December 12, 2025 — Eli Lilly and Company announced updated results from the Phase 3 EMBER-3 clinical trial of the oral estrogen receptor antagonist imlunestrant. The study enrolled patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) advanced or metastatic breast cancer (MBC) who had experienced disease progression after prior treatment with an aromatase inhibitor (AI) with or without a CDK4/6 inhibitor.

Compared to endocrine therapy, imlunestrant monotherapy demonstrated a clinically meaningful 38% reduction in the risk of disease progression or death in patients with an ESR1 mutation (median progression-free survival (PFS): 5.5 months vs. 3.8 months; HR = 0.62; 95% CI: 0.47–0.82; nominal p = 0.0007). It also extended median overall survival (OS) by 11.4 months (34.5 months vs. 23.1 months; HR = 0.60; 95% CI: 0.43–0.86; p = 0.0043, did not meet the prespecified threshold for statistical significance).

Among all patients, imlunestrant in combination with abemaciclib reduced the risk of disease progression or death by 41% compared to imlunestrant monotherapy, showed a trend toward OS benefit, and numerically delayed the time to chemotherapy (TTC) by more than a year.
The related study results have been published in Annals of Oncology and were presented as a late-breaking oral presentation at the San Antonio Breast Cancer Symposium (SABCS).

Jake VanNaarden, Executive Vice President of Lilly and President of Lilly Oncology, stated: "Following the recent FDA approval of imlunestrant monotherapy, these latest data demonstrate continued clinically meaningful benefits for both monotherapy and combination therapy with abemaciclib, further solidifying its role in this treatment setting. Given the central role of CDK4/6 inhibitors in managing ER+, HER2– metastatic breast cancer, we are encouraged by the potential of this all-oral combination of imlunestrant and abemaciclib and have submitted the combination data for the treatment of ESR1-mutated metastatic breast cancer to U.S. regulatory authorities."

The results for imlunestrant combined with abemaciclib are consistent with previous efficacy data and demonstrate sustained benefits across all efficacy endpoints, regardless of the patient's ESR1 mutation status. Among all patients, the median progression-free survival (PFS) for the combination group was nearly double that of the monotherapy group (10.9 months vs. 5.5 months; HR = 0.59; 95% CI: 0.47–0.74; nominal p < 0.0001), with a trend towards overall survival (OS) benefit (HR = 0.82; 95% CI: 0.59–1.16) and sustained separation of survival curves. Compared to the monotherapy group, the median time to chemotherapy (TTC) for the combination group was numerically delayed by over a year (27.8 months vs. 15.5 months). In patients with ESR1 mutations, the combination extended median PFS to 11.0 months, versus 5.6 months with monotherapy (HR = 0.55; 95% CI: 0.41–0.74; nominal p < 0.001). Notably, the majority of patients (65%) in the combination group had received prior CDK4/6 inhibitor treatment.

Dr. Komal Jhaveri, Chief of the Endocrine Therapy Research Program, Clinical Director of Early Drug Development at Memorial Sloan Kettering Cancer Center, and principal investigator of the EMBER-3 trial, commented: "With an additional year of follow-up, these findings further reinforce the clinical value of imlunestrant-based regimens in ER+, HER2– metastatic breast cancer. A median PFS of 11 months places it among the leading results in studies of this patient population. Equally important is the fact that patients achieved longer survival without needing chemotherapy."

The safety profile of imlunestrant-based regimens remains consistent with prior reports, with no new safety signals identified during this extended follow-up. The most common adverse reactions (occurring in ≥10% of patients treated with imlunestrant) (including laboratory abnormalities) were: decreased hemoglobin (30%), musculoskeletal pain (30%), decreased blood calcium (26%), decreased neutrophil count (26%), increased aspartate aminotransferase (AST) (25%), fatigue (23%), diarrhea (22%), increased alanine aminotransferase (ALT) (21%), increased triglycerides (21%), nausea (17%), decreased platelet count (16%), constipation (10%), increased cholesterol (10%), and abdominal pain (10%). OS follow-up is ongoing, and further analyses are expected as the data mature.

Furthermore, imlunestrant is also being investigated as an adjuvant treatment for patients with ER+, HER2- early breast cancer (EBC) at higher risk of recurrence. The Phase 3 EMBER-4 clinical trial has completed enrollment of approximately 8,000 participants who have received two to five years of adjuvant endocrine therapy in the context of existing standard-of-care CDK4/6 inhibitors.

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