Phase II Study Supports Further Investigation of Neoadjuvant Carboplatin in Stage II to III Triple-Negative Breast Cancer
In the phase II Cancer and Leukemia Group B (CALGB) 40603/Alliance trial reported in the Journal of Clinical Oncology, Sikov et al found that the addition of carboplatin or bevacizumab (Avastin) to standard neoadjuvant chemotherapy significantly improved pathologic complete response rate in patients with triple-negative breast cancer.
As noted by the investigators, the finding that adding bevacizumab to adjuvant anthracycline- or taxane-based adjuvant chemotherapy failed to improve invasive disease-free survival in the recently reported BEATRICE trial (in triple-negative breast cancer) and E5103 trial (approximately one-quarter of patients with triple-negative disease) has dampened interest in further of investigation of this agent in early-stage disease.
Study Details
In the current 2×2 factorial, open-label trial, 443 patients with stage II or III triple-negative breast cancer were randomly assigned to receive paclitaxel at 80 mg/m2 once per week for 12 weeks followed by doxorubicin plus cyclophosphamide once every 2 weeks for four cycles without (n = 108) or with (n = 113) concurrent carboplatin (area under curve = 6) once every 3 weeks for four cycles and independently randomized to receive bevacizumab at 10 mg/kg once every 2 weeks for nine cycles with (n = 112) or without (n = 110) carboplatin.
Adverse Events
Patients receiving carboplatin or bevacizumab were less likely to complete weekly paclitaxel or doxorubicin/cyclophosphamide without skipped doses, dose modification, or early discontinuation due to toxicity. Grade ≥ 3 adverse events occurring more frequently in particular treatment groups vs other treatment groups consisted of neutropenia (56%) and thrombocytopenia (20%) in the carboplatin group, hypertension (12%) in the bevacizumab group, and neutropenia (67%), thrombocytopenia (26%), leukopenia (25%), febrile neutropenia (24%), hypertension (10%), fatigue (20%), and pain (11%) in the carboplatin/bevacizumab group.
Response Rates
Complete pathologic response in the breast was observed in 60% of patients in groups receiving carboplatin vs 46% of those in groups not receiving carboplatin (odds ratio [OR] = 1.76, P = .0018) and in 59% of patients receiving bevacizumab vs 48% of those not receiving bevacizumab (OR = 1.58, P = .0089).
Complete pathologic response in the breast/axilla was found in 54% of carboplatin patients vs 41% of those not receiving carboplatin (OR = 1.71, P = .0029) and in 52% of patients receiving bevacizumab vs 44% of those not receiving bevacizumab (OR = 1.36, P = .0570).
More-than-additive interactions between carboplatin and bevacizumab could not be demonstrated.
The investigators concluded, “In stage II to III [triple-negative breast cancer], addition of either carboplatin or bevacizumab to [standard neoadjuvant chemotherapy] increased [pathologic complete response] rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.”
William M. Sikov, MD, of Women and Infants Hospital, Providence, Rhode Island, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by National Cancer Institute grants, Breast Cancer Research Foundation, American Recovery and Reinvestment Act, and Genentech, a division of F. Hoffman-La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.
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