As reported in The Lancet by Yelena Y. Janjigian, MD, 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 HER2-negative gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma with a tumor PD-L1 combined positive score (CPS) of ≥ 5 (primary endpoints) and among all randomly assigned patients.
The study supported the April 2021 approval of nivolumab for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, irrespective of PD-L1 status.
Yelena Y. Janjigian, MD
Study Details
The open-label trial included 1,581 patients with unresectable disease from sites in 29 countries. They were randomly assigned between March 2017 and April 2019 to receive nivolumab at 360 mg every 3 weeks or 240 mg every 2 weeks for a maximum of 2 years plus chemotherapy (n = 789) or chemotherapy alone (n = 792). Patients were enrolled without regard to PD-L1 status. Chemotherapy in both groups consisted of capecitabine and oxaliplatin every 3 weeks, or leucovorin, fluorouracil, and oxaliplatin every 2 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoints were overall and progression-free survival on blinded independent central review in the population with tumors with CPS ≥ 5, consisting of 473 patients in nivolumab group and 482 in the control group. Overall and progression-free survival were also analyzed in the total trial population.
Survival Outcomes
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 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). 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).
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, 95% CI = 0.68–0.94, P = .0002), with 12-month rates 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 12-month rates of 33% vs 23%.
KEY POINTS
- 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.
Adverse Events
Grade 3 and 4 treatment-related adverse events occurred in 59% of patients in 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, diarrhea, and peripheral neuropathy in both groups. 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 36% 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 PD-1 inhibitor to show superior overall survival, along with [a] progression-free survival benefit and an acceptable safety profile, in combination with chemotherapy vs chemotherapy alone in previously untreated patients with advanced gastric, GEJ, or esophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.”
Kohei Shitara, MD, of the Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Bristol Myers Squibb, in collaboration with Ono Pharmaceutical. For full disclosures of the study authors, visit thelancet.com.
