FDA Approves Imlunestrant Plus Abemaciclib for ESR1-Mutated Advanced Breast Cancer

Clinical Summary: 

• Regulatory Update: The FDA approved imlunestrant in combination with abemaciclib for adults with ESR1-mutated, ER-positive, HER2-negative advanced or metastatic breast cancer whose disease progressed following at least 1 line of endocrine therapy.
• Key Outcomes: In an exploratory subgroup of patients with ESR1-mutated tumors in the phase 3 EMBER-3 trial, imlunestrant plus abemaciclib prolonged progression-free survival and produced a higher objective response rate compared with imlunestrant alone. Overall survival data remain immature.
• Clinical Relevance: The approval establishes an ESR1 mutation–selected treatment strategy combining an oral estrogen receptor antagonist with CDK4/6 inhibition following endocrine therapy, with the Guardant360 CDx assay approved as a companion diagnostic to identify eligible patients.

The US Food and Drug Administration (FDA) has approved imlunestrant (Inluriyo; Eli Lilly and Company) in combination with abemaciclib (Verzenio; Eli Lilly and Company) for adults with ESR1-mutated, ER-positive, HER2-negative advanced or metastatic breast cancer whose disease progressed following at least 1 line of endocrine therapy.

This approval was supported by findings from the randomized, open-label, phase 3 EMBER-3 trial, which enrolled 874 patients previously treated with an aromatase inhibitor alone or in combination with a CDK4/6 inhibitor. Patients were randomized 1:1:1 to receive either imlunestrant monotherapy, investigator’s choice of endocrine therapy with fulvestrant or exemestane, or imlunestrant plus abemaciclib. Randomization was stratified according to prior CDK4/6 inhibitor treatment, presence of visceral metastases, and geographic region. Patients eligible for treatment with a PARP inhibitor were excluded from trial enrollment. 

ESR1 mutation status was determined through blood-based circulating tumor DNA (ctDNA) testing using the Guardant360 CDx assay and was limited to specified mutations within the ESR1 ligand-binding domain.

The major efficacy end point for the combination was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1 in the overall population, comparing imlunestrant plus abemaciclib with imlunestrant monotherapy. Additional efficacy end points included overall survival (OS) and investigator-assessed objective response rate (ORR).

In an exploratory analysis of 159 patients with ESR1-mutated tumors, median PFS was 11.1 months with imlunestrant plus abemaciclib compared with 5.5 months with imlunestrant alone. The combination was associated with a 47% reduction in the risk of disease progression or death (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.35 to 0.80).

ORR was 35% with imlunestrant plus abemaciclib compared with 15% with imlunestrant monotherapy.

At the interim analysis, OS data remained immature, with 35% of deaths required for the analysis having occurred among patients with ESR1-mutated tumors.

Although imlunestrant plus abemaciclib significantly improved PFS compared with imlunestrant monotherapy in the overall study population, imlunestrant monotherapy did not demonstrate a PFS improvement over investigator’s choice of endocrine therapy in the overall population or among patients without detected ESR1 mutations. According to the FDA, these findings indicated that the relevant benefit was observed in the ESR1-mutated population.

The recommended dose of imlunestrant is 400 mg orally once daily on an empty stomach, administered at least 2 hours before or 1 hour after food. Abemaciclib is administered at 150 mg orally twice daily, with or without food. Treatment should continue until disease progression or unacceptable toxicity.

The imlunestrant prescribing information includes a warning and precaution for embryo-fetal toxicity. Warnings and precautions for abemaciclib include diarrhea, neutropenia, interstitial lung disease/pneumonitis, hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.

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

The approval provides a biomarker-selected treatment option for patients with ESR1-mutated disease following endocrine therapy and incorporates blood-based ctDNA testing to identify patients eligible for the combination.

Source: 

US Food and Drug Administration. FDA approves imlunestrant in combination with abemaciclib for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Accessed on 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