Adjuvant Bevacizumab in High-Risk HER2-Negative Breast Cancer
In an article in the Journal of Clinical Oncology, Miller et al reported final results of the Eastern Cooperative Oncology Group phase III E5103 trial, initiated in 2007, which showed no benefit of adding bevacizumab (Avastin) to adjuvant therapy in patients with HER2-negative, node-positive or high-risk node-negative breast cancer.
In the double-blind trial, 4,994 patients were randomized 1:2:2 between November 2007 and February 2011 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A; n = 1,000); bevacizumab only during AC and paclitaxel (arm B, n = 1,986); or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C; n = 2,008). Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C.
Patients had a median age of 52 years, 64% were estrogen receptor–positive, 27% were lymph node–negative, and 78% received dose-dense AC. The primary endpoint was invasive disease-free survival.
Toxicity and Survival
Early discontinuation of bevacizumab was substantial, occurring in approximately 24% of patients in arm B and approximately 55% of patients in arm C. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but not thrombosis, proteinuria, or hemorrhage. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively.
Five-year invasive disease–free survival was 77% in arm A, 76% in arm B, and 80% in arm C, with no significant between-group differences. Overall survival at 5 years was 90%, 86%, and 90%, with no significant between-group differences. Longer duration of bevacizumab therapy was associated with a nonsignificant increase in invasive disease–free survival among patients with hormone receptor–negative disease. No other subsets of patients showed evidence of benefit from bevacizumab treatment.
The investigators concluded, “Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve [invasive disease–free survival] or overall survival in patients with high-risk [HER2]-negative breast cancer. Longer-duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.”
They also noted, “E5103 may have been a negative study for many reasons. First, delivery of both chemotherapy and bevacizumab may have been inadequate. The addition of bevacizumab attenuated delivery of chemotherapy, and early drug discontinuation severely limited bevacizumab exposure. The overall rate of bevacizumab discontinuation, particularly in patients randomly assigned to arm C (approximately 70%), was predicted by [a pilot trial]. Although the withdrawal of U.S. Food and Drug Administration approval for bevacizumab in the metastatic setting may have led some patients to discontinue therapy, most stopped as a result of an adverse event.”
E5103 was conducted under a corporate research and development agreement between Genentech and the National Cancer Institute. Genentech provided bevacizumab and partial funding but did not participate in data collection. The study was also supported by the Breast Cancer Research Foundation and Susan G. Komen Foundation.
Kathy D. Miller, MD, of the Indiana University Melvin and Bren Simon Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
