FDA Approves Imlunestrant for ER+, HER2-Negative, ESR1-Mutated Metastatic Breast Cancer

The FDA has approved imlunestrant (Inluriyo) for the treatment of adult patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations whose disease has progressed following 1 or more prior lines of endocrine therapy.1,2

The FDA has also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with ESR1-mutated breast cancer who are eligible to receive treatment with imlunestrant.2

This regulatory decision was supported by data from the phase 3 EMBER-3 trial (NCT04975308), in which treatment with imlunestrant monotherapy led to a 38% reduction in the risk of progression or death compared with endocrine therapy in patients with ESR1-mutated metastatic breast cancer (n = 256).1,2 In this population, the median progression-free survival (PFS) was 5.5 months (95% CI, 3.9-7.4) with imlunestrant (n = 138) vs 3.8 months (95% CI, 3.7-5.5) with fulvestrant (Faslodex) or exemestane (Aromasin; n = 118; HR, 0.62; 95% CI, 0.46-0.82; P = .0008).1,2,3

"This represents an important advancement for patients with ESR1-mutated metastatic breast cancer, a mutation found in nearly half of patients who have taken hormone therapies, often contributing to treatment resistance," Komal Jhaveri, MD, FACP, FASCO, section head of Endocrine Therapy Research and clinical director of Early Drug Development at Memorial Sloan Kettering Cancer Center in New York, New York, as well as a principal investigator of EMBER-3, stated in a news release.1 "With its demonstrated efficacy, tolerability profile and oral administration, this therapy provides a meaningful alternative treatment option for this patient population."

What Was the Design of the EMBER-3 Trial?

EMBER-3 enrolled adult patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who had disease recurrence or progression during or following treatment with an adjuvant aromatase inhibitor with or without a CDK4/6 inhibitor.1,4

Investigator-assessed PFS served as the trial's primary end point.4 Key secondary end points in the population of patients with ESR1 mutations included overall survival, PFS by blinded independent central review, overall response rate (ORR), duration of response, and clinical benefit rate.

Patients were randomly assigned to receive imlunestrant, investigator's choice of endocrine therapy, or imlunestrant plus abemaciclib (Verzenio). Patients in the imlunestrant arms received imlunestrant at 400 mg oraly once daily on days 1 through 28 of each 28-day cycle. All patients were treated until disease progression or until they met criteria for treatment discontinuation.

What Additional Efficacy Findings Were Seen in EMBER-3?

In total, 874 patients were enrolled, 32% of whom were enrolled from the adjuvant setting into first-line metastatic breast cancer treatment, and 64% of whom were enrolled following progression on initial metastatic breast cancer therapy into the second-line setting.1

Among patients in the imlunestrant arm with measurable disease (n = 112), the ORR was 14.3% (95% CI, 7.8%-20.8%), the complete response rate was 0.9%, and the partial response rate was 13.4%.2,3 Among patients with measurable disease in the endocrine therapy arm (n = 91), the ORR was 7.7% (95% CI, 2.2%-13.2%); all responses were partial.

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

What Was the Safety Profile of Imlunestrant in EMBER-3?

Most adverse effects (AEs) observed with imlunestrant were grade 1/2.1,2 The most common AEs occurring in at least 10% of patients included decreased hemoglobin levels, musculoskeletal pain, decreased calcium levels, decreased neutrophil levels, increased aspartate aminotransferase levels, fatigue, diarrhea, increased alanine aminotransferase levels, increased triglyceride levels, nausea, decreased platelet counts, constipation, increased cholesterol levels, and abdominal pain. In total, 4.6% of patients who received imlunestrant permanently discontinued treatment due to AEs. Additionally, 2.4% of patients in this population required imlunestrant dose reductions, and 10% of patients required imlunestrant dose interruptions.

"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, added in the news release.1 "We are deeply grateful to the patients, investigators, Lilly team members and clinical care teams who made this advancement possible. This therapy has the potential to make the treatment journey more manageable for those living with breast cancer."

What Are the Next Steps for Evaluating Imlunestrant in Breast Cancer?

Imlunestrant is under further investigation in the ongoing phase 3 EMBER-4 trial (NCT05514054) as adjuvant therapy in patients with ER-positive, HER2-negative early breast cancer at increased risk of recurrence.

References

1. U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. 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. FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. September 25, 2025. Accessed September 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
3. Inluriyo. Prescribing information. Lilly; September 2025. Accessed September 25, 2025. https://pi.lilly.com/us/inluriyo-uspi.pdf?s=pi&redirect-referrer=https%3A%2F%2Finvestor.lilly.com%2F
4. 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. Updated July 11, 2025. Accessed September 25, 2025. https://clinicaltrials.gov/study/NCT04975308?term=ember-3&rank=1