First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial

Abstract

Summary Background First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction (GEJ) adenocarcinoma results in median overall survival (OS) <1 year. The phase 3 CheckMate 649 study evaluated first-line programmed death (PD)-1 inhibitor-based therapies in gastric/GEJ/oesophageal adenocarcinoma; we report first results for nivolumab-plus-chemotherapy versus chemotherapy. Methods We enrolled adults with previously untreated, unresectable, non-HER2-positive gastric/GEJ/oesophageal adenocarcinoma, regardless of PD-ligand (L)1 expression. Patients were randomised to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks)-plus-chemotherapy (XELOX every 3 weeks or FOLFOX every 2 weeks), nivolumab-plus-ipilimumab, or chemotherapy. Primary endpoints for nivolumab-plus-chemotherapy versus chemotherapy were OS or progression-free survival (PFS) by blinded independent central review, in PD-L1 combined positive score (CPS) ≥5 patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. Findings From March 2017 through April 2019, we concurrently randomised 1581 patients to treatment (nivolumab-plus-chemotherapy, 789; chemotherapy, 792). The median follow-up for OS was: nivolumab-plus-chemotherapy, 13·1 months (IQR, 6·7–19·1) and chemotherapy, 11·1 months (5·8–16·1). Nivolumab-plus-chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59–0·86]; p<0·0001) and PFS (HR 0·68 [98% CI 0·56–0·81]; p<0·0001) versus chemotherapy in PD-L1 CPS ≥5 patients (minimum follow-up, 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in PD-L1 CPS ≥1 and all-randomised patients. Among all-treated patients, 462 (59%, nivolumab-plus-chemotherapy) and 341 (44%, chemotherapy) patients had grade 3–4 treatment-related adverse events. No new safety signals were identified. Interpretation Nivolumab is the first PD-1 inhibitor to demonstrate superior OS, along with PFS benefit, and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric/GEJ/oesophageal adenocarcinoma. Nivolumab-plus-chemotherapy represents a potential standard first-line treatment for these patients. Funding Bristol Myers Squibb (Princeton, NJ, USA), in collaboration with Ono Pharmaceutical Co., Ltd. ClinicalTrials.gov number, NCT02872116.