Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance)

Abstract

Purpose: One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab.

Patients and methods: Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed.

Results: Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated.

Conclusion: In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR 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.

Trial registration: ClinicalTrials.gov NCT00861705.

Fig 1.

Schema of randomized phase II CALGB (Cancer and Leukemia Group B) 40603 trial. ddAC, dose-dense doxorubicin plus cyclophosphamide. (*) Research biopsies if residual tumor. (†) Physician discretion.

Fig 2.

CONSORT diagram. Bev, bevacizumab; Carbo, carboplatin; ddAC, dose-dense doxorubicin plus cyclophosphamide; pCR, pathologic complete response; PD, progressive disease; wP, paclitaxel once per week.

Fig 3.

(A) Pathologic complete response (pCR) breast (ypT0/is); (B) pCR breast/axilla (ypT0/is N0); 95% CIs shown in parentheses.

Fig 4.

Once-per-week paclitaxel (wP) and dose-dense doxorubicin plus cyclophosphamide (ddAC) treatment by delivery arm. Bev, bevacizumab; Carbo, carboplatin.