Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer

作者：Erika Hamilton, Timothy Pluard, Judy S. Wang, Aki Morikawa, Stephen Johnston, E. Claire Dees, Christos Vaklavas, Anne Armstrong, Pamela N. Münster, Nisha Unni, Gail S. Wright, Fadi Kayali, Tingting Song, Yuanxin Rong, Kohei Yamaguchi, Dejan Juric · 发表于：Breast Cancer Research · 年份：2025 · DOI：10.1186/s13058-025-02069-8 · 被引用次数：1 · 研究领域：Advanced Breast Cancer Therapies、Cancer-related Molecular Pathways、Breast Cancer Treatment Studies

BACKGROUND: Although endocrine therapies, alone or in combination with CDK4/6 inhibitors, have led to notable improvements in the treatment of estrogen receptor-positive (ER+) breast cancer, progression is inevitable for most patients. We report dose escalation and expansion data from a trial of H3B-6545 (a novel selective ER covalent antagonist that inactivates wild-type and mutant ERα) in women with locally advanced/metastatic ER+, HER2-negative breast cancer (BC). METHODS: This study was a multicenter, open-label, phase 1/2 trial. Women ≥ 18 years of age with ER+, HER2 − BC whose disease progressed on their most recent therapy were eligible. Prior therapy must have included at least 2 hormonal therapies (HTs), or 1 HT and 1 chemotherapy, or 1 HT and a CDK4/6 inhibitor. In phase 1, H3B-6545 was administered orally once daily at doses of 100–600 mg. In phase 2, the efficacy of the recommended phase 2 dose (RP2D) determined in phase 1 was examined in additional patients, including those with/without ERα mutation. The primary endpoints were RP2D determination (phase 1) and objective response rate (ORR) (phase 2, investigator-assessed per RECIST v1.1). Additional primary endpoints (phase 2) included progression-free survival (PFS) and overall survival (OS), per Kaplan-Meier estimates. RESULTS: 151 Patients were treated across phases. During phase 1, 2 DLTs (drug eruption and fatigue, both grade 3) were observed at the 600 mg dose, and 450 mg was deemed the RP2D. In the total po...