In late September, the US Food and Drug Administration (FDA) approved imlunestrant (Inluriyo®, Eli Lilly and Company), an estrogen receptor (ER) antagonist, for the treatment of adults patients diagnosed with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.[1][2]
In addition, the FDA also approved the Guardant360 CDx assay as a companion diagnostic designed to identify patients with breast cancer with ESR1 mutations for treatment with imlunestrant.
The efficacy of imlunestrant was evaluated in EMBER-3 (NCT04975308), a randomized, open-label, active-controlled, multicenter clinical study that enrolled 874 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor either alone or in combination with a CDK4/6 (cyclin-dependent kinase 4 and 6) inhibitor or as second-line treatment for MBC following progression on Al, +/- CDK4/6 inhibitor
Patients were excluded from participating in the study if they were eligible to receive a PARP inhibitor.
Participating patients were randomized 1:1:1 to imlunestrant, an investigator’s choice of endocrine therapy (fulvestrant or exemestane), or an additional investigational combination regimen. Randomization was stratified by previous treatment with a CDK4/6 inhibitor, presence of visceral metastasis, and geographic region. ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) analysis using the Guardant360 CDx assay and was limited to specific ESR1 mutations in the ligand-binding domain.
Study outcomes
The major efficacy outcome was investigator-assessed progression-free survival (PFS) according to RECIST v1.1 comparing imlunestrant to the investigator’s choice of endocrine therapy in patients with ESR1-mutated tumors. Other efficacy outcome measures included overall survival (OS) and objective response rate (ORR).
In population of 256 patients with ESR1-mutated tumors, a statistically significant difference in investigator-assessed PFS for imlunestrant compared to investigator’s choice of endocrine therapy was observed. The median PFS was 5.5 months (95% confidence interval [CI] 3.9, 7.4) in the imlunestrant arm and 3.8 months (95% CI 3.7, 5.5) in the investigator’s choice arm (hazard ratio 0.62, 95% CI 0.46, 0.82; p-value 0.0008).
The ORR was 14.3% in the imlunestrant arm and 7.7% in the investigator’s choice arm. At the time of the PFS analysis, OS data was immature with 31% of deaths in the ESR1-mutated population.
“This represents an important advancement for patients with ESR1-mutated MBC, a mutation found in nearly half of patients who have taken hormone therapies, often contributing to treatment resistance,” noted Komal Jhaveri, M.D., FACP, FASCO, section head of Endocrine Therapy Research and clinical director of Early Drug Development at Memorial Sloan Kettering Cancer Center, and a principal investigator of EMBER-3.
“With its demonstrated efficacy, tolerability profile and oral administration, this therapy provides a meaningful alternative treatment option for this patient population,” Jhaveri added.
Expanding treatment options
“The approval of imlunestrant expands the metastatic breast cancer treatment landscape for patients who test positive for the ESR1 mutation,” said Jean Sachs, CEO, Living Beyond Breast Cancer.
“Eligible patients will now have access to an additional treatment option, offering them the potential for flexibility in their daily lives and disease management, and—above all—renewed hope for the future,” Sachs concluded.
Adverse events
The most common adverse events (≥10%), including laboratory abnormalities were decreased haemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased AST, fatigue, diarrhoea, increased ALT, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.
The recommended imlunestrant dose is 400 mg orally once daily (on an empty stomach at least 2 hours before food, or 1 hour after food) until disease progression or unacceptable toxicity.
Imlunestrant is also being studied in the ongoing Phase 3 EMBER-4 trial in the adjuvant setting for people with ER+, HER2– early breast cancer (EBC) at increased risk of recurrence, which is enrolling approximately 8,000 patients worldwide.
__
Clinical trials
A 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 ID NCT04975308
Highlights of prescribing information
Imlunestrant (Inluriyo®, Eli Lilly and Company)[Prescribing Information]
Fulvestrant (Faslodex®; AstraZeneca) [Prescribing Information]
Exemestane (Aromasin®; Pfizer)[Prescribing Information]
Reference
[1] Jhaveri KL, Lim E, Jeselsohn R, Ma CX, Hamilton EP, Osborne C, Bhave M, Kaufman PA, Beck JT, Manso Sanchez L, Parajuli R, Wang HC, Tao JJ, Im SA, Harnden K, Yonemori K, Dhakal A, Neven P, Aftimos P, Pierga JY, Lu YS, Larson T, Jerez Y, Sideras K, Sohn J, Kim SB, Saura C, Bardia A, Sammons SL, Bacchion F, Li Y, Yuen E, Estrem ST, Rodrik-Outmezguine V, Nguyen B, Ismail-Khan R, Smyth L, Beeram M. Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study. J Clin Oncol. 2024 Dec 10;42(35):4173-4186. doi: 10.1200/JCO.23.02733. Epub 2024 Sep 6. Erratum in: J Clin Oncol. 2025 Jan;43(1):114. doi: 10.1200/JCO-24-02470. PMID: 39241211; PMCID: PMC11637582.
[2] Bhagwat SV, Mur C, Vandekopple M, Zhao B, Shen W, Marugán C, Capen A, Kindler L, Stephens JR, Huber L, Castanares MA, Garcia-Tapia D, Cohen JD, Bastian J, Mattioni B, Yuen E, Baker TK, Rodriguez Cruz V, Fei D, Manro JR, Pulliam N, Dowless MS, Ortiz Ruiz MJ, Yu C, Puca L, Klippel A, Bacchion F, Ismail-Khan R, Rodrik-Outmezguine V, Peng SB, Lallena MJ, Gong X, de Dios A. 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 Feb 17;85(4):777-790. doi: 10.1158/0008-5472.CAN-24-2608. PMID: 39652577; PMCID: PMC11831106.
Featured image: Pink breast cancer awareness. Photo courtesy: © 2019 – 2025 Fotolia/Adobe. used with permission.
DOI
 approved imlunestrant (Inluriyo®, Eli Lilly and Company), an estrogen receptor (ER) antagonist, for the treatment of adults patients diagnosed with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.[1][2]){kind=link}