Adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage HER2-negative breast cancer significantly improves pathological complete response, according to preliminary reports from two large randomized clinical trials.
The published results are likely to reopen debate over the recent U.S. Food and Drug Administration decision to revoke an indication for bevacizumab (Avastin) in metastatic breast cancer and the use of surrogate end points for survival in breast cancer trials.
Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial and the GeparQuinto (GBG44) trial appear in the Jan. 26 issue of The New England Journal of Medicine.
Docetaxel-Based Chemo in NSABP B-40
In NSABP B-40, 1,206 patients were enrolled between Jan. 5, 2007 and June 20, 2101 and randomly assigned to receive docetaxel (Taxotere), docetaxel plus capecitabine (Xeloda), or docetaxel plus gemcitabine (Gemzar) for four cycles. All groups received doxorubicin and cyclophosphamide for an additional four cycles, and the participants were additionally assigned to receive or not receive bevacizumab (Avastin) – an antiangiogenic monoclonal antibody against vascular endothelial growth factor (VEGF), for the first 6 of the 8 treatment cycles.
The addition of the antimetabolites capecitabine or gemcitabine had no significant effect on pathological complete response in the breast, with, respectively 29.7% and 31.8% of patients achieving that primary end point, compared with 32.7% of those receiving only docetaxel, Dr. Harry D. Bear of Virginia Commonwealth University, Richmond and his colleagues reported (N. Engl. J. Med. 2012;366:310-20).
Adding bevacizumab, however, increased the rate of pathological complete response in the breast significantly from 28.2% to 34.5%. Subgroup analysis indicated the effect was more pronounced in patients with hormone receptor–positive tumors (the rate increasing significantly from 15.1% without bevacizumab to 23.2% with bevacizumab) than in hormone receptor–negative tumors (47.1% and 51.5%, respectively), the investigators said. The benefit of bevacizumab tended to be seen more in patients with a high tumor grade.
Epirubicin-based Chemo in GeparQuinto
In the GeparQuinto trial, 1,948 patients were enrolled from November 2007 through June 2010 and randomized to receive neoadjuvant epirubicin (Ellence) and cyclophosphamide followed by docetaxel either with or without bevacizumab.
Dr. Gunter von Minckwitz
Pathological complete response occurred in 18.4% of those who received bevacizumab, compared with 14.9% of those who did not (odds ratio, 1.29), Dr. Gunter von Minckwitz of the German Breast Group, Neu-Isenburg, Germany and his colleagues reported. (N. Engl. J. Med. 2012;366:299-309). After adjusting for age, clinical tumor and nodal stage, hormone-receptor status, tumor grade, and histologic type, the odds ratio was 1.36.
In contrast with the findings from NSABP B-40, the greatest effects of bevacizumab in GBG44 were seen in the 633 patients with triple-negative tumors (27.9% without vs. 39.3% with bevacizumab), compared with the 1,262 patients with hormone-receptor-positive tumors (7.8% and 7.7%, respectively). The test for interaction for this finding was not significant, but the study was not powered to show these differential effects, the investigators noted.
Investigators from both trials suggested that possible reasons for the divergent findings between the studies include differences in inclusion criteria and drug dosing and/or sequencing.
The NSABP B-40 investigators noted that "the increased rate of pathological complete response in patients with hormone receptor–positive tumors is encouraging, since this group tends to have low rates of pathological complete response with chemotherapy."
Bevacizumab was associated with toxic effects in both studies, including hand-foot syndrome, mucositis, hypertension, and left ventricular systolic dysfunction in NSABP B-40, and with bleeding, febrile neutropenia, mucositis, hand-foot syndrome, infection, and hypertension in GBG44.
Survival Results Pending
The NSABP B-40 investigators said that the potential for bevacizumab to improve patient outcomes should be clarified when disease-free and overall survival results become available for those who underwent surgery in this study, and for those in other ongoing studies.
They also noted that "the collection of tissue samples from all our patients before treatment, a major advantage of the neoadjuvant approach, offers an opportunity to discover molecular markers that might predict a benefit from bevacizumab."
The GBG44 investigators noted that because of the short follow-up in their study, it cannot be confirmed that the observed increases in the rate of pathological complete response will translate into a survival advantage.
"However, given that pathological complete response has been shown to be highly correlated with outcome, particularly in patients with triple-negative disease, we speculate that the beneficial effects will be sustained," they said, adding, "Long-term follow-up data are needed before this treatment option can be fully understood."
Dosing in the studies was as follows:
In NSABP B-40, docetaxel was administered intravenously at 100 mg/m2 on day 1 of the cycle every 3 weeks in the docetaxel-only group, followed by four cycles of doxorubicin-cyclophosphamide at 60 mg/m2 and 600 mg/m2, respectively, administered intravenously every 3 weeks. Docetaxel was administered at a dose of 75 mg/m2 on day 1 in the docetaxel plus capecitabine or gemcitabine groups followed by the doxorubicin-cyclophosphamide. The capecitabine dose was 825 mg/m2 twice daily on days 1-14; the gemcitabine dose was 1,000 mg/m2 on days 1 and 8. The bevacizumab dose was 15 mg/kg administered intravenously for the first six cycles.