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Imlunestrant
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Does imlunestrant cross the blood brain barrier?
Initial results from the EMBER-3 trial were consistent with preclinical data demonstrating central nervous system penetrance and activity of imlunestrant.
Imlunestrant Brain Penetration and Activity in Brain Metastasis: Preclinical Data
Imlunestrant is a next-generation, oral selective estrogen receptor degrader (SERD) and pure estrogen receptor alpha antagonist with potent activity against both estrogen receptor 1 (ESR1)-mutant and wild-type tumor models.1
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 estrogen receptor-positive (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 1 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 2 description: Imlunestrant demonstrated central nervous system penetrance and improved survival probability in an estrogen receptor-positive brain orthotopic model.
Abbreviations: CNS = central nervous system; SEM = standard error of the mean.
EMBER-3: Post Hoc Analyses of Central Nervous System Progression
Post hoc analyses of the phase 3 EMBER-3 study demonstrated the percentage of patients with central nervous system (CNS) progression was somewhat lower with imlunestrant monotherapy compared with standard-of-care endocrine therapy among all patients (EMBER-3 Post Hoc Analysis: Imlunestrant Versus SOC ET Cumulative Incidence Rates of CNS Progression in All Patients). The cumulative incidence rates of CNS progression for patients with ESR1m is presented in EMBER-3 Post Hoc Analysis: Imlunestrant Versus SOC ET Cumulative Incidence Rates of CNS Progression in Patients With ESR1 Mutations. These data should be interpreted with caution given the small numbers of patients and lack of mandated serial CNS imaging in all patients.3
Figure 3 description: The 12-month cumulative incidence of central nervous system progression was 1.6% with imlunestrant monotherapy and 3.0% with standard-of-care endocrine therapy among all patients resulting in a cause-specific hazard ratio equal to 0.47 and 95% confidence interval of 0.16 to 1.38.
Abbreviations: CIR = cumulative incidence rate; CNS = central nervous system; HR = hazard ratio; SOC ET = standard-of-care endocrine therapy.
Note: Baseline CNS imaging was required in all patients; serial CNS imaging was required only in patients with CNS metastases at baseline, otherwise performed as clinically indicated. Eleven of 15 events were due to new lesions (imlunestrant, n=3; standard therapy, n=8); and 4 of 15 events were due to progressing existing lesions (imlunestrant, n=2; standard therapy, n=2).
Figure 4 description: The 12-month cumulative incidence of central nervous system progression was 1.5% with imlunestrant monotherapy and 6.7% with standard-of-care endocrine therapy among patients with ESR1 mutations resulting in a cause-specific hazard ratio equal to 0.18 and 95% confidence interval of 0.04 to 0.90.
Abbreviations: CIR = cumulative incidence rate; CNS = central nervous system; ESR1 = estrogen receptor 1 gene; HR = hazard ratio; SOC ET = standard-of-care endocrine therapy.
Note: Baseline CNS imaging was required in all patients; serial CNS imaging was required only in patients with CNS metastases at baseline, otherwise performed as clinically indicated.
EMBER-3 Study Design
EMBER-3 (NCT04975308) is a phase 3, randomized, open-label study of imlunestrant monotherapy, investigator's choice of endocrine therapy (fulvestrant or exemestane), and imlunestrant in combination with abemaciclib in patients with ER+, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer previously treated with endocrine therapy (aromatase inhibitor) ± a cyclin-dependent kinase 4/6 inhibitor.3,5
Enrollment Criteria Related to Brain Metastasis
According to the EMBER-3 clinical study protocol, patients with treated brain metastases (BM) were eligible to enroll in the EMBER-3 study if they
- completed prior therapy for their BM (including radiation and/or surgery) ≥28 days prior to the first dose of study treatment
- were not receiving corticosteroids and/or anticonvulsants for ≥14 days prior to the first dose of study treatment, and
- had asymptomatic and radiographically stable disease for ≥28 days prior to randomization, as confirmed by repeat imaging during study screening.3
Additionally, all patients must have undergone baseline brain imaging.3
- For patients without a history of BM, either a brain computed tomography (CT) or brain magnetic resonance imaging (MRI) was required, with contrast recommended.3
- For patients with treated BM, contrast-enhanced brain MRI was preferred; however, if MRI contrast was contraindicated, then MRI (without contrast) or brain CT (recommended with contrast) were acceptable alternatives.3
Serial brain imaging was required only in patients with BM at baseline, otherwise performed as clinically indicated.4
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
3Jhaveri KL, Neven P, Casalnuovo ML, et al; EMBER-3 Study Group. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189-1202. https://doi.org/10.1056/NEJMoa2410858
4Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant, an oral selective estrogen receptor degrader (SERD), as monotherapy and combined with abemaciclib, for patients with ER+, HER2- advanced breast cancer (ABC), pretreated with endocrine therapy (ET): results of the phase 3 EMBER-3 trial. Poster presented at: 47th Annual Meeting of the San Antonio Breast Cancer Symposium (SABCS); December 10-13, 2024; San Antonio, TX.
5A study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2- advanced breast cancer (EMBER-3). ClinicalTrials.gov identifier: NCT04975308. Updated April 8, 2025. Accessed April 25, 2025. https://clinicaltrials.gov/ct2/show/NCT04975308
Date of Last Review: April 11, 2025