Elsevier

The Lancet

Volume 383, Issue 9911, 4–10 January 2014, Pages 31-39
The Lancet

Articles
Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(13)61719-5Get rights and content

Summary

Background

Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.

Methods

We did an international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North America, Central and South America, Europe, Asia, Australia, and Africa. Patients aged 24–87 years with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression after first-line platinum-containing or fluoropyrimidine-containing chemotherapy were randomly assigned (2:1), via a central interactive voice-response system, to receive best supportive care plus either ramucirumab 8 mg/kg or placebo, intravenously once every 2 weeks. The study sponsor, participants, and investigators were masked to treatment assignment. The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00917384.

Findings

355 patients were assigned to receive ramucirumab (n=238) or placebo (n=117). Median overall survival was 5·2 months (IQR 2·3–9·9) in patients in the ramucirumab group and 3·8 months (1·7–7·1) in those in the placebo group (hazard ratio [HR] 0·776, 95% CI 0·603–0·998; p=0·047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors (multivariable HR 0·774, 0·605–0·991; p=0·042). Rates of hypertension were higher in the ramucirumab group than in the placebo group (38 [16%] vs nine [8%]), whereas rates of other adverse events were mostly similar between groups (223 [94%] vs 101 [88%]). Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.

Interpretation

Ramucirumab is the first biological treatment given as a single drug that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. Our findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.

Funding

ImClone Systems.

Introduction

Worldwide, gastric cancer is the fourth most common malignant disease and the second leading cause of cancer mortality.1 Standard cytotoxic chemotherapy is typically used as first-line treatment for advanced gastric adenocarcinoma, with median survival ranging from 8 months to 10 months.2 After first-line treatment of gastric cancer, no second-line treatment is yet approved by the US Food and Drug Administration, European Medicines Agency, or most other governmental drug regulatory agencies. New targeted systemic drugs are needed to improve the outcome of patients with advanced disease.

Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signalling and angiogenesis seem to have an important role in the pathogenesis of gastric cancer. In animal models of gastric adenocarcinoma, VEGFR-2 inhibition has reduced tumour growth and vascularity.3 In patients with gastric cancer, circulating and tumoral concentrations of VEGF are associated with increased tumour aggressiveness and reduced survival.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Ramucirumab is a fully human IgG1 monoclonal antibody VEGFR-2 antagonist that prevents ligand binding and receptor-mediated pathway activation in endothelial cells.14

We assessed the safety and efficacy of ramucirumab in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who had disease progression after first-line chemotherapy.

Section snippets

Study design and patients

We did this international, randomised, double-blind, placebo-controlled, phase 3 trial between Oct 6, 2009, and Jan 26, 2012, at 119 centres in 29 countries in North, Central, and South America, and Europe, Asia, Australia, and Africa. Eligible patients aged 24–87 years had metastatic or unresectable, locally recurrent gastric or gastro-oesophageal junction adenocarcinoma; had had disease progression within 4 months of the last dose of first-line platinum-containing or

Results

Figure 1 shows the trial profile. 355 patients were randomly assigned to either the ramucirumab group (n=238) or the placebo group (n=117). Baseline characteristics were mostly similar between groups (table 1). Slightly fewer patients in the ramucirumab group had peritoneal metastases than did those in the placebo group (table 1).

At the time of data cutoff, 278 patients had died: 179 (75%) patients given ramucirumab and 99 (85%) of those given placebo. Treatment with ramucirumab significantly

Discussion

Ramucirumab significantly prolonged overall survival in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma that had progressed after first-line chemotherapy. This drug reduced the risk of death from any cause compared with placebo and reduced risk of disease progression by half. The survival benefit with ramucirumab was consistent across almost all subgroups. Although the effect on overall survival was attenuated in women, the progression-free survival estimate in

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