SAN FRANCISCO—Combining ramucirumab with paclitaxel increased median overall survival (OS) by 2.3 months versus paclitaxel alone in patients with metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression after first-line combination therapy, investigators concluded at the 2014 Gastrointestinal Cancers Symposium.
Results of the largest clinical trial of second-line therapy in this patient population to date were “not only statistically significant, but clinically meaningful,” Hansjochen Wilke, MD, Director of the Department of Oncology, Hematology and Center of Palliative Care at Kliniken Essen-Mitte in Essen, Germany, said in a press briefing. Progression-free survival (PFS) was also “markedly improved.”
Patients with metastatic gastric cancer who progress on first-line therapy platinum- and fluoropyrimidine-containing chemotherapy typically have a median OS of 4 to 5 months. To investigate whether the human IgG1 monoclonal antibody vascular endothelial growth factor (VEGF)-receptor 2 antagonist, ramucirumab, had a positive effect on tumor regression and survival, the global phase 3 RAINBOW trial randomly assigned 665 patients to ramucirumab 8 mg/kg intravenously every 2 weeks plus paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n=330) or placebo plus paclitaxel (n=335) until disease progression, unacceptable toxicity, or death. Patients were stratified by geographic region, measurable versus nonmeasurable disease, and time to progression on first-line therapy (less than 6 months vs. greater than 6 months).
Median OS, the primary endpoint, was 9.63 months (95% CI: 8.48-10.81 months) for ramucirumab plus paclitaxel and 7.36 months (95% CI: 6.31-8.38 months) for paclitaxel alone (hazard ratio [HR], 0.807; 95% CI: 0.678-0.962; P = 0.0169). For the ramucirumab plus paclitaxel arm, 6-month OS was 72% and 12-month OS, 40%, compared with 57% and 30% in the placebo plus paclitaxel arm. A subgroup analysis found that OS favored ramucirumab plus paclitaxel for nearly all patient-/disease-related subgroups.
Median PFS was 4.40 months (95% CI: 4.24-5.32 months) and 2.86 months (95% CI: 2.79-3.02 months), respectively (HR, 0.635; 95% CI: 0.536-0.752; P < 0.0001). Median time to progression was 5.5 months in the ramucirumab plus paclitaxel arm versus 3.0 months in the paclitaxel-alone arm (P < 0.0001). Overall response rate was 28% versus 16% (P = 0.0001) and disease control rate, 80% versus 64% (P < 0.0001).
Grade 3 or higher adverse events (AEs) were neutropenia (40.7% in the ramucirumab plus paclitaxel arm vs. 18.8% in the paclitaxel-alone arm), febrile neutropenia (3.1% vs. 2.4%), leukopenia (17.4% vs. 6.7%), hypertension (14.1% vs. 2.7%), bleeding/hemorrhage (4.3% vs. 2.4%), GI hemorrhage (3.7% vs. 1.5%), and fatigue (11.9% vs. 5.5%). Proteinuria and GI perforation each occurred in 1.2% of patients in the combination arm compared with none in the paclitaxel-alone arm. Thromboembolic events were observed at a similar incidence on both arms and no fistula or wound healing complications or grade 4 or higher hypertension or proteinuria were observed on either arm. All AEs were manageable, with few patients discontinuing treatment due to toxicities.
Dr. Wilke noted that patients who received ramucirumab and paclitaxel also reported a reduction in pain and other improvements in quality of life.
The RAINBOW investigators will next analyze tumor samples with the goal of identifying biomarkers predictive of treatment with ramucirumab as well as investigate the agent in the first-line setting.
An estimated 30% of patients in the United States receive an additional line of treatment, compared with 70% to 80% of patients in Japan, which has higher rates of gastric cancer. Dr. Wilke said this geographic difference in treatment may be attributed to lack of large randomized clinical trials demonstrating clinical benefit of second-line chemotherapy in Western countries.
The first positive study, REGARD, showed single-agent ramucirumab improved OS and PFS in patients with advanced gastric cancer who had disease progression after initial chemotherapy. The U.S. Food and Drug Administration assigned ramucirumab a priority review designation in October 2013 as a second-line treatment for advanced gastric cancer. No agents are currently approved for this population.
The 2014 Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association (AGA) Institute, the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SSO).