Nivolumab/Chemo Yields Long-Term Survival in Advanced Gastric Cancers

Nivolumab (Opdivo) in combination with chemotherapy yielded a significant and durable improvement in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in patients with previously untreated advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma, according to long-term follow-up findings from the phase 3 CheckMate 649 trial (NCT02872116) published in Annals of Oncology. These results represent the first 5-year follow-up of a PD-1 inhibitor plus chemotherapy for this patient population.

Clinical Efficacy Across Patient Subgroups

With a minimum follow-up of 60.1 months, nivolumab plus chemotherapy maintained a survival benefit over chemotherapy across various patient populations, with the most pronounced benefit observed in patients with a PD-L1 combined positive score (CPS) of 5 or higher. In this high-expression subgroup, the median OS was 14.4 months (95% CI, 13.1-16.2) for the nivolumab combination arm compared with 11.1 months (95% CI, 10.1-12.1) for the chemotherapy alone arm, representing a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.61-0.81). At the 5-year mark, the OS rate was 16% for patients receiving the combination vs 6% for those receiving chemotherapy alone.

Survival advantages were also sustained in the overall population, which showed a median OS of 13.7 months (95% CI, 12.4-14.5) with nivolumab plus chemotherapy vs 11.6 months (95% CI, 10.9-12.5) with chemotherapy (HR, 0.79; 95% CI, 0.71-0.88). For patients with a PD-L1 CPS of 1 or higher, the median OS was 13.8 months (95% CI, 12.4-14.8) compared with 11.4 months (95% CI, 10.7-12.3) in the control group (HR, 0.76; 95% CI, 0.67-0.85).

Long-term PFS was also improved; in the PD-L1 CPS of 5 or higher group, the 5-year PFS rate was 10% for the combination and 6% for chemotherapy (HR, 0.71; 95% CI, 0.61-0.82). In the overall population, the 5-year PFS rate was 8% vs 4% (HR, 0.79; 95% CI, 0.71-0.89).

The combination therapy further demonstrated superior response metrics. In the overall population, the investigator-assessed objective response rate (ORR) was 58% (95% CI, 54%-62%) with nivolumab plus chemotherapy compared with 46% (95% CI, 42%-50%) with chemotherapy alone. The median duration of response (DOR) was 8.5 months (95% CI, 7.7-9.9) and 6.9 months (95% CI, 5.9-7.6) for the combination and chemotherapy arms, respectively.

Exploratory analysis based on microsatellite status revealed that patients with microsatellite instability-high (MSI-H) tumors experienced a profound benefit from nivolumab plus chemotherapy, with an OS HR of 0.37 (95% CI, 0.18-0.75), while those with microsatellite stable (MSS) tumors still derived benefit (HR, 0.80; 95% CI, 0.71-0.89).

“The data from 5 years of follow-up of CheckMate 649 show continued clinical benefit with no new safety signals, further supporting nivolumab plus chemotherapy as standard first-line treatment for patients with gastric cancer, [GEJ] cancer, and esophageal adenocarcinoma,” wrote the study investigators led by Yelena Y. Janjigian, MD, Carroll and Milton Petrie Chair and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in the study.

Trial Breakdown

The open-label CheckMate 649 trial randomly assigned patients 1:1:1 to receive either nivolumab plus chemotherapy, nivolumab plus ipilimumab (Yervoy), or chemotherapy alone. The chemotherapy regimen was chosen by the investigator and consisted of either FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) every 2 weeks or XELOX (capecitabine and oxaliplatin) every 3 weeks.

Patient eligibility required participants to be adults with previously untreated, unresectable advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma. The primary end points were OS and PFS by blinded independent central review (BICR) in patients with a PD-L1 CPS of 5 or higher.

Safety and Long-Term Tolerability

The safety profile of nivolumab plus chemotherapy remained consistent with previous reports, with no new safety signals identified during the long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in 95% of patients in the nivolumab combination arm and 89% in the chemotherapy alone arm. Grade 3 or 4 TRAEs were reported in 60% of patients receiving the combination compared with 45% receiving chemotherapy.

Discontinuation due to TRAEs occurred in 42% of patients in the nivolumab plus chemotherapy arm compared with 26% in the chemotherapy arm. With longer follow-up, no treatment-related deaths were reported.

Reference

Janjigian YY, Shitara K, Ajani JA, et al. Nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 5-year follow-up results from CheckMate 649. Ann Oncol. Published online February 6, 2026. doi:10.1016/j.annonc.2026.02.003