Abstract 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)
Authors: Sikov WM , Berry DA , Perou CM , Singh B , Cirrincione C , Tolaney S , Kuzma CS , Pluard TJ , Somlo G , Port E , Golshan M , Bellon JR , Collyar D , Hahn OM , Carey LA , Hudis C , Winer EP 
Published: August 2014

Abstract
Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAC) results in a pCR in 30-35% of TNBC patients (pts), which is associated with improved recurrence-free and overall survival (RFS/OS). 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 2×2 randomized phase II study designed to determine if the addition of either Cb or B to standard NAC significantly increases pCR rates in TNBC.
Methods: Pts had operable clinical stage II-III TNBC, defined as hormone receptors &lt;10% and HER2 IHC 0-1+ or FISH &lt;2.0 in IHC 2+. Pretreatment biopsies for correlative studies were required. Using a factorial design, pts received P 80 mg/m2 weekly x 12 followed by doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 q2wks x 4 (ddAC) with or without Cb AUC 6 q3wks x 4 during P and with or without B 10 mg/kg q2wks x 9. Surgery was performed 4-8 wks later. Post-op therapy was not specified. The primary endpoint is pCR (breast), defined as the absence of residual invasive disease (ypT0/is). Secondary endpoints include pCR (breast/axilla) (ypT0/isN0), toxicities, adverse events (AEs), RFS and OS. The primary analysis is factorial for main effects of Cb and B and their interaction; statistical power assumed no interaction. Analysis is by intent-to-treat; pts not taken to surgery are considered non-pCRs.
Results: 454 pts enrolled, median age 48, stage II 68%/stage III 32%. Of 354 pts with treatment data, 59 did not complete NAC, 30 withdrew due to AEs, more often with B vs. not (11.5% vs. 3.5%). B was discontinued in 23% of assigned pts vs. 6-13% for other agents. Grade 3-4 neutropenia (56% vs. 20%) and thrombocytopenia (22% vs. 4%) were more common with Cb vs. not, while grade 3 hypertension was more common with B vs. not (11% vs. &lt;1%). Febrile neutropenia, usually during ddAC, was more common in pts who received both Cb and B (19% vs. others 7%). Unaudited pCR results for the first 369 pts, with effects reported as increments in pCR (95% CI), assuming no interaction, are as follows:
pCR (breast) pCR (breast/axilla) No CbCbB effectNo CbCbB effectNo B30/89 33.7%44/94 47.8%14.9% (4.8-25.0%)25/89 28.2%39/92 42.4%10.5% (0.5-20.5%)B48/94 51.1%57/94 60.6%p = 0.00440/94 42.6%47/94 50.0%p = 0.031Cb effect11.7% (1.6-21.8%) p = 0.022 10.3% (0.3-20.3%) p = 0.034
There is no evidence of an interaction between the effects of Cb and B (p = 0.64 and 0.44, for breast and breast/axilla, respectively).
Conclusions: Preliminary results suggest that adding Cb or B to standard NAC significantly increases pCR rates in stage II-III TNBC. These increases are additive, with pCR (breast) in 60.6% and pCR (breast/axilla) in 50% of pts who received both. Complete and confirmed results will be reported, including pCR rates for basal-like tumors vs. not. Pts will be followed for RFS/OS to assess the impact of pCR on these endpoints. Conduct of the trial was supported by grants from the NIH (ACTNOW and CA31946/CA33601), Genentech and the BCRF. Clinical trial information: NCT00861705.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-01.