Methods for treating cancer with anti-pd-1 antibodies

Abstract

The present invention relates to methods for treating cancer in a patient comprising administering a PD-1 antagonist, e.g., an anti-PD-1 antibody or antigen binding fragment thereof (e.g. pembrolizumab), in specific amounts to the patient about every six weeks. In some embodiments, the amount of anti-PD-1 antibody or antigen binding fragment thereof is about 400 mg. In certain embodiments, the PD-1 antagonist is pembrolizumab, or an antigen binding fragment thereof. Also provided are compositions and kits comprising a dosage of an anti-PD-1 antibody, or antigen-binding fragment thereof, and uses thereof for treating cancer.

What is claimed is: 
     
         1 . A method of treating cancer in a human patient comprising administering about 400 mg of an anti-PD-1 antibody, or antigen binding fragment thereof, to the patient every approximately six weeks, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises:
 (a) light chain complementarity determining regions (CDRs) comprising a sequence of amino acids as set forth in SEQ ID NOs: 1, 2 and 3 and heavy chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 6, 7 and 8; or   (b) light chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 11, 12 and 13 and heavy chain CDRs comprising a sequence of amino acids as set forth in SEQ ID NOs: 14, 15 and 16.   
     
     
         2 . The method of  claim 1 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region comprising a sequence of amino acids as set forth in SEQ ID NO:9, or a variant of SEQ ID NO:9, and   (b) a light chain variable region comprising:
 (i) a sequence of amino acids as set forth in SEQ ID NO:4, or a variant of SEQ ID NO:4, 
 (ii) a sequence of amino acids as set forth in SEQ ID NO:22, or a variant of SEQ ID NO:22, or 
 (iii) a sequence of amino acids as set forth in SEQ ID NO:23, or a variant of SEQ ID NO:23. 
   
     
     
         3 . The method of  claim 2 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a sequence of amino acids as set forth in SEQ ID NO:9 and a light chain variable region comprising a sequence of amino acids as set forth in SEQ ID NO:4. 
     
     
         4 . The method of  claim 2 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof is a monoclonal antibody comprising:
 (a) a heavy chain comprising a sequence of amino acids as set forth in SEQ ID NO:10, or a variant of SEQ ID NO:10, and   (b) a light chain comprising a sequence of amino acids as set forth in SEQ ID NO:5, a variant of SEQ ID NO:5, SEQ ID NO:24, a variant of SEQ ID NO:24, SEQ ID NO:25, or a variant of SEQ ID NO:25.   
     
     
         5 . The method of  claim 4 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof is a monoclonal antibody comprising a heavy chain comprising a sequence of amino acids as set forth in SEQ ID NO:10 and a light chain comprising a sequence of amino acids as set forth in SEQ ID NO:5. 
     
     
         6 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: melanoma, non-small cell lung cancer, head and neck cancer, urothelial cancer, breast cancer, gastrointestinal cancer, multiple myeloma, hepatocellular cancer, non-Hodgkin lymphoma, renal cancer, Hodgkin lymphoma, mesothelioma, ovarian cancer, small cell lung cancer, esophageal cancer, anal cancer, biliary tract cancer, colorectal cancer, cervical cancer, thyroid cancer, endometrial cancer, squamous cell carcinoma, or salivary cancer. 
     
     
         7 . The method of  claim 1 , wherein the patient has a tumor with a high mutational burden. 
     
     
         8 . The method of  claim 1 , wherein the patient has a microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumor. 
     
     
         9 . The method of  claim 1 , wherein the cancer is unresectable or metastatic melanoma. 
     
     
         10 . The method of  claim 1 , wherein the cancer is metastatic non-small cell lung cancer (NSCLC). 
     
     
         11 . The method of  claim 10 , wherein the patient has a tumor with high PD-L1 expression [(Tumor Proportion Score (TPS)≥50%)] and was not previously treated with platinum-containing chemotherapy. 
     
     
         12 . The method of  claim 10 , wherein the patient has a tumor with PD-L1 expression (TPS≥1%) and was previously treated with platinum-containing chemotherapy. 
     
     
         13 . The method of  claim 11 , wherein, the patient's tumor has no EGFR or ALK genomic aberrations. 
     
     
         14 . The method of  claim 10 , wherein the method further comprises administering pemetrexed and carboplatin to the patient. 
     
     
         15 . The method of  claim 14 , wherein the patient has nonsquamous non-small cell lung cancer and the pemetrexed is administered to the patient in an amount of 500 mg/m 2  about every 21 days. 
     
     
         16 . The method of  claim 14 , further comprising administering about 400 μg to about 1000 μg of folic acid to the patient once per day, beginning about 7 days prior to administering pemetrexed to the patient and continuing until about 21 days after the patient is administered the last dose of pemetrexed. 
     
     
         17 . The method of  claim 14 , further comprising administering about 1 mg of vitamin B 12  to the patient about 1 week prior to the first administration of pemetrexed and about every three cycles of pemetrexed administration. 
     
     
         18 . The method of  claim 14 , further comprising administering dexamethasone to the patient twice a day on the day before, the day of, and the day after pemetrexed administration. 
     
     
         19 . The method of  claim 10 , wherein the NSCLC is squamous and the patient is also treated with carboplatin-paclitaxel or nab-paclitaxel. 
     
     
         20 . The method of  claim 1 , wherein the cancer is recurrent or metastatic head and neck squamous cell cancer (HNSCC). 
     
     
         21 . The method of  claim 1 , wherein the cancer is (1) refractory classical Hodgkin lymphoma (cHL), or (2) cHL and the patient has relapsed after 3 or more lines of therapy for cHL. 
     
     
         22 . The method of  claim 1 , wherein the cancer is locally advanced or metastatic urothelial carcinoma. 
     
     
         23 . The method of  claim 22 , wherein the patient's tumor expresses PD-L1 [Combined Positive Score >10]. 
     
     
         24 . The method of  claim 22 , wherein the patient is not eligible for platinum-containing chemotherapy or has disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
     
     
         25 . The method of  claim 1 , wherein the cancer is locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. 
     
     
         26 . The method of  claim 1 , wherein the cancer is cervical cancer. 
     
     
         27 . The method of  claim 26 , wherein the cervical cancer is recurrent or metastatic cervical cancer and the patient had disease progression on or after chemotherapy. 
     
     
         28 . The method of  claim 25 , wherein the patient's tumor expresses PD-L1 [Combined Positive Score (CPS)≥1]. 
     
     
         29 . The method of  claim 1 , wherein the cancer is primary mediastinal large B-cell lymphoma (PMBCL). 
     
     
         30 . The method of  claim 29 , wherein the patient has refractory PMBCL or has relapsed after 2 or more prior lines of therapy. 
     
     
         31 . The method of  claim 1 , wherein the cancer is resected high-risk stage III melanoma. 
     
     
         32 . The method of  claim 1 , wherein the cancer is hepatocellular carcinoma. 
     
     
         33 . The method of  claim 1 , wherein the cancer is renal cell carcinoma (RCC). 
     
     
         34 . The method of  claim 32 , wherein the cancer is advanced clear cell RCC. 
     
     
         35 . The method of  claim 1 , wherein the cancer is recurrent, locally advanced or metastatic Merkel cell carcinoma (MCC). 
     
     
         36 . The method of  claim 1 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the patient by intravenous or subcutaneous administration. 
     
     
         37 . The method of  claim 1 , wherein the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. 
     
     
         38 . A composition comprising about 400 mg of pembrolizumab and a pharmaceutically acceptable carrier. 
     
     
         39 . The composition of  claim 38 , further comprising 10 mM histidine, pH 5.5, 7% sucrose, and 0.02% polysorbate 80. 
     
     
         40 . A kit for treating a patient with cancer, the kit comprising:
 (a) about 400 mg of an anti-PD-1 antibody or antigen binding fragment thereof, and   (b) instructions for using the anti-PD-1 antibody or antigen binding fragment thereof, in the method of  claim 1 .   
     
     
         41 . The kit of  claim 40 , wherein the anti-PD-1 antibody is pembrolizumab. 
     
     
         42 . The method of  claim 1 , wherein the cancer is endometrial cancer. 
     
     
         43 . The method of  claim 1 , wherein the cancer is squamous cell carcinoma.