Abstract PS5-08-07: Open-label Single-arm Phase 2 Trial of Trastuzumab Deruxtecan in Previously Treated HER2-Immunohistochemistry (IHC) 0 Advanced Breast Cancer - HER2 PARADIGM trial

Abstract Background: Trastuzumab-deruxtecan (T-DXd) showed impressive efficacy in patients whose breast cancers are either human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) positive or HER2-low/ultralow. In a phase 2 trial, patients with HER2-IHC 0 who received T-DXd had an objective response rate of approximately 30%, revealing activity regardless of HER2-IHC status. In this study, we will treat patients with advanced HER2 IHC 0 breast cancers with T-DXd and assess biomarkers of response and resistance to therapy. We will investigate patients’ tumor biopsies for more precise quantitative HER2 tests, including the High-Sensitivity (HS)-HER2 Troplex testing, that could help determine if T-DXd is active in patients with HER2-IHC 0 tumors regardless of HER2 quantitative expression or if there is a potentially optimal cutoff value of HER2 expression with respect to clinical outcomes for response, improving patient selection and prevention of unnecessary toxicity. Methods: This is a non-randomized, single-arm, open-label, phase 2 study to assess the efficacy and safety of T-DXd in patients whose breast cancer is HER2-IHC 0 (including 0-null and 0-ultralow) in all prior biopsies, with unresectable and/or metastatic disease regardless of hormone receptor (HR) status (NCT06750484). Key eligibility criteria include ECOG-PS 0-2; up to 2 prior lines of systemic cytotoxic therapy for treatment in the metastatic setting; no upper limit of prior endocrine, immunologic or targeted therapy lines. Fifty subjects will be included to achieve 82% power to detect a difference in ORR of 0.15 from historical control (ORR in experimental arm of 0.3 vs. ORR in historical control of 0.15) using a two-sided exact test with a target significance level of 0.1. The study treatment with T-DXd administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight will be continued in the absence of withdrawal of subject consent, progressive disease (PD), death, or unacceptable toxicity. Patients will be followed and evaluated by RECIST v1.1 criteria. Objective response to T-DXd will be evaluated in the entire study population and separately in the High-Sensitivity (HS)-HER2 Troplex detectable and non-detectable cohorts (defined by the limit of detection LOD of the analytic HS-HER2 Troplex assay). In addition, HER2 tissue concentrations (measured by the HS-HER2 Troplex assay in attomole/mm2) will be plotted and analyzed as a function of response to determine levels of tumor expression and potential cut-points associated with benefit from T-DXd. Since the Troplex assay simultaneously provides TROP2 levels in attomole/mm2, the influence of TROP2 levels on response to T-DXd will also be exploratorily investigated. Additional objectives are to assess efficacy in terms of progression-free survival and overall survival, safety, and explore potential biomarkers of response and resistance to therapy with T-DXd. The trial is currently open and enrolling patients. Citation Format: A. Kahn, J. Du, N. Casasanta, S. Schellhorn, M. Digiovanna, T. Sanft, M. Rozenblit, A. Silber, L. Pusztai, Z. Rahman, D. O'Neil, R. Legare, W. Kidwai, J. Kanowitz, A. Bulgaru, N. Fischbach, S. Hall, K. Fenn, K. Blenman, O. Blaha, E. Winer, I. Krop, D. Rimm, M. Lustberg. Open-label Single-arm Phase 2 Trial of Trastuzumab Deruxtecan in Previously Treated HER2-Immunohistochemistry (IHC) 0 Advanced Breast Cancer - HER2 PARADIGM trial 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 PS5-08-07.