On September 18, the U.S. Food and Drug Administration (FDA) approved imlunestrant (Inluriyo) in combination with abemaciclib (Verzenio) for adults with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.
The FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with imlunestrant and abemaciclib.
EMBER-3
Efficacy was evaluated in EMBER-3 (ClinicalTrials.gov identifier NCT04975308), a randomized, open-label, active-controlled, multicenter trial that enrolled 874 adults with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor either alone or in combination with a CDK4/6 inhibitor. Patients were excluded if they were eligible to receive a PARP inhibitor.
Patients were randomly assigned 1:1:1 to receive either imlunestrant, an investigator’s choice of endocrine therapy (fulvestrant or exemestane), or imlunestrant in combination with abemaciclib. Randomization was stratified by previous treatment with a CDK4/6 inhibitor, presence of visceral metastasis, and geographic region. ESR1 mutational status was determined by blood circulating tumor DNA analysis using the Guardant360 CDx assay and was limited to specific ESR1 mutations in the ligand-binding domain.
The major efficacy outcome measure for the combination of imlunestrant with abemaciclib was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 in the overall population, comparing imlunestrant plus abemaciclib to imlunestrant monotherapy. Other efficacy outcome measures included overall survival and investigator-assessed objective response rate.
While the comparison of progression-free survival between imlunestrant in combination with abemaciclib vs imlunestrant monotherapy in the overall population was statistically significant, a progression-free survival improvement was not demonstrated for imlunestrant monotherapy compared to investigator’s choice of endocrine therapy in either the overall or ESR1 mutation–not-detected populations, indicating that the benefit was only observed in the ESR1-mutant population.
In an exploratory subgroup analysis in 159 patients with ESR1-mutated tumors for the combination, the progression-free survival hazard ratio estimate was 0.53 (95% confidence interval [CI] = 0.35–0.80). Median progression-free survival in patients with ESR1-mutated tumors was 11.1 months (95% CI = 7.4–13.7 months) in the imlunestrant and abemaciclib arm and 5.5 months (95% CI = 3.8–7.2 months) in the imlunestrant alone arm. Objective response rate was 35% (95% CI = 22%–48%) and 15% (95% CI = 7%–23%) in the respective arms. At the time of interim analysis, overall survival data were immature, with 35% of deaths in patients with ESR1-mutated tumors.
The imlunestrant prescribing information includes warnings and precautions for embryo-fetal toxicity. The abemaciclib prescribing information includes warnings and precautions for diarrhea, neutropenia, interstitial lung disease or pneumonitis, hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.
Recommended Dosage
The recommended dosage of imlunestrant is 400 mg orally once daily (on an empty stomach at least 2 hours before food or 1 hour after food) and the recommended dosage of abemaciclib in combination is 150 mg orally twice daily (with or without food) until disease progression or unacceptable toxicity.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
