Authors: Nadia Harbeck, Michael Braun, Oleg Gluz, Peter Schmid, Monika Karla Graeser, Andreas D. Hartkopf, Oliver Hoffmann, Athina Kostara, Silke Polata, Lea Louise Volmer, Raquel von Schumann, Sarah Wetzig, Stefanie Wiebe, Matthias R. Zaiss, Lotta Ada Fischer, Iris Scheffen, Matthias Christgen, Hans Heinrich Kreipe, Ulrike Nitz, Sherko Kuemmel
Published: 2024-05-29
DOI: 10.1200/jco.2024.42.16_suppl.tps631
Source: Full article
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 .