P-106 Pembrolizumab (MK-3475) versus paclitaxel as second-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: Randomized, open-label, phase 3 KEYNOTE-061 study

Introduction: Paclitaxel is standard therapy for advanced gastric cancer that progresses on first-line therapy with a platinum and fluoropyrimidine. The programmed death receptor 1 (PD-1) pathway is used by tumors to suppress the immune response. The anti-PD-1 antibody pembrolizumab has shown an acceptable safety profile and clinical activity in patients with advanced solid tumors and hematologic malignancies, including advanced gastric cancer. In KEYNOTE-012, pembrolizumab 10 mg/kg given every 2 weeks (Q2W) until disease progression provided a manageable safety profile and a 22% objective response rate (RECIST v1.1, central review). The randomized, open label, phase 3, KEYNOTE-061 study (ClinicalTrials.gov, NCT02370498) is designed to compare the efficacy and safety of pembrolizumab with that of paclitaxel in second-line treatment of advanced gastric cancer.Methods: This study is designed for patients with metastatic or unresectable gastric or GEJ adenocarcinoma that progressed after first-line treatment with platinum and fluoropyrimidine doublet chemotherapy. Patients with HER2/neu-positive tumors are eligible if they have documented progression on a regimen that included a platinum, fluoropyrimidine, and trastuzumab. Other key eligibility criteria include measurable disease per RECIST v1.1, ECOG performance status 0-1, no chemotherapy within 2 weeks of the first dose of study drug, and provision of a newly obtained or archival tumor sample for central evaluation of PD-L1 status. Eligible patients will be randomized in a 1:1 ratio to receive pembrolizumab 200 mg Q3W or paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of each 28-day cycle. Study treatment will be continued until disease progression, intolerable toxicity, investigator decision, or withdrawal of consent. In the pembrolizumab arm, patients who experience complete response after ≥24 weeks of treatment may discontinue treatment after receiving ≥2 doses following initial complete response; the maximum duration of pembrolizumab treatment is 24 months. Clinically stable patients who experience disease progression per standard RECIST v1.1 may continue pembrolizumab at the discretion of the investigator until a confirmatory scan is performed ≥4 weeks later. Imaging will occur every 6 weeks for the first 6 months and every 12 weeks thereafter. Response will be assessed per RECIST v1.1 by central review and per RECIST adapted to account for unique responses seen with immunotherapy. Adverse events will be assessed throughout treatment and for 30 days thereafter (up to 90 days for serious events). Primary efficacy end points are progression-free survival (PFS) per RECIST v1.1 and overall survival (OS) in patients with PD-L1–positive tumors. Secondary end points include PFS and OS in all patients, time to progression, objective response rate, and duration of response. KEYNOTE-061 enrollment began in March 2015 and will continue until as many as 720 patients are enrolled. Introduction: Paclitaxel is standard therapy for advanced gastric cancer that progresses on first-line therapy with a platinum and fluoropyrimidine. The programmed death receptor 1 (PD-1) pathway is used by tumors to suppress the immune response. The anti-PD-1 antibody pembrolizumab has shown an acceptable safety profile and clinical activity in patients with advanced solid tumors and hematologic malignancies, including advanced gastric cancer. In KEYNOTE-012, pembrolizumab 10 mg/kg given every 2 weeks (Q2W) until disease progression provided a manageable safety profile and a 22% objective response rate (RECIST v1.1, central review). The randomized, open label, phase 3, KEYNOTE-061 study (ClinicalTrials.gov, NCT02370498) is designed to compare the efficacy and safety of pembrolizumab with that of paclitaxel in second-line treatment of advanced gastric cancer. Methods: This study is designed for patients with metastatic or unresectable gastric or GEJ adenocarcinoma that progressed after first-line treatment with platinum and fluoropyrimidine doublet chemotherapy. Patients with HER2/neu-positive tumors are eligible if they have documented progression on a regimen that included a platinum, fluoropyrimidine, and trastuzumab. Other key eligibility criteria include measurable disease per RECIST v1.1, ECOG performance status 0-1, no chemotherapy within 2 weeks of the first dose of study drug, and provision of a newly obtained or archival tumor sample for central evaluation of PD-L1 status. Eligible patients will be randomized in a 1:1 ratio to receive pembrolizumab 200 mg Q3W or paclitaxel 80 mg/m2 IV on days 1, 8, and 15 of each 28-day cycle. Study treatment will be continued until disease progression, intolerable toxicity, investigator decision, or withdrawal of consent. In the pembrolizumab arm, patients who experience complete response after ≥24 weeks of treatment may discontinue treatment after receiving ≥2 doses following initial complete response; the maximum duration of pembrolizumab treatment is 24 months. Clinically stable patients who experience disease progression per standard RECIST v1.1 may continue pembrolizumab at the discretion of the investigator until a confirmatory scan is performed ≥4 weeks later. Imaging will occur every 6 weeks for the first 6 months and every 12 weeks thereafter. Response will be assessed per RECIST v1.1 by central review and per RECIST adapted to account for unique responses seen with immunotherapy. Adverse events will be assessed throughout treatment and for 30 days thereafter (up to 90 days for serious events). Primary efficacy end points are progression-free survival (PFS) per RECIST v1.1 and overall survival (OS) in patients with PD-L1–positive tumors. Secondary end points include PFS and OS in all patients, time to progression, objective response rate, and duration of response. KEYNOTE-061 enrollment began in March 2015 and will continue until as many as 720 patients are enrolled.