Advanced breast cancer, whether locally advanced or metastatic, is associated with significantly worse outcomes. Approximately 30% of high-risk early-stage cases eventually progress to metastatic disease, and 6–10% are metastatic at diagnosis. In the US, the overall five-year relative survival rate for all breast cancer cases is 91%, but this varies sharply by stage—99% for localized disease, 87% for regional, and just 32% for metastatic. These figures highlight the critical need for early detection, accurate risk stratification, and effective therapies to prevent or delay disease progression.

Imlunestrant is an investigational, brain-penetrant oral SERD that provides continuous ER inhibition, including in ESR1-mutant cancers. ER remains a key target in ER+, HER2- breast cancer, and novel degraders like Imlunestrant may overcome endocrine resistance while offering consistent oral dosing and convenience. It is being studied in both advanced and early breast cancer settings. As monotherapy or combined with abemaciclib, it offers a fully oral targeted therapy option.

At ASCO, the company presented safety findings as outlined below:

Safety was evaluated in 859 patients: Imlunestrant (n=327), standard of care (n=324), and Imlunestrant + Abemaciclib (n=208). Adverse event (AE) rates were similar between Imlunestrant (83%) and standard therapy (84%), but higher with the combination (98%). Grade ≥3 AEs occurred in 17%, 21%, and 49% of patients, respectively, and serious AEs in 10%, 12%, and 17%. Common AEs with Imlunestrant were fatigue (23%), diarrhea (21%), and nausea (17%); with the combination, diarrhea (86%), nausea (49%), and neutropenia (48%)—mostly Grade 1. Incidences of elevated transaminases, VTE, ILD, bradycardia, and photopsia were low across groups. Dose reductions were seen in 2% (Imlunestrant) vs 39% (combo), with low AE-related discontinuation rates (4% and 6%).

Eli Lilly also presented patient-reported outcomes from the EMBER-3 trial in ER+, HER2- advanced breast cancer treated with imlunestrant alone or with abemaciclib.

• Imlunestrant plus abemaciclib showed superior progression-free survival but was associated with higher adverse event rates, including nausea/vomiting and diarrhea.

• Imulunestrant With/without abemaciclib generates improved patient-reported outcomesin ER+/HER2– advanced breast cancer.

• Regarding safety, treatment-emergent adverse events (TEAEs) of any grade occurred in 83% of patients with imlunestrant, 98% of patients with imlunestrant plus abemaciclib, and 84% of patients with endocrine therapy; of Grade 3 or higher, TEAEs occurred in 17%, 49%, and 21%, respectively.

KOL insights:

“Consistent with the primary results from EMBER-3, these patient response outcomes results reinforce the benefit of imunestrant, as monotherapy or combined with abemaciclib, as an all-oral targeted therapy option after progression on [endocrine therapy] for patients with ER-positive, HER2-negative [advanced breast cancer].”– Expert Opinion.

Conclusion:

ORSERDU’s approval as the oral SERD monotherapy for ESR1-mutant breast cancer marked an important milestone. However, the EMBER-3 trial underscores the need to move beyond monotherapy toward combination strategies that can benefit a broader patient population. The study demonstrated that Imlunestrant, particularly when combined with Abemaciclib, significantly improved progression-free survival (PFS), especially in patients with ESR1 mutations, while maintaining a manageable safety profile. In ESR1-mutant patients, Imlunestrant alone extended median PFS to 5.5 months vs 3.8 months with standard therapy. In the overall population, the combination achieved a median PFS of 9.4 months vs. 5.5 months.

Patient-reported outcomes were also favorable and aligned with the primary efficacy results, reinforcing imlunestrant alone or with abemaciclib as a convenient, all-oral targeted therapy option for ER+, HER2− advanced breast cancer after progression on endocrine therapy.

As the first Phase III trial to validate the benefit of an oral SERD plus CDK4/6 inhibitor post-CDK4/6 progression, EMBER-3 represents a pivotal shift in the treatment landscape. These findings support a broader role for oral SERDs in combination regimens and position Imlunestrant as a well-tolerated, versatile therapy with potential utility across a wider spectrum of patients.