Pharmacist's Application to Practice: Imlunestrant

FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer

What is the potential role for imlunestrant in the treatment of ESR1-mutated advanced/metastatic ER+, HER2- breast cancer?

• Imlunestrant is an oral selective estrogen receptor (ER) degrader (SERD) that provides ERα inhibition, including in estrogen receptor 1 (ESR1) mutant cancers. The degradation of ERα leads to inhibition of ER-dependent gene transcription and cellular proliferation in ER+ breast cancer cells.1
• Currently, imlunestrant is utilized in the setting of progression on at least one line of endocrine therapy (an aromatase inhibitor with or without a cyclin-dependent kinase 4 and 6 [CDK 4/6] inhibitor) in the advanced or metastatic setting of hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), and ESR1-mutation breast cancer.1
• ESR1 mutation testing is indicated at progression on endocrine therapy with or without early relapse via ctDNA assay.1,2 Although ESR1 mutations are rare in primary tumors (~1%), approximately 20-40% of patients with HR+ advanced metastatic breast cancer who have received prior endocrine therapy have detectable ESR1 mutations.3 This mutation is often a major mechanism of acquired resistance to aromatase inhibitors but enhanced sensitivity to SERDs such as imlunestrant.4
• Imlunestrant was granted accelerated approval by the FDA on September 25, 2025 for the above indication, based on the EMBER-3 trial.5,6
  • The EMBER-3 trial recruited 874 patients and evaluated the efficacy and safety of imlunestrant either alone or in combination with a CDK 4/6 inhibitor (abemaciclib) in patients with ER+, HER2-, locally advanced or metastatic breast cancer who had disease progression or recurrence during or after endocrine therapy with or without CDK4/6 inhibitor. Patients were randomized in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy (fulvestrant or exemestane), or imlunestrant with abemaciclib.6
  • Among the patients with ESR1 mutations, the median progression-free survival (PFS) was higher in patients who received imlunestrant at 5.5 months compared to 3.8 months in patients who received standard therapy.6
  • At the time of the interim analysis, overall survival (OS) at 18 months was 77% in the imlunestrant group and 58.6% in the standard therapy group with hazard ratio for death at 0.55, P=0.008 (OS data immature at this time)6.
  • The most common adverse events were fatigue (22.6%), diarrhea (21.4%). Each individual grade 3 adverse events occurred in <1% of patients.6
• Several other agents share similarities with imlunestrant as discussed below:
  • Fulvestrant is an injectable SERD approved both as a monotherapy and as part of combination therapy for HR+, metastatic breast cancer settings. In comparison to imlunestrant, fulvestrant’s intramuscular route of administration can be burdensome; fulvestrant has also demonstrated limited efficacy in ESR1 mutation patients.4,7
  • Elacestrant was the first oral SERD approved for ER+, HER-, ESR1-mutated advanced breast cancer. Elacestrant also acts similarly by degrading the ERα, but it exhibits a dose-dependent mixed ER agonist-antagonist activity. In contrast, imlunestrant is a SERD designed for continuous ER inhibition and has CNS penetration properties.1,8
  • Similar to imlunestrant, elacestrant demonstrated a statistically significant PFS benefit compared to standard endocrine therapy in patients with ESR1 mutations.9 At this time, the overall survival benefit for both elacestrant and imlunestrant is unclear.
  • Both elacestrant and imlunestrant are in the same line of therapy, however it is rational to utilize imlunestrant in the setting of brain metastases with its CNS penetration properties.6

What role can the pharmacist play in the management of patients on imlunestrant?

• Pharmacists can play a critical role in the management of imlunestrant, ensuring appropriateness of therapy, dosing and administration, dose adjustments, and safety management.1
• Appropriateness of therapy
  • Imlunestrant requires mandatory ESR1 mutation testing using the FDA approved companion diagnostic, Guardant 360 CDx. Patients are eligible to receive imlunestrant for ER+, HER-, ESR1 mutated advanced or metastatic breast cancer who have progressed on at least one prior line of endocrine therapy (with or without CDK4/6 inhibitor).1
• Dosing and administration1
  • The recommended dose of imlunestrant is 400 mg orally once daily (2x 200 mg tablets) taken on an empty stomach – at least 2 hours before food or 1 hour after food, and is continued until disease progression or unacceptable toxicity. (A low-fat meal can double the area under the curve [AUC] and increase peak concentrations [Cmax] by 3.6-fold).1
  • If a patient misses a dose by 6 or more hours, or if vomiting occurs after taking a dose, patient can be instructed to skip the dose and take the next dose the following day at its regular schedule.1 Two doses should not be taken in the same day.
  • Imlunestrant should not be split, crushed, or chewed and patients should be instructed to swallow tablets whole.1
  • Pre/perimenopausal patients should receive gonadotropin-releasing hormone agonists (GnRH) such as goserelin and leuprolide during treatment with imlunestrant.1
  • Renal impairment: no dose adjustments recommended.1
  • Hepatic impairment1:
    • Mild hepatic impairment (Child-Pugh A): no dose adjustment required
    • Moderate hepatic impairment (Child-Pugh B): 200 mg once daily
    • Severe hepatic impairment (Child-Pugh C): 200 mg once daily
  • The package insert provides instructions regarding dosing, holding, and discontinuation for hepatotoxicity and general adverse events based on severity. Refer to the package insert for specific instructions.1
  • When a dose reduction is recommended, the first recommended reduced dose is 200 mg once daily. If another dose reduction is recommended but the patient is unable to tolerate the 200 mg dose, then permanent discontinuation of the agent is recommended.1
  • Drug-drug interactions
    • Imlunestrant is a CYP3A substrate
      • If concurrent use with strong CYP3A inhibitors are unavoidable, reduce imlunestrant dose to 200 mg once daily.1
      • If concurrent use with strong CYP3A inducers are unavoidable, increase imlunestrant dose to 600 mg daily.1
    • Imlunestrant is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor.1
      • Clinically significant P-gp substrates include digoxin, dabigatran, and colchicine.1
      • Notable BCRP substrates include rosuvastatin and sulfasalazine.1
      • Interactions may increase the risk of adverse reactions related to the substrates; dose adjustments or close monitoring may be necessary especially when imlunestrant is co-administered with narrow therapeutic index medications.1
• Adverse Events
  • The safety profile of imlunestrant monotherapy was evaluated in 327 patients who received imlunestrant monotherapy in EMBER-3. All-grade adverse events occurred in 83% of patients, with Grade ≥3 adverse events occurred in 17% of patients. The majority of adverse events were Grade 1.6
  • The most common adverse events were fatigue (22.6%), diarrhea (21.4%), nausea (17.1%), arthralgia (14.1%). Each individual grade 3 adverse event occurred in <1% of the patients.6
  • The discontinuation rate due to adverse events was low at 4%, with dose reductions only occurring in 2% of the patients.1,6
  • Hepatotoxicity: Monitor AST/ALT regularly and adjust doses per package insert instructions. Discontinue if severe or if concurrent hyperbilirubinemia develops.1
  • GI toxicity: For nausea and diarrhea, provide supportive care such as antiemetics and antidiarrheals. If grade 3/4 toxicity occurs, suspend imlunestrant and resume at a lower dose.1
  • Metabolic effects: hypercholesterolemia and hypertriglyceridemia may happen with imlunestrant. Monitor lipid levels prior to and during treatment, and manage as appropriate.1

Clinical Pearls

• Biomarker testing
  • ESR1 mutation testing is required via circulating tumor DNA (ctDNA) to identify eligible patients for imlunestrant. The Guardant360 CDx assay is the FDA-approved companion diagnostic affiliated with imlunestrant.5
• Dosage form and storage
  • Imlunestrant is available as a white 200 mg, film-coated tablet, provided in a 28-count or 56-count bottle.1
  • The medication should be stored at room temperature between 68°F to 77°F (20°C to 25°C).1
• Brain Penetration
  • EMBER-3 trial allowed enrollment of patients with clinically stable brain metastases. The CNS progression was 1.6% with imlunestrant vs 3.0% with standard therapy. Imlunestrant appears to have CNS activity, though CNS-specific assessment evidence is limited due to small sample size.6
• Treatment sequencing
  • Imlunestrant is indicated after the progression on at least one line of endocrine therapy. In the EMBER-3 trial, 67% of ESR1-mutation patients in the imlunestrant arm received a CDK4/6 inhibitor in a prior line of therapy. The optimal sequencing of SERDs for ESR1 mutations with other treatment options such as PI3K inhibitors require further assessment. Of note, exclusion criteria of the EMBER-3 trial included those that were previously on any SERD, PI3K-, mTOR-, or AKT-inhibitor.6
• Combination Therapy
  • While the FDA has approved imlunestrant as a monotherapy indication, the EMBER-3 trial also evaluated imlunestrant plus abemaciclib, which achieved median PFS of 9.4 months versus 5.5 months of imlunestrant alone, regardless of ESR1 mutation status. While there were increased safety concerns with the combination, this regimen may represent a future treatment option pending additional regulatory review.5,6,10
• Patient Access – Eli Lilly provides several support programs for imlunestrant:
  • Inluriyo Savings Card: patients can potentially pay $0 a month if eligible with commercial insurance and coverage with imlunestrant.11
  • Interim Access Program for Inluriyo: may provide a no-cost, temporary supply to insured, eligible patients who are experiencing a delay in an insurance coverage decision.11
  • Assistance Determining Insurance Coverage: may help patients minimize copay or out-of-pocket costs by analyzing the lowest cost, specialty pharmacy option.11

References

1.Inluriyo (imlunestrant) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2025.

2.Burstein HJ, DeMichele A, Somerfield MR, Henry NL. Testing for ESR1 mutations to guide therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. 2023;41(18):34233425. doi:10.1200/JCO.23.00638

3.Zundelevich A, Dadiani M, Kahana-Edwin S, et al. ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis. Breast Cancer Res. 2020;22(1):16. doi:10.1186/s13058-020-1246-5

4.Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. Published 2021 Aug 15. doi:10.1186/s13058-021-01462-3

5.U.S. Food and Drug Administration. FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. September 2025. Accessed November 1st, 2025.

6.Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med. 2025;392(12):1090-1104. doi:10.1056/NEJMoa2410858

7.Robertson JF, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997-3005. doi:10.1016/S0140-6736(16)32389-3

8.Orserdu (elacestrant) [prescribing information]. Stemline Therapeutics, Inc.; January 2023.

9.Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.0033

10.O'Shaughnessy J, Bidard FC, Neven P, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Safety analyses from the phase III EMBER-3 trial. J Clin Oncol. 2025;43(16_suppl):1060. doi:10.1200/JCO.2025.43.16_suppl.1060

11.Eli Lilly and Company. Inluriyo (imlunestrant). Patient support information. www.inluriyo.com. Accessed October 25, 2025.