Imlunestrant: A Novel Weapon Against Endocrine-ResistantBreast Cancer
DOI:
https://doi.org/10.66765/acobs.2026.004Keywords:
Imlunestrant, Endocrine-resistant breast cancer, ESR1 mutations, Oral SERD, ER-positive/HER2-negative breast cancerAbstract
Background: Breast cancer, particularly Estrogen Receptor-positive (ER+) and Human Epidermal Growth Factor Receptor 2-negative (HER2-) disease, frequently develops resistance to endocrine therapy due to ESR1 gene mutations, highlighting the need for more effective estrogen receptor-targeted therapies.
Methods: This review summarizes available preclinical and clinical evidence on IMLUNESTRANT, a next-generation oral Selective Estrogen Receptor Downregulator (SERD), including findings from Phase Ia/Ib EMBER trials, EMBER-2, and Phase 3 EMBER-3 trial.
Results: Imlunestrant demonstrated meaningful monotherapy activity in early-phase trials with an Objective Response Rate (ORR) of 11.8%, Clinical Benefit Rate (CBR) of 54.9%, and Progression-Free Survival (PFS) of 7.2 months. Combination therapy, particularly with ABEMACICLIB, showed improved outcomes (ORR up to 61.8%, PFS ~19 months). EMBER-2 confirmed strong biological activity, with reductions in ER and PR expression (~80%) and Ki-67 (~70%), establishing 400 mg once daily as the optimal dose. In the Phase 3 EMBER-3 trial, IMLUNESTRANT significantly improved PFS in ESR1-mutated patients (5.5 vs 3.8 months; RMST difference 2.6 months; P < 0.001), while showing comparable outcomes to standard therapy in the overall population (5.6 vs 5.5 months; HR 0.87). The combination with ABEMACICLIB demonstrated the greatest benefit (PFS 9.4 vs 5.5 months; HR 0.57; P < 0.001).
Conclusion: Imlunestrant is a potent and well-tolerated oral SERD with strong biological activity and clinically meaningful efficacy, particularly in ESR1-mutated breast cancer and when combined with CDK4/6 inhibitors, offering a promising strategy to overcome endocrine resistance.
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