Neoadjuvant dynamic marker-adjusted personalized therapy comparing trastuzumab-deruxtecan versus pacli-/docetaxel + carboplatin + trastuzumab + pertuzumab in HER2+ early breast cancer: WSG-ADAPT-HER2-IV.
Authors: Harbeck Nadia , Braun Michael , Gluz Oleg , Schmid Peter , Graeser Monika Karla , Hartkopf Andreas D. , Hoffmann Oliver , Kostara Athina , Polata Silke , Volmer Lea Louise , von Schumann Raquel , Wetzig Sarah , Wiebe Stefanie , Zaiss Matthias R. , Fischer Lotta Ada , Scheffen Iris , Christgen Matthias , Kreipe Hans Heinrich , Nitz Ulrike , Kuemmel Sherko 
Published: May 2024

TPS631 Background: In HER2+ early breast cancer (EBC), combination of standard chemotherapy (CTx) with anti-HER2-antibodies has shown higher efficacy versus CTx alone and/or anti-HER2-antibodies alone. Next to a need for treatment escalation in high-risk disease, there is also a substantial subset of patients (pts) (e.g., elderly pts; those with low - intermediate clinical risk) who need de-escalated but still effective treatment. Based on results from WSG ADAPT HER2+ subtrials, antibody-drug-conjugates (e.g., trastuzumab-emtansine (T-DM1), trastuzumab-deruxtecan (T-DXd)) are excellent candidates for de-escalation approaches in HER2+ EBC due to their high efficacy and low toxicity. Methods: WSG-ADAPT-HER2-IV (NCT05704829) is a multicenter, interventional, prospective, two-arm, randomized, open-label, controlled (neo-)adj., phase-II trial evaluating the efficacy and safety of T-DXd vs. standard-of-care (SOC) PAC+T+P in low-intermediate-risk or DOC/PAC+CARBO+T+P in intermediate-high-risk HER2+ EBC in pre- and postmenopausal pts. Pts will be assigned to 2 treatment groups, depending on risk of recurrence: Cohort 1 (HER2+ EBC, low-intermediate risk of recurrence per Investigator´s decision, 12 wks treatment) and cohort 2 (HER2+ EBC, intermediate-high risk, 18 wks treatment) will be randomized 2:1 to either T-DXd or SOC neoadj. treatment. After 12/18-wks of neoadj. treatment, pathological response (pCR) assessment is performed. Pts with pCR will receive further SOC post-neoadj. treatment according to AGO guidelines. Those with non-pCR qualify for a cross-over treatment: Pts with neoadj. T-DXd will receive SOC CTx + anti-HER2-treatment. Pts. with neoadj. SOC treatment and non-pCR (≥ 5mm residual tumor) receive T-DXd until completion of 52 wks of treatment. After post-neoadj. Treatment, 2 – 5.5 years follow-up will be performed, during which pts may receive any SOC treatment according. Co-primary objectives are comparison of pCR-rates after 12/18 wks of neoadj. treatment with T-DXd vs. SOC (PAC+T+P or PAC/DOC+Carbo+T+P) in pooled risk cohorts and to evaluate whether 3-year dDFS equals or exceeds 92% in T-DXd-treated pts from both risk cohorts. It is planned to randomize 402 pts (269 pts to cohort 1; 133 to cohort 2). Study start was in January 2024 (45 sites, enrollment period 24 months). Estimated trial duration of is 5.5 years. Translational analyses:Potential resistance markers and molecular alterations will be assessed in tumor tissue from primary diagnosis, after 3 wks and after neoadj. treatment, and at recurrence. ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant in HER2+ EBC. Clinical trial information: NCT05704829 .