medwireNews: Imlunestrant, either alone or alongside abemaciclib, could be an option after progression on endocrine therapy for patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, suggest phase 3 findings.
In the EMBER-3 trial, imlunestrant monotherapy significantly prolonged the progression-free survival (PFS) of patients harboring ESR1 mutations relative to standard therapy, while combining imlunestrant with abemaciclib boosted PFS irrespective of ESR1 mutation status.
The researchers explain in The New England Journal of Medicine that imlunestrant is a next-generation, oral selective estrogen-receptor degrader (SERD) “that delivers continuous ER inhibition, even in ESR1-mutated breast cancer.”
They add that it is one of the new oral selective ER degraders developed to overcome the limitations of fulvestrant by “improving both efficacy and patient experience by means of ease of administration.”
The study enrolled 874 patients with ER-positive, HER2-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, given alone or with a CDK4/6 inhibitor. The participants were randomly assigned to receive oral imlunestrant 400 mg/day (n=331), investigator’s choice of standard endocrine monotherapy (oral exemestane 25 mg/day or intramuscular fulvestrant 500 mg on days 1 and 15 of the first 28-day cycle and on day 1 of subsequent cycles; n=330), or imlunestrant 400 mg/day plus oral abemaciclib 150 mg twice a day (n=213).
The median age of the participants was 61 years and almost two-thirds (59.8%) had previously received a CDK4/6 inhibitor. Of those in the imlunestrant and standard therapy groups, 38.7% had at least one oncogenic or likely oncogenic ESR1 mutation at baseline as determined by central assessment.
Analysis of the first primary endpoint of PFS with imlunestrant versus standard therapy among participants with ESR1 mutations gave median durations of 5.5 and 3.8 months, respectively. But there was evidence of nonproportional hazards, so the team conducted a restricted mean survival time analysis at 19.4 months, which gave times of 7.9 versus 5.4 months, and a significant between-group difference favoring imlunestrant.
With regard to the second primary endpoint of PFS with imlunestrant versus standard therapy among all participants, there was no significant difference between the treatments, with nearly identical median PFS durations of 5.6 and 5.5 months, respectively.
The third primary endpoint was PFS with imlunestrant plus abemaciclib versus imlunestrant alone among patients who underwent randomization concurrently. In this case, the addition of abemaciclib to imlunestrant significantly improved PFS, at a median of 9.4 months compared with 5.5 months for imlunestrant alone, equating to a hazard ratio for progression or death of 0.57 in favor of the combination.
Moving onto the adverse event (AE) data, Komal Jhaveri (Memorial Sloan Kettering Cancer Center, New York, USA) and collaborators report that “[t]he safety profile of imlunestrant was similar to that of standard therapy, and the safety profile of imlunestrant–abemaciclib was consistent with the known profile of fulvestrant–abemaciclib.”
Grade 3 or more severe AEs occurred in 17.1% of imlunestrant-treated patients and 20.7% of those given standard therapy, with the most common events being anemia (2.1 vs 2.8%) and neutropenia (2.1 vs 1.9%). Dose reductions due to AEs were required by 2.4% of patients given imlunestrant versus none of those given standard therapy, and the corresponding rates of AE-related discontinuations were 4.3% and 1.2%. One death in the imlunestrant group – a case of right ventricular failure – was judged by the investigator to be related to treatment.
The incidence of AEs of grade 3 or worse was higher in the imlunestrant plus abemaciclib group, at 48.6%. The most frequently observed events of this severity were neutropenia (19.7%), diarrhea (8.2%), and anemia (7.7%). AEs led to dose reductions of one or both of the study drugs in 39.4% of patients and discontinuation in 6.3%. One death from an unknown cause was considered related to treatment.
Jhaveri and colleagues summarize in conclusion that “[i]mlunestrant, as monotherapy or in combination with abemaciclib, provides an oral targeted-therapy option after progression during endocrine therapy in patients with ER-positive, HER2-negative advanced breast cancer.”
The findings were presented simultaneously at the 2024 San Antonio Breast Cancer Symposium in Texas, USA.
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N Engl J Med 2024; doi:10.1056/NEJMoa2410858
SABCS 2024; San Antonio, Texas, USA: 10–13 December
