FDA Approves Imlunestrant Plus Abemaciclib for ER+, HER2–, ESR1-Mutated Metastatic Breast Cancer

The FDA has approved imlunestrant (Inluriyo) plus abemaciclib (Verzenio) for the treatment of adult patients with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, who experience disease progression after 1 or more lines of endocrine therapy.¹

This regulatory decision was backed by data from the phase 3 EMBER-3 trial (NCT04975308). An exploratory subgroup analysis in patients with ESR1-mutated disease (n = 159) showed a median progression-free survival (PFS) of 11.1 months (95% CI, 7.4-13.7) with imlunestrant plus abemaciclib (n = 67) vs 5.5 months (95% CI, 3.8-7.2) in the imlunestrant monotherapy arm (n = 92; estimated HR, 0.53; 95% CI, 0.35-0.80).^1,2 The overall response rates (ORRs) were 35% (95% CI, 22%-48%) vs 15% (95% CI, 7%-23%) in these respective arms, including complete response rates of 1.9% vs 1.4%, and partial response rates of 33% vs 14%, respectively. At the time of the interim analysis, the overall survival (OS) data were immature, and the death rate was 35% in the population of patients with ESR1-mutated disease.

The FDA simultaneously approved the Guardant360 CDx assay as a companion diagnostic to identify patients with breast cancer harboring ESR1 mutations who may be eligible for treatment with imlunestrant plus abemaciclib.¹

What was the design of EMBER-3?

This randomized, open-label, active-controlled, multicenter trial enrolled 874 adult patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had previously received an aromatase inhibitor either alone or in combination with a CDK4/6 inhibitor. Patients were not eligible to enroll if they were eligible for PARP inhibitor–based therapy.

Patients were randomly assigned 1:1:1 to receive imlunestrant, investigator’s choice of endocrine therapy (fulvestrant [Faslodex] or exemestane [Aromasin]), or imlunestrant plus abemaciclib. Randomization was stratified by prior treatment with a CDK4/6 inhibitor, the presence of visceral metastasis, and geographic region. ESR1 mutational status was determined by blood circulating tumor DNA analysis using the Guardant360 CDx assay.

Investigator-assessed PFS per RECIST 1.1 criteria in the overall population of patients in the imlunestrant/abemaciclib vs imlunestrant monotherapy arms served as the primary end point. Other key end points included OS and ORR.

What additional findings were seen in EMBER-3?

A PFS benefit was not seen with imlunestrant monotherapy vs investigator’s choice of endocrine therapy in either the overall population or the population of patients in whom ESR1 mutations were not detected.

Among safety-evaluable patients who received imlunestrant plus abemaciclib (n = 208), the most common grade 3/4 adverse effects were diarrhea (9%), infections (7%), fatigue (5%), nausea (1.9%), abdominal pain (1.9%), musculoskeletal pain (1.4%), rash (1.4%), decreased appetite (1%), vomiting (0.5%), and headache (0.5%). The most common laboratory abnormalities that worsened from baseline in patients who received the combination included decreased neutrophil counts (21%), decreased hemoglobin levels (9%), decreased lymphocyte counts (9%), increased alanine aminotransferase levels (5%), increased aspartate aminotransferase levels (2.5%), decreased platelet counts (2.4%), increased triglyceride counts (2.3%), and increased creatinine levels (1.1%).

The prescribing information for imlunestrant includes warnings and precautions for embryo-fetal toxicity.^1,2 The prescribing information for abemaciclib includes warnings and precautions for neutropenia, diarrhea, hepatotoxicity, interstitial lung disease or pneumonitis, venous thromboembolism, and embryo-fetal toxicity.¹

How is imlunestrant plus abemaciclib dosed?

The recommended dose of imlunestrant is 400 mg orally once daily, on an empty stomach 2 or more hours before eating or 1 hour after eating. The recommended dose of abemaciclib in this imlunestrant combination is 150 mg orally twice daily, with or without food, until disease progression or unacceptable toxicity.

References

1. FDA approves imlunestrant in combination with abemaciclib for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. September 18, 2026. Accessed September 18, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-combination-abemaciclib-er-positive-her2-negative-esr1-mutated-advanced-or
2. Inluriyo. Prescribing information. Lilly. Updated September 2026. Accessed September 18, 2026. https://pi.lilly.com/us/inluriyo-uspi.pdf?s=pi