Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.

Erika P. Hamilton Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN info_outline 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

Authors Erika P. Hamilton Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN info_outline 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 Organizations Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN, Johns Hopkins Medical Institutions, Baltimore, MD, St Luke's Cancer Institute, Kansas City, MO, The Royal Marsden NHS Foundation Trust, London, United Kingdom, University of Michigan, Ann Arbor, MI, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, Velindre Cancer Centre, Cardiff, United Kingdom, University of Texas Southwestern Medical Center, Internal Medicine, Dallas, TX, Christie Hospital NHS Foundation Trust, Manchester, United Kingdom, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, University of California San Francisco, San Francisco, CA, Sarah Cannon Research Institute and Florida Cancer Specialists, New Port Richey, FL, Arcadia Medcl Assocs, Arcadia, FL, H3 Biomedicine, Cambridge, MA, Eisai Inc., Cambridge, MA, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company H3 Biomedicine / Eisai 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 estimates. 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 interval 1 Based on 72 pts who are response-evaluable. All 12 pts had confirmed partial responses. 2 Not estimated due to small number of responders.