ArticlesRamucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial
Introduction
Gastric cancer is the fifth most common malignancy, and the third leading cause of cancer mortality worldwide.1 Currently, platinum-based and fluoropyrimidine-based combinations are accepted worldwide as established first-line drug regimens.2 There are not many treatment options after failure of first-line therapy. In randomised trials, selected second-line chemotherapy significantly improved overall survival compared with best supportive care,3, 4, 5 however, median survival was less than 6 months. Therefore, new, more active second-line treatment options are needed.
VEGF and VEGFR-2-mediated signalling and angiogenesis contribute to the pathogenesis of gastric cancer. In patients with gastric cancer, circulating VEGF levels are associated with increased tumour aggressiveness and reduced survival.6, 7 In animal models of gastric adenocarcinoma, VEGFR-2 inhibition reduced tumour growth and vascularity.8 First-line treatment with bevacizumab, a VEGF-A-directed monoclonal antibody, in combination with chemotherapy was associated with significantly improved proportions of patients achieving an objective response and progression-free survival, and non-significantly improved overall survival in patients with metastatic gastric cancer.9, 10 Ramucirumab, a human IgG1 monoclonal antibody VEGFR-2 antagonist, prevents ligand binding and receptor-mediated pathway activation in endothelial cells.11 Paclitaxel was chosen for the combination based on single-agent second-line trials;12, 13, 14 the results of a retrospective analysis in gastric cancer indicated similar efficacy between frequently used second-line drugs (taxanes or irinotecan).15 Weekly paclitaxel is better tolerated and more efficacious than 3-weekly paclitaxel in metastatic breast cancer.16 More recently, in a Japanese randomised trial, weekly paclitaxel was associated with a good toxicity profile compared with irinotecan as second-line therapy in patients with gastric cancer.17
We assessed the safety and efficacy of ramucirumab plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma with disease progression after first-line combination chemotherapy.
Section snippets
Study design and patients
RAINBOW was a double-blind, placebo-controlled phase 3 trial. Eligibility criteria included age 18 years and older; having metastatic or non-resectable, locally advanced gastric or gastro-oesophageal junction adenocarcinoma; documented objective radiological or clinical disease progression during or within 4 months of the last dose of first-line platinum and fluoropyrimidine doublet with or without anthracycline; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
Results
Between Dec 23, 2010, and Sept 23, 2012, 665 (84%) of 794 screened patients were randomly assigned to receive ramucirumab plus paclitaxel (n=330) or placebo plus paclitaxel (n=335) at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia (appendix). Figure 1 shows the trial profile. All patients were included in the efficacy analyses. As of data cutoff (July 12, 2013), with a median follow-up for overall survival of 7·9 months (IQR 4·2–13·0), 516 (78%) of 665
Discussion
Ramucirumab plus paclitaxel significantly increased overall survival compared with placebo plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma that had progressed after first-line chemotherapy. Patients treated with ramucirumab plus paclitaxel also had significantly longer progression-free survival, and a higher proportion of patients achieving an overall response and disease control than did those treated with placebo plus paclitaxel. Increased
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