The U.S. Food and Drug Administration (FDA) has approved imlunestrant, an estrogen receptor antagonist, for adults with estrogen receptor (ER)-positive, HER2-negative, estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after 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.
EMBER-3
Efficacy was evaluated in EMBER-3 (ClinicalTrials.gov identifier NCT04975308), a randomized, open-label, active-controlled, multicenter trial that enrolled 874 patients 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 an additional investigational combination regimen. 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 was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 comparing imlunestrant with the investigator’s choice of endocrine therapy in patients with ESR1-mutated tumors. Other efficacy outcome measures included overall survival and objective response rate.
In the ESR1-mutated population (n = 256), a statistically significant difference in investigator-assessed progression-free survival for imlunestrant compared with investigator’s choice of endocrine therapy was observed. The median progression-free survival was 5.5 months (95% confidence interval [CI] = 3.9–7.4 months) in the imlunestrant arm and 3.8 months (95% CI = 3.7–5.5 months) in the investigator's choice arm (hazard ratio = 0.62. 95% CI = 0.46–0.82; P = .0008). The objective response rate was 14.3% in the imlunestrant arm and 7.7% in the investigator’s choice arm. At the time of the progression-free survival analysis, overall survival data were immature, with 31% of deaths occurring in the ESR1-mutated population.
The most common adverse events (occurring in at least 10% of patients receiving imlunestant), including laboratory abnormalities, were decreased hemoglobin, musculoskeletal pain, decreased calcium, decreased neutrophils, increased aspartate transaminase, fatigue, diarrhea, increased alanine transaminase, increased triglycerides, nausea, decreased platelets, constipation, increased cholesterol, and abdominal pain.
The recommended imlunestrant dose is 400 mg orally once daily (on an empty stomach at least 2 hours before food or 1 hour after 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. Imlunestrant was granted Fast Track designation.
