(W0930-02-10) Evaluation of the Disposition and Absolute Bioavailability of Imlunestrant in Healthy Volunteers

Purpose: Imlunestrant is a next-generation oral selective estrogen receptor degrader designed to deliver continuous estrogen receptor (ER) inhibition.¹ Imlunestrant is being investigated for the treatment of ER-positive advanced breast and endometrial cancers.^2-5 Orally delivered drugs have a bioavailability of < 100% due to incomplete absorption, gut wall metabolism, or elimination during the first-pass through the liver. This study quantified the elimination pathways and absolute oral bioavailability (F) of imlunestrant.

Methods: This was a phase 1, open-label, 2-part US study (NCT04991766) conducted between August 2021 and May 2022 in healthy females (35–65 years) of nonchildbearing potential. Participants were screened 28 days before enrolment, admitted to a clinical research unit (CRU) on day -1, administered study treatment on day 1 after an overnight fast of ≥10h, and received a follow-up call 7 days after discharge from the CRU. Part 1 participants received an oral dose of 400-mg [¹⁴C]-imlunestrant solution (100µCi). Blood, fecal, and urine samples were collected until ≥90% of the radioactive dose was recovered and ≤1% of the radioactive dose/day was recovered in urine and feces for 2 consecutive days or until discharge from the CRU (day 22). Part 2 participants received a single oral dose of 400-mg imlunestrant (2×200-mg tablets) followed by an IV dose of ~45µg [¹⁴C]-imlunestrant (1µCi) given as a 15-minute infusion 4h later. Blood samples were collected during infusion and for at least 2h post-infusion. Part 2 participants remained in the CRU until Day 9. Key endpoints were urinary and fecal excretion of total radioactivity over time; F of imlunestrant; area under the concentration-time curve from time zero extrapolated to infinite time (AUC[0-∞]); maximum observed drug concentration (C_max) for total radioactivity, imlunestrant, and [¹⁴C]-imlunestrant in plasma; total radioactivity recovered in urine and feces; number of metabolites and identification of metabolites; and treatment-emergent AEs (TEAEs). Plasma [¹⁴C]-imlunestrant concentrations were measured using high performance liquid chromatography and tandem mass spectrometry (HPLC/MS/MS). Plasma [¹⁴C]-imlunestrant concentrations (Part 2) were measured using HPLC and accelerator mass spectrometry (HPLC/AMS). The amounts of radioactivity were determined using liquid scintillation counting (LSC) (urine and feces, Part 1), LSC/AMS (plasma, Part 1) or AMS (plasma, Part 2). Radioprofiling and metabolite identification was conducted using radioprofiling techniques and HPLC/MS/MS (feces, Part 1) or HPLC/AMS (plasma, Part 1).

Results: Sixteen females (N=8 each in Part 1 and Part 2) were included in the study (age: 36–65 years; BMI, mean [SD]: 27.5 [3.9] kg/m²). In Part 1, after administration of [¹⁴C]-imlunestrant as an oral solution, the overall arithmetic mean recovery of total radioactivity in urine and feces was 97.5% through 480h post-dose in 5 participants (Image 1). Three participants were excluded due to early termination/elimination of a large portion of the dose as vomitus. Total radioactivity was primarily eliminated via the feces (97.3%) and a trace amount eliminated in the urine (0.3%). Approximately 20% of the dose was recovered in feces as a sulfate conjugate (M2), 10% as products of oxidation, and the remainder as parent drug. Total radioactivity and [¹⁴C]-imlunestrant appeared rapidly in plasma with a median t_max of 2h (Images 2 and 3). Imlunestrant was eliminated with a geometric mean t_1/2 of 33.4h and total radioactivity decreased with a geometric mean t_1/2 of 110h. The ratio of geometric mean plasma imlunestrant and total radioactivity was 0.19 for AUC(0-t_last), 0.18 for AUC(0-∞), and 0.20 for C_max. Imlunestrant and its metabolite M1 (glucuronide conjugate) accounted for most of the radioactivity in circulation (20% each), followed by metabolites M2 (sulfate conjugate; 4.5%) and M12 (mono-hydroxy sulfate conjugate, 4.6%). Imlunestrant, M1, M2, and M12 were detectable in the plasma up to 264h. Imlunestrant accounted for most of the radioactive dose in feces (61.8%), followed by metabolite M2 (20.9%), and metabolites M5+M10 (co-eluted), M7, M8, M9, and M11 (≤5.1% for each). In Part 2, after a single oral administration as 2×200-mg tablets, imlunestrant appeared in plasma with a median t_max of 4.37h and was eliminated with a geometric mean t_1/2 of 31.2h (Images 2 and 3). C_max of total radioactivity and [¹⁴C]-imlunestrant was achieved 15 minutes after start of IV dose with [¹⁴C]-imlunestrant. The geometric mean t_1/2 of [¹⁴C]-imlunestrant and total radioactivity after IV administration was 29.6h and 73.2h, respectively. The geometric mean F of imlunestrant after oral administration relative to IV administration based on dose-normalized AUC(0-∞) was 10.5%. Imlunestrant was well-tolerated as an oral solution or as a tablet/IV dose. Five participants in Part 1 and 3 participants in Part 2 reported TEAEs that were considered treatment-related. All TEAEs were mild/moderate and resolved by the end of the study.

Conclusion: Imlunestrant and its metabolites were primarily eliminated in the feces with low urinary excretion. The oral bioavailability of imlunestrant was ~10%. These findings indicate that conjugation and oxidation in the gut wall/liver are the principal routes of elimination. A single oral dose of 400-mg imlunestrant was well-tolerated in healthy females.

References: 1. Patel, R. et al., An emerging generation of endocrine therapies in breast cancer: a clinical perspective. npj Breast Cancer. 2023;9(1):20.
2. Shripad V. et al., Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1236.
3. Lim et al., A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial 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 OT-09-03.
4. Komal L. et al., A phase 1a/b trial of imlunestrant (LY3484356), an oral selective estrogen receptor degrader (SERD) in ER-positive (ER+) advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Monotherapy results from EMBER. JCO 40, 1021-1021(2022).
5. Jhaveri K. et al, EMBER-3: A randomized phase 3 study of LY3484356, a novel, oral selective estrogen receptor degrader vs investigator’s choice of endocrine therapy of either fulvestrant or exemestane, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer previously treated with endocrine-based therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-01.

Acknowledgements: Conflict of Interest: Authors are employees and stockholders of Eli Lilly and Company.

Funding: This study was funded by Eli Lilly and Company.
Acknowledgments: Medical writing was provided by Surayya Taranum, PhD, CMPP in accordance with Good Publication Practice guidelines (GPP 2022) and was funded by Eli Lilly and Company.


Image 1. Mean (±SD) cumulative radioactive dose recovered after a single 400-mg oral dose of [14C]-imlunestrant (100 μCi) solution


Image 2. Summary of imlunestrant, [14C]-imlunestrant, and total radioactivity PK parameters


Image 3. Arithmetic mean plasma concentration profile of (A) Total radioactivity and [14C]-Imlunestrant (100 µCi), and (B) Total radioactivity, imlunestrant, and [14C]-Imlunestrant (1 µCi)