FDA Approves Imlunestrant Combo in ESR1-Mutated Breast Cancer

The FDA has granted full approval to imlunestrant (Inluriyo) plus abemaciclib (Verzenio) for adult patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations as detected by an FDA-approved test following progression on at least 1 line of endocrine therapy, according to a press release from the developer, Eli Lilly and Company.¹

Supporting data for the approval came from the phase 3 EMBER-3 trial (NCT04975308), which demonstrated a clinical benefit when switching to combination therapy with imlunestrant plus abemaciclib at the time of progression. Among patients with ESR1-mutated metastatic breast cancer, the median progression-free survival (PFS) was 11.1 months in patients who received imlunestrant plus abemaciclib (n = 67) following an aromatase inhibitor vs 5.5 months in patients who received imlunestrant alone (n = 92; HR, 0.53; 95% CI, 0.35-0.80).

Most adverse effects (AEs) with the combination in the EMBER-3 trial were grades 1 or 2. The most common toxicities included decreased neutrophils, diarrhea, decreased hemoglobin, decreased lymphocytes, nausea, decreased platelets, fatigue, increased triglycerides, infections, increased aspartate aminotransferase, and increased creatinine. In the combination arm, 1% of patients discontinued imlunestrant due to AEs, and 3.4% discontinued abemaciclib due to toxicities.

“We have an urgent need for effective and safe treatment options for patients with disease progression on adjuvant or first-line therapy. Combining therapies that work on two distinct drivers of tumor growth—the [ER] and CDK4/6—is an important strategy to help address treatment resistance,” principal investigator Komal Jhaveri, MD, FACP, FASCO, an associate attending in Breast Medicine and Early Drug Development Services and section head of the Endocrine Therapy Research Program at Memorial Sloan Kettering Cancer Center, stated in the press release regarding the approval.¹ “In EMBER-3, switching both the endocrine therapy and CDK 4/6 inhibitor, for the majority of patients, to imlunestrant plus abemaciclib at disease progression achieved a median [PFS] of 11.1 months and a safety profile consistent with that of each medicine individually, establishing a meaningful new treatment option.”

Developers designed imlunestrant as an orally available agent that continuously inhibits ER, even in patients with ESR1-mutated disease. Abemaciclib was designed as a CDK4/6 inhibitor to treat patients with hormone receptor–positive, HER2-negative breast cancer in the adjuvant and advanced or metastatic settings.

In the EMBER-3 trial, 874 patients with previously treated, ER-positive, HER2-negative advanced breast cancer were randomly assigned to imlunestrant monotherapy (n = 331), imlunestrant plus abemaciclib (n = 213), or investigator’s choice of standard-of-care endocrine therapy with exemestane or fulvestrant (n = 330).² Imlunestrant was given at 400 mg orally once daily, and abemaciclib was administered at 150 mg orally twice daily. Treatment cycles occurred across 28 days.

The trial’s primary end points were PFS per investigator assessment for single-agent imlunestrant vs standard of care in all patients and in patients with ESR1 mutations, as well as PFS for imlunestrant plus abemaciclib vs imlunestrant in all patients. Overall survival was a key secondary end point.

Previously, the FDA approved imlunestrant monotherapy for those with ER-positive HER2-negative ESR1-mutated breast cancer in September 2025 based on findings from the EMBER-3 trial.³

“Today’s full approval extends what [imlunestrant] in combination with [abemaciclib] can do for patients, with a regimen that has confirmed benefit, is aligned to the clinically proven treatment paradigm of changing therapy at clinical progression, and doesn’t introduce burdensome monitoring requirements for patients or physicians. In fact, all available evidence suggests that switching endocrine therapy and CDK4/6 inhibitor at clinical progression improves patient outcomes more than switching therapy earlier. Utilizing this evidence-based practice spares early exposure to additional [AEs], reduces patient anxiety from unnecessary testing, and mitigates avoidable costs to the healthcare system,” Jacob Van Naarden, executive vice president and president of Lilly Oncology, noted in the press release.¹

References

1. U.S. FDA approves Inluriyo (imlunestrant) in combination with Verzenio (abemaciclib) for adults with ER+, HER2–, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 18, 2026. Accessed September 18, 2026. https://tinyurl.com/yp8x9r9x
2. Jhaveri KL, Neven P, Casalnuovo M, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. GS3-08.
3. 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 18, 2026. https://tinyurl.com/2fexwcem