H3B-6545用于局部晚期/转移性雌激素受体阳性、人表皮生长因子受体2阴性乳腺癌女性患者的1/2期研究。

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

作者信息

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

机构信息

Breast Cancer Research Program, Sarah Cannon Research Institute, Nashville, TN, USA.

Sarah Cannon Research Institute, 335 24th Avenue North, Suite 300, Nashville, TN, 37203, USA.

出版信息

Breast Cancer Res. 2025 Aug 19;27(1):151. doi: 10.1186/s13058-025-02069-8.

DOI:10.1186/s13058-025-02069-8

PMID:40830892

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12363031/

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 ( = 94) was 20.2% (95% CI 12.6–29.8). Patients with clonal 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.

摘要

背景

尽管内分泌疗法单独或与细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂联合使用，已在雌激素受体阳性（ER+）乳腺癌的治疗中取得了显著进展，但大多数患者的疾病进展仍不可避免。我们报告了一项关于H3B-6545（一种新型选择性雌激素受体共价拮抗剂，可使野生型和突变型ERα失活）治疗局部晚期/转移性ER+、人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）女性患者的剂量递增和扩展试验数据。

方法

本研究为多中心、开放标签的1/2期试验。年龄≥18岁、ER+、HER2-、且在最近一次治疗中疾病进展的乳腺癌女性患者符合入组条件。既往治疗必须包括至少2种激素疗法（HTs），或1种HT和1种化疗，或1种HT和1种CDK4/6抑制剂。在1期试验中，H3B-6545的给药剂量为100-600mg，每日口服1次。在2期试验中，对1期试验确定的推荐2期剂量（RP2D）在更多患者中进行疗效评估，包括有/无ERα突变的患者。主要终点为确定RP2D（1期试验）和客观缓解率（ORR）（2期试验，根据实体瘤疗效评价标准第1.1版由研究者评估）。其他主要终点（2期试验）包括根据Kaplan-Meier估计法得出的无进展生存期（PFS）和总生存期（OS）。

结果

151例患者在各阶段接受了治疗。在1期试验中，600mg剂量组观察到2例剂量限制性毒性（DLTs）（药物疹和疲劳，均为3级），450mg被确定为RP2D。在总体人群（1期和2期试验）中，所有患者均经历了≥1次治疗中出现的不良事件（TEAE），50.3%的患者发生3-4级TEAE，未观察到5级TEAE。在1期试验中，总体ORR为7.5%（95%置信区间1.6-20.4）。接受450mg治疗的所有可评估疗效患者（n=94）的ORR为20.2%（95%置信区间12.6-29.8）。携带克隆性Y537S突变的患者ORR为32.1%（95%置信区间15.9-52.4）。所有接受450mg H3B-6545治疗的患者，中位PFS为4.6个月（95%置信区间3.5-6.7），中位OS为21.5个月（95%置信区间16.6-25.5）。