Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN
Erika P. Hamilton , Judy S. Wang , Timothy J. Pluard , Stephen R. D. Johnston , Aki Morikawa , Elizabeth Claire Dees , Robert Hugh Jones , Barbara B. Haley , Anne Caroline Armstrong , Adam Louis Cohen , Pamela N. Munster , Gail Lynn Shaw Wright , Fadi Kayali , Manav Korpal , Jianjun Alan Xiao , Jenny Long , Benoit Destenaves , Lei Gao , Antonio Gualberto , Dejan Juric
Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676.
Efficacy endpoint | All pts (N = 94) | Pts with clonal Y537S (N = 10) | Pts with clonal D538G (N = 19) |
---|---|---|---|
ORR (n, %) | 12 (17%)1 | 3 (30%) | 0 (0%) |
Median duration of response (mo, 95% CI) | 7.6 (5.4, NE) | --2 | -- |
CBR (%) | 30 (32%) | 6 (60%) | 6 (32%) |
Median PFS (mo, 95% CI) | 5.1 (3.2, 6.2) | 7.3 (0.8, 11.2) | 5.4 (1.7, 7.2) |
CI: Confidence interval1 Based on 72 pts who are response-evaluable. All 12 pts had confirmed partial responses.2 Not estimated due to small number of responders.
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Abstract Disclosures
2022 ASCO Annual Meeting
First Author: Erika P. Hamilton
2023 ASCO Annual Meeting
First Author: Mafalda Oliveira
2021 ASCO Annual Meeting
First Author: Kelvin K H Bao
2023 ASCO Annual Meeting
First Author: Timothy A. Yap