The primary results of an intergroup phase III randomized controlled trial comparing ramucirumab plus irinotecan with irinotecan in the third or later line treatment beyond progression after ramucirumab for advanced gastric cancer (RINDBeRG trial)

Ramucirumab is a monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and has been shown to improve survival of patients with advanced gastric cancer. It has been reported that sustained VEGF blockade beyond progression had a survival benefit in various cancers. This is a multicenter, open-label, randomized phase III study that enrolled patients with unresectable gastric cancer who had received previously ramucirumab containing chemotherapy. Patients were randomly allocated to either irinotecan plus ramucirumab arm or irinotecan alone arm in a 1:1 ratio. Irinotecan was administered at a dose of 150 mg/m2, every two weeks, in both arms, and ramucirumab at a dose of 8 mg/kg was added biweekly. The primary endpoint was overall survival (OS), expecting a hazard ratio (HR) of 0.77 (a power of 80% with significance level of one-sided 0.05) for full analysis set (FAS). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), and safety. From February 2019 to August 2022, 402 patients from 121 institutions participating 9 Japanese clinical trial groups were recruited. As of the data cutoff, 362 events for OS were observed. Median OS in the combination of irinotecan plus ramucirumab and irinotecan alone were 9.4 months and 8.5 months (adjusted HR 0.909, 95% confidence interval [CI] 0.738 – 1.119; p=0.369). Median PFS were 3.8 months and 2.8 months (HR 0.722, 95% CI 0.590 - 0.884; p=0.001) and ORR were 22.1% (33/149) and 15.0% (25/167), respectively. The safety profile was consistent with the known profiles of both irinotecan and ramucirumab, and there were no new safety findings. This is the first report of the phase III trial to evaluate sustained anti-angiogenic therapy in advanced gastric cancer. In this study, although the addition of ramucirumab to irinotecan after disease progression of ramucirumab improved PFS and ORR with manageable toxicity, the primary endpoint of OS was not met.