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Imlunestrant
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What preclinical information is available for imlunestrant?
Imlunestrant is a next-generation, oral, brain-penetrant selective estrogen receptor degrader (SERD) with pure antagonistic properties resulting in sustained inhibition of estrogen receptor (ER)-dependent gene transcription and cell growth.
Imlunestrant Preclinical Data
Introduction: Preclinical Summary
Imlunestrant (shown in Imlunestrant Structural Formula) is a potent degrader and selective pure antagonist of wild-type and mutant estrogen receptor α (ERα).1
In cell proliferation assays, imlunestrant selectively inhibits the proliferation of estrogen receptor-positive (ER+) breast cancer cell lines and has equivalent potency in both wild-type and mutant estrogen receptor gene 1 (ESR1) cell lines.1
In in vivo target inhibition studies, imlunestrant has shown sustained and prolonged inhibition of expression of progesterone receptor, a transcriptional target of ERα and a pharmacodynamic biomarker in ESR1 wild-type and ESR1 (Y537S) mutant xenograft or patient derived xenograft (PDX) tumor models in mice.1
In in vivo efficacy studies, imlunestrant has demonstrated robust single agent activity and tumor regressions in ESR1 wild-type (MCF7, T47D, ZR-75-1, HCC1428) xenograft models and ESR1 mutant (Y537S, E380Q) PDX models.1
In preclinical combination efficacy studies, imlunestrant has shown good tolerability and enhanced efficacy with abemaciclib, alpelisib, and everolimus.1
In ER+ breast cancer intracranial models, imlunestrant treatment reduced tumor growth and prolonged overall survival compared to control and other approved and investigational selective estrogen receptor degraders (SERDs).1
Figure 1 description: The structural formula for the imlunestrant molecule is shown.
Detailed Information on Preclinical Characterization
Previous research demonstrated that imlunestrant has activity in ER-dependent cell lines and in vivo models.3
A more comprehensive evaluation across a panel of breast cancer cell lines as well as multiple in vivo models showed that imlunestrant
- degraded ER and decreased ER-mediated gene expression across cell lines
- inhibited cell proliferation and tumor growth in both ESR1 wild-type and mutant models, and
- further enhanced efficacy across cell lines and in vivo models when combined with abemaciclib, alpelisib, or everolimus, regardless of ER mutation status.2,4
In Vitro Characterization
Imlunestrant has binding affinity of 0.64 nM and 2.8 nM against wild-type ERα and Y537S mutant ERα proteins, respectively. It is a potent and highly efficient degrader of wild-type ERα and Y537N mutant ERα proteins in cells, with half maximal inhibitory concentration (IC50) values of 3.0 nM and 9.6 nM, respectively.3
Breast Cancer Cell Line Panel shows the antiproliferative activity of imlunestrant.
Figure 2 description: In a panel of breast cancer cell lines, 11 out of 12 estrogen receptor-positive breast cancer cell lines were sensitive to imlunestrant (half maximal inhibitory concentration <100nM), whereas all estrogen receptor-negative cell lines tested were insensitive.
Abbreviations: ER+ = estrogen receptor-positive; ER- = estrogen receptor-negative; HER2+ = human epidermal growth factor receptor 2-positive.
Cell Proliferation in ESR1 Wild-type and Mutant Models
Imlunestrant, alone and in combination with abemaciclib, alpelisib, or everolimus inhibits proliferation in breast cancer cell lines in in vitro (Breast Cancer Cell Line Panels Treated With Imlunestrant in Combination With Abemaciclib, Alpelisib, and Everolimus).1
Figure 3 description: Imlunestrant + abemaciclib showed synergistic (combination index at 50% inhibition <0.5) antiproliferative activity in most breast cancer cell lines tested. Additionally, Imlunestrant + alpelisib, and imlunestrant + everolimus showed improved combination activity (additivity [>0.5 combination index at 50% inhibition <2], or synergy) in most breast cancer cell lines tested.
Abbreviations: ER+ = estrogen receptor-positive; ER- = estrogen receptor-negative; HER2+ = human epidermal growth factor receptor 2-positive.
Note: Half maximal inhibitory concentration values from the single agent and combination treatment were used to calculate the combination index at 50% inhibition.
PK/PD Analysis
Pharmacokinetic/pharmacodynamic analysis of imlunestrant in vivo showed
- dose dependent exposure in multiple tissues
- persistent exposure over time
- sustained progesterone receptor (PgR) gene expression inhibition, and
- reduction of ERα and PgR by immunohistochemistry.2
Brain Penetration and Activity in Brain Metastasis
Imlunestrant showed sustained exposure in the brains of mice, demonstrating its ability to effectively cross the blood-brain barrier (Imlunestrant Brain Exposure in Preclinical Analyses). In an ER+ brain orthotopic mouse model, imlunestrant treatment prolonged overall survival compared to control, fulvestrant, and alternative SERD therapies (Imlunestrant CNS Activity and Overall Survival in a Brain Orthotopic Model).1,2
Figure 4 description: In pharmacokinetic/pharmacodynamic analyses of mice bearing MCF7 xenografts, imlunestrant demonstrated dose dependent exposure in the brain, prolonged brain exposure, sustained progesterone receptor gene expression inhibition, and reduction of estrogen receptor alpha and progesterone receptor by immunohistochemistry (not shown).
Abbreviations: MCF7 = Michigan Cancer Foundation-7; PGR = progesterone receptor; PK = pharmacokinetics; PO = by mouth; QD = daily; SEM = standard error of the mean.
Figure 5 description: Imlunestrant demonstrated central nervous system penetrance and improved survival probability in an estrogen receptor-positive brain orthotopic model.
Abbreviation: CNS = central nervous system.
Selective Estrogen Receptor Degrader: Overview and Background
A SERD is an antiestrogen that degrades estrogen receptors and inhibits the ER pathway. In contrast to selective estrogen receptor modulators, which have agonist activity at some ERs, SERDs act as an ER antagonist at all receptors.5
Estrogen signaling plays an important role in organ development and growth. In certain cancers, abnormal estrogen signaling via the ER is a key component of tumor growth.6 Disruption of estrogen signaling by SERDs is a treatment option for ER+ cancers.5,7
Nearly 70% of newly diagnosed breast cancers are ERα positive. While endocrine therapy is a primary treatment for these cancers, 40% of these patients go on to develop resistance through mutations in ERα (ESR1) that drive constitutive activation of the receptor. Novel degraders and antagonists of ERα are being developed to deliver more ERα target coverage, provide a more convenient dosing, and overcome ESR1-mutation-mediated acquired resistance.3
Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Bhagwat SV, Mur C, Vandekopple M, et al. Imlunestrant is an oral, brain-penetrant selective estrogen receptor degrader with potent antitumor activity in ESR1 wild-type and mutant breast cancer. Cancer Res. 2025;85(4):777-790. https://dx.doi.org/10.1158/0008-5472.CAN-24-2608
2Vandekopple M, Mur C, Shen W, et al. Preclinical characterization of imlunestrant, an oral brain-penetrant selective estrogen receptor degrader with activity in a brain metastasis (BM) model. Poster presented at: 5th European Society for Medical Oncology Breast Cancer (ESMO-BC) Congress; May 11-13, 2023; Berlin, Germany. Accessed October 11, 2023. https://cslide.ctimeetingtech.com/breast23hybrid/public/download_uploaded_media/pdf/125
3Bhagwat SV, Zhao B, Shen W, et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD). Cancer Res. 2021;81(13 suppl):1236. American Association for Cancer Research abstract 1236. https://doi.org/10.1158/1538-7445.AM2021-1236
4Vandekopple M, Mur C, Shen W, et al. Preclinical characterization of imlunestrant, an oral brain-penetrant selective estrogen receptor degrader with activity in a brain metastasis (BM) model. ESMO Open. 2023;8(1 suppl 4):101265. European Society for Medical Oncology abstract 41P. https://doi.org/10.1016/j.esmoop.2023.101265
5Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1-24. https://doi.org/10.1016/j.pharmthera.2017.12.012
6Lee HR, Hwang KA, Park MA, et al. Treatment with bisphenol A and methoxychlor results in the growth of human breast cancer cells and alteration of the expression of cell cycle-related genes, cyclin D1 and p21, via an estrogen receptor-dependent signaling pathway. Int J Mol Med. 2012;29(5):883-890. https://doi.org/10.3892/ijmm.2012.903
7Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res. 2015;21(22):5121-5130. https://doi.org/10.1158/1078-0432.CCR-15-0360
Date of Last Review: May 23, 2025