CheckMate 649 is a global, randomized phase III trial that established nivolumab plus chemotherapy as a first-line standard of care for patients with previously untreated, HER2-negative advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma. Earlier analyses demonstrated significant improvements in overall survival and progression-free survival, particularly in patients with PD-L1 combined positive score (CPS) ≥5. The newly reported 5-year follow-up provides the longest survival data to date for a PD-1 inhibitor combined with chemotherapy in this disease setting, offering important insight into the durability of benefit and long-term safety.
Title: Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649
Authors: Y.Y. Janjigian, K. Shitara, J.A. Ajani, L. Shen, M. Garrido, C. Gallardo, L. Wyrwicz, K. Yamaguchi, J.M. Cleary, E. Elimova, R. Bruges, M. Karamouzis, T. Skoczylas, A. Bragagnoli, T. Liu, M. Tehfe, T. Zander, R. Kowalyszyn, R. Pazo-Cid, M. Schenker, K. Feeny, S. McCraith, N. Hu, M. Lei, J. Zhang, M. Moehle
Published in Annals of Oncology, Feb 2026
Background
Advanced gastric cancer (GC), gastroesophageal junction cancer (GEJC), and esophageal adenocarcinoma (EAC) remain aggressive malignancies with historically poor long-term survival in the metastatic setting. Immune checkpoint inhibitors targeting PD-1 have reshaped first-line treatment strategies, particularly in PD-L1–positive disease.
The phase III CheckMate 649 trial previously demonstrated that nivolumab plus chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with PD-L1 combined positive score (CPS) ≥5. Earlier updates at 3 years confirmed durability of benefit. The newly reported 5-year follow-up from CheckMate 649 provides the longest survival data to date for a PD-1 inhibitor combined with chemotherapy in gastroesophageal adenocarcinoma and offers critical insight into long-term disease control, survival durability, and safety.
Methods and Study Design
CheckMate 649 was a global, randomized, open-label, phase III trial evaluating nivolumab plus chemotherapy versus chemotherapy alone as first-line treatment in patients with previously untreated, non-HER2–positive, unresectable, advanced or metastatic GC, GEJC, or EAC.
The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS ≥5. Secondary analyses evaluated outcomes in additional PD-L1 subgroups (CPS ≥1, CPS ≥10) and in the overall randomized population.
Efficacy outcomes included:
- Overall survival (OS)
- Progression-free survival (PFS)
- Objective response rate (ORR) per blinded independent central review
- Duration of response (DoR)
Safety was assessed through treatment-related adverse events (TRAEs), including grade 3/4 events.The present analysis reports outcomes after a minimum follow-up of 60.1 months.
A total of 1,581 patients were randomized:
- Nivolumab plus chemotherapy: n = 789
- Chemotherapy alone: n = 792
Eligible patients had:
- Previously untreated advanced or metastatic disease
- HER2-negative tumors
- Adequate organ function
The study population included gastric, gastroesophageal junction, and esophageal adenocarcinoma. PD-L1 expression was evaluated using the combined positive score (CPS), and subgroup analyses were pre-specified according to CPS thresholds.
The long-term follow-up analysis focuses on durability of benefit across biomarker-defined subgroups and the overall randomized population.
Results
After a minimum follow-up of 60.1 months, nivolumab plus chemotherapy continued to demonstrate a sustained overall survival benefit in patients with PD-L1 CPS ≥5. The overall survival hazard ratio was 0.71 (95% CI 0.61–0.81), corresponding to a 29% reduction in the risk of death compared with chemotherapy alone. The five-year overall survival rate was 16% in the nivolumab plus chemotherapy arm versus 6% with chemotherapy, representing a 10% absolute improvement at five years and confirming a meaningful long-term survival gain in advanced gastroesophageal adenocarcinoma.
A durable progression-free survival benefit was also observed in the PD-L1 CPS ≥5 population. The progression-free survival hazard ratio was 0.71 (95% CI 0.61–0.82). At five years, 10% of patients treated with nivolumab plus chemotherapy remained progression-free compared with 6% in the chemotherapy arm, supporting sustained disease control beyond the initial treatment period.
Tumor response outcomes further favored the nivolumab-containing regimen. The objective response rate was 58% (95% CI 54–62) with nivolumab plus chemotherapy compared with 46% (95% CI 42–50) with chemotherapy alone. In addition, responses were more durable in the combination arm, with a median duration of response of 8.5 months (95% CI 7.7–9.9) versus 6.9 months (95% CI 5.9–7.6) with chemotherapy.
Importantly, survival and response benefits were maintained across additional PD-L1 subgroups, including patients with CPS ≥1, CPS ≥10, and in the overall randomized population. As observed in earlier analyses, the magnitude of benefit was enriched at higher PD-L1 CPS cutoffs, reinforcing PD-L1 expression as a predictive biomarker for immunotherapy benefit in gastroesophageal adenocarcinoma.
Regarding safety, grade 3/4 treatment-related adverse events occurred in 60% of patients receiving nivolumab plus chemotherapy compared with 45% of those receiving chemotherapy alone. No new safety signals were identified with extended follow-up, and the overall safety profile remained consistent with previous reports.
Key Findings
First 5-year survival data with PD-1 plus chemotherapy in gastroesophageal adenocarcinoma.This represents the longest follow-up reported for a PD-1 inhibitor combined with chemotherapy in this disease setting.
- A hazard ratio of 0.71 and 16% 5-year OS rate demonstrate durable survival advantage.
- Five-year PFS of 10% with nivolumab plus chemotherapy indicates persistent benefit in a subset of patients.
- Higher response rate and longer duration of response.-ORR increased by 12 percentage points, and median DoR was extended by approximately 1.6 months.
- Efficacy was strongest in PD-L1 CPS ≥5 and enriched at CPS ≥10, confirming the relevance of PD-L1 testing.
- The 5-year safety profile remained consistent and acceptable.
Clinical Context
CheckMate 649 established nivolumab plus chemotherapy as a global standard of care in PD-L1–positive, HER2-negative advanced gastroesophageal adenocarcinoma. The 5-year update confirms that early immunotherapy integration translates into sustained long-term benefit.
These results are particularly relevant given the evolving treatment landscape, which includes other PD-1 inhibitors and biomarker-driven strategies. However, CheckMate 649 provides the longest and most mature survival data for PD-1 plus chemotherapy in this setting.
Conclusion
The 5-year follow-up of CheckMate 649 confirms that first-line nivolumab plus chemotherapy delivers sustained overall survival and progression-free survival benefits compared with chemotherapy alone in PD-L1–positive advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma.
With a hazard ratio of 0.71 for overall survival and a 16% five-year survival rate, these findings reinforce nivolumab plus chemotherapy as a standard first-line treatment in appropriately selected patients. The durability of benefit and stable long-term safety profile mark a significant advancement in the management of advanced gastroesophageal adenocarcinoma.