FDA Approves Imlunestrant Tablets for ER+, HER2–, ESR1-Mutated Advanced or Metastatic Breast Cancer

The FDA approved imlunestrant 200-mg tablets (Inluriyo; Eli Lilly & Co) for the treatment of adults with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2–), ESR1-mutated advanced or metastatic breast cancer (MBC) whose disease has progressed following at least 1 line of endocrine therapy. The approval is supported by results from the EMBER-3 clinical trial (NCT04975308), according to a news release from the manufacturer.^1,2

Imlunestrant is an oral estrogen receptor antagonist that delivers continuous ER inhibition, even in ESR1-mutant cancers. ER is the key therapeutic target for patients with ER+, HER2– breast cancer. It is recommended that imlunestrant is administered as a once-daily dose of 400 mg taken on an empty stomach, at least 2 hours before or 1 hour after eating. Currently, the treatment is also undergoing investigation when used in combination with abemaciclib (Verzenio; Eli Lilly & Co) for advanced breast cancer and as an adjuvant treatment in early breast cancer.¹

"This therapy reflects our commitment to developing treatments that improve outcomes for people with breast cancer and represents an important step toward advancing innovative, all-oral treatment approaches," Jacob Van Naarden, executive vice president and president of Lilly Oncology, said in a news release.¹

EMBER-3 is a randomized, open-label phase 3 clinical trial that assessed imlunestrant compared with imlunestrant and abemaciclib and endocrine therapy in patients with ER+, HER2–, locally advanced or MBC whose disease has either recurred or progressed following therapy with an aromatase inhibitor with or without a CDK4/6 inhibitor. A total of 874 patients were randomly assigned to a treatment group (imlunestrant alone: n = 331; imlunestrant with abemaciclib: n = 213; endocrine therapy: n = 330), and among this population, 256 were observed to have ESR1 mutations.^1-3

The primary end point of the study was investigator-assessed progression-free survival (PFS), and secondary end points included PFS between treatment arms, duration of response, objective response rate, clinical benefit rate, overall survival, and safety. Results were published in The New England Journal of Medicine.^1-3

Among the subpopulation of 256 patients with ESR1 mutations, the median PFS was about 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% CI 6.8–9.1) with imlunestrant and 5.4 months (95% CI 4.6–6.2) with endocrine therapy (difference: 2.6 months [95% CI 1.2–3.9]; P < .001).³

In the overall population, the median PFS was 5.6 months with imlunestrant and 5.5 months with endocrine therapy (HR for progression or death: 0.87 [95% CI 0.72–1.04]; P = .12). Among the 426 patients in the comparison of imlunestrant plus abemaciclib with imlunestrant alone, the median PFS was 9.4 months for the combination therapy and 5.5 months for the monotherapy (HR: 0.57 [95% CI, 0.44–0.73]; P < .001).³

"This [approval] 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," principal study investigator Komal Jhaveri, MD, FACP, FASCO, section head of endocrine therapy research and clinical director of early drug development at Memorial Sloan Kettering Cancer Center, said in a news release. "With its demonstrated efficacy, tolerability profile and oral administration, this therapy provides a meaningful alternative treatment option for this patient population."¹

Regarding adverse events (AEs), the investigators observed an incidence of grade 3 or higher AEs of about 17.1% with imlunestrant, 20.7% with endocrine therapy, and 48.6% with imlunestrant plus abemaciclib.³ Most AEs with imlunestrant were low grade, and the most common included laboratory abnormalities, musculoskeletal pain, fatigue, diarrhea, nausea, constipation, and abdominal pain, among others. Throughout the trial, only 4.6% of patients permanently discontinued treatment because to AEs. Dose reductions and dose interruptions occurred in approximately 2.4% and 10% of patients, respectively.¹

"The approval of [imlunestrant] expands the metastatic breast cancer treatment landscape for patients who test positive for the ESR1 mutation," Jean Sachs, CEO of Living Beyond Breast Cancer, said in the news release. "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."¹

REFERENCES

1. Lilly. U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. September 25, 2025. Accessed September 25, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-inluriyo-imlunestrant-adults-er-her2-esr1

2. 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 identifier: NCT04975308. Updated July 11, 2025. Accessed September 25, 2025. https://clinicaltrials.gov/study/NCT04975308

3. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med. 2025;392:1189-1202. doi:10.1056/NEJMoa241085