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Imlunestrant Is an Oral, Brain-Penetrant Selective Estrogen Receptor Degrader with Potent Antitumor Activity in ESR1
Shripad V Bhagwat1, Cecilia Mur2, Matthew Vandekopple1
1Eli Lilly and Company, Indianapolis, Indiana.
Abstract:
Targeting of the estrogen receptor (ER) by antiestrogens is the standard of care for patients with ER+ HER2- advanced/metastatic breast cancer. Although antiestrogens that degrade ERα (fulvestrant) or block estrogen production (aromatase inhibitors) have improved patient outcomes, clinically important challenges remain related to drug administration, limited bioavailability, lack of brain exposure, and acquired resistance due to ESR1 mutations. These limitations indicate a need for more robust ER-targeted therapies. Here, we discovered and characterized imlunestrant, a next-generation potent, brain-penetrant oral selective ER degrader. Imlunestrant degraded ERα and decreased ERα-mediated gene expression both in vitro and in vivo. Cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant models were significantly inhibited by imlunestrant. Combining imlunestrant with abemaciclib (CDK4/6 inhibitor), alpelisib (PI3K inhibitor), or everolimus (mTOR inhibitor) further enhanced tumor growth inhibition, regardless of ESR1 mutational status. In an ER+ breast cancer intracranial tumor model, imlunestrant prolonged survival compared with vehicle or alternative selective ER degrader therapies. Together, these findings support the potential of imlunestrant to degrade ERα and suppress the growth of ESR1-WT and mutant breast cancer, including brain metastatic tumors. Significance: Imlunestrant, a next-generation, brain-penetrant oral ERα degrader, displays potent activity in ESR1 wild-type and mutant breast cancer, enhances combination activity with standard-of-care agents, and inhibits growth of ER+ intracranial tumors.
Insights
Imlunestrant, a new oral therapy, effectively degrades the estrogen receptor (ERα) in ER+ breast cancer. This potent drug shows promise against both wild-type and mutant ESR1 tumors, including brain metastases.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Estrogen receptor (ER)-positive (ER+) advanced/metastatic breast cancer is typically treated with antiestrogens targeting ERα or estrogen production.
- Current therapies like fulvestrant and aromatase inhibitors face challenges including administration, bioavailability, limited brain penetration, and acquired resistance from ESR1 mutations.
- These limitations highlight the need for improved ER-targeted therapeutic strategies.
Purpose of the Study:
- To discover and characterize imlunestrant, a novel, potent, brain-penetrant, oral selective ER degrader.
- To evaluate the efficacy of imlunestrant in preclinical models of ER+ breast cancer, including those with ESR1 mutations.
- To assess the potential of imlunestrant in combination therapies and its activity against brain metastases.
Main Methods:
- In vitro and in vivo studies to assess imlunestrant's ability to degrade ERα and inhibit ERα-mediated gene expression.
- Evaluation of imlunestrant's effect on cell proliferation and tumor growth in ESR1 wild-type (WT) and mutant breast cancer models.
- Assessment of combination therapy effects with abemaciclib, alpelisib, or everolimus.
- Testing imlunestrant in an ER+ breast cancer intracranial tumor model.
Main Results:
- Imlunestrant demonstrated potent degradation of ERα and decreased ERα-mediated gene expression both in vitro and in vivo.
- Significant inhibition of cell proliferation and tumor growth was observed with imlunestrant in both ESR1 WT and mutant models.
- Combination therapies with imlunestrant and CDK4/6, PI3K, or mTOR inhibitors further enhanced tumor growth inhibition.
- Imlunestrant treatment prolonged survival in an ER+ breast cancer intracranial tumor model compared to controls.
Conclusions:
- Imlunestrant is a next-generation, brain-penetrant oral selective ERα degrader with potent anti-tumor activity.
- It effectively suppresses the growth of both ESR1 WT and mutant ER+ breast cancers, including brain metastases.
- Imlunestrant shows enhanced efficacy in combination with standard-of-care agents and holds potential for treating advanced/metastatic ER+ breast cancer.
