Komal Jhaveri, MD, FACP
Imlunestrant, an investigational next-generation oral selective estrogen receptor degrader (SERD), significantly improved progression-free survival vs standard of care in patients with ESR1-mutated breast cancer, according to data from the phase III EMBER-3 trial, presented by Komal Jhaveri, MD, FACP, of Memorial Sloan Kettering Cancer Center, New York, during the 2024 San Antonio Breast Cancer Symposium. In addition, imlunestrant plus abemaciclib significantly improved progression-free survival in all patients regardless of ESR1-mutation status (Abstract GS1-01).
Study Methodology
In this phase III open-label trial (ClinicalTrials.gov identifier NCT04975308), 874 patients with estrogen receptor–positive, HER2-negative advanced breast cancer were randomly assigned (1:1:1) to receive imlunestrant alone (n = 331), standard-of-care endocrine therapy (fulvestrant or exemestane) alone (n = 330), or imlunestrant plus abemaciclib (n = 213). A total of 256 patients had ESR1-mutated breast cancer (138 imlunestrant recipients, 118 in the standard-of-care group).
The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival (tested if the corresponding progression-free survival was statistically significant), progression-free survival by blinded independent central review (BICR), objective response rate, and safety.
Key Results
The researchers found that imlunestrant significantly improved progression-free survival vs the standard of care in patients with ESR1-mutated breast cancer (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.46–0.82; P < .001). Median progression-free survival was 5.5 vs 3.8 months.
KEY POINTS
- Compared to standard endocrine therapy, imlunestrant significantly improved progression-free survival in patients with ESR1-mutated breast cancer, but not in the overall population. In patients harboring ESR1 mutations, imlunestrant reduced the risk of progression or death by 38%.
- Compared to imlunestrant alone, imlunestrant plus abemaciclib was associated with a 43% reduction in risk of progression or death, resulting in median progression-free survival of 9.4 months and 5.5 months, respectively, for the combination and monotherapy groups.
Imlunestrant did not significantly improve progression-free survival in the overall population (n = 661; HR = 0.87; 95% CI = 0.72–1.04; P = .12). However, imlunestrant plus abemaciclib significantly improved progression-free survival vs imlunestrant in all patients (n = 426; HR = 0.57; 95% CI = 0.44–0.73; P < .001; median = 9.4 vs 5.5 months), with benefit observed regardless of ESR1-mutated or PI3K pathway mutation status and in CDK4/6 inhibitor–pretreated patients.
Investigator and BICR assessments were consistent across all endpoints. In all patients with measurable disease, the overall response rate was 12% with imlunestrant, 8% with the standard of care, and 27% with imlunestrant plus abemaciclib.
All overall survival analyses were immature and ongoing. Favorable trends were observed for imlunestrant vs the standard of care in patients with ESR1-mutated breast cancer (HR = 0.55; 95% CI = 0.35–0.86; P < .01) and in all patients (HR = 0.69; 95% CI = 0.50–0.96).
Common all-grade treatment-emergent adverse events with imlunestrant included fatigue (23% vs 13% with the standard of care), diarrhea (21% vs 12%), and nausea (17% vs 13%), mostly grade 1. Of note, all-grade bradycardia (2% vs 0%), photopsia (0% each), and dyslipidemia (7% vs 9%) were infrequent or not observed with imlunestrant. Common grade ≥ 3 treatment-emergent adverse events with imlunestrant included anemia (2% vs 3%) and neutropenia (2% each). Common all-grade/grade ≥ 3 treatment-emergent adverse events with imlunestrant plus abemaciclib included diarrhea (86% vs 8%), nausea (49% vs 2%), and neutropenia (48% vs 20%). Grade ≥ 3 treatment-emergent adverse event rates were 17% with imlunestrant, 21% with the standard of care, and 49% with imlunestrant plus abemaciclib. Discontinuation of imlunestrant or imlunestrant plus abemaciclib because of adverse events was low (4% and 6%, respectively).
Clinical Significance
“Imlunestrant significantly improved progression-free survival vs standard of care in patients with ESR1-mutated breast cancer, and imlunestrant plus abemaciclib significantly improved progression-free survival vs imlunestrant in all patients regardless of ESR1-mutated status,” concluded the study authors. “Imlunestrant had a favorable safety profile alone and combined with abemaciclib, thus providing an all-oral targeted therapy option for endocrine therapy-pretreated patients with [estrogen receptor–positive], HER2-negative advanced breast cancer.”
Disclosure: Funding for this study was provided by Eli Lilly and Company. For full disclosures of the study authors, visit sabcs.org.
