Adding First-Line Nivolumab to Chemotherapy Improves Survival in Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinomas

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As reported in The Lancet by Yelena Y. Janjigian, MD, of the Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, and colleagues, the phase III CheckMate 649 trial has shown that the addition of first-line nivolumab to chemotherapy resulted in improved overall and progression-free survival among patients with advanced non–HER2-positive gastric, gastroesophageal junction, and esophageal adenocarcinomas with a PD-L1 Combined Positive Score (CPS) ≥ 5 (primary endpoints) and among all randomly assigned patients.1

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD

The study supported the April 2021 approval of nivolumab for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for treatment of advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinomas, irrespective of PD-L1 status.

Study Details

In the open-label trial, 1,581 patients with unresectable disease from sites in 29 countries were randomly assigned between March 2017 and April 2019 to receive nivolumab at 360 mg every 3 weeks or at 240 mg every 2 weeks for a maximum of 2 years plus the investigator’s choice of chemotherapy (n = 789) or chemotherapy alone (n = 792). Patients were enrolled without regard to PD-L1 status. Chemotherapy in both groups consisted of XELOX (capecitabine and oxaliplatin) every 3 weeks or FOLFOX (leucovorin, fluorouracil, and oxaliplatin) every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. Randomization was stratified by tumor cell PD-L1 status (≥ 1% vs < 1% or indeterminate), region (Asia vs United States and Canada vs the rest of the world), Eastern Cooperative Oncology Group performance status (0 vs 1), and type of chemotherapy (XELOX vs FOLFOX). Patients with known HER2-positive status were excluded from the study.

Primary endpoints were overall and progression-free survival on blinded independent central review in the population with tumors with a CPS ≥ 5, consisting of 473 in the nivolumab group and 482 in the control group. Overall survival and progression-free survival were also analyzed in the total trial population. Chemotherapy consisted of XELOX and FOLFOX in 46% and 54% of the nivolumab group and 47% and 53% of the control group in the total population and 49% and 51% and 48% and 52% in the CPS ≥ 5 population.

Median follow-up for overall survival was 13.1 months (interquartile range [IQR] = 6.7–19.1 months) in the nivolumab group and 11.1 months (IQR = 5.8–16.1 months) in the chemotherapy group. Among patients with a PD-L1 CPS ≥ 5, median overall survival was 14.4 months (95% confidence interval [CI] = 13.1–16.2 months) in the nivolumab group vs 11.1 months (95% CI = 10.0–12.1 months) in the control group (hazard ratio [HR] = 0.71, 98.4% CI = 0.59–0.86, P < .0001); overall survival at 12 months was 57% vs 46%. Median progression-free survival was 7.7 months (95% CI = 7.0–9.2 months) in the nivolumab group vs 6.0 months (95% CI = 5.6–6.9 months) in the control group (HR = 0.68, 98% CI = 0.56–0.81, P < .0001); the 12-month rate was 36% vs 22%.

Among all patients, median overall survival was 13.8 months (95% CI = 12.6–14.6 months) in the nivolumab group vs 11.6 months (95% CI = 10.9–12.5 months) in the control group (HR = 0.80, 99.3% CI = 0.68–0.94, P = .0002), with a 12-month rate of 55% vs 48%. Median progression-free survival (not formally tested) was 7.7 months (95% CI = 7.1–8.5 months) in the nivolumab group vs 6.9 months (95% CI = 6.6–7.1 months) in the control group (HR = 0.77, 95% CI = 0.68–0.87), with a 12-month rate of 33% vs 23%.


  • The addition of nivolumab to chemotherapy resulted in improved overall and progression-free survival among patients with tumor PD-L1 CPS ≥ 5.
  • The addition of nivolumab was associated with overall and progression-free survival benefit among all randomly assigned patients.

In a subgroup analysis of overall survival among all patients, hazard ratios for the nivolumab vs control groups included 0.81 (95% CI = 0.68–0.96) among patients receiving XELOX and 0.78 (95% CI = 0.66–0.91) among those receiving FOLFOX; 0.80 (95% CI = 0.71–0.91) among 1,377 patients with microsatellite-stable tumors and 0.37 (95% CI = 0.16–0.87) among 44 with microsatellite instability–high tumors; and 0.85 (95% CI = 0.75–0.96) among 1,323 patients with tumor PD-L1 expression < 1% and 0.57 (95% CI = 0.42–0.77) among 253 with PD-L1 expression ≥ 1%.

In a subgroup analysis of overall survival in the CPS ≥ 5 population, hazard ratios for the nivolumab vs control groups included 0.69 (95% CI = 0.55–0.85) among patients receiving XELOX and 0.71 (95% CI = 0.57–0.88) among those receiving FOLFOX; 0.73 (95% CI = 0.62–0.85) among 846 with microsatellite-stable tumors and 0.33 (95% CI = 0.12–0.87) among 34 with microsatellite instability–high tumors; and 0.75 (95% CI = 0.63–0.90) among 724 patients with tumor PD-L1 expression < 1% and 0.56 (95% CI = 0.40–0.77) among 230 with PD-L1 expression ≥ 1%.

Hazard ratios according to study region were 0.76 (95% CI = 0.59–0.97) among 356 patients from Asia, 0.67 (95% CI = 0.50–0.90) among 263 from the United States and Canada, and 0.84 (95% CI = 0.72–0.97) among 962 from the rest of the world in the total population; respective hazard ratios in the CPS ≥ 5 population were 0.64 (95% CI = 0.47–0.87) among 228 patients, 0.67 (95% CI = 0.43–1.03) among 137 patients, and 0.74 (95% CI = 0.61–0.89) among 590 patients.

Among all randomly assigned patients, 297 of 789 (38%) in the nivolumab plus chemotherapy group and 326 of 792 (41%) in the chemotherapy alone group received at least one subsequent therapy, with the most common in both groups being systemic anticancer therapy (34% vs 39%). The most common systemic therapies were taxanes (20% vs 21%) and targeted therapy (14% vs 15%).

Adverse Events

Among all treated patients, grade 3 or 4 treatment-related adverse events occurred in 59% of the nivolumab plus chemotherapy group and 44% of the chemotherapy group, with the most common in the nivolumab group being neutropenia (15% vs 12% in control group) and anemia (6% vs 3%). The most common treatment-related adverse events of any grade (≥ 25%) were nausea (42% vs 38%), diarrhea (32% vs 27%), and peripheral neuropathy (28% vs 25%) across both groups. The most common treatment--related potentially immune-related adverse events of any grade in the nivolumab group were gastrointestinal events (34% vs 27% in the control group), skin events (27% vs 14%), hepatic events (26% vs 17%), and endocrine events (14% vs < 1%).

Treatment-related serious adverse events occurred in 22% vs 12% of patients. Treatment-related adverse events led to discontinuation of any component of treatment in 37% vs 24%. A total of 16 deaths in the nivolumab group (2%) vs 4 in the control group (1%) were considered related to treatment.

The investigators concluded: “Nivolumab is the first [programmed cell death 1 receptor] inhibitor to show superior [overall survival], along with [progression-free survival] benefit and an acceptable safety profile, in combination with chemotherapy vs chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.” 

DISCLOSURE: The study was funded by Bristol Myers Squibb, in collaboration with Ono Pharmaceutical. Dr. Janjigian holds stock or other ownership interests in Rgenix; has served as a consultant or advisor to AstraZeneca, Basilea Pharmaceutical, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Imugene, Merck, Merck Serono, Pfizer, Rgenix, Seattle Genetics, and Zymeworks; has received institutional research funding from Bayer, Bristol Myers Squibb, Cycle for Survival, Department of Defense, Eli Lilly, Fred’s Team, Genentech/Roche, Merck, NCI, and Rgenix; and has held other relationships with Axis Medical Education, Clinical Care Options, Michael J. Hennessy Associates, Paradigm Medical Communications LLC, and Research to Practice.


1. Janjigian YY, Shitara K, Moehler M, et al: 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. Lancet 398:27-40, 2021.

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