Methods of treating lung cancer with a pd-1 axis binding antagonist, a platinum agent, and a topoisomerase ii inhibitor

Abstract

The present disclosure provides methods for treating lung cancer (such as small cell lung cancer, e.g., extensive stage small cell lung cancer) in an individual. The methods comprise administering to the individual a PD-1 axis binding antagonist (such as an anti-PD-L1 antibody, e.g., atezolizumab), a platinum agent (e.g., cisplatin or carboplatin), and a topoisomerase II inhibitor (e.g., etoposide).

1 . A method of treating an individual having lung cancer, comprising administering to the individual an effective amount of an anti-PD-L1 antibody, a platinum agent, and a topoisomerase II inhibitor, wherein the treatment extends progression free survival (PFS) of the individual. 
     
     
         2 . The method of  claim 1 , wherein the treatment extends overall survival (OS) of the individual. 
     
     
         3 . A method of treating an individual having lung cancer, comprising administering to the individual an effective amount of an anti-PD-L1 antibody, a platinum agent, and a topoisomerase II inhibitor, wherein the treatment extends overall survival (OS) of the individual. 
     
     
         4 . The method of  claim 1 , wherein the treatment extends the PFS of the individual by at least about 5 months. 
     
     
         5 . The method of  claim 3 , wherein the treatment extends the OS of the individual is extended by at least about 11 months. 
     
     
         6 . The method of  claim 1 , wherein the anti-PD-L1 antibody comprises:
 (a) a heavy chain variable region (V H ) that comprises an HVR-H1 comprising an amino acid sequence of GFTFSDSWIH (SEQ ID NO:1), an HVR-2 comprising an amino acid sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 comprising an amino acid RHWPGGFDY (SEQ ID NO:3), and   (b) a light chain variable region (VL) that comprises an HVR-L1 comprising an amino acid sequence of RASQDVSTAVA (SEQ ID NO:4), an HVR-L2 comprising an amino acid sequence of SASFLYS (SEQ ID NO:5), and an HVR-L3 comprising an amino acid sequence of QQYLYHPAT (SEQ ID NO:6).   
     
     
         7 . The method of  claim 1 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region (V H ) comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 8. 
     
     
         8 . The method of  claim 1 , wherein the anti-PD-L1 antibody is atezolizumab. 
     
     
         9 . The method of  claim 1 , wherein the platinum agent is carboplatin or cisplatin. 
     
     
         10 . The method of  claim 9 , wherein the platinum agent is carboplatin. 
     
     
         11 . The method of  claim 1 , wherein the topoisomerase II inhibitor is etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, an ellipticine, aurintricarboxylic acid, or HU-331. 
     
     
         12 . The method of  claim 11 , wherein the topoisomerase inhibitor is etoposide. 
     
     
         13 . The method of  claim 1 , wherein the anti-PD-L1 antibody is administered at a dose of 1200 mg, the platinum agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min, and the topoisomerase II inhibitor is administered at a dose of 100 mg/m 2 . 
     
     
         14 . The method of  claim 1 , wherein the anti-PD-L1 antibody, the platinum agent, and the topoisomerase II inhibitor are administered in four 21-day Cycles, and wherein the anti-PD-L1 antibody is administered at a dose of 1200 mg on Day 1, the platinum agent is administered at a dose sufficient to achieve AUC=5 mg/ml/min on Day 1, and the topoisomerase II inhibitor is administered at a dose of 100 mg/m 2  on each of Days 1, 2, and 3 of each 21-day cycle for Cycles 1-4. 
     
     
         15 . The method of  claim 14 , wherein the anti-PD-L1 antibody is further administered following Cycle 4, and wherein the anti-PD-L1 antibody is administered at a dose of 1200 mg on Day 1 of each 21-day cycle for every cycle after Cycle 4. 
     
     
         16 . The method of  claim 13 , wherein the anti-PD-L1 antibody, the platinum agent, and the topoisomerase II inhibitor are administered sequentially on Day 1 of Cycles 1-4. 
     
     
         17 . The method of  claim 16 , wherein the anti-PD-L1 antibody is administered prior to the platinum agent, and wherein the platinum agent is administered prior to the topoisomerase II inhibitor on Day 1 of Cycles 1-4. 
     
     
         18 . The method of  claim 1 , wherein the lung cancer is small cell lung cancer (SCLC). 
     
     
         19 . The method of  claim 18 , wherein the SCLC is extensive stage SCLC (ES-SCLC). 
     
     
         20 . The method of  claim 19 , wherein the individual is treatment-naïve for ES-SCLC. 
     
     
         21 . The method of  claim 1 , wherein the individual has a blood tumor mutational burden (bTMB) of at least about 10. 
     
     
         22 . The method of  claim 21 , wherein the individual has a bTMB of at least about 16. 
     
     
         23 . The method of  claim 1 , wherein the lung cancer has metastasized to the brain. 
     
     
         24 . The method of  claim 1 , wherein the lung cancer has metastasized to the liver. 
     
     
         25 . The method of  claim 1 , wherein the lung cancer has metastasized to the lymph nodes. 
     
     
         26 . The method of  claim 1 , wherein the lung cancer has metastasized to the adrenal gland. 
     
     
         27 . The method of  claim 1 , wherein the individual is at least 65 years old. 
     
     
         28 . The method of  claim 1 , wherein the individual is PD-L1 negative. 
     
     
         29 . The method of  claim 28 , wherein the patient is PD-L1 negative if less than 1% of the tumor cells or tumor-infiltrating immune cells in a sample from the patient express PD-L1. 
     
     
         30 . The method of  claim 1 , wherein the anti-PD-L1 antibody, the platinum agent, and the topoisomerase II inhibitor are each administered intravenously. 
     
     
         31 . A method of treating an individual having extensive-stage small cell lung cancer (ES-SCLC), comprising administering to the individual an effective amount of atezolizumab, carboplatin, and etoposide, wherein the atezolizumab is administered at a dose of 1200 mg, the carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min, and the etoposide is administered at a dose of 100 mg/m 2 , and wherein the treatment extends progression free survival (PFS) and overall survival (OS) of the individual. 
     
     
         32 . The method of  claim 31 , wherein atezolizumab, carboplatin, and etoposide are administered in four 21-day Cycles and atezolizumab is further administered following Cycle 4, wherein atezolizumab is administered at a dose of 1200 mg on Day 1 of each 21-day cycle of Cycles 1-4, carboplatin is administered at a dose sufficient to achieve AUC=5 mg/ml/min on Day 1 of each 21-day cycle of Cycles 1-4, and etoposide is administered at a dose of 100 mg/m 2  on each of Days 1, 2, and 3 of each 21-day cycle for Cycles 1-4; and wherein atezolizumab is further administered at a dose of 1200 mg on Day 1 of each 21-day cycle for every cycle after Cycle 4. 
     
     
         33 . The method of  claim 31 , wherein the individual is treatment-naïve for ES-SCLC. 
     
     
         34 . The method of  claim 31 , wherein the treatment extends the PFS of the individual by at least about 5 months. 
     
     
         35 . The method of  claim 31 , wherein the treatment extends the OS of the individual by at least about 11 months. 
     
     
         36 . The method of  claim 31 , wherein the individual has a blood tumor mutational burden (bTMB) of at least about 10. 
     
     
         37 . The method of  claim 36 , wherein the individual has a bTMB of at least about 16. 
     
     
         38 . The method of  claim 31 , wherein the ES-SCLC has metastasized to the brain. 
     
     
         39 . The method of  claim 31 , wherein the ES-SCLC has metastasized to the liver. 
     
     
         40 . The method of  claim 31 , wherein the lung cancer has metastasized to the lymph nodes. 
     
     
         41 . The method of  claim 31 , wherein the lung cancer has metastasized to the adrenal gland. 
     
     
         42 . The method of  claim 31 , wherein the individual is at least 65 years old. 
     
     
         43 . The method of  claim 31 , wherein the individual is PD-L1 negative. 
     
     
         44 . The method of  claim 43 , wherein the patient is PD-L1 negative if less than 1% of the tumor cells or tumor-infiltrating immune cells in a sample from the patient express PD-L1. 
     
     
         45 . The method of  claim 31 , wherein the atezolizumab, the carboplatin, and the etoposide are administered sequentially on Day 1 of each 21-day cycle for Cycles 1-4. 
     
     
         46 . The method of  claim 45 , wherein the atezolizumab is administered prior to the carboplatin, and wherein the carboplatin is administered prior to the etoposide on Day 1 of each 21-day cycle for Cycles 1-4. 
     
     
         47 . The method of  claim 31 , wherein the atezolizumab, the carboplatin, and the etoposide are each administered intravenously. 
     
     
         48 . The method of  claim 1 , wherein the individual is human. 
     
     
         49 . A kit comprising an anti-PD-L1 antibody for use in combination with a platinum agent and a topoisomerase II inhibitor for treating an individual having lung cancer according to the method of  claim 1 . 
     
     
         50 . A kit comprising atezolizumab for use in combination with carboplatin and etoposide for treating an individual having lung cancer according to the method of  claim 1 . 
     
     
         51 .- 54 . (canceled) 
     
     
         55 . The method of  claim 31 , wherein the individual is human.