(T1130-02-10) Pharmacokinetic Drug-Drug Interactions of Imlunestrant in Healthy Female Participants of Nonchildbearing Potential

Purpose: Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER inhibition¹ and is being investigated for the treatment of ER-positive advanced breast and endometrial cancers.^2-5 Imlunestrant is eliminated in part by CYP3A4 oxidation and conjugation with glucuronic acid and sulfate. Three Phase 1 studies evaluated the drug-drug interactions (DDI) potential of imlunestrant and assessed its effect on the activity of CYP2C8 (repaglinide), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan), CYP3A4/5 (midazolam), P-gp (digoxin), and BCRP (rosuvastatin) using prototypical substrates. Additionally, the effects of CYP3A4 inhibition (itraconazole), CYP3A4 induction (carbamazepine), and P-gp inhibition (quinidine) on imlunestrant pharmacokinetics were examined.

Methods: All 3 studies were open-label, fixed-sequence, crossover Phase 1 trials in healthy volunteers (aged 18-65 years). Study cohorts and dosing schedules are presented in Table 1. Safety, tolerability, and pharmacokinetics were assessed. Plasma concentrations of drugs and metabolites were quantified using validated LC/MS assays. Pharmacokinetic parameters were determined using standard noncompartmental analyses. Log-transformed maximum plasma concentrations (C_max) and area under the plasma concentration-time curve from zero to infinity (AUC_0-∞) parameters were analyzed using a linear mixed-effects model with a fixed effect for treatment and random effect for participant. Geometric least-squares mean ratios and corresponding 90% confidence intervals were reported.

Results: A summary of treatment-emergent adverse events is presented in Table 2. Overall, across all cohorts and treatments, the most frequent treatment-emergent adverse events among study participants were headache (all-cause, n=26; treatment-related, n=16), diarrhea (all-cause, n=15; treatment-related, n=12), constipation (all-cause, n=14; treatment-related, n=9), and dizziness (all-cause, n=12; treatment-related, n=11). In JZLD study Cohort 4, 10 participants discontinued due to an adverse event, and 1 participant experienced a serious adverse event (hepatitis E; not related to study treatment). All events in the JZLI and JZLK studies were mild in severity, and none resulted in treatment discontinuation. The effect of imlunestrant as both a precipitant and object of the DDI studies is shown in Table 3. Statistically significant increases in the AUC_0-∞ and C_max were observed for dextromethorphan (AUC_0-∞,33%; C_max, 43%), digoxin (AUC_0-∞, 39%; C_max, 60%), and rosuvastatin (AUC_0-∞, 49%; C_max, 65%). The P-gp inhibitor quinidine resulted in a slight decrease (AUC_0-∞, 13%) in imlunestrant exposure, itraconazole led to an approximately 2-fold increase (AUC_0-∞, 111%; C_max, 87%) in exposure, and a significant decrease (AUC_0-∞, 42%; C_max 29%) in exposure occurred following carbamazepine coadministration. No significant effects on t_max values were observed.

Conclusion: Imlunestrant was well tolerated for the oral doses of 200 mg, 400 mg, and 800 mg, alone and in the presence of CYP substrates, in healthy volunteers. As a precipitant, imlunestrant had no effect on repaglinide, omeprazole, and midazolam pharmacokinetics, indicating low/no DDI potential with CYP2C8-, CYP2C19- and CYP3A4/5-mediated metabolism, respectively. Imlunestrant is a weak inhibitor of dextromethorphan, digoxin, and rosuvastatin oral clearance and thus may have some DDI potential with drugs dependent on CYP2D6, P-gp, and BCRP, respectively. As an object, imlunestrant was not a sensitive substrate for the effects of quinidine, itraconazole, and carbamazepine, indicating that imlunestrant exposures are not significantly impacted by drugs that inhibit P-gp or CYP3A4, or induce CYP3A4, respectively.

References: 1. Jhaveri K, Jeselsohn R, Ma CX, et al. Imlunestrant with or without everolimus or alpelisib, in ER+, HER2- advanced breast cancer (aBC): results from the phase Ia/b EMBER study [abstract]. Ann Oncol. 2023;34(2 suppl):S338-S339.
2. Bhagwat SV, Zhao B, Shen W, et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD) [abstract]. Cancer Res. 2021;81(13 suppl):1236.
3. Lim E, Beeram M, Prawira A, et al. EMBER: 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]. Cancer Res. 2021;81(4 suppl):OT-09-03.
4. Jhaveri KL, Jeselsohn R, Lim E, 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 [abstract]. J Clin Oncol. 2022;40(16 suppl):1021.
5. Jhaveri K, Harbeck N, Aftimos P, 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]. Cancer Res. 2022;82(4 suppl):OT2-11-01.

Acknowledgements: We thank all the volunteers for participation in this trial. We thank all the investigators and their support staff who generously participated in this work. Medical writing support was provided by Anchal Sood of Syneos Health, funded by Eli Lilly and Company.

Funding: The study was funded by Eli Lilly and Company.
Disclosure: The authors are stockholders and employees of Eli Lilly and Company.

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