Research Summary:
The EMBER-3 trial1 was a Phase III, open-label study that evaluated imlunestrant, a next-generation oral selective estrogen-receptor degrader (SERD) with brain-penetrant properties, in patients with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. The study enrolled patients whose disease had recurred or progressed during or after aromatase inhibitor therapy, administered alone or in combination with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, and investigated imlunestrant as monotherapy compared with standard endocrine therapy and imlunestrant combined with abemaciclib compared with imlunestrant monotherapy.
A total of 874 patients were enrolled at 195 sites across 22 countries from October 2021 through November 2023 and were assigned in a 1:1:1 ratio to receive imlunestrant 400mg once daily, standard endocrine monotherapy (oral exemestane 25mg once daily or intramuscular fulvestrant 500mg administered on Days 1 and 15 of Cycle 1 and on Day 1 of following 28-day cycles), or imlunestrant 400mg once daily plus oral abemaciclib 150mg twice daily. Eligible patients were women of any menopausal status or men 18 years of age or older with locally confirmed ER-positive, HER2-negative advanced breast cancer. Randomization was stratified according to previous CDK4/6 inhibitor treatment, presence or absence of visceral metastases, and geographic region. The three primary endpoints were investigator-assessed progression-free survival (PFS) with imlunestrant compared with standard therapy among patients with ESR1 mutations, with imlunestrant compared with standard therapy among all patients, and with imlunestrant–abemaciclib compared with imlunestrant monotherapy among all patients who had undergone randomization concurrently. Tumor assessments were performed at baseline, every eight weeks for the first 12 months, and then every 12 weeks until progression, and ESR1-mutation status was centrally determined in pretreatment blood samples.
A total of 331 patients were assigned to imlunestrant, 330 to standard therapy (with 292 receiving fulvestrant), and 213 to imlunestrant–abemaciclib. Among the 256 patients with ESR1 mutations across the imlunestrant and standard-therapy groups, the median PFS was 5.5 months (95% confidence interval [CI]: 3.9–7.4) with imlunestrant and 3.8 months (95% CI: 3.7–5.5) with standard therapy, and the estimated restricted mean survival time at 19.4 months was 7.9 months (95% CI: 6.8–9.1) with imlunestrant and 5.4 months (95% CI: 4.6–6.2) with standard therapy, yielding a difference of 2.6 months (95% CI: 1.2–3.9; p<0.001). In the overall population of 661 patients, the median PFS was 5.6 months (95% CI: 5.3–7.3) with imlunestrant and 5.5 months (95% CI: 4.6–5.6) with standard therapy (hazard ratio [HR] for progression or death: 0.87; 95% CI: 0.72–1.04; p=0.12). Post hoc analyses showed that the 12-month cumulative incidence of central nervous system (CNS) progression was 1.5 percent with imlunestrant and 6.7 percent with standard therapy among patients with ESR1 mutations.
Among the 426 patients in the imlunestrant–abemaciclib versus imlunestrant comparison, the median PFS was 9.4 months (95% CI: 7.5–11.9) with imlunestrant–abemaciclib and 5.5 months (95% CI: 3.8–5.6) with imlunestrant monotherapy (HR: 0.57; 95% CI: 0.44–0.73; p<0.001), with similar treatment effects observed regardless of ESR1 mutation status or phosphatidylinositol 3-kinase (PI3K) pathway mutation status.
The incidence of Grade 3 or greater adverse events (AEs) was 17.1 percent with imlunestrant monotherapy, 20.7 percent with standard therapy, and 48.6 percent with imlunestrant–abemaciclib. The most frequently reported any-grade AEs in the imlunestrant monotherapy group were fatigue, diarrhea, and nausea (predominantly Grade 1). In the imlunestrant–abemaciclib group, the most commonly reported any-grade AEs were diarrhea, nausea, neutropenia, and anemia.
The EMBER-3 trial demonstrated that treatment with imlunestrant led to significantly longer PFS compared to standard therapy among patients with ER-positive, HER2-negative advanced breast cancer with ESR1 mutations, while imlunestrant–abemaciclib significantly improved PFS compared with imlunestrant alone regardless of ESR1-mutation status. The benefit of imlunestrant over standard therapy was more pronounced in patients with ESR1 mutations than in those without such mutations, which was consistent with findings from other trials of new SERDs. The safety profile of imlunestrant monotherapy was favorable, with mainly low-grade AEs and low percentages of dose reduction and discontinuation, and the safety profile of imlunestrant–abemaciclib was consistent with the known profile of fulvestrant–abemaciclib. Additionally, the lower incidence of CNS progression with imlunestrant versus standard therapy among patients with ESR1 mutations suggests a potential benefit related to the brain-penetrant properties of imlunestrant. Although PFS was not significantly prolonged with imlunestrant monotherapy in the overall population, the combination of imlunestrant–abemaciclib led to a substantial advantage in PFS among all patients, and this treatment effect was consistent across clinically relevant subgroups, including patients with prior CDK4/6 inhibitor treatment.
Reference
Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189–1202.