Abstract PS5-12-21: Herthena-breast03: a phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan (HER3-DXd) + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− breast cancer

Abstract The standard of care for patients with high-risk, early-stage triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab. Patients with HR-low+/HER2− breast cancer are often managed according to TNBC recommendations. There is a need for improved neoadjuvant therapy to increase the rate of pathological complete response (pCR), as patients who do not achieve pCR have a high risk of recurrence, and to reduce risk of long-term toxicities associated with cyclophosphamide and anthracyclines. HER3 is frequently expressed in breast cancer and overexpression is associated with drug resistance. Patritumab deruxtecan (HER3-DXd) is an antibody-drug conjugate comprising a fully human anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor (DXd) via a stable tetrapeptide-based linker that is selectively cleaved within tumor cells. In a phase 2 study, HER3-DXd monotherapy showed antitumor activity and manageable safety in heavily pretreated participants with HER3-high expressing TNBC. This phase 2 study (NCT06797635) is evaluating neoadjuvant HER3-DXd + pembrolizumab administered before or after carboplatin + paclitaxel + pembrolizumab for early-stage TNBC or HR-low+/HER2− breast cancer. Eligible participants are adults (≥18 y) with untreated, locally advanced nonmetastatic (AJCC stage cT1c, N1-N2 or cT2-cT4, N0-N2) TNBC or HR-low+/HER2− breast cancer. Participants (N ≥10 and ≤30) in Part 1 of the study (safety lead-in) will receive neoadjuvant HER3-DXd + pembro followed by carboplatin + paclitaxel + pembro (Table) followed by surgery. Dose-limiting toxicity evaluation and dose finding for HER3-DXd (up to three dose levels of 5.6 mg/kg Q3W, 4.8 mg/kg Q3W and 3.2 mg/kg Q3W) during cycle 1 of neoadjuvant HER3-DXd + pembrolizumab will be performed in Part 1 to determine an optimal dose of HER3-DXd for Part 2. Participants (N ∼342) in Part 2 will be randomly assigned 1:1:1 to Arm A, B or C (Table) for neoadjuvant treatment. Randomization will be stratified by cancer type (TNBC vs HR-low+/HER2−) and, in the TNBC subgroup, PD-L1 status (combined positive score ≥10 vs <10), overall clinical stage (II vs III) and HER3 expression per IHC (low vs high). After neoadjuvant treatment, participants will undergo surgery (with postoperative radiotherapy if clinically indicated) and receive adjuvant pembrolizumab 400 mg Q6W for 5 cycles. Participants with residual disease may receive additional adjuvant treatment of physician’s choice. Primary endpoints are safety (Part 1 and 2) and pCR (ypT0/Tis ypN0) rate (Part 2). Enrollment is ongoing. Citation Format: J. O'Shaughnessy, J. M. Collins, L. Yao, K. L. Smith, J. A. Mejia, M. Danso. Herthena-breast03: a phase 2, randomized, open-label study evaluating neoadjuvant patritumab deruxtecan (HER3-DXd) + pembrolizumab before or after pembrolizumab + chemotherapy for early-stage TNBC or HR-low+/HER2− 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 PS5-12-21.