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Imlunestrant
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What preclinical information is available for imlunestrant?
Imlunestrant is a novel, orally bioavailable 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 alpha (ERα).1-4
- 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.
- 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.
- 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.
- In preclinical combination efficacy studies, imlunestrant has shown good tolerability and enhanced efficacy with abemaciclib, alpelisib, and everolimus.
Figure 1 description: The structural formula for the imlunestrant molecule is shown.
Detailed Information on Preclinical Characterization
Imlunestrant has inhibition constant values of 0.31 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.1
In a panel of breast cancer cell lines, 11 out of 12 ER+ breast cancer cell lines were sensitive to LY3484356 (IC50 <100nM), whereas all estrogen receptor-negative (ER-) cell lines tested were insensitive.1
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
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.4
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. In an ER+ brain orthotopic mouse model, imlunestrant treatment prolonged overall survival compared to control, fulvestrant, and alternative SERD therapies (see Imlunestrant CNS Activity and Overall Survival in a Brain Orthotopic Model).4
Figure 2 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 (SERD) 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
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Bhagwat 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;18(13 suppl):1236. American Association of Cancer Research abstract 1236. https://doi.org/10.1158/1538-7445.AM2021-1236
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. ESMO Open. 2023;8(1 suppl 4):101265. European Society for Medical Oncology abstract 41P. https://doi.org/10.1016/j.esmoop.2023.101265
3Bhagwat SV, Zhao B, Shen W, et al. Preclinical characterization of LY3484356, a novel, potent and orally bioavailable selective estrogen receptor degrader (SERD). Poster presented at: 112th Annual Meeting of the American Association for Cancer Research (AACR Virtual); April 10-15, May 17-21, 2021.
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. 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
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: August 04, 2023