Hitting Angiogenesis in Gastric Cancer

The results of a phase III study of ramucirumab in previously-treated advanced gastric or gastro-oesophageal junction adenocarcinoma

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, according to Prof. Charles Fuchs and the REGARD Trial Investigators who published results from an international, randomised, multicentre, placebo-controlled, phase III trial as an early online article in The Lancet on 3 October 2013. 

Gastric cancer is the fourth leading cause of cancer-related mortality worldwide. Survival in gastric cancer has improved with the validation and implementation of adjuvant therapy combined with surgery, including postoperative adjuvant chemotherapy, perioperative chemotherapy, and postoperative combined chemotherapy and radiotherapy. However, little progress has been made in the treatment of advanced gastric cancer. Recently, more evidence has emerged that gastric cancer is a molecularly enriched type of cancer and the oncology community became involved in testing novel targeted treatments.

Targeting the VEGFR2-mediated signalling

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. The REGARD Trial Investigators aimed to assess whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, prolonged survival in patients with advanced gastric cancer.

This study was an international, randomised, double-blind, placebo-controlled, phase III trial conducted between 6 October 2009 and 26 January 2012 at 119 centres in 29 countries in North, 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) to receive best supportive care plus either ramucirumab 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.

In total, 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.

The authors concluded that 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.

The study findings validate VEGFR-2 signalling as an important therapeutic target in advanced gastric cancer.

The trial registration number with ClinicalTrials.gov is NCT00917384.

The study was funded by ImClone Systems.

Reference:

C. Fuchs, J. Tomasek, C. Yong, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet, Early Online Publication, 3 October 2013. doi:10.1016/S0140-6736(13)61719-5.