Imlunestrant, an investigational next-generation selective estrogen receptor antagonist (SERD), improved progression-free survival in patients with advanced endocrine therapy, ER-positive, HER2-negative advanced breast cancer- as monotherapy in patients with ESR1 mutations and as combination therapy with abemaciclib (Verzenio) in all patients, regardless of ESR1 mutation status – according to results from the phase III EMBER-3 clinical trial presented at the San Antonio Breast Cancer Symposium (SABCS), held on December 10-13, 2024.
The results of this study were simultaneously published in New England Journal of Medicine.
The primary objective of this EMBER-3 trial was to evaluate the role of immunosuppressant, a brain-penetrating oral SERD, as monotherapy or in combination with the CDK4/6 inhibitor, abemaciclib, in patients with advanced ER-positive, negative HER2. cancer whose disease had relapsed or progressed during or after an aromatase inhibitor alone or with a CDK4/6 inhibitor’.
Komal Jhaveri, MD, the Patricia and James Cayne Chair for Junior Faculty, division chief of the Endocrine Therapy Research Program and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and study presenter
“CDK4/6 inhibitors have been a critical addition to standard endocrine therapy with aromatase inhibitors, and if progression occurs, combining a SERD with a CDK4/6 inhibitor may be beneficial. However, given the limitations of existing SERDs such as fulvestrant, including lack of oral bioavailability and need for monthly intramuscular injection, along with limited efficacy in patients developing ESR1 mutations; new SERDs such as imlunestrant are being developed with the goal of improving both efficacy and patient experience through ease of administration,” Jhaveri said, noting that ESR1 mutations are seen in 40%-50% of patients who progress to endocrine therapy.
Unlike fulvestrant, imlunestrant can be taken orally and can penetrate the blood-brain barrier, offering the potential to target central nervous system metastases, explained Jhaveri, who is also an associate professor at Weill Cornell Medical College.
In the multicenter study, 874 patients with ER-positive, HER2-negative advanced breast cancer were randomized (1:1:1) to receive either dementia alone, standard endocrine therapy (fulvestrant or exemestane) alone, or refractory and abemaciclib.
Compared with standard endocrine therapy, ilunestrant significantly improved progression-free survival in patients with ESR1 mutations but not in the overall population. In patients carrying ESR1 mutations, ilunestrant reduced the risk of progression or death by 38%.
“These promising results mean that ilunestrant is potentially another drug option for the many patients whose recurrent breast cancers harbor ESR1 mutations,” said Jhaveri.
Additionally, compared with ilunestrant alone, imlunestrant and abemaciclib together were associated with a 43% reduction in the risk of progression or death, resulting in a median progression-free survival of 9.4 months and 5.5 months, respectively, for the combination and monotherapy groups. The benefit of combining these two therapies, which can both be taken orally, was seen in all patients, including those with and without ESR1 mutations or PI3K pathway mutations and including those previously treated with a CDK4 inhibitor /6.
“The consistency of these results in clinically relevant subgroups is reassuring given that most patients eligible for second-line therapy have received a CDK4/6 inhibitor in the past and many currently available second-line therapies require biomarker selection,” noted Jhaveri , who called the data practice changing.
Imlunestrant was well tolerated, both as monotherapy and in combination, Jhaveri said. Imlunestrant showed a favorable safety profile, with generally low-grade and manageable adverse events, and no oral SERD-specific safety signals for eye or cardiac problems. The safety profile of the combination was consistent with the known fulvestrant-abemaciclib profile with a relatively low discontinuation rate of 6.3% comparing favorably with available combination regimens. Additionally, in patient-reported outcome data from the study, 72% of patients who received fulvestrant reported pain, swelling, or redness at the injection site.
Taken together, these data are encouraging for patients and indicate that ilunestrant, as monotherapy or in combination with abemaciclib, could offer an oral targeted therapy option after progression to endocrine therapy for patients with advanced breast cancer positive in ER, HER2 negative. “
A limitation of the study is that unlike the postMONARCH and EMERALD phase III trials, EMBER-3 did not require prior CDK4/6 inhibitor therapy. However, most patients (65%) in the combination therapy comparison in EMBER-3 were previously treated with a CDK4/6 inhibitor, and the therapeutic effect of imlunestrant-abemaciclib in these patients was consistent with the overall population.
This study was supported by Eli Lilly and Company. Jhaveri has advisory or consulting roles with Novartis, Pfizer, Taiho Oncology, Genentech, AbbVie, Eisai, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Sun Pharma Advanced Research Company Ltd., Menarini/Stemline Therapeutics, Gilead, Scorpion Bicycles, Pharmaceutics Therapeutics , Lilly/Loxo Oncology and Zymeworks. Jhaveri also has research funding support at her institution from Novartis, Genentech, AstraZeneca, Pfizer, Lilly/Loxo Oncology, Zymeworks, Immunomedics/Gilead, Puma Biotechnology, Merck Pharmaceuticals, Context Therapeutics, Scorpion Therapeutics, Eisai, Blueprinticio.
