion at 350 mg Q3W for up to 108 weeks.

[0275] Reference medication: Standard of care chemotherapy (one of the options outlined in the protocol for platinum doublet chemotherapy treatment, Table 13) will be administered for 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 endpoints The primary endpoint is PFS assessed using RECIST 1.1. Key secondary endpoints in the study are OS and ORR. Other secondary endpoints include DOR and QOL, as well as the safety and tolerability of REGN2810.

[0278] Procedures and Evaluation Procedures performed at screening include: informed consent; recording of medical, oncology, and concomitant medication history; recording of demographics; collection of tumor tissue for PD-L1 assessment; examination of tumor tissue for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations and human homolog of avian sarcoma virus UR2 transforming gene v-ros (ROS1) fusion; 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 testing. Samples for any genomic substudies may also be obtained. During the treatment and follow-up phase, the following procedures will be performed to assess safety: physical examination; ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for females of childbearing potential; ECG and chest x-ray (at the investigator's discretion); and recording of adverse events (AEs) and concomitant medications. Computed tomography (CT) or magnetic resonance imaging (MRI) for tumor assessment will be performed at time points throughout the study. Quality of life will be measured using validated patient self-administered questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13). Other assessments will include samples for biomarker evaluation, REGN2810 concentration, Samples for measurement, and samples for REGN2810 immunogenicity assessment are included.

[0279] result In patients with advanced 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: Combination of 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 whose tumors express PD-L1 <50% This example describes a clinical study of standard and high-dose REGN2810 (cemiplimab; an anti-PD-1 antibody) in combination with ipilimumab (an anti-CTLA-4 antibody) in the second-line treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1 <50%.

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

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

[0283] research design A clinical study of HDREGN2810 and SDREGN2810 / ipi versus SDREGN2810 treatment in the second-line treatment of patients with advanced or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 <50%. The study consists of three periods: screening, treatment, and follow-up. Patients will undergo a screening evaluation to determine their eligibility within 28 days prior to randomization. Eligible patients will be randomized 1:1:1 to receive one of the following treatment regimens: Treatment Arm A: REGN2810 350mg every 3 weeks (Q3W) for 108 weeks (hereinafter referred to as "SDREGN2810") Treatment Arm B: REGN2810 350 mg Q3W for 108 weeks and ipilimumab 50 mg every 6 weeks (Q6W) for up to 4 doses (hereafter referred to as "SDREGN2810 / ipi") Treatment Arm C: REGN2810 1050 mg Q3W for 108 weeks (hereinafter "HDREGN2810") At randomization, patients will be stratified by histology (squamous vs. non-squamous) and PD-L1 expression level (<1% vs. 1% to <50%). Patients will receive their assigned treatment (as indicated above) for the treatment period. Treatment may be stopped early due to progressive disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anticancer treatment, or in certain circumstances, confirmed complete response (CR), partial response (PR), or stable disease (SD). Patients who experience RECIST 1.1-defined progressive disease during treatment may continue on study treatment if the investigator determines that the patient is experiencing clinical benefit and if the patient has not completed the 108-week treatment period. If further progressive disease (defined as an increase in tumor burden of another 10% from the time of initial progressive disease) is identified, REGN2810 (and ipilimumab, if applicable) must be discontinued, and other anticancer therapies will be considered if appropriate. After discontinuing study treatment, patients will enter a follow-up phase. Each patient will have their first follow-up visit 14-30 days (± 7 days) after the last study treatment if treatment is discontinued early due to progressive disease, toxicity, or for another reason. Otherwise, each patient will have their first follow-up visit 14-30 days (± 7 days) after the last cycle visit. Follow-up Visits 2 through 7 will be conducted 28 days (± 7 days) from the previous visit. Survival data will then be collected by telephone or at clinic visits every 3 months until death, loss to follow-up, or withdrawal of study consent.

[0284] Study population Patients in this study included men and women aged ≥18 years diagnosed with advanced or metastatic non-squamous or squamous NSCLC, who had received only first-line treatment for advanced or metastatic NSCLC, and whose tumors expressed PD-L1 <50%.

[0285] Inclusion criteria 1. Males and females aged ≥18 years; 2. Patients with histologically or cytologically documented squamous or non-squamous NSCLC stage IIIB disease who are not candidates for treatment with confirmed concurrent chemoradiotherapy, or patients with stage IV disease if they have previously received systemic treatment for advanced or metastatic NSCLC and have previously received first-line treatment for advanced NSCLC; 3. Availability of archival or formalin-fixed paraffin-embedded tumor tissue biopsy samples obtained during the study. Guidance to biopsy site: a. Archival or fresh biopsies are acceptable; b. If an archival biopsy is used, it must be less than 5 months old; c. The biopsy should be from a metastatic or recurrent site that has not been previously irradiated. Exceptions: the primary tumor is still in place and other metastatic sites are inaccessible (brain) or cannot be used (bone) or biopsy would endanger the patient. 4. PD-L1 expression in <50% of tumor cells as determined by PD-L1 IHC 22C3 pharmDx assay performed by a central laboratory;5. Radiographically measurable disease 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 life expectancy of at least 3 months.

[0286] Exclusion criteria 1. Patients who have never smoked, defined as smoking ≤100 cigarettes in their lifetime; 2. Patients with active or untreated brain metastases or spinal cord compression. Central nervous system (CNS) metastases must be adequately treated and patients must have returned to baseline neurological status at least 2 weeks prior to enrollment. Patients are eligible if they have had any of the following symptoms (excluding residual signs or symptoms related to CNS treatment): 1. Patients must have discontinued corticosteroid treatment (in immunosuppressive doses) (see Exclusion Criterion 7 for details regarding timing of steroid discontinuation); 2. Patients with tumors testing positive for EGFR mutations, ALK translocations, or ROS1 fusions. All patients will have their tumors evaluated for EGFR mutations, ALK rearrangements, and ROS1 fusions; 3. Encephalitis, meningitis, or uncontrolled epilepsy in the year prior to informed consent; 4. Interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia that has required immunosuppressive doses of glucocorticoids to aid in management, or a history of pneumonitis within the last 5 years. A history of radiation pneumonitis in the radiation field is acceptable as long as the pneumonitis has resolved in the ≥ 6 months prior to enrollment. 6. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that required treatment with immunosuppressive measures, which may indicate risk for immune-related treatment-emergent adverse events (irTEAEs). The following are not excluded: vitiligo, resolved childhood asthma, residual hypothyroidism requiring only hormone replacement, or psoriasis not requiring systemic treatment. 7. Patients with a condition requiring corticosteroid therapy (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiologic replacement doses are permitted even if they are >10 mg prednisone / day or equivalent, as long as they are not administered with an immunosuppressive intent. Inhaled or topical steroids are permitted, provided they are not for the treatment of autoimmune disorders.

[0287] Study Procedures REGN2810 ("SDREGN2810") administered at 350mg as an intravenous (IV) infusion Q3W for 108 weeks REGN2810 ("SDREGN2810 / ipi") administered at 350mg as an IV infusion Q3W for 108 weeks in combination with ipilimumab administered IV at 50mg Q6W for up to four doses. REGN2810 ("HDREGN2810") administered at 1,050 mg as an IV infusion Q3W for 108 weeks Study endpoints The primary endpoint was ORR, defined as the proportion of patients achieving CR or PR per RECIST 1.1, as assessed by a blinded Independent Review Committee (IRC).

[0288] Secondary endpoints in the study were: (1) overall survival (OS), defined as the time from randomization to the date of death. Patients who did not die were censored at the last known date the patient was alive. (2) progression-free survival (PFS), defined as the time from randomization to the date of first documented tumor progression as assessed by a blinded IRC and determined by RECIST 1.1, or the date of death from any cause; (3) overall survival at 12 months, 18 months, and end of treatment; (4) safety and tolerability of SDREGN2810, HDREGN2810, and SDREGN2810 / ipi combination therapy, as measured by the incidence of treatment-emergent adverse events, dose-limiting toxicities, serious adverse events, deaths, and laboratory abnormalities; (5) quality of life, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13); (6) characterization of the PK of REGN2810 when administered in combination with ipilimumab or as HDREGN2810. (7) Evaluation of immunogenicity as measured by ADA titer against REGN2810; (8) Investigator assessment of hair pigmentation; (9) Foundation Medicine FoundationOne (R) (10) assessment of tumor volume; and (11) assessment of ICOS+CD4 T cell frequency and other markers of T cell activation.

[0289] Procedures and Evaluation Procedures to be performed at screening include informed consent; evaluation 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 epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations and C-ros oncogene receptor tyrosine kinase (ROS1) fusion; radiographic tumor assessment; tumor burden assessment; chest x-ray; serum pregnancy test; 12-lead electrocardiogram; adverse event (AE) recording; physical examination including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; and laboratory tests. Samples for any genomic substudies may also be obtained. During the treatment period, the following procedures will be performed to evaluate efficacy and safety: quality of life measurements using validated patient questionnaires; physical examination; ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for women of childbearing potential; recording of AEs and concomitant medications. Radiographic tumor burden assessment and computed tomography for tumor burden assessment based on RECIST 1.1 criteria will be performed at pre-specified time points during the study. Other assessments will include investigator assessment of hair pigmentation, REGN2810 concentration measurements, REGN2810 ADA assessment, and biomarker assessment. Biomarker procedures will include the use of tumor tissue samples for further PD-L1 assay validation. Survival data will then be collected by phone or at clinic visits every 3 months until death, loss to follow-up, or withdrawal of study consent.

[0290] result It is expected that SDREGN2810 / ipi or HDREGN2810 will 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% to <50% PD-L1 expression treated with SDREGN2810, it is expected that HDREGN2810 or SDREGN2810 / ipi will achieve an ORR of 30%; an absolute increase of 20% compared to SDREGN2810.

[0291] Example 14: Clinical study of the combination of REGN2810 (anti-PD-1 antibody), ipilimumab (anti-CTLA4 antibody) and platinum doublet chemotherapy in the first-line treatment of patients with advanced or metastatic non-small cell lung cancer whose tumors express PD-L1 <50% 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 advanced or metastatic non-small cell lung cancer whose tumors express PD-L1 <50% 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 REGN2810 in combination with four to six cycles of standard of care platinum-based doublet chemotherapy (REGN2810 / chemo-f) and REGN2810 in combination with only two cycles 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 advanced squamous or non-squamous non-small cell lung cancer (NSCLC) in the subgroup of patients whose tumors express programmed cell death-ligand 1 (PD-L1) on 1% to <50% of tumor cells, and in the overall study patient population whose tumors express PD-L1 on <50% of tumor cells.

[0293] Secondary objectives are: (1) to compare overall survival (OS) of REGN2810 / chemo-f and REGN2810 / chemo-l / ipi in the first-line treatment of patients with advanced squamous or non-squamous NSCLC in the subgroup of patients whose tumors express PD-L1 on 1% to <50% of tumor cells, and in the overall study patient population whose tumors express PD-L1 on <50% of tumor cells, compared with standard of care platinum-based doublets; (2) To compare the objective response rate (ORR) 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 advanced squamous or non-squamous NSCLC in the subgroup of patients whose tumors express PD-L1 on 1% to <50% of tumor cells, and in the overall study patient population whose tumors express PD-L1 on <50% of tumor cells. (3) To evaluate the safety and tolerability of REGN2810 and 4 to 6 cycles of platinum doublet chemotherapy and REGN2810 and ipilimumab. (4) To characterize the pharmacokinetics of REGN2810 and 4 to 6 cycles of platinum doublet chemotherapy and REGN2810 and ipilimumab. (5) To compare the OS at 12 and 18 months of REGN2810 / chemo-f or REGN2810 / chemo-l / ipi versus standard of care platinum-based doublet chemotherapy in the first-line treatment of patients with advanced squamous or non-squamous NSCLC in the subgroup of patients whose tumors express PD-L1 on 1% to <50% of tumor cells, and in the overall study patient population whose tumors express PD-L1 on <50% of tumor cells. (6) To assess immunogenicity as measured by anti-drug antibodies to REGN2810.

[0294] Study population The target population includes men and women 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 advanced disease.

[0295] Inclusion criteria : 1) Males and females aged 18 and over 2) Patients with histologically or cytologically documented squamous or non-squamous NSCLC with stage IIIB or IV disease who have not received prior systemic treatment for recurrent or metastatic NSCLC 3) Patients who received adjuvant or neoadjuvant platinum-doublet chemotherapy (following surgery and / or radiation therapy) and developed recurrent or metastatic disease more than 6 months after completing treatment were eligible. 4) Patients who received adjuvant or neoadjuvant PD-1 or PD-L1 blockade and developed recurrent or metastatic disease >12 months after completing treatment are eligible. 5) Archived or freshly 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 radiographically measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. Target lesions may be located in previously irradiated areas if there is documented (radiographic) disease progression at that site. 8) ECOG performance status ≤ 1 9) Expected life span of at least 3 months 10) Adequate organ and bone marrow function as defined below: 11) Hemoglobin level ≥ 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 x upper limit of normal (ULN) (≤ 3 x ULN in the case of liver metastases) except for patients with clinically confirmed Gilbert's hypoplasia 16) Aspartate aminotransferase (AST) and alanine aminotransferase (A LT) ≤ 3 × ULN or ≤ 5 × ULN in case of liver metastasis 17) Alkaline phosphatase ≤ 2.5 x ULN (or ≤ 5.0 x ULN for liver or bone metastases) 18) Hy's rule does not meet the criteria (ALT>3×ULN and bilirubin>2×ULN) 19) Willing and able to comply with clinic and study-related procedures 20) Provide signed informed consent 21) Able to understand and complete all study-related questionnaires.

[0296] Exclusion criteriaPatients are eligible if: 1. Patients who have never smoked, defined as smoking ≦100 cigarettes in their lifetime; 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases have been adequately treated and patients have returned to baseline neurologically (excluding residual signs or symptoms related to CNS treatment) for at least 2 weeks prior to enrollment. Patients must have discontinued corticosteroid treatment (in immunosuppressive doses) (see Exclusion Criteria 7) for details regarding timing of steroid discontinuation); 3. Patients with tumors testing 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 in the 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 aid in management, or history of pneumonia within the last 5 years. A history of radiation pneumonitis in the radiation field is acceptable as long as the pneumonitis has resolved ≥6 months prior to enrollment. 6. Ongoing or recent evidence of significant autoimmune disease that has required treatment with systemic immunosuppressive treatment, which may indicate risk for immune-related treatment-emergent adverse events (irTEAEs). The following are not exclusions: leukoplakia, resolved childhood asthma, residual hypothyroidism requiring only hormone 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 they are >10 mg prednisone / day or equivalent, as long as they are not administered with an immunosuppressive intent. Inhaled or topical steroids are permitted, but they are not for the treatment of autoimmune disorders.

[0297] research 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 stage 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) will be provided for PD-L1 assessment using a validated PD-L1 assay.

[0298] Patients with progressive, untreated NSCLC were randomized 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 to 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 to 6 cycles (hereafter referred to as "REGN2810 / chemo-f") 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 ) up to 4 doses (hereinafter referred to as "REGN2810 / chemo-l / ipi") Randomization will be stratified by histology (non-squamous vs. squamous) and level of PD-L1 expression (<1% vs. 1%-24% vs. 25%-<50%).

[0299] Patients will receive their assigned treatment for the treatment period (as indicated above). Treatment may be discontinued early due to progressive disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anticancer treatment, or, for patients in treatment arms B and C, in the specific circumstances of complete response (CR) or partial response (PR).

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

[0301] Procedures and Evaluation The procedures to be performed at screening include: informed consent; evaluation of inclusion / exclusion criteria; recording of medical, histological and concomitant medication history; recording of demographics; collection and examination 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; and radiographic tumor evaluation. These include: tumor burden assessment; chest x-ray; serum pregnancy test; 12-lead electrocardiogram; adverse event (AE) records; physical examination including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; and laboratory tests. Samples for any genomic substudies may also be obtained.

[0302] During the treatment period, the following procedures will be performed to evaluate efficacy and safety: quality of life measurements using validated patient questionnaire tests, physical examination, ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for women of childbearing potential; recording of AEs and concomitant medications. Radiographic tumor burden assessment and computed tomography or magnetic resonance imaging (or positron emission tomography) for tumor burden assessment based on RECIST 1.1 criteria will be performed at prespecified time points during the study.

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

[0304] result The R2810 combination regimens are expected to increase median PFS by 4 months (from 6 months for standard of care platinum doublet chemotherapy to 10 months for either R2810 combination regimen) in patients with tumors expressing PD-L1 between 1% and <50% and in the overall study population. REGN2810 and 4-6 cycles of platinum doublet chemotherapy or REGN2810 or REGN2810 and ipilimumab prolongs OS and improves 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 in the First-Line Treatment of Patients with Advanced or Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 >= 50% This example describes a clinical study of pembrolizumab monotherapy versus a combination of REGN2810 monotherapy, platinum-based doublet chemotherapy, and ipilimumab (administered in up to four doses) in patients with advanced or metastatic squamous or non-squamous NSCLC whose tumors express PD-L1 on >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 progression-free survival (PFS) of REGN2810 (cemiplimab) in combination with ipilimumab (hereafter referred to as REGN2810 / ipi) and REGN2810 in combination with only two cycles of platinum-based doublet chemotherapy and ipilimumab (hereafter referred to as "REGN2810 / chemo / ipi") to standard of care pembrolizumab monotherapy in the first-line treatment of patients with advanced 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. Additional objectives include further characterization of overall survival, tumor response, patient-reported outcomes, safety, and pharmacokinetics (PK).

[0307] Study population The target population includes men and women 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.

[0308] Inclusion criteria : 1) Males and females aged 18 and over 2) Patients with histologically or cytologically documented squamous or non-squamous NSCLC with stage IIIB or stage IV disease who have not received prior systemic treatment for recurrent or metastatic NSCLC 3) Patients who received adjuvant or neoadjuvant platinum doublet chemotherapy (following surgery and / or radiation therapy) and developed recurrent or metastatic disease more than 6 months after completing treatment. 4) Patients who received adjuvant or neoadjuvant PD-1 or PD-L1 blockade and developed recurrent or metastatic disease >12 months after completing treatment are eligible 5) Archival or freshly obtained formalin-fixed tumor tissue from a previously unirradiated metastatic / recurrent site 6) Tumor cells expressing PD-L1 in ≥ 50% of tumor cells by IHC performed by a central laboratory 7) At least one lesion radiographically measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. The target lesion may be located in a previously irradiated field if there is documented (radiographic) disease progression at that site. 8) ECOG performance status ≤ 1 9) Expected life span of at least 3 months 10) Adequate organ and bone marrow function as defined below: 11) Hemoglobin level ≥ 8.0g / 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 for liver metastases) except for patients with clinically confirmed Gilbert syndrome 16) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 3 × ULN or ≤ 5 × ULN in the case of liver metastasis 17) Alkaline phosphatase ≤ 2.5 x ULN (or ≤ 5.0 x ULN for liver or bone metastases) 18) Not meeting the criteria for Hy's rule (ALT>3×ULN and bilirubin>2×ULN) 19) Willing and able to comply with clinic and study-related procedures 20) Provide signed informed consent 21) Able to understand and complete all study-related questionnaires.

[0309] Exclusion criteriaPatients are eligible if: 1. Patients who have never smoked, defined as smoking ≦100 cigarettes in their lifetime; 2. Active or untreated brain metastases or spinal cord compression. Patients are eligible if central nervous system (CNS) metastases have been adequately treated and patients have returned to baseline neurologically (excluding residual signs or symptoms related to CNS treatment) for at least 2 weeks prior to enrollment. Patients must have discontinued corticosteroid treatment (in immunosuppressive doses) (see Exclusion Criteria 7) for details regarding timing of steroid discontinuation); 3. Patients with tumors testing 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 in the year prior to informed consent. 5. Interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, non-infectious interstitial pneumonia that has required immunosuppressive doses of glucocorticoids to aid in management, or history of pneumonia within the last 5 years. A history of radiation pneumonitis in the radiation field is acceptable as long as the pneumonitis has resolved ≥6 months prior to enrollment. 6. Ongoing or recent evidence of significant autoimmune disease that has required treatment with systemic immunosuppressive measures, which may indicate risk for immune-related treatment-emergent adverse events (irTEAEs). The following are not exclusions: leukoplakia, Resolved childhood asthma, residual hypothyroidism requiring only hormone replacement, or psoriasis not requiring systemic treatment. 7. Patients with conditions requiring corticosteroid therapy (>10 mg prednisone / day or equivalent) within 14 days of randomization. Physiologic replacement doses are permitted even if they are >10 mg prednisone / day or equivalent, as long as they are not administered with immunosuppressive intent. Inhaled or topical steroids are permitted, provided they are not for the treatment of autoimmune disorders.

[0310] research design This clinical trial is a study of the efficacy and safety of REGN2810 / ipi vs. REGN2810 / chemo / ipi vs. 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 three periods: screening, treatment, and follow-up. Patients will undergo a screening assessment to determine their eligibility within 28 days prior to randomization. Eligible patients will be randomized 1:1:1 to one of the following treatment arms: · Treatment arm A Pembrolizumab monotherapy 200mg every 3 weeks (Q3W) for 108 weeks · Treatment arm B REGN2810 350mg Q3W for 108 weeks and up to 4 doses of ipilimumab 50mg every 6 weeks (Q6W) · Treatment arm C : REGN2810 350mg Q3W for 108 weeks and platinum-based doublet chemotherapy Q3W for 2 cycles and ipilimumab 50mg every 6 weeks (Q6W) up to 4 doses Patients will receive their assigned treatment for a treatment period of 108 weeks. Treatment may be stopped early due to progressive disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), unacceptable toxicity, withdrawal of consent, death, initiation of another anticancer treatment, or, for treatment arms B and C, patients, in the specific circumstances of complete remission (CR) or partial response (PR). Patients who experience progressive disease as defined by RECIST 1.1 during treatment may continue study treatment if the investigator determines that the patient is experiencing clinical benefit and if the patient has not completed the 108-week treatment period. If further progressive disease (defined as an increase in tumor burden of an additional 10% from the time of initial progressive disease) is identified, REGN2810 (and ipilimumab, if applicable) must be discontinued, and other anticancer therapy will be considered if appropriate. A similar approach to treatment beyond first evidence of progression is offered to patients receiving pembrolizumab in treatment arm A.

[0312] Study Procedures 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 over approximately 90 minutes at 50 mg Q6W for up to four doses. 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 two cycles, and ipilimumab administered IV over approximately 90 minutes at 50 mg Q6W for up to four doses.

[0313] Procedures and Evaluation The steps to be taken in screening are: informed consent; inclusion / exclusion criteria; The procedures include: baseline evaluation; medical, oncology, and concomitant medication history records; demographic records; 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; baseline radiographic tumor assessment and tumor burden assessment; chest x-ray; serum pregnancy test; 12-lead electrocardiogram; complete physical exam including vital signs, height, and weight assessment; Eastern Cooperative Oncology Group (ECOG) performance status assessment; adverse event (AE) records; and laboratory tests. Samples for optional genomic substudies may also be obtained.

[0314] During the treatment period, the following procedures will be performed to evaluate efficacy and safety: quality of life measurements using validated patient questionnaire tests, physical examination, ECOG performance status assessment; vital signs; laboratory tests including pregnancy tests for women of childbearing potential; recording of AEs and concomitant medications. Radiographic tumor burden assessment and computed tomography or magnetic resonance imaging (or positron emission tomography) for tumor burden assessment based on RECIST 1.1 criteria will be performed at prespecified time points during the study.

[0315] Survival data will be collected by telephone or at clinic visits every 3 months until death, loss to follow-up, or withdrawal of study consent.

[0316] result Both REGN2810 combinations are expected to extend PFS by 1-5 months compared to pembrolizumab monotherapy. REGN2810 in combination with chemotherapy and / or anti-CTLA-4 antibodies extends OS and improves ORR compared to pembrolizumab monotherapy.

[0317] The present 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 accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. 1. A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that specifically binds to Programmed Cell Death 1 (PD-1) for use in a method of treating lung cancer or increasing survival of a lung cancer patient, the method comprising: (a) selecting a patient with non-small cell lung cancer, wherein tumor tissue in the patient expresses programmed cell death ligand 1 (PD-L1) in <50% of tumor cells, and the patient has not tested positive for epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and / or ROS1 fusions; 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. Including, wherein the antibody or antigen-binding fragment thereof that specifically binds to PD-1 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:

8. The above pharmaceutical composition.

2. Patients: (a) has not been previously treated with systemic treatment for lung cancer; or (b) had been previously treated with an anti-tumor therapy; The pharmaceutical composition of claim 1.

3. The pharmaceutical composition of claim 1 or 2, wherein the non-small cell lung cancer is locally advanced and the patient is not a candidate for definitive chemoradiotherapy, or the non-small cell lung cancer is metastatic.

4. The pharmaceutical composition of claim 2 or 3, wherein the antitumor therapy comprises platinum-based chemotherapy.

5. (a) the patient has squamous or non-squamous stage III or IV lung cancer; or (b) the patient has progressive or recurrent non-small cell lung cancer; The pharmaceutical composition according to any one of claims 1 to 4.

6. Each dose of antibody was: (a) administered once weekly, once every two weeks, once every three weeks, or once every four weeks; and / or (b) comprising 20-1500 mg of an antibody; The pharmaceutical composition according to any one of claims 1 to 5.

7. Each dose of antibody was: (a) 200, 250, 300, 350, 450, 600, 750, 800, 1000 or 1050 mg of antibody; and / or (b) 350 mg of the antibody, for administration every three weeks; The pharmaceutical composition according to any one of claims 1 to 5, comprising:

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein each dose of the antibody comprises 0.1 to 10 mg / kg of patient body weight.

9. 9. The pharmaceutical composition of claim 8, wherein each dose of the antibody comprises 1, 3, 4, 5, 6 or 10 mg / kg of patient body weight.

10. 10. The pharmaceutical composition of claim 9, wherein each dose is administered once per week, once every two weeks, once every three weeks, or once every four weeks.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is administered as an intravenous infusion to the patient.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the antibody or antigen-binding fragment thereof is administered in combination with a second therapeutic agent or regimen selected from the group consisting of chemotherapy, anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) antibody, radiation, surgery, anti-lymphocyte activation gene 3 (LAG-3) antibody, anti-PD-L1 antibody, cyclophosphamide, a vaccine, an anti-glucocorticoid-inducible tumor necrosis factor receptor (GITR) antibody, a vascular endothelial growth factor (VEGF) inhibitory fusion protein, an anti-VEGF antibody, sunitinib, sorafenib, pazopanib, an antibody against a tumor-specific antigen, granulocyte-macrophage colony-stimulating factor, a cytotoxin, a cytokine, a T-cell therapy, an anti-inflammatory drug, and a nutritional supplement.

13. The antibody: (a) in combination with platinum-based chemotherapy; and / or (b) in combination with an anti-CTLA-4 antibody, The pharmaceutical composition according to claim 12,

14. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein administration of at least one dose of the 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.

15. (a) PFS was at least 1 month longer than in patients receiving platinum-based chemotherapy Increase; (b) OS is increased by at least 1 month compared to patients receiving platinum-based chemotherapy; 15. The pharmaceutical composition of claim 14.

16. The pharmaceutical composition according to any one of claims 1 to 15, 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.

17. The antibody: (a) 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; or (b) cemiplimab. The pharmaceutical composition according to any one of claims 1 to 16.

18. 1. A pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof that specifically binds to Programmed Cell Death 1 (PD-1) for use in a method of treating lung cancer or increasing survival of a lung cancer patient, the method comprising: (a) selecting a patient with non-small cell lung cancer, where: (i) tumor tissue in the patient expresses programmed cell death-ligand 1 (PD-L1) in <50% of tumor cells; (ii) the patient has not tested positive for epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and / or ROS1 fusions; (iii) the patient is not a confirmed chemoradiotherapy candidate or the non-small cell lung cancer is metastatic; and (iv) the patient has not been previously treated with a systemic treatment for lung cancer; and (b) administering to the patient one or more doses of a therapeutically effective amount of the antibody, thereby treating the lung cancer in the patient. Including; wherein the antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:3; HCDR2 comprises the amino acid sequence of SEQ ID NO:4; HCDR3 comprises the amino acid sequence of SEQ ID NO:5; LCDR1 comprises the amino acid sequence of SEQ ID NO:6; LCDR2 comprises the amino acid sequence of SEQ ID NO:7; and LCDR3 comprises the amino acid sequence of SEQ ID NO:8; and The antibody is administered intravenously at a dose of 350 mg every three weeks. The above pharmaceutical composition.

19. 19. The pharmaceutical composition of claim 18, 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.

20. The pharmaceutical composition of claim 18 or 19, 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.

21. The pharmaceutical composition according to any one of claims 18 to 20, wherein the anti-PD-1 antibody is cemiplimab.

Images