Imlunestrant Regimens Sustain Efficacy Benefit in ER+/HER2– Breast Cancer

Imlunestrant (Inluriyo) as monotherapy and combined with abemaciclib (Verzenio) continued to show a significant benefit in progression-free survival (PFS) vs standard-of-care (SOC) endocrine therapy in patients with previously treated ER-positive (ER+)/HER2-negative (HER2–) advanced breast cancer. Positive, but not statistically significant, overall survival (OS) results were also observed with the imlunestrant-based regimens, according to updated data from the phase 3 EMBER-3 trial (NCT04975308) presented at SABCS 2025.^1,2

In patients with ESR1 mutations (ESR1m), updated PFS data at a median follow up of 27.6 months showed that the median PFS in the imlunestrant cohort (n = 138) was 5.5 months vs 3.8 months in the SOC group (n = 118; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). Among all patients, the median PFS was 10.9 months with imlunestrant plus abemaciclib (n = 213) vs 5.5 months with imlunestrant alone (n = 213; HR, 0.59; 95% CI, 0.47-0.74; P <.0001). This PFS benefit for the combination was maintained regardless of ESR1m status. Also of note, among patients who had previously received a CDK4/6 inhibitor, the median PFS was 9.1 months with imlunestrant plus abemaciclib (n = 139) vs 3.7 months with imlunestrant alone (n = 140; HR, 0.53; 95% CI, 0.40-0.69; P < .0001).

At 50% OS maturity, results showed that at a median follow-up of 29.5 months in patients with ESR1m, the median OS in the imlunestrant cohort was 34.5 months vs 23.1 months in the SOC group (HR, 0.60; 95% CI, 0.43-0.86; P = .0043). While not statistically significant, this 11.4-month numerical OS benefit was considered by the investigators to be clinically meaningful. This OS improvement was consistent with imlunestrant across all prespecified subgroups of patients with ESR1m. At 33% OS maturity, results showed that at a median follow-up of 27.1 months, the median OS was not reached with imlunestrant plus abemaciclib vs 34.4 months with imlunestrant alone (HR, 0.82; 95% CI, 0.59-1.16; P = .2622).

The EMBER-3 update also included data showing a clinically meaningful improvement in time to chemotherapy (TTC) and PFS2 with the imlunestrant-based regimens.

TTC data showed that in patients with ESR1m, the median TTC in the imlunestrant cohort was 15.6 months vs 10.2 months in the SOC group (HR, 0.66; 95% CI, 0.48-0.92). Among all patients, the median TTC was 27.8 months with imlunestrant plus abemaciclib vs 15.5 months with imlunestrant alone (HR, 0.78; 95% CI, 0.59-1.03).

PFS2 results in patients with ESR1m showed a median PFS2 of 19.2 months in the imlunestrant cohort vs 13.5 months in the SOC group (HR, 0.71; 95% CI, 0.53-0.95). Among all patients, the median PFS2 was 22.6 months with imlunestrant plus abemaciclib vs 18.5 months with imlunestrant alone (HR, 0.79; 95% CI, 0.61-1.02).

Overall response rates were higher with imlunestrant vs SOC and higher with imlunestrant/abemaciclib vs imlunestrant monotherapy, regardless of ESR1m status.

Safety data were consistent with previously reported outcomes for imlunestrant and abemaciclib with no new safety signals.

“Imlunestrant, as monotherapy or in combination with abemaciclib, provides an all-oral chemotherapy-free option after progression on endocrine therapy for patients with ER+, HER2– advanced breast cancer,” said lead study author Komal Jhaveri, MD, FACP, section head of the Endocrine Therapy Research Program Clinical, director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

EMBER-3 Trial Design

Between October 2021 and November 2023, the open-label phase 3 EMBER-3 trial enrolled patients with ER+, HER2– advanced breast cancer previously treated with aromatase inhibitors with/without CDK4/6 inhibitors.

Overall, 874 patients with a median age of 62 were randomized to imlunestrant monotherapy (n = 331), imlunestrant plus abemaciclib (n = 213), or SOC (n = 330; investigator’s choice of endocrine therapy: exemestane or fulvestrant). Imlunestrant was administered at 400 mg orally once daily and abemaciclib was administered at 150 mg orally twice daily. Treatment cycles were 28 days.

At the data cutoff date of August 18, 2025, 10.1% of patients overall remained on treatment. This included 10%, 5%, and 18%, of the single-agent imlunestrant, SOC, and imlunestrant plus abemaciclib, arms, respectively. When patients discontinued treatment, first subsequent anticancer treatments were similar across the treatment arms.

The primary endpoints were PFS per investigator assessment for single-agent imlunestrant vs SOC in all patients and in patients with ESR1m, as well as PFS for imlunestrant plus abemaciclib vs imlunestrant in all patients OS was a secondary end point and exploratory end points included TTC and PSF2.

FDA Approval and Next Steps

Based on the primary PFS analysis of EMBER-3, the FDA approved single-agent imlunestrant in September 2025 for the treatment of patients with ER+/HER2– ESR1m advanced breast cancer with disease progression following at least 1 line of endocrine therapy.³ 

Regarding next steps for imlunestrant, Jhaveri said the randomized, open-label, global, multicenter phase 3 EMBER-4 study (NCT05514054) has completed enrollment, accruing approximately 8000 patients with ER+/HER2– early breast cancer who have received 2 to 5 years of adjuvant endocrine therapy with or without a CDK4/6 inhibitor who are at increased risk of recurrence. Patients are being randomized in a 1:1 ratio to single-agent imlunestrant or SOC endocrine therapy of aromatase inhibitor or tamoxifen.

REFERENCES

1.Jhaveri KL, Neven P, Casalnuovo M, et al. Imlunestrant with or without abemaciclib in advanced breast cancer (ABC): Updated efficacy results from the phase 3 EMBER-3 trial. Presented at: San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. GS3-08.

2.A study of imlunestrant, investigator’s choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2– advanced breast cancer (EMBER-3). ClinicalTrials.gov. Updated July 11, 2025. Accessed December 12, 2025. https://clinicaltrials.gov/study/NCT04975308

3.Food and Drug Administration. FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. U.S. Food & Drug Administration. Published September 25, 2025. Accessed December 12, 2025. https://tinyurl.com/mtsv3fpu