Abstract PD8-06: Phase I/II trial 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
Authors: Hamilton Erika P , Wang Judy S , Pluard Timothy , Johnston Stephen , Morikawa Aki Aki , Dees Claire E , Jones Robert H , Haley Barbara , Armstrong Anne , Cohen Adam L , Munster Pamela , Wright Gail , Kayali Fadi , Korpal Manav , Yu Lihua , Cantagallo Lisa , Destenaves Benoit , Zhang Zhaojie , Gao Lei , Pipas Marc J , Sahmouud Tarek , Gualberto Antonio , Juric Dejan 
Published: February 2021

Abstract
Background: Addition of CDK 4/6 inhibitors to endocrine therapy has provided significant improvements in outcomes for patients (pts) with metastatic breast cancer (mBC). However, acquired resistance to front-line therapy remains a challenge, and response to late lines of therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα) H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins, including Y537S. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα).Methods: This is a multicenter phase I/II trial. The primary objective of the phase I is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in pretreated pts with ER+, HER2- mBC. Secondary objectives include safety and antitumor activity. The primary objective of the phase II is to estimate the objective response rate (ORR) and secondary objectives include clinical benefit rate (CBR), progression-free survival (PFS) and safety. The trial was designed to exclude a lower limit of ORR of 5% at one-sided level of significance of 0.05 and a power of 90%.
Results: Between August 2017 and February 2020, 130 pts were enrolled; 47 in the Phase I part and 83 in the Phase II part of the trial. A total of 105 pts, including 73 patients on 450 mg, were response-evaluable. The phase I evaluated once daily doses from 100 to 600 mg. No dose-limiting toxicities (DLT) were observed at doses up to 450 mg and 2 DLTs were observed in 2 (grade 3 fatigue and grade 3 drug eruption) of 7 pts on the 600 mg cohort. Consequently, the dose of 450 mg was selected as the RP2D. Median age was 62 years (range: 31 to 87 years), 82% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 10), with 41% of the pts receiving ≥ 4 prior therapies in the metastatic setting. Prior CDK4/6 inhibitors, fulvestrant, and chemotherapy were received by 87%, 71%, and 54% of the pts, respectively. 75 pts (58%) had detectable ESR1 mutations. As of May 31, 2020, grade 2 or higher adverse events reported in ≥10% were anemia (20%), fatigue (16%), nausea (14%), diarrhea (11%) and AST increase (11%). Three cases of grade 4 AE were reported (serum bilirubin, urinary tract obstruction, and hyponatremia), all considered related to disease progression. Grade 1 sinus bradycardia (asymptomatic) was reported in 35% and grade 2 (symptomatic, no intervention needed) was reported in 4%. Grade 2 and 3. QTcF prolongation were reported in 2 and 3 patients, respectively. There were no treatment-related deaths. In the response-evaluable group, 13 confirmed partial responses (PR, 12%. 90% confidence limits: 7.5%-19%), including 11 PRs (15%, 90% confidence limits: 8.7%-23.7) on 450 mg dose, were observed, thus achieving the primary objective of the trial. Stable disease (SD) and clinical benefit rates (≥23 weeks) were 45% and 33% respectively at 450 mg and 46% and 34%, respectively on all doses. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, prior CDK4/6 inhibitor, and/or prior chemotherapy, in the metastatic setting. Three PRs (25%) and 4 SDs were observed in 12 pts in whom clonal ESR1 Y537S was the main ERα driver. Median PFS, in all pts and in pts with clonal ESR1 Y537S was 3.7 months and 7.3 months, respectively. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation.
Citation Format: Erika P Hamilton, Judy S Wang, Timothy Pluard, Stephen Johnston, Aki Aki Morikawa, Claire E Dees, Robert H Jones, Barbara Haley, Anne Armstrong, Adam L Cohen, Pamela Munster, Gail Wright, Fadi Kayali, Manav Korpal, Lihua Yu, Lisa Cantagallo, Benoit Destenaves, Zhaojie Zhang, Lei Gao, Marc J Pipas, Tarek Sahmouud, Antonio Gualberto, Dejan Juric. Phase I/II trial 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 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-06.