FDA Approves Imlunestrant Plus Abemaciclib in ESR1-Mutated Breast Cancer

The FDA has approved imlunestrant (Inluriyo) in combination with abemaciclib (Verzenio) for adults with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, whose disease has progressed following at least 1 line of endocrine therapy.¹ The agency also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with ESR1 mutations who are eligible for treatment with the combination.

Imlunestrant is an oral selective estrogen receptor degrader (SERD), and abemaciclib is a CDK4/6 inhibitor; both are manufactured by Eli Lilly and Company.¹^,² The approval is based on the phase 3 EMBER-3 trial (NCT04975308). In an exploratory subgroup analysis of 159 patients with ESR1-mutated tumors (n = 67 for the combination; n = 92 for imlunestrant alone), imlunestrant plus abemaciclib produced a median progression-free survival (PFS) of 11.1 months (95% CI, 7.4-13.7) vs 5.5 months (95% CI, 3.8-7.2) with imlunestrant alone (HR, 0.53; 95% CI, 0.35-0.80). The objective response rate (ORR) was 35% (95% CI, 22%-48%) vs 15% (95% CI, 7%-23%), respectively.¹

EMBER-3 Study Design

EMBER-3 was a randomized, open-label, active-controlled, multicenter trial that enrolled 874 adults with ER-positive, HER2-negative, locally advanced or metastatic breast cancer previously treated with an aromatase inhibitor alone or with a CDK4/6 inhibitor; patients eligible for a PARP inhibitor were excluded. Patients were randomized 1:1:1 to imlunestrant, investigator's choice of endocrine therapy (fulvestrant or exemestane), or imlunestrant plus abemaciclib. ESR1 status was determined by circulating tumor DNA analysis with the Guardant360 CDx assay. The major efficacy outcome measure for the combination was investigator-assessed PFS per RECIST v1.1 in the overall population, comparing imlunestrant plus abemaciclib vs imlunestrant monotherapy.

Scope of the Approval

The indication is limited to patients with ESR1-mutated disease. In its review, the FDA noted that although the PFS comparison of imlunestrant plus abemaciclib vs imlunestrant alone was statistically significant in the overall population, imlunestrant monotherapy did not demonstrate a PFS improvement vs investigator's choice of endocrine therapy in either the overall population or the population without detectable ESR1 mutations, indicating that the benefit was observed only in the ESR1-mutated population.

In the primary analysis, median PFS in the overall population was 9.4 months (95% CI, 7.5-11.9) with the combination vs 5.5 months (95% CI, 3.8-5.6) with imlunestrant alone (HR, 0.57; 95% CI, 0.44-0.73; P < .001).³ Overall survival data were immature at interim analysis, with 35% of deaths reported in patients with ESR1-mutated tumors.¹

"Combining therapies that work on 2 distinct drivers of tumor growth—the estrogen receptor and CDK4/6—is an important strategy to help address treatment resistance,” said Komal Jhaveri, MD, FACP, FASCO, associate attending in Breast Medicine and Early Drug Development Services, section head of the Endocrine Therapy Research Program, and principal investigator of EMBER-3, Memorial Sloan Kettering Cancer Center in New York, New York, in a news release.²

Safety Profile

The imlunestrant label includes a warning and precaution for embryo-fetal toxicity, and the abemaciclib label includes warnings and precautions for diarrhea, neutropenia, interstitial lung disease or pneumonitis, hepatotoxicity, venous thromboembolism, and embryo-fetal toxicity.¹

In EMBER-3, diarrhea occurred in 86% of patients who received the combination (grade 3 or 4, 9%) and decreased neutrophil count in 86% (grade 3 or 4, 21%).² Serious adverse reactions occurred in 21% and fatal adverse reactions in 3.8%.² Permanent discontinuation of imlunestrant alone due to adverse reactions occurred in 1% of patients and of abemaciclib alone in 3.4%.

Prior Approval and Ongoing Development

The FDA approved imlunestrant monotherapy in September 2025 for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease progressed after at least 1 line of endocrine therapy, based on a median PFS of 5.5 months vs 3.8 months with fulvestrant or exemestane (HR, 0.62; 95% CI, 0.46-0.82; P = .0008).⁴ The combination received full approval and is now available in the US.² Imlunestrant is also being evaluated in the phase 3 EMBER-4 trial (NCT05514054) in the adjuvant setting, with initial results anticipated in 2027.²

REFERENCES

1. US Food and Drug Administration. FDA approves imlunestrant in combination with abemaciclib for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Published September 18, 2026. Accessed September 18, 2026. https://tinyurl.com/bdcz685w

2. US FDA approves Inluriyo (imlunestrant) in combination with Verzenio (abemaciclib) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 18, 2026. Accessed September 18, 2026. https://tinyurl.com/yrdwxtk7

3. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392:1189-1202. doi:10.1056/NEJMoa2410858

4. US FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 25, 2025. Accessed September 18, 2026. https://tinyurl.com/2hzrbabe