RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy for Second-Line Treatment of Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer

Abstract

This phase III study compared the efficacy and safety of bevacizumab combined with standard chemotherapy regimens versus chemotherapy alone as second-line treatment of patients with human epidermal growth factor receptor 2 (HER2) -negative metastatic breast cancer. Patients were randomly assigned 2:1 to chemotherapy + bevacizumab or to chemotherapy + placebo. Before random assignment, investigators chose capecitabine, a taxane (paclitaxel, nab-paclitaxel, or docetaxel), gemcitabine, or vinorelbine. Dosing for bevacizumab or placebo was 15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, depending on chemotherapy regimen. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, PFS by chemotherapy cohort, objective response rate (ORR), duration of objective response, 1-year survival rate, and safety. RIBBON-2 enrolled 684 patients (225, chemotherapy + placebo; 459, chemotherapy + bevacizumab). The combination of bevacizumab with chemotherapy demonstrated a statistically significant benefit. Median PFS increased from 5.1 to 7.2 months (stratified hazard ratio for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). The 10% improvement in ORR between the placebo- and bevacizumab-containing arms (39.5% v 29.6%; P = .0193), although not statistically significant, was consistent with previous trials. There was no statistically significant difference in overall survival. The most common grade ≥ 3 adverse events (AEs) related to bevacizumab treatment were hypertension (9.0%) and proteinuria (3.1%). There was an increased number of AEs leading to study discontinuation in the chemotherapy + bevacizumab arm compared with the chemotherapy + placebo arm (13.3% v 7.2%). The combination of bevacizumab with commonly used chemotherapies improved PFS in the second-line treatment of patients with HER2-negative metastatic breast cancer, with a safety profile comparable with that in prior phase III studies.