Five-year follow-up data from the phase 3 CheckMate 649 trial demonstrates that first-line nivolumab (Opdivo) in combination with chemotherapy continues to provide a significant overall survival (OS) benefit compared to chemotherapy alone in patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma (EAC). The study's extended follow-up reinforces nivolumab plus chemotherapy as a standard first-line treatment option for these cancers.
The updated results, presented at the 2025 ASCO Gastrointestinal Cancers Symposium, showed that in the subgroup of patients with a PD-L1 combined positive score (CPS) of 5 or higher, the median OS was 14.4 months (95% CI, 13.1-16.2) with nivolumab plus chemotherapy compared to 11.1 months (95% CI, 10.1-12.1) with chemotherapy alone (HR, 0.71; 95% CI, 0.61-0.81). The 5-year OS rates were 16% and 6%, respectively. These results highlight the lasting impact of the nivolumab combination in this patient population.
Sustained Progression-Free Survival
The progression-free survival (PFS) benefit initially reported with the addition of nivolumab to chemotherapy was also sustained with longer follow-up. In patients with a PD-L1 CPS of ≥5, the median PFS at 5 years was 8.3 months (95% CI, 7.0-9.4) in the nivolumab/chemotherapy arm versus 6.1 months (95% CI, 5.6-6.9) in the chemotherapy-alone arm (HR, 0.71; 95% CI, 0.61-0.82). Across all randomized patients, the 5-year median PFS was 7.8 months (95% CI, 7.1-8.6) versus 6.9 months (95% CI, 6.7-7.2), respectively (HR, 0.79; 95% CI, 0.71-0.89).
Durable Responses Observed
Five-year response data underscored the durability of the clinically meaningful activity of the nivolumab combination in the frontline setting. The objective response rate (ORR) in the CPS ≥5 subgroup was 60% in the nivolumab/chemo arm compared with 45% in the control arm. The median duration of response (mDOR) was 9.6 months versus 7.0 months, respectively. Among all patients, the ORR was 58% versus 46% and the mDOR was 8.5 versus 6.9 months, respectively.
Outcomes in Chinese Patients
Analysis of Chinese patients enrolled in the CheckMate 649 trial revealed consistent benefits with the nivolumab combination. At a minimum follow-up of 61.2 months, nivolumab plus chemotherapy (n = 99) yielded a median OS of 14.3 months (95% CI, 11.5-16.5) compared with 10.3 months (95% CI, 8.1-12.1) for chemotherapy alone (n = 109; HR, 0.63; 95% CI, 0.46-0.85). The 60-month OS rates were 20% and 7%, respectively. In patients with a PD-L1 CPS of at least 5, the nivolumab arm (n = 75) achieved a median OS of 15.5 months (95% CI, 11.9-21.1) vs 9.6 months (95% CI, 8.09-12.1) for the chemotherapy arm (n = 81; HR, 0.57; 95% CI, 0.40-0.82), with 60-month OS rates of 24% and 8%, respectively.
Safety Profile
No new safety signals were observed with the extended follow-up. The most common grade 3/4 treatment-related adverse events (TRAEs) in the nivolumab plus chemotherapy arm were neutropenia (16%), decreased neutrophil count (11%), anemia (6%), and increased lipase (6%). In the chemotherapy-alone arm, the most common grade 3/4 TRAEs were neutropenia (13%), decreased neutrophil count (9%), diarrhea (3%), peripheral neuropathy (3%), anemia (3%), and vomiting (3%).
Study Design
The CheckMate 649 trial was an open-label, randomized, global phase 3 study that enrolled patients with previously untreated, unresectable, advanced or metastatic gastric cancer, GEJ cancer, and EAC. Patients had no known HER2 positivity and an ECOG performance status of 0 or 1. Patients were randomized to nivolumab plus chemotherapy (XELOX or FOLFOX), chemotherapy alone (XELOX or FOLFOX), or nivolumab plus ipilimumab. The primary endpoints were OS and PFS in patients with a PD-L1 CPS of 5 or higher.
