De-escalation strategies in HER2-positive early breast cancer (EBC): Final analysis of the WSG-ADAPT HER2+/HR- phase II trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant dual blockade with trastuzumab and pertuzumab ± weekly paclitaxel

Abstract

Background: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy.Patients and Methods: Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T+P ± weekly paclitaxel (pac) at 80 mg/m². Early response was defined as proliferation decrease ≥30% of Ki-67 (vs. baseline) or low cellularity (<500 invasive tumor cells) in the three-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T+P arm versus all chemotherapy-treated patients. Results: From 2/2014 to 12/2015, 160 patients were screened; 92 were randomized to T+P and 42 to T+P+pac. Baseline characteristics were well balanced (median age 54 vs. 51.5 years, cT2 51.1 vs. 52.4%, cN0 54.3 vs. 61.9%); 91.3% of patients completed T+P per protocol and 92.9% T+P+pac. The pCR rate in the T+P+pac arm was 90.5%, compared to 36.3% in the T+P arm as a whole. In the T+P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared to 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92).No new safety signals were observed in the study population.Conclusion: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared to dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.

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