Report of Secondary Outcomes in NSABP B-40 Indicates Improved Overall Survival With Neoadjuvant Plus Adjuvant Bevacizumab in Early Breast Cancer
The phase III NSABP B-40 (NRG Oncology) trial showed that the addition of bevacizumab (Avastin) to docetaxel-based neoadjuvant chemotherapy improved pathologic complete response rate, the primary endpoint, in patients with early HER2-negative breast cancer. In a report of secondary outcomes in The Lancet Oncology, Bear et al found that overall survival was improved with the addition of neoadjuvant plus adjuvant bevacizumab. The addition of capecitabine or gemcitabine to neoadjuvant chemotherapy did not improve disease-free or overall survival.
Study Details
In the 3×2 factorial trial, 1,206 patients with clinical stage T1c–3, cN0, cN1, or cN2a disease without metastases were randomly assigned between January 2007 and June 2010 to four cycles of neoadjuvant docetaxel alone (100 mg/m²) or with capecitabine (825 mg/m² oral twice daily on days 1–14, docetaxel 75 mg/m²) or gemcitabine (1,000 mg/m² days 1 and 8, docetaxel 75 mg/m²), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m² and 600 mg/m²) every 3 weeks. In addition, all patients were randomly assigned to receive or not receive neoadjuvant bevacizumab (15 mg/kg every 3 weeks for six cycles) and postoperative bevacizumab for 10 doses.
Disease-free survival was a prespecified secondary endpoint; overall survival was not but was prospectively followed. Follow-up data were collected between October 2007 and March 2014 and were available for overall survival in 1,186 and disease-free survival in 1,184 (591 with and 593 without bevacizumab).
Disease-Free and Overall Survival
Median follow-up was 4.7 years. No significant differences between docetaxel alone vs with capecitabine or gemcitabine were observed in 5-year disease-free survival (hazard ratios [HRs] = 1.01, 95% confidence interval [CI] = 0.77–1.33, and 0.90, 95% CI = 0.67–1.19) or 5-year overall survival (HRs = 0.95, 95% CI = 0.68–1.32, and 0.73, 95% CI = 0.51–1.04).
The addition of bevacizumab was associated with a borderline increase in disease-free survival (HR = 0.80, 95% CI = 0.63–1.01, P = .06) and a significant increase in overall survival (HR = 0.65, 95% CI = 0.49–0.88, P = .004). An exploratory analysis suggested somewhat greater benefit of bevacizumab among patients with hormone receptor–positive tumors (HR = 0.73, P = .05, for disease-free survival; HR = 0.63, P = .03 for overall survival), but the interaction between hormone receptor status and bevacizumab effect was not significant for either outcome.
Toxicity
The most common grade 3 or 4 adverse events in the bevacizumab group were neutropenia (17% grade 3, 6% grade 4), hand-foot syndrome (11% grade 3), and hypertension (10% grade 3, < 1% grade 4), and the most common in the no-bevacizumab group were neutropenia (16% grade 3, 6% grade 4), fatigue (9% grade 3), and hand-foot syndrome (7% grade 3). Four deaths occurred during treatment, due to vascular disorder (docetaxel-capecitabine group), sudden death (docetaxel-capecitabine group), infective endocarditis (docetaxel plus bevacizumab group), and visceral arterial ischemia (docetaxel group).
The investigators concluded: “The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent.”
Harry D. Bear, MD, of NSABP/NRG Oncology and Virginia Commonwealth University School of Medicine and Massey Cancer Center, is the corresponding author for the Lancet Oncology article.
The study was funded by the National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics. For full disclosures of the study authors, visit www.thelancet.com/journals/lanonc.
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®.
