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Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer
Hamilton, E. Pluard, T. Wang, J. S. Morikawa, A. Johnston, S. Dees, E. C. Vaklavas, C. Armstrong, A. Munster, P. Unni, N.
Hamilton, E.
Pluard, T.
Wang, J. S.
Morikawa, A.
Johnston, S.
Dees, E. C.
Vaklavas, C.
Armstrong, A.
Munster, P.
Unni, N.
Abstract
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 population (phases 1 and 2), all patients experienced ≥ 1 treatment-emergent adverse event (TEAE), and 50.3% had grade 3–4 TEAEs, with no grade 5 TEAEs observed. In phase 1, the overall ORR was 7.5% (95% CI 1.6–20.4). The ORR in all response-evaluable patients treated at 450 mg (n = 94) was 20.2% (95% CI 12.6–29.8). Patients with clonal ESR1 Y537S mutation had an ORR of 32.1% (95% CI 15.9–52.4). For all patients who received H3B-6545 450 mg, median PFS was 4.6 months (95% CI 3.5–6.7) and median OS was 21.5 months (95% CI 16.6–25.5). CONCLUSIONS: Results suggest that H3B-6545 may be further investigated as an endocrine therapy option for patients with previously treated metastatic ER + BC. TRIAL REGISTRATION: NCT03250676. Registered August 11, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-025-02069-8.
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Date
2025
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Hamilton E, Pluard T, Wang JS, Morikawa A, Johnston S, Dees EC, et al. Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer. Breast cancer research : BCR. 2025 Aug 19;27(1):151. PubMed PMID: 40830892. Pubmed Central PMCID: PMC12363031. Epub 2025/08/20. eng.