Phase III Studies of Bevacizumab (B) in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer (MBC): Summary of Selected Adverse Events.
Authors: Robert N. , Dieras V. , Glaspy J. , Brufsky A. , Miller K. , Miles D. , Koralewski P. , Bhattacharya S. , Phan S. 
Published: December 2010

Abstract
BackgroundA number of chemotherapy agents are used in the first-line treatment of patients with HER2-negative MBC. Three multicenter, randomized Phase III trials have demonstrated significant improvements in progression-free survival (PFS) when adding B to chemotherapy (C) in the first line treatment of women with MBC. These include E2100 (n=722), an open-label trial evaluating weekly paclitaxel (P) +/- B 15 mg/kg; AVADO (n=736), a placebo-controlled, double-blind trial evaluating docetaxel every 3 weeks +/- B 7.5mg/kg or B 15 mg/kg; RIBBON-1 (n=1237), a placebo-controlled, double-blind trial assessing capecitabine (C), Taxane (T) or Anthracycline (A) +/- B 15 mg/kg.Bevacizumab has a characteristic safety profile across a number of different tumor types when used as either a single agent or in combination with chemotherapy. Selected adverse events from breast cancer phase III trials will be summarized to show how different types of chemotherapy affect the adverse event (AE) rates in the first-line MBC setting.MethodsGrade 3–5 non-hematological events and Grade 4 or 5 hematological events using the NCI-CTC Version 2 (E2100) and the NCI CTCAE Version 3 (AVADO and RIBBON-1) are recorded and are summarized for B-related AEs by individual treatment arm from these three studies. These AEs included arterial tumor embolism (ATE), gastrointestinal perforation, hypertension, left ventricular systolic dysfunction, venous thromboembolism, proteinuria, bleeding, and wound-healing complications.ResultsAnalyzing the incidence of known B-related AEs in the placebo arms and B-containing arms of the E2100, AVADO, and RIBBON-1 studies, we found that hypertension ranged from 0 to 2% for patients in the placebo arms and from 2.8 to 16% for patients in the B-containing arms (E2100, 16.0%; the AVADO study, B 7.5 mg/kg cohort, 0%; the AVADO study B 15 mg/kg cohort, 2.8% for; the RIBBON-1 capecitabine cohort, 9.4%; the RIBBON-1 taxane cohort, 8.9%; and the RIBBON-1 anthracycline cohort, 10.0%). For all other B-related AEs the differences between the placebo arms and the B-containing arms were of smaller magnitude. Treatment discontinuation rates in the B-containing arms varied across trials, ranging from 11.9% to 27.9% compared with 4.0 to 19% for the placebo arms. By chemotherapy backbone, treatment discontinuation rates for patients receiving B were higher relative to the placebo arm for the taxane cohort (7.8% vs. 24.1%) and the anthracycline cohort (4.0% vs. 14.3%). There was no difference in treatment discontinuations for patients in the capecitabine cohort (11.9% for both arms).ConclusionsThe addition of B to chemotherapy is associated with an increased frequency of selected adverse events that have been observed across randomized MBC studies. Treatment discontinuation rates for adverse events vary across trials and may be a function of the chemotherapy agent, dose, and schedule. With the exception of hypertension, bevacizumab-related Grade 3–5 adverse events occurred in fewer than 5% of patients.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6083.