In the the phase IA/B dose-escalation and -expansion EMBER study reported in the Journal of Clinical Oncology by Jhaveri et al, the next-generation oral selective estrogen receptor degrader imlunestrant (alone and in combination with other targeted therapies) demonstrated a manageable safety profile and preliminary antitumor activity in patients with estrogen receptor–positive, HER2-negative advanced breast cancer.

“Optimal use of the estrogen receptor degrader fulvestrant has been limited by the need for intramuscular administration and questions about optimal dosing, especially in obese patients,” commented Senior Deputy Editor Kathy D. Miller, MD, FASCO, of The Indiana University Melvin and Bren Simon Comprehensive Cancer Center Women’s Clinic in Indianapolis, in a statement. “Imlunestrant provides an oral option with significant activity in previously treated patients, and ongoing phase III trials will determine its role in our therapeutic armamentarium.”

Study Details

This global trial included 262 patients with estrogen receptor–positive, HER2-negative advanced breast cancer. In phase IA (n = 74), an i3+3 dose-escalation design was used; five dose levels of imlunestrant (range: 200–1,200 mg once daily) were evaluated. Phase IB of the trial (n = 188) evaluated imlunestrant alone and in combination with either abemaciclib with or without an aromatase inhibitor, everolimus, or alpelisib; the partner agents were dosed per their respective labels.

The primary objective was to establish the recommended phase II dose of imlunestrant alone and in combination with other targeted therapies. Safety, tolerability, pharmacokinetics, overall response rate, clinical benefit rate, and progression-free survival were evaluated as key secondary objectives.

Imlunestrant Monotherapy

Among the 114 patients who received single-agent imlunestrant during the dose-escalation phase, no dose-limiting toxicities or treatment discontinuations were documented, and the maximum tolerable dose was not reached.

In patients treated at a dose of 400 mg once daily (n = 51), the most frequently reported treatment-emergent adverse events were grade 1 and 2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). This population, having previously received CDK4/6 inhibitor therapy (92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for advanced breast cancer, achieved a median progression-free survival of 7.2 months.

“At the 400-mg once-daily dose, imlunestrant exhibited a low incidence of gastrointestinal toxicities, sustained exposures above the [concentration needed for 80% of the maximum effect] and the maximum concentration of fulvestrant, and encouraging preliminary efficacy,” the investigators commented. “These data supported the selection of 400 mg once daily as the recommended phase II dose.”

Imlunestrant in Combination With Targeted Therapy

Most of the patients (69.4%) who received imlunestrant plus abemaciclib with (n = 43) and without (n = 42) an aromatase inhibitor were treatment-naive for advanced breast cancer; all were CDK4/6 inhibitor–naive. All patients who received imlunestrant plus everolimus (n = 42) or alpelisib (n = 21) had previously received treatment for advanced breast cancer, including CDK4/6 inhibitor therapy (100%), fulvestrant (34.9%), and chemotherapy (17.5%).

The investigators observed no new safety signals or interactions with the partnered drugs. The median progression-free survival was 19.2 months with imlunestrant plus abemaciclib and was not reached with the addition of an aromatase inhibitor. The 18-month progression-free survival rates were 60.7% and an estimated 73.4%, respectively. The median progression-free survival was 15.9 months with imlunestrant plus everolimus and 9.2 months with imlunestrant plus alpelisib.

Of note, according to the investigators, an exploratory analysis of imlunestrant revealed antitumor activity regardless of baseline ESR1 mutation status.

“Taken together, these results show promise for imlunestrant as an oral alternative to fulvestrant and support the ongoing development of imlunestrant in phase III studies as monotherapy or in combination with abemaciclib for endocrine therapy–pretreated patients with advanced breast cancer (EMBER-3: ClinicalTrials.gov identifier NCT04975308) and as adjuvant monotherapy for early-stage breast cancer (EMBER-4: NCT05514054),” the investigators concluded.

Komal L. Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center, New York, is the corresponding author of the Journal of Clinical Oncology article. 

Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit ascopubs.org.