Ramucirumab in Combination With Paclitaxel Improves Overall Survival in Second Line Treatment for Metastatic Gastric Cancer

The phase III RAINBOW study met primary endpoint

A randomised, international phase III RAINBOW study met its primary endpoint of improved overall survival with a monoclonal antibody ramucirumab when given in combination with paclitaxel as second-line treatment for metastatic gastric cancer. Median overall survival for patients receiving ramucirumab plus paclitaxel was 9.6 months, compared to 7.4 months for those receiving only paclitaxel. The study results were presented by Dr Hansjochen Wilke of the Kliniken Essen-Mitte, Essen, Germany at 2014 Gastrointestinal Cancer Symposium (16-18 January, San Francisco, USA).

The achieved difference in overall survival is very good result in this poor-prognosis population. Patients whose disease progress after first-line treatment have a poor prognosis, with a median survival of about 3 months. RAINBOW is the largest clinical trial of second-line therapy in this patient population to date and the results are not only statistically significant but clinically meaningful.

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. Ramucirumab is a human IgG1 monoclonal antibody that blocks the VEGFR-2.  

The study results

The study included 665 patients with metastatic gastro-oesophageal junction or gastric adenocarcinoma whose disease progressed while on or within 4 months of standard first-line platinum- and fluoropyrimidine-based combination chemotherapy. Patients were randomly assigned to receive paclitaxel alone or with ramucirumab. 

Median overall survival was 9.6 months for the combination and 7.4 months for paclitaxel alone. The overall survival curves split early, by 2 months of treatment, and remained separated beyond 1 year. The difference between arms ultimately translated into a 19% reduction in the risk of death (p = 0.0169) with ramucirumab.

Median progression-free survival was 4.4 months and 2.9 months, respectively, a 27% reduction in risk (p < 0.0001). The objective response rate associated with the combination was 28% vs. 16% with paclitaxel alone (p = 0.0001). At 6 months, the progression-free survival rate was 36% vs. 17%, and at 9 months was 22% vs. 10%, respectively. In addition, the disease control rate was much better with ramucirumab, 80% vs. 64%, respectively (p< 0.0001). 

Ramucirumab was relatively well tolerated, although adverse events of grade ≥ 3 were somewhat greater with combination treatment and included neutropenia (40.7% vs. 18.8%) - but the incidence of febrile neutropenia was comparable (3.1% vs. 2.4%) - leukopenia (17.4% vs. 6.7%), hypertension (14.1% vs. 2.4%) and fatigue (7.0% vs. 4.0%). These adverse events did not lead to increased treatment discontinuation in the ramucirumab arm, nor were rates of treatment-related deaths different between the two arms (4.0% with ramucirumab/paclitaxel vs. 4.6% with paclitaxel alone). Other adverse events were anaemia (9.2% vs. 10.3%), abdominal pain (5.5% vs. 3.3%) and asthenia (5.5% vs. 3.3%).

The study investigators concluded that ramuricumab is an effective new drug for patients with metastatic or locally advanced gastric cancer for whom first-line combination chemotherapy has failed. It also shows that an effective second-line therapy improves overall survival.  It is the only study to show a two-month improvement in survival in this setting.

Ramucirumab in the second line treatment for advanced gastric cancer

On 4 January 2014, Prof. Charles Fuchs and colleagues published in the Lancet results from an international, randomised, multicentre, placebo-controlled, phase III trial (REGARD) of ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma. A total of 355 patients were assigned to receive ramucirumab or placebo. Median overall survival was 5.2 months in the ramucirumab group and 3.8 months in the placebo group (p = 0.047). The survival benefit with ramucirumab remained unchanged after multivariable adjustment for other prognostic factors.

Rates of hypertension were higher in the ramucirumab group than in the placebo group (16% vs. 8%), whereas rates of other adverse events were mostly similar between groups. Five (2%) deaths in the ramucirumab group and two (2%) in the placebo group were considered to be related to study drug.

The investigators interpreted the study results by concluding that ramucirumab is the first biological treatment given as a single agent that has survival benefits in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma progressing after first-line chemotherapy. The findings also validate VEGFR-2 signaling as an important therapeutic target in advanced gastric cancer.

Now the RAINBOW represents the second phase III trial of ramucirumab-based therapy for advanced gastric or gastro-oesophageal junction adenocarcinoma that support this VEGFR-2 antagonist in the second-line setting. The USA Food and Drug Administration (FDA) granted ramucirumab priority review status in October 2013 as a second-line treatment option for patients with advanced gastric cancer.