The U.S. Food and Drug Administration (FDA) has approved imlunestrant (Inluriyo) in combination with abemaciclib (Verzenio) for adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer. The approval applies to patients whose disease has progressed following at least one line of endocrine therapy, with ESR1 mutations identified using an FDA-authorised test. Eli Lilly and Company manufactures both Inluriyo and Verzenio. In addition, the FDA approved the Guardant360 CDx assay as a companion diagnostic to identify patients with breast cancer who have ESR1 mutations and may be treated with the imlunestrant and abemaciclib combination.
Approval Supported by EMBER-3 Clinical Trial
The FDA based the efficacy evaluation on the EMBER-3 trial (NCT04975308), a randomised, open-label, active-controlled, multicentre study involving 874 adults with ER-positive, HER2-negative, locally advanced or metastatic breast cancer. Participants had previously received an aromatase inhibitor, either alone or with a CDK4/6 inhibitor. Patients eligible to receive a PARP inhibitor were excluded from the study.
Researchers randomly assigned participants in a 1:1:1 ratio to receive:
Imlunestrant
Investigator’s choice of endocrine therapy — fulvestrant or exemestane
Imlunestrant combined with abemaciclib
The trial stratified randomisation according to previous CDK4/6 inhibitor treatment, visceral metastasis and geographic region.
ESR1 Mutations Identified Using Companion Diagnostic
Researchers determined ESR1 mutational status through blood-based circulating tumour DNA (ctDNA) analysis using the Guardant360 CDx assay. The analysis focused on specific ESR1 mutations located in the ligand-binding domain. The results indicated that the observed treatment benefit was concentrated in patients with ESR1-mutated tumours. In contrast, imlunestrant monotherapy did not demonstrate improved progression-free survival (PFS) compared with investigator-selected endocrine therapy in either the overall population or the ESR1 mutation-not-detected population.
Imlunestrant Combination Improves Progression-Free Survival
The primary efficacy endpoint for the combination was investigator-assessed progression-free survival (PFS) according to RECIST v1.1. Investigators compared imlunestrant plus abemaciclib with imlunestrant alone in the overall study population. In an exploratory analysis involving 159 patients with ESR1-mutated tumours, the estimated PFS hazard ratio was 0.53 (95% CI: 0.35–0.80).
Among these patients:
| Treatment | Median PFS | Objective Response Rate |
| Imlunestrant + abemaciclib | 11.1 months | 35% |
| Imlunestrant alone | 5.5 months | 15% |
The median PFS was 11.1 months (95% CI: 7.4–13.7) with the combination compared with 5.5 months (95% CI: 3.8–7.2) with imlunestrant alone.
The objective response rate (ORR) was 35% (95% CI: 22–48) for the combination and 15% (95% CI: 7–23) for imlunestrant alone.
At the interim analysis, overall survival (OS) data remained immature, with 35% of deaths reported among patients with ESR1-mutated tumours.
Safety Warnings and Precautions
The prescribing information for imlunestrant includes warnings and precautions related to embryo-fetal toxicity.
Meanwhile, abemaciclib carries warnings and precautions for:
Diarrhea
Neutropenia
Interstitial lung disease or pneumonitis
Hepatotoxicity
Venous thromboembolism
Embryo-fetal toxicity
Healthcare professionals should refer to the approved prescribing information for complete safety and administration details.
Recommended Dosage
The recommended dosage of imlunestrant is 400 mg orally once daily. Patients should take it on an empty stomach at least two hours before food or one hour after food. When used in combination with imlunestrant, the recommended dose of abemaciclib is 150 mg orally twice daily, with or without food. Patients should continue treatment until disease progression or unacceptable toxicity, as determined according to the prescribing information.
New Treatment Option for ESR1-Mutated Breast Cancer
The FDA approval introduces an imlunestrant and abemaciclib combination for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following progression on at least one line of endocrine therapy. As per the FDA press release, the approval also highlights the role of companion diagnostics in identifying specific tumour mutations and supporting treatment selection in advanced breast cancer.