Nivolumab plus chemotherapy in HER2-negative metastatic gastric, GEJ, and esophageal adenocarcinoma: A CheckMate 649 real-world validation study.

326 Background: CheckMate 649 established nivolumab plus chemotherapy as first-line standard of care for HER2-negative advanced gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma. We conducted a real-world validation of these findings using a U.S. electronic health record–based network. Methods: Adults (≥18 years) with HER2-negative metastatic gastric/GEJ/esophageal adenocarcinoma initiating chemotherapy with or without nivolumab were identified in the TriNetX US Network. The index date was first treatment exposure; patients with HER2-directed therapy were excluded. Propensity score matching balanced demographics and comorbidities. Kaplan–Meier survival analyses were performed with hazard ratios (HR, 95% CI) and log-rank tests. Results: After matching, they were 1,782 per arm and follow-up was for 1 year. Nivolumab+chemotherapy significantly improved OS versus chemotherapy alone (HR 0.90, 95% CI 0.82–0.99; log-rank p=0.039). By 365 days, death occurred in 41.3% versus 46.3% of patients (RR 0.89, 95% CI 0.83–0.96; p=0.003). Healthcare utilization showed no difference in hospitalizations, but ER visits were higher with nivolumab+chemotherapy (HR 1.32, 95% CI 1.10–1.58; p=0.003). Hematologic toxicities were increased, including anemia (HR 1.19, 95% CI 1.01–1.39; p=0.035), thrombocytopenia (HR 1.21, 95% CI 1.00–1.47; p=0.048), and a trend toward neutropenia (HR 1.17, 95% CI 0.99–1.38; p=0.054). Septic shock trended higher (HR 1.30, 95% CI 0.98–1.72; p=0.065). Non-hematologic toxicities included increased pneumonia (HR 1.28, 95% CI 1.07–1.54; p=0.008), fatigue (HR 1.30, 95% CI 1.12–1.50; p