In an Asian phase II/III trial (ATTRACTION-4) reported in The Lancet Oncology, Yoon-Koo Kang, MD, and colleagues found that the addition of nivolumab to oxaliplatin-based chemotherapy improved progression-free survival—but not overall survival—as first-line treatment of HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer.
Study Details
The double-blind trial included 724 patients from sites in Japan, South Korea, and Taiwan. Patients were randomly assigned between March 2017 and May 2018 to receive nivolumab at 360 mg every 3 weeks (n = 362) or placebo (n = 362) with chemotherapy consisting of 3-week cycles of oxaliplatin at 130 mg/m² on day 1, plus either S-1 (an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil) at 40 mg/m² (SOX) or capecitabine at 1,000 mg/m² (CAPOX) twice daily on days 1 to 14.
The primary endpoints were centrally assessed progression-free survival and overall survival in the intention-to-treat population.
Yoon-Koo Kang, MD
Progression-Free and Overall Survival
At a prespecified interim analysis of progression-free survival, median follow-up was 11.6 months (interquartile range [IQR] = 8.7–14.1 months) at data cutoff in October 2018. Median progression-free survival was 10.5 months (95% confidence interval [CI] = 8.4–14.8 months) in the nivolumab group vs 8.3 months (95% CI = 7.0–9.4 months) in the control group (hazard ratio [HR] = 0.68, 98.51% CI = 0.51–0.90, P = .0007). Hazard ratios were 0.70 (95% CI = 0.53–0.92) among 232 vs 232 patients receiving SOX and 0.71 (95% CI = 0.49–1.01) among 130 vs 130 receiving CAPOX.
Subsequent anticancer therapy was received by 72% of patients in the nivolumab group vs 73% of the control group. At data cutoff for final analysis of overall survival, median follow-up was 26.6 months (IQR = 24.1–29.0 months). Median overall survival was 17.5 months (95% CI = 15.7–20.8 months) in the nivolumab group vs 17.2 months (95% CI = 15.2–19.7 months) in the control group (HR = 0.90, 95% CI = 0.75–1.08, P = .26). Hazard ratios were 0.94 (95% CI = 0.75–1.17) among patients receiving SOX and 0.84 (95% CI = 0.62–1.14) among those receiving CAPOX.
Objective response was observed in 57% of the nivolumab group vs 48% of the control group, with median response durations of 12.9 months vs 8.7 months. Analysis of progression-free survival at the time of overall survival analysis showed the benefit was maintained in the nivolumab group (median = 10.94 vs 8.41 months, HR = 0.70, 95% CI = 0.57–0.86).
KEY POINTS
- The addition of nivolumab to chemotherapy significantly prolonged progression-free survival.
- No overall survival benefit was observed.
Adverse Events
Grade 3 or 4 adverse events occurred in 57% of the nivolumab group vs 49% of the control group. The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (20% vs 16%), and decreased platelet count (9% vs 9%).
Treatment-related serious adverse events of any grade occurred in 25% vs 14% of patients; most commonly, decreased appetite (5% vs 3%). Treatment-related death occurred in three patients in the nivolumab group (due to febrile neutropenia, hepatic failure, and sudden death) and three patients in the control group (due to sepsis, hemolytic anemia, and interstitial lung disease).
The investigators concluded, “Nivolumab combined with oxaliplatin-based chemotherapy significantly improved progression-free survival, but not overall survival, in Asian patients with untreated, HER2-negative, unresectable advanced or recurrent gastric or gastroesophageal junction cancer, and could potentially be a new first-line treatment option for these patients.”
Narikazu Boku, MD, of the Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Ono Pharmaceutical and Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
