Abstract PS3-11-28: EmpowHER-208: A phase 2 neoadjuvant study of zanidatamab in combination with chemotherapy in patients with stage II-III HER2-positive early breast cancer

Abstract Background: In human epidermal growth factor receptor 2-positive (HER2+) early breast cancer, pathologic complete response (pCR) is strongly associated with favorable long-term outcomes, with 93%-97.5% of patients who achieve pCR remaining event-free at 3-year follow-up. One standard-of-care (SOC) neoadjuvant regimen for patients with stage II-III HER2+ early breast cancer is docetaxel (T) and carboplatin (C) + dual HER2-directed therapy (trastuzumab [H] and pertuzumab [P]; collectively TCHP), with single-agent taxane (docetaxel or paclitaxel [T]) + HP regimens becoming increasingly common. Despite pCR rates >50% with these regimens, a substantial proportion of patients have residual disease at surgery, requiring toxic adjuvant therapies, and some patients will experience recurrence and death. TCHP is also associated with short- and long-term toxicities that substantially impact quality of life, hence the need for novel neoadjuvant regimens to increase pCR rate, improve long-term outcomes, and reduce toxicity. Zanidatamab is a bispecific HER2-directed antibody that binds 2 distinct sites on HER2 (juxtamembrane extracellular domain and dimerization domain), facilitating receptor clustering and exerting multiple antitumor mechanisms of action, including HER2 internalization and downregulation and immune-mediated effects (complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity and phagocytosis). Zanidatamab demonstrated promising antitumor activity with a manageable safety profile combined with chemotherapy in HER2+ metastatic breast cancer and as a neoadjuvant monotherapy in stage I HER2+ early breast cancer. The phase 2 EmpowHER-208 study is designed to evaluate neoadjuvant zanidatamab combined with chemotherapy and may inform further investigations in HER2+ early breast cancer. Methods: EmpowHER-208 is a phase 2, randomized, open-label study assessing the pCR rate of neoadjuvant zanidatamab + paclitaxel (ZT), zanidatamab + docetaxel + carboplatin (ZTC), or TCHP in patients with untreated, histologically confirmed stage II-III HER2+ early breast cancer (including inflammatory early breast cancer). Eligible patients must have a tumor ≥2 cm and no clinical or radiographic evidence of distant metastasis. Patients will be randomized (2:2:1) to receive six 3-week cycles of ZT, ZTC, or TCHP. Randomization will be stratified by local assessment of hormone receptor status (positive vs negative) and clinical stage (II-IIIA vs IIIB-IIIC). In the ZT and ZTC arms, patients will receive intravenous (IV) zanidatamab every 2 weeks during cycles 1 and 2, then every 3 weeks (Q3W) + a standard regimen of the assigned chemotherapy. Following neoadjuvant therapy, patients will proceed to surgery followed by response-tailored adjuvant therapy. Patients who achieve pCR will receive 12 additional 3-week cycles of zanidatamab IV Q3W (ZT and ZTC arms) or H ± P (TCHP arm). Patients who do not achieve pCR will receive fourteen 3-week cycles of SOC ado-trastuzumab emtansine (T-DM1). Adjuvant endocrine therapy, extended neratinib, radiotherapy, or additional chemotherapy (ZT arm only) may be administered based on investigator preference and institutional SOC. The primary endpoint is pCR rate by blinded local assessment. Key secondary endpoints include pathologic response by residual cancer burden score at time of surgery, breast-conserving surgery rate, safety and tolerability, event-free survival, and overall survival. Citation Format: A. G. Waks, S. Hurvitz, E. Hamilton, J. O’Shaughnessy, V. Valero, A. Combest, B. Salim, F. Herbst, S. Faderl, S. M. Tolaney. EmpowHER-208: A phase 2 neoadjuvant study of zanidatamab in combination with chemotherapy in patients with stage II-III HER2-positive early breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-11-28.