The U.S. Food and Drug Administration (FDA) today approved ramucirumab (Cyramza) for use in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan) for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab (Avastin)-, oxaliplatin- and fluoropyrimidine-containing regimen. Ramucirumab is a recombinant human monoclonal IgG1 antibody that binds to the human vascular endothelial growth factor- receptor 2 (VEGF-R2), preventing the interaction of VEGF-R2 to its ligands.
This approval is based on the results of the phase III RAISE trial, a randomized, double-blind, multinational trial enrolling patients with metastatic colorectal cancer that progressed during or within 6 months of discontinuation of bevacizumab-, oxaliplatin- and fluoropyrimidine-based combination chemotherapy.1
The clinical trial accrued 1,072 patients who were randomly allocated (1:1) to receive FOLFIRI plus placebo or FOLFIRI plus ramucirumab (N = 536 per arm). Treatment cycles on both arms were repeated every 2 weeks, and ramucirumab was administered at a dose of 8 mg/kg by intravenous infusion every 2 weeks. Ramucirumab was continued until disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall survival. Treatment assignment was stratified by geographic region (North America vs Europe vs other regions), KRAS status (wild-type vs mutant) and time to progression for the beginning of first-line treatment (< 6 months vs ≥ 6 months).
The median age of the study population was 62 years, 57% were men, and 99% had an ECOG performance status of 0 or 1. A statistically significant overall survival improvement was observed in patients receiving FOLFIRI plus ramucirumab compared to those receiving FOLFIRI plus placebo (hazard ratio [HR] = 0.85; 95% confidence interval [CI] = 0.73–0.98; P = .023, stratified log-rank test). Median overall survival was 13.3 and 11.7 months for patients on the FOLFIRI-plus-ramucirumab and FOLFIRI-plus-placebo arms, respectively. Progression-free survival was also significantly improved in patients who received ramucirumab in combination with FOLFIRI (HR = 0.79; 95% CI = 0.70–0.90; P < .001). Median progression-free survival was 5.7 and 4.5 months, respectively.
In general, the safety data were consistent with the known safety profile established in previously approved indications. However, hypothyroidism was reported in 2.6% of patients based on thyroid monitoring in patients with metastatic colorectal cancer.
The recommended dose and schedule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizumab-containing regimen is 8 mg/ kg administered every 2 weeks as a 60-minute intravenous infusion. ■
1. Tabernero J, Cohn AL, Obermannova R, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. April 10, 2015 (early release online).