Abstract P4-10-07: Evaluation of pharmacokinetics and safety of imlunestrant in participants with hepatic impairment

• Published in: Clinical cancer research Vol. 31; no. 12_Supplement; pp. P4 - P4-10-07
• Main Authors: White, Stephanie, Shanks, Elaine, Yuen, Eunice, Hall, Stephen David, Cruz, Vivian Rodriguez, Wang, Xuejing
• Format: Journal Article
• Language: English
• Published: 13.06.2025
• ISSN: 1557-3265; 1557-3265
• DOI: 10.1158/1557-3265.SABCS24-P4-10-07

Background: Imlunestrant is a next-generation, oral selective estrogen receptor (ER) degrader designed to deliver continuous ER-target inhibition. Imlunestrant is under study for the treatment of ER+ advanced breast and endometrial cancers. Hepatic impairment (HI) is a common condition, particularly in cancer patients, and it can alter the pharmacokinetics (PK) of anticancer drugs, impacting their safety. Given that the intended patient population for imlunestrant may include cancer patients with HI, it is crucial to determine whether HI can impact the imlunestrant PK and safety profile. Here we present PK and safety data of imlunestrant in postmenopausal females of nonchildbearing potential (FONCBP) with and without HI following a single oral dose in a fasted state. Methods: This phase 1, open-label, 3-site study was conducted between July 2022 and February 2024 in FONCBP with normal hepatic function or HI. Participants (pts) were assigned to 4 different treatment arms, according to the Child-Pugh (CP) score: Group (G) 1 - normal hepatic function; G2: mild HI; G3: moderate HI, and G4 - severe HI. Pts were screened 28 days prior to enrollment, admitted to a clinical research unit (CRU) on Day -1, where they remained resident for PK and safety assessment following drug administration. In G 1, 2 and 3, pts received a single dose of 400 mg of imlunestrant, whereas pts in G4 received a single dose of 200 mg, while fasted. Plasma samples were collected for PK analyses. Key endpoints included PK parameters (AUC(0-tlast), AUC(0-∞), and Cmax) and safety. Results: Twenty-seven females (G1: n=9; G2: n=6; G3: n=6; G4: n=6) were included in the study (age: 45-71 years). Compared to pts with normal hepatic function, the AUC(0-tlast) geometric least square mean (GLSM) ratios for pts with mild or moderate HI by the CP scores were 1.2 (90% confidence interval (CI); 0.82, 1.8) and 2.2 (1.5, 3.3), respectively. Compared to pts with normal hepatic function, the dose-normalized (DN)-AUC(0-tlast) in pts with severe HI by the CP scores was 2.9 (90% CI;1.8, 4.7). The AUC (0-∞) GLSM ratios were 1.2 (90% CI; 0.8, 1.8) and 2.2 (90% CI; 1.5, 3.3) for the mild and moderate HI groups, respectively. The AUC(0-∞) normalized ratio of the severe HI group was 3.1 (90% CI; 1.9, 4.9). The imlunestrant Cmax GLSM ratio was similar between pts with normal hepatic function and those with mild (1.3 (90% CI; 0.8, 2.0)), moderate (1.5 (90% CI; 1, 2.4)) and severe (1.6 (90% CI; 1, 2.7)) HI. The median elimination half-life was 33.1 hours in pts with normal hepatic function, 42.8, 46.3 and 67.0 hours in pts with mild, moderate and severe HI, respectively. Additional exploratory analysis of PK parameters based on the National Cancer Institute (NCI) classification of HI, showed there were significant differences in imlunestrant PK when administered to pts with mild and moderate HI compared to pts with normal hepatic function. Only 1 pt was categorized with severe HI by NCI classification as such, this group was excluded from NCI based analyses. The average fraction unbound in plasma was similar across groups. Most TEAEs were mild or moderate in severity. TEAEs were reported by 2 pts with moderate HI and severe HI, respectively. Nausea and headache were the only TEAEs reported by more than 1 pt. Conclusions: Imlunestrant administered as a single oral dose in the fasted state was well tolerated in healthy FONCBP, as well as pts with mild, moderate and severe HI determined by the CP classification. There were no significant differences in the exposure profiles of imlunestrant in pts with mild HI in comparison to pts with normal hepatic function. However, in pts with moderate and severe HI, statistically significant increases in imlunestrant AUC (but not Cmax) were observed when compared with normal hepatic function. This data will inform the recommendations for dosing patients with HI under treatment with imlunestrant. Citation Format: Stephanie White, Elaine Shanks, Eunice Yuen, Stephen David Hall, Vivian Rodriguez Cruz, Xuejing Wang. Evaluation of pharmacokinetics and safety of imlunestrant in participants with hepatic impairment [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-10-07.