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Background <p>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).</p> Methods <p>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&#xa0;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.</p> Results <p>151 Patients were treated across phases. During phase 1, 2 DLTs (drug eruption and fatigue, both grade 3) were observed at the 600&#xa0;mg dose, and 450&#xa0;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&#xa0;mg (<i>n</i> = 94) was 20.2% (95% CI 12.6–29.8). Patients with clonal <i>ESR1</i> Y537S mutation had an ORR of 32.1% (95% CI 15.9–52.4). For all patients who received H3B-6545 450&#xa0;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).</p> Conclusions <p>Results suggest that H3B-6545 may be further investigated as an endocrine therapy option for patients with previously treated metastatic ER + BC.</p> Trial registration <p>NCT03250676. Registered August 11, 2017.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年8月19日

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  • Erika Hamilton,
  • Timothy Pluard,
  • Judy S. Wang,
  • Aki Morikawa,
  • Stephen Johnston,
  • E. Claire Dees,
  • Christos Vaklavas,
  • Anne Armstrong,
  • Pamela Munster,
  • Nisha Unni,
  • Gail S. Wright,
  • Fadi Kayali,
  • Tingting Song,
  • Yuanxin Rong,
  • Kohei Yamaguchi,
  • Dejan Juric

摘要

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.