Primary progression-free survival (PFS) results from the phase III EMBER-3 study of imlunestrant as compared with standard therapy and of imlunestrant–abemaciclib as compared with imlunestrant in patients with ER-positive, HER2-negative advanced breast cancer (ABC) that had progressed during or after aromatase inhibitor (AI) therapy with or without a CDK4/6 inhibitor indicate that imlunestrant significantly improved PFS over standard therapy among patients with ESR1 mutations and imlunestrant–abemaciclib improved PFS over imlunestrant in all patients.
Imlunestrant showed mainly low-grade side effects as monotherapy and in combination with abemaciclib and provides an oral targeted therapy option after progression during endocrine therapy in patients with ER-positive, HER2-negative ABC according to Dr. Komal L. Jhaveri of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues, who presented the findings at San Antonio Breast Cancer Symposium along with a simultaneous publication in The New England Journal of Medicine on 11 December 2024.
The authors wrote in the background that enhancements to endocrine therapy have incrementally improved outcomes by means of continued ER targeting by different mechanisms. These mechanisms include selective ER modulators and selective ER degraders that directly antagonise ER as well as aromatase inhibitors that block oestrogen production and that can subsequently lead to resistance by ESR1 mutation. New oral selective ER degraders may effectively target the ESR1 mutations. CDK4/6 inhibitors have been a critical addition to endocrine therapy and are commonly combined with AIs as first-line therapy for ER-positive, HER2-negative ABC.
Fulvestrant is the only selective ER degrader that has been broadly approved both as monotherapy and as part of combination therapy, in which it is most combined with PI3K, AKT, and mTOR or CDK4/6 inhibitors. Despite its broad use, fulvestrant has substantial disadvantages. Poor oral bioavailability necessitates intramuscular administration, which limits its dose and thereby its dose-dependent efficacy. Furthermore, the injections can be painful and burdensome to patients, mainly requiring in-office administration, and oral options may be preferred. The efficacy of fulvestrant is also limited in patients with ESR1 mutations.
Given these limitations, new oral selective ER degraders have been developed with the goal of improving both efficacy and patient experience by means of ease of administration. Imlunestrant is a next-generation, brain-penetrant, oral selective ER degrader and pure ER antagonist that delivers continuous ER inhibition, even in ESR1-mutated breast cancer. In the phase I EMBER study, imlunestrant, as monotherapy and in combination with abemaciclib, showed mainly low-grade side effects, favourable pharmacokinetics, and encouraging antitumour activity in patients with ER-positive, HER2-negative ABC.
In a phase III, open-label EMBER-3 study, the investigators enrolled patients with ER-positive, HER2-negative ABC that recurred or progressed during or after AI therapy. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant–abemaciclib. Primary endpoints were investigator-assessed PFS with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant–abemaciclib as compared with imlunestrant among all patients who had undergone randomisation concurrently.
Overall, 874 patients underwent randomisation, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant–abemaciclib. Among 256 patients with ESR1 mutations, the median PFS was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI] 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI 4.6 to 6.2) with standard therapy (difference 2.6 months, 95% CI 1.2 to 3.9; p < 0.001).
In the overall population, the median PFS was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio [HR] for progression or death 0.87, 95% CI 0.72 to 1.04; p = 0.12). Among 426 patients in the comparison of imlunestrant–abemaciclib with imlunestrant, the median PFS was 9.4 months and 5.5 months, respectively (HR 0.57, 95% CI 0.44 to 0.73; p < 0.001).
Imlunestrant showed favourable safety, with generally low-grade adverse events, mainly fatigue, diarrhoea, and nausea, each at relatively low incidences, and low percentages of patients with dose reduction and discontinuation. Preliminary analysis suggests that imlunestrant therapy involves lower risks of bradycardia, dyslipidaemia, and photopsia than other new selective ER degraders.
Imlunestrant–abemaciclib had a predictable safety profile, which was similar to that seen in previous studies of fulvestrant–abemaciclib. The incidence of discontinuation of imlunestrant–abemaciclib (6.3%) also compares favourably with that of available combination regimens. The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant–abemaciclib.
The authors commented that the EMBER-3 study lacked a direct comparison of imlunestrant–abemaciclib with fulvestrant–abemaciclib, and unlike the EMERALD and postMONARCH trials, it did not require previous treatment with a CDK4/6 inhibitor. However, most patients (65%) in the imlunestrant–abemaciclib group in the EMBER-3 study had received a CDK4/6 inhibitor previously, and the treatment effect of imlunestrant–abemaciclib with HR for progression or death of 0.51 in these patients was consistent with that in the overall population, and the median PFS was 9.1 months. In addition, the treatment effect of imlunestrant–abemaciclib was similar in patients with or without ESR1 or PI3K pathway mutations.
The consistency of these results across clinically relevant subgroups is reassuring given that most patients who are eligible for second-line therapy have received a CDK4/6 inhibitor previously and that many available second-line therapies require biomarker selection. In the context of combination therapy that can effectively target and overcome other (non-ESR1) mechanisms of resistance, it is possible that an oral selective ER degrader combined with CDK4/6 inhibition more completely inhibits the ER signalling cascade, which would drive efficacy in populations of patients with ESR1 mutations and in those without such mutations and would possibly have more synergy than fulvestrant in this context according to the authors.
The study was supported by Eli Lilly.
Reference
Jhaveri KL, Neven P, Casalnuovo ML, et al. for the EMBER-3 Study Group. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. NEJM; Published online 11 December 2024. DOI: 10.1056/NEJMoa2410858