Elsevier

The Lancet Oncology

Volume 15, Issue 11, October 2014, Pages 1224-1235
The Lancet Oncology

Articles
Ramucirumab 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

https://doi.org/10.1016/S1470-2045(14)70420-6Get rights and content

Summary

Background

VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel.

Methods

This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase.

Findings

Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment—330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5–10·8] vs 7·4 months [95% CI 6·3–8·4], hazard ratio 0·807 [95% CI 0·678–0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]).

Interpretation

The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer.

Funding

Eli Lilly and Company.

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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    *

    Principal investigators from the participating centres are listed in the appendix

    Now employed at Eli Lilly and Company, Indianapolis, IN, USA

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