SABCS 2013 - CARE Breast Cancer Faculty Update - Triple-Negative Breast Cancer

SABCS 2013 S5-01: Impact of the Addition of Carboplatin (Cb) and/or Bevacizumab (B) to Neoadjuvant Weekly Paclitaxel (P) Followed by Dose-Dense AC on Pathologic Complete Response (pCR) Rates in Triple-Negative Breast Cancer (TNBC): CALGB 40603 (Alliance). WM. Sikov et al.

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAC) results in a pCR of 30–35% in TNBC patients, which is associated with improved recurrence-free and overall survival (RFS/OS) as demonstrated in a recent meta-analysis. Thus, pCR rates may be useful in evaluating novel regimens in TNBC. In advanced TNBC, platinum analogues like Cb are active and addition of B to chemotherapy increases response rates and time to progression. CALGB 40603 is a 2 x 2 randomized phase 2 study designed to determine if the addition of either Cb or B to standard NAC (weekly paclitaxel x 12 followed by AC q2 weekly x 4) significantly increases pCR rates in TNBC.

Conclusions: 443 patients with clinical stage II (68%) and stage III (32%) were enrolled with an ER ≤ 10% and HER2- profile. 45% of patients were clinical N0 and 66% clinical T2 at baseline. The carboplatin arms had increased G 3/4 neutropenia, febrile neutropenia (12% C; 24% CbB) and thrombocytopenia (20% C; 26% CbB), while the B arms had greater rates of hypertension, bleeding and VTE. A greater proportion of the experimental arms discontinued treatment due to toxicity (6% Cb; 10% B; 12% CbB vs. 0% in control arm). pCR in breast/axilla was significantly increased with the addition of carboplatin 41% (no carboplatin) vs. 54% (carboplatin); OR 1.71 (p = .0029). Whereas the pCR (breast/axilla) was not significantly different with the addition of bevacuzimab 44% (no B) vs. 52% (B); OR 1.36 (p = .057). Though the CbB arm numerically had the highest pCR (60%), the interaction test between carboplatin and bevacuzimab was not significant. RFS/OS to assess the impact of pCR on these endpoints will be reported at a later time.

pCR (breast and axilla) is a validated and regulatory recognized surrogate end-point of long term clinical outcomes following neoadjuvant systemic therapy, with the strongest correlations in the ER-/PR-/HER2- and ER-/PR-/HER2+ cohorts.

Carboplatin, when added to a weekly paclitaxel backbone, increased the pCR rate in TNBC in two randomized phase 2 trials (CALGB 40603 and GeparSixto).

The addition of carboplatin to a weekly paclitaxel backbone however also increased toxicity — in particular neutropenia, febrile neutropenia, thrombocytopenia and ultimately led to greater dose reductions and/or discontinuations of treatment due to toxicity.

As TNBC is a heterogeneous disease, there are likely subtypes within TNBC that may be predictive of greater efficacy to both a taxane and platinum regimen.

At present, it is not likely that carboplatin will be broadly integrated as a standard of care to the current backbone of neoadjuvant regimens, however may be worth considering in high-risk inoperable triple-negative LABC.
— CARE Breast Cancer Faculty