30 Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and Combined With Abemaciclib, for Patients with ER+, HER2– Advanced Breast Cancer, Pretreated With Endocrine Therapy: Results of the Phase 3 EMBER-3 Trial

30 Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and Combined With Abemaciclib, for Patients with ER+, HER2– Advanced Breast Cancer, Pretreated With Endocrine Therapy: Results of the Phase 3 EMBER-3 Trial

Background

Imlunestrant is a brain-penetrant oral selective estrogen receptor degrader (SERD) and pure estrogen receptor (ER) antagonist that delivers continuous ER inhibition, including in ESR1-mutant cancers.

Materials and Methods

In this phase 3 open-label trial, we evaluated progression-free survival (PFS) and safety of imlunestrant monotherapy and combination with abemaciclib in patients who are pretreated with endocrine therapy (ET) and have ER–positive (ER+), HER2-negative (HER2–) advanced breast cancer (ABC) that recurred or progressed on/after an aromatase inhibitor, alone or with a CDK4/6 inhibitor (CDK4/6i). Patients were randomized 1:1:1 to imlunestrant (400mg daily), physician’s choice standard-of-care (SOC; fulvestrant or exemestane) ET or imlunestrant plus abemaciclib (150mg twice daily). Primary end points were investigator-assessed PFS of imlunestrant vs SOC in patients with ESR1 mutations and all patients, and imlunestrant plus abemaciclib vs imlunestrant in all concurrently randomized patients. Secondary end points included OS (tested if the corresponding PFS was statistically significant), PFS by BICR, overall response rate, and safety.

Results

Of 874 randomized patients (imlunestrant, n = 331; SOC, n = 330; imlunestrant plus abemaciclib, n = 213), 256 had ESR1 mutation (imlunestrant, n = 138; SOC, n = 118). Imlunestrant significantly improved PFS vs SOC in patients with ESR1 mutations (HR, 0.62; 95% CI, 0.46-0.82; P <.001; median PFS 5.5 months vs 3.8 months) but not in the overall population (n = 661; HR, 0.87; 95% CI, 0.72-1.04; P = .12). Imlunestrant plus abemaciclib significantly improved PFS vs imlunestrant in all patients (n = 426; HR, 0.57; 95% CI, 0.44-0.73; P <.001; median PFS 9.4 months vs 5.5 months) regardless of presence of mutations in ESR1 or PI3K pathway and regardless of prior treatment with CDK4/6i. OS analyses were immature. Common all-grade treatment-emergent adverse effects (TEAEs) with imlunestrant vs SOC were fatigue (23% vs 13%), diarrhea (21% vs 12%), and nausea (17% vs 13%), mostly grade 1. Common grade 3 or higher TEAEs were anemia (2% vs 3%), and neutropenia (2% each). Common all-grade/grade 3 or higher TEAEs with imlunestrantplus abemaciclib were diarrhea (86%/8%), nausea (49%/2%), and neutropenia (48%/20%). Grade 3 or higher TEAEs rates for imlunestrant, SOC, and imlunestrantplus abemaciclib were 17%, 21%, and 49%, respectively. Discontinuation of imlunestrant and imlunestrantplus abemaciclib due to AEs was low (4% and 6%, respectively).

Conclusion

Imlunestrant significantly improved PFS vs SOC in patients with ESR1 mutations, and imlunestrant plus abemaciclib significantly improved PFS vs imlunestrant in all patients regardless of ESR1 mutation status. Imlunestrant as monotherapy had a favorable safety profile alone and combined with abemaciclib, thus providing an all-oral targeted therapy option for ET-pretreated patients with ER+, HER2– antibody-drug conjugate.