55O - Phase I study of H3B-6545 in patients (pts) with estrogen receptor-positive (ER+) breast cancer

Background

H3B-6545 is a novel selective ERα covalent antagonist. This phase 1 study (NCT04568902) evaluated the efficacy, tolerability/safety, and pharmacokinetics (PK) of H3B-6545 up to 450 mg in Japanese women with ER+, human epidermal growth factor receptor 2 (HER2)-negative, advanced/metastatic breast cancer (mBC).

Methods

This study consisted of dose escalation (DE) followed by cohort expansion (CE). In the DE part, 2 dose levels, 300 and 450 mg once daily (QD), were evaluated in a 3+3 design. In the CE, the prophylactic effect of oral antihistamine (AH; administered in the first 28 days) on rash from H3B-6545 was evaluated.

Results

Thirty-three pts were enrolled to receive H3B-6545 (DE: 300 mg, n=3; 450 mg, n=6; CE: 450 mg without prophylactic AH, n=9; 450 mg with prophylactic AH, n=15). Median age was 57 years. Median number of prior therapies for mBC was 3, including fulvestrant (79%), CDK4/6 inhibitors (73%), and chemotherapies (42%). As of 16 March 2023, 3 pts had treatment ongoing. The primary reason for treatment discontinuation was disease progression (76%). No dose-limiting toxicities (DLTs) were observed with H3B-6545 300 mg; 1 DLT (Grade 3 electrocardiogram QT-corrected- interval prolonged [QT pro]) occurred in the H3B-6545 450 mg cohort of the DE part. Overall, the most common adverse events (AEs) were sinus bradycardia (94%), anemia (61%), and QT pro (55%). The most common grade 3 AEs were anemia (15%), QT pro (12%), and rash maculopapular (12%). No grade 4 or 5 AEs were reported. Rash maculopapular or rash occurred in 10/15 pts (67%) given H3B-6545 450 mg QD with prophylactic AH and in 4/15 pts (27%) not given prophylactic AH. AEs leading to drug discontinuation occurred in 3/33 pts (9.1%); most AEs were well managed through monitoring, dose modifications and supportive care. Plasma concentration of H3B-6545 increased in a dose-dependent manner, with no substantial changes in PK profiles between cycle 1 day 1 and day 15. Among 33 pts, 1 pt had a partial response (PR) and 19 had stable disease (SD). Clinical benefit rate (CR + PR + durable SD ≥23 weeks) was 33%. Among 6 pts with ESR1 Y537S, CBR was 83% with 1 PR.

Conclusions

H3B-6545 450 mg QD had a manageable safety profile and showed preliminary antitumor effect in pts with heavily pretreated, ER+, HER2-negative mBC.

Clinical trial identification

NCT04568902.

Editorial acknowledgement

Medical writing support was provided by Oxford PharmaGenesis Inc., Newtown, PA, USA.

Legal entity responsible for the study

Eisai Inc., Nutley, NJ, USA.

Funding

Eisai Inc., Nutley, NJ, USA.

Disclosure

M. Ono: Financial Interests, Personal, Speaker’s Bureau: Chugai, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Principal Investigator: Astellas, Eisai. T. Kogawa: Financial Interests, Personal, Invited Speaker: Eli Lilly, AstraZeneca, Taiho, Eisai, Pfizer, Daiichi Sankyo, Chugai; Financial Interests, Institutional, Research Grant: Eli Lilly, Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo, Eisai, AstraZeneca; Financial Interests, Personal, Advisory Role: Eli Lilly, Daiichi Sankyo, Onco Therapy Science. S. Kitano: Financial Interests, Personal, Other, Lecture fee: AstraZeneca, Bristol Myers Squibb, Chugai, Eisai, GSK, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Taiho, Takeda; Non-Financial Interests, Personal, Advisory Board, Scientific Advisor: ImmuniT Research; Non-Financial Interests, Personal, Other, Lecture fee, Scientific adviser: Ono Pharmaceutical Co., Ltd.; Non-Financial Interests, Personal, Expert Testimony: PMDA(Pharmaceuticals and Medical Devices Agency); Financial Interests, Personal, Advisory Board, Scientific advisor: Rakuten Medical, Sumitomo Pharma, United Immunity; Financial Interests, Personal and Institutional, Local PI, Clinical Trial: AbbVie, Astellas, AstraZeneca, Eisai, Eli Lilly Japan K.K., GSK, Incyte, LOXO Oncology, MSD, Pfizer, Takeda; Financial Interests, Personal and Institutional, Local PI, Clinical Trial, Research Grant: Chugai, Daiichi Sankyo; Financial Interests, Personal and Institutional, Local PI, Clinical trial, Research Grant: Nippon Boehringer Ingelheim; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal and Institutional, Research Grant, Clinical trial, Research Grant: Takara Bio Inc. S. Kobayashi,Y. Ichikawa, K. Yamaguchi, Y. Otake, S. Hojo: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. K. Yonemori: Financial Interests, Personal, Invited Speaker, Honorarim for lecture: Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR pharma, MSD, Boehringer Ingelheim, Ono, Daiichi Sankyo, Bayer, Jansen, Sanofi; Financial Interests, Personal, Advisory Board: Eisai, AstraZeneca, Sanofi, Genmab, Gliad, OncXerna, Takeda, Novartis, MSD; Financial Interests, Institutional, Research Grant: MSD, Daiichi Sankyo, Merk Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe; Financial Interests, Institutional, Principal Investigator: MSD, Daiichi Sankyo, AstraZeneca, Taiho, Merk Biopharma, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, Haihe. All other authors have declared no conflicts of interest.