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

518 Background: In HER2+ EBC pCR rates after neoadjuvant chemo (CT)+/- anti-HER2 therapy differ according to hormone receptor (HR) status. The neoadjuvant ADAPT HER2+/HR- phase II trial aims to identify early responders (at 3 weeks) and evaluates the impact of additional paclitaxel (Pac) on pCR in patients receiving dual anti-HER2 blockade with trastuzumab + pertuzumab (T+P). Methods: 134 HER2+/HR-, cT1-4c, cN0/+ patients were randomized (2.5:1) to 12 weeks of neoadjuvant T+P ± weekly Pac (2/14-12/15). After surgery, standard therapy (CT+T) was recommended. Trial (planned n=220) tests non-inferiority of pCR (ypT0/is, ypN0) in T+P responders vs. T+P+Pac. Biomarkers are measured in baseline and 3-week biopsies. At the pre-planned interim analysis (IA), DSMB recommended 2ndIA (n=120) for validation of trial assumptions and re-evaluation of responder definition (Ki-67 drop > 30% or low cellularity). Results: Of the IA cohort 82 patients were evaluable for T+P and 38 for T+P+Pac. Baseline characteristics (T+P/T+P+Pac): median age: 54/51.5; cT2: 51/53%, cT3/4: 8.5/ 2.6%, cN+ 48 /39%. pCR rate was 36.3% with T+P and 89.2% with T+P+Pac (n=3 missing values). Second biopsy was not available in 28% (T+P) vs. 46% (T+P+Pac). 3 weeks early response defined as low cellularity (<500 tumor cells) and/or Ki-67 drop > 30% was observed in 50% (T+P) vs. 51.4% (T+P+Pac). With T+P pCR was achieved in 38.5% of responders vs. in 11.8% of non- reponders (n.s.). So far, only 10 SAEs have been reported (total of n=5 in both arms). The DSMB recommended premature study closure due to a clear superiority of the Pac-containing arm and a <1% probability for demonstrating non-inferiority with the preplanned sample size. Complete efficacy /safety data for all 134 patients will be presented at the meeting. Conclusions: For the first time, WSG ADAPT focused on HR- HER2+ eBC in a phase II trial. pCR rate is substantial (89.2%) with T+P+Pac and clearly higher than with P+T (all: 36.3%; responders: 38.5%). Early response at 3 weeks seems to be positively correlated with pCR. Further biomarker analysis will help to further characterize this population. Clinical trial information: 2011-001462-17.