Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649

BACKGROUND: We report efficacy and safety results from the CheckMate 649 trial after 5 years of follow-up. PATIENTS AND METHODS: Adults with previously untreated, non-human epidermal growth factor receptor 2-positive, unresectable, advanced or metastatic gastroesophageal adenocarcinoma were randomized to receive nivolumab plus chemotherapy (n = 789) or chemotherapy (n = 792). Primary endpoints were met and reported previously, with nivolumab plus chemotherapy demonstrating superior overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥5. RESULTS: With a minimum follow-up of 60.1 months, the OS benefit [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.61-0.81] and PFS benefit (HR 0.71, 95% CI 0.61-0.82) with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥5 were sustained. Five-year OS and PFS rates were 16% versus 6% and 10% versus 6%, respectively. Objective response rate per blinded independent central review was 58% (95% CI 54% to 62%) versus 46% (95% CI 42% to 50%), and median duration of response was 8.5 months (95% CI 7.7-9.9 months) versus 6.9 months (95% CI 5.9-7.6 months), respectively. Survival and response benefits were also maintained in patients with PD-L1 CPS ≥1, patients with PD-L1 CPS ≥10, and all randomized patients. Grade 3/4 treatment-related adverse events occurred in 60% of patients receiving nivolumab plus chemotherapy and 45% of patients receiving chemotherapy. No new safety concerns were observed. CONCLUSIONS: To our knowledge, these are the first reported 5-year results of a programmed cell death protein 1 inhibitor plus chemotherapy in gastroesophageal adenocarcinoma. Nivolumab plus chemotherapy continued to demonstrate long-term survival benefit and acceptable safety after 5 years of follow-up, reinforcing its use as a standard first-line treatment for PD-L1-positive patients.