Imlunestrant Combo Will Not Be Pursued for FDA Approval in Breast Cancer

Broad FDA approval will not be sought for imlunestrant (Inluriyo) plus abemaciclib (Verzenio), despite promising results observed among patients with breast cancer, according to a press release from Eli Lilly.¹

The company, however, will only pursue a label for the combination among those who have ESR1 gene mutations in the select patient population with estrogen receptor (ER)–positive/HER2-negative advanced breast cancer. This would follow the indication recently obtained from the FDA for imlunestrant monotherapy, which covers patients with ER–positive, HER2-negative advanced breast cancer with ESR1 gene mutations who have tried at least 1 line of endocrine therapy.²

“I don’t think there’s a path to an [intent-to-treat] indication. It’s just not been where the conversation has been,” Jake Van Naarden, president of Lilly Oncology, said in the press release.¹ “We’re not going to fight with [the FDA] on that.”

Updated results from the phase 3 EMBER-3 trial (NCT04975308) were presented at the 2025 San Antonio Breast Cancer Symposium.³ The results showed a significant and sustained progression-free survival (PFS) benefit with imlunestrant alone or in combination with abemaciclib vs standard of care therapy.

At a median follow-up of 27.6 months, the median PFS in patients with ESR1 mutations who received imlunestrant was 5.5 months vs 3.8 months in the standard of care arm (HR, 0.62; 95% CI, 0.47-0.82; P = .0007). In the overall population, the median PFS was 10.9 months in the combination arm vs 5.5 months with imlunestrant alone (HR, 0.59; 95% CI, 0.47-0.74; P <.0001). If patients had previously received a CDK4/6 inhibitor, the median PFS was 9.1 months in the combination arm vs 3.7 months in the imlunestrant alone arm (HR, 0.53; 95% CI, 0.40-0.69; P <.0001).

With the overall survival (OS) analysis was at 50% maturity, the median follow-up was 29.5 months. For patients with ESR1 mutations, the median OS with imlunestrant was 34.5 months vs 23.1 months in the standard of care arm (HR, 0.60; 95% CI, 0.43-0.86; P = .0043). There was no statistical significance, but investigators noted the results were clinically meaningful.

At 33% OS maturity, and a median follow-up of 27.1 months, the median OS was not reached with the combination vs 34.4 months with imlunestrant alone (HR, 0.82; 95% CI, 0.59-1.16; P = .2622).

Regardless of ESR1 mutation status, the overall response rates were higher with imlunestrant vs standard of care and were higher with imlunestrant/abemaciclib vs imlunestrant alone.

“Imlunestrant, as monotherapy or in combination with abemaciclib, provides an all-oral chemotherapy-free option after progression on endocrine therapy for patients with ER-positive, HER2-negative advanced breast cancer,” 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, said during the presentation.

The EMBER-3 trial enrolled 874 patients with a median age of 62 years, and were randomly assigned to either imlunestrant monotherapy (n = 331), imlunestrant plus abemaciclib (n = 213), or standard of care (n = 330; investigator’s choice of endocrine therapy: exemestane or fulvestrant). Patients were given imlunestrant at 400 mg orally once daily, and abemaciclib was given at 150 mg orally twice daily. Treatment cycles were 28 days long.

The press release also highlighted the ongoing EMBER-4 trial (NCT05514054), which is investigating imlunestrant vs standard endocrine therapy in patients with ER–positive, HER2-negative early breast cancer with increased risk of recurrence who have received 2 to 5 years of adjuvant endocrine therapy, and were allowed to have previously received a CDK4/6 inhibitor.⁴

The primary end point will be invasive disease-free survival, with secondary end points of distant recurrence-free survival, OS, and pharmacokinetics. The study plans to enroll 8000 patients and is actively recruiting.

References

1. Lilly shifts ambition for broader oral SERD label to largest oncology trial in company history. News release. Fierce Pharma. December 12, 2025. Accessed December 16, 2025. https://tinyurl.com/y6fyjahr
2. Eli Lilly's oral SERD Inluriyo passes muster with FDA in breast cancer. News release. Fierce Pharma. September 25, 2025. Accessed December 16, 2025. https://tinyurl.com/2269jct4
3. 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.
4. A study of imlunestrant versus standard endocrine therapy in participants with early breast cancer (EMBER-4). ClinicalTrials.gov. Updated December 12, 2025. Accessed December 16, 2025. https://tinyurl.com/4c5vv92y