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<0.001), and elevated liver enzymes (HR 2.79, 95% CI 1.95–3.99; p<0.001). Nausea/vomiting did not differ (HR 0.98, 95% CI 0.83–1.14; p=0.754). Among irAEs, hypothyroidism was significantly increased (HR 2.62, 95% CI 1.90–3.61; p<0.001). Peripheral neuropathy (HR 0.94, 95% CI 0.62–1.43; p=0.772) and pneumonitis (HR 0.90, 95% CI 0.54–1.50; p=0.685) were not significantly different. Adrenal insufficiency, hypophysitis, hyperthyroidism, myositis, encephalitis, and pericarditis were evaluated but event counts were too low for analysis. Conclusions: In this real-world analysis, nivolumab+chemotherapy conferred a modest but significant OS benefit versus chemotherapy alone, consistent with CheckMate 649. This benefit was accompanied by increased risks of cytopenias, infectious complications, hepatic enzyme elevation, fatigue, and hypothyroidism, highlighting the importance of vigilant monitoring in clinical practice.