Nadia Harbeck, Oleg Gluz, Matthias Christgen, Sherko Kuemmel, Eva-Maria Grischke, Michael Braun, Jochem Potenberg, Katja Krauss, Claudia Schumacher, Helmut Forstbauer, Toralf Reimer, Andrea Stefek, Hans Holger Fischer, Enrico Pelz, Monika Graeser, Christine zu Eulenburg, Ronald E. Kates, Rachel Wuerstlein, Hans Heinrich Kreipe, Ulrike Nitz, West German Study Group

Background: Optimal use of de-escalated, particularly chemotherapy(CT)-free, neoadjuvant regimens in HER2+ early breast cancer (EBC) is currently unclear as there are limited survival data so far. In ADAPT-HR-/HER2+, we previously showed an excellent pCR rate of 90% after 12-week neoadjuvant paclitaxel (Pac) +pertuzumab (P) +trastuzumab (T) and a substantial and clinically meaningful pCR rate of 34% after P+T alone in HR-/HER2+ EBC. Here, we present first survival data.

Methods: The prospective multicenter WSG-ADAPT-HR-/HER2+ phase II-trial is part of the ADAPT-umbrella protocol. Patients with cT1-cT4c, cN0-3 HR-/HER2+ EBC (n = 134) were randomized to 4 cycles of P+T +/- pac d1,8,15 q3w. All tumors were HR-negative (ER and PR < 1%) and HER2-positive (central lab, i.e., 2+ FISH positive or 3+ by immunohistochemistry. Primary endpoint was pCR (ypT0/is/ypN0); omission of further CT was allowed in pts with pCR. Trial objective was to compare pCR in P+T+pac arm vs. early responders in P+T arm (defined as low cellularity and/or Ki67 decrease >30% after 3 weeks). The trial was stopped early due to the observed pCR superiority in the P+T+pac arm. Secondary endpoints included safety, 5-y (distant)-DFS, OS and translational research. Cox-regression analysis was applied. PAM50 subtype was assessed using the BC360 panel.

Results: 134 patients were randomized to P+T (n = 92) or P+T+pac (n = 42). 60% of tumors were cT2-4, 42% clinically node-positive. After a median follow-up of 5 years, no significant differences between study arms were observed regarding DFS, dDFS, and OS; only 13 iDFS events (7 dDFS) were observed in the whole ITT population. pCR (vs. nonpCR) after the 12-week study treatment (irrespective of study arm) was strongly associated with improved iDFS (5y DFS 98.5% vs. 82%, HR = 0.14, 95% CI 0.03-0.64). Of the 69 patients with pCR, 39 (56.5%) received no further CT (P+T arm: n = 9, 29% vs. (P+T+pac arm n = 30, 79%); only 1 distant relapse (1.4%) was observed in these patients. In the CT-free P+T arm, no pCR was observed in patients with low HER2 expression (IHC 1+/2+ and FISH positive) and/or basal-like subtype by PAM50 (n = 17, 19%). In the total study population, low HER2 expression and/or no early response was strongly associated with worse dDFS (p =.029) and iDFS (p =.068). No new safety signals were observed.

Conclusions: For the first time, we have shown both excellent pCR and survival in patients treated by de-escalated neoadjuvant CT+P+T irrespective of further CT use in a prospective multicenter study. Investigation of CT-free regimens may need to be focussed on selected patients only (e.g. with high HER2 expression/non-basal-like tumors). In ADAPT HR-/HER2+, early pCR after only 12 weeks of neoadjuvant P+T+pac was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment (de)-escalation.

Clinical trial information: NCT01779206. Research Sponsor: Roche, AOK.