Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer
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 tria...
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BMC
2025-08-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-025-02069-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Erika Hamilton |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-536ec439cc814d819e67a84cafb34f2d |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Breast Cancer Research |
| spelling | doaj-art-536ec439cc814d819e67a84cafb34f2d2025-08-24T11:58:45ZengBMCBreast Cancer Research1465-542X2025-08-0127111110.1186/s13058-025-02069-8Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancerErika Hamilton0Timothy Pluard1Judy S. Wang2Aki Morikawa3Stephen Johnston4E. Claire Dees5Christos Vaklavas6Anne Armstrong7Pamela Munster8Nisha Unni9Gail S. Wright10Fadi Kayali11Tingting Song12Yuanxin Rong13Kohei Yamaguchi14Dejan Juric15Breast Cancer Research Program, Sarah Cannon Research InstituteKoontz Center for Advanced Breast Cancer, Saint Luke’s Cancer InstituteHematology and Oncology, Florida Cancer Specialists/Sarah Cannon Research InstituteDepartment of Internal Medicine, University of MichiganBreast Unit, Royal Marsden NHS Foundation TrustDepartment of Medicine, Division of Oncology, Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Internal Medicine, Huntsman Cancer Institute, University of UtahDivision of Cancer Studies, University of ManchesterDivision of Hematology and Oncology, University of CaliforniaDepartment of Internal Medicine, UT Southwestern Medical CenterMedical Oncology, Florida Cancer Specialists & Research Institute/Sarah Cannon Research InstituteHematology and Oncology, Florida Cancer SpecialistsEisai IncEisai IncEisai Co., LtdMassachusetts General Hospital, Harvard Medical SchoolAbstract 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.https://doi.org/10.1186/s13058-025-02069-8H3B-6545Breast cancerEndocrine therapyHER2-negativeEstrogen receptor-positive |
| spellingShingle | 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 Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer Breast Cancer Research H3B-6545 Breast cancer Endocrine therapy HER2-negative Estrogen receptor-positive |
| title | Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer |
| title_full | Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer |
| title_fullStr | Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer |
| title_full_unstemmed | Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer |
| title_short | Phase 1/2 study of H3B-6545 in women with locally advanced/metastatic estrogen receptor-positive, HER2-negative breast cancer |
| title_sort | phase 1 2 study of h3b 6545 in women with locally advanced metastatic estrogen receptor positive her2 negative breast cancer |
| topic | H3B-6545 Breast cancer Endocrine therapy HER2-negative Estrogen receptor-positive |
| url | https://doi.org/10.1186/s13058-025-02069-8 |
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