Imlunestrant Benefit Holds After CDK4/6 Therapy Progression

Combination therapy with imlunestrant and the CDK4/6 inhibitor abemaciclib led to a significant progression-free survival (PFS) benefit compared with imlunestrant alone in women with estrogen receptor (ER)–positive and human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had experienced disease progression following CDK4/6 inhibitor therapy, according to a subgroup analysis from the EMBER-3 trial. 

This is the first phase 3 trial to show a benefit of this combination after disease progression on CDK4/6 inhibitor therapy, according to Cristina Saura, MD, PhD, who presented the results at the European Society for Medical Oncology (ESMO) Breast Cancer 2025 congress in Barcelona, Spain. The combination represents “an effective, tolerable, and all-oral, targeted therapy option” in the patient population across relevant subgroups, including those with ESR1 and PI3K pathway mutations, said Saura, with Vall d’Hebron Institute of Oncology, Barcelona. 

Previous results from the EMBER-3 trial revealed that the combination of imlunestrant and abemaciclib led to a significant improvement in PFS compared with imlunestrant alone, regardless of ESR1 mutation status, but this population included patients who had not previously received CDK4/6 inhibitor therapy, as well as those who had. 

The current analysis looked at PFS in all clinically relevant subgroups — patients with ERS1 mutations, PI3K pathway mutations, or visceral metastases — focusing on the 279 patients from EMBER-3 who had previously received a CDK4/6 inhibitor — 139 in the combination therapy group and 140 in imlunestrant monotherapy group. Among these pretreated patients, 38% in the combination group and 51% in the imlunestrant monotherapy had ESR1 mutations, 44% and 45%, respectively, had PI3K pathway mutations, and 58% in both groups presented with visceral metastases. 

Most patients had received their CDK4/6 inhibitor treatment in the advanced setting, with palbociclib being the most common agent used, and most had been on CDK4/6 inhibitor therapy for at 1 year prior to enrollment.

The combination of imlunestrant plus abemaciclib demonstrated a consistent PFS benefit across all CDK4/6 inhibitor-pretreated subgroups compared with imlunestrant alone, Saura said. 

Overall, median PFS was 9.1 months with the combination vs 3.7 months with monotherapy in the CDK4/6 inhibitor–pretreated patients (hazard ratio [HR], 0.51), which is in line with the PFS benefit observed in the overall EMBER-3 population (9.4 months vs 5.5 months, respectively; HR, 0.57). 

In CDK4/6 inhibitor–pretreated patients with visceral metastases, median PFS was 7.5 months with the combination vs 1.9 months with monotherapy (HR, 0.39) — also in line with the median PFS benefit observed in all patients (8.1 months vs 3.7 months, respectively; HR, 0.55). 

In CDK4/6 inhibitor–pretreated patients with bone-only metastases, median PFS was 16.4 months with the combination vs 9.5 months with monotherapy (HR, 0.57) and, in all patients, median PFS was 16.4 months and 10.4 months, respectively (HR, 0.55). 

The PFS benefit was similar in pretreated and all patients with ESR1 and PI3K pathway mutations as well. Among patients with ESR1 mutations, for instance, median PFS was 11.1 months with the combination vs 5.4 months with monotherapy in the pretreated population (HR, 0.44) and, in all patients, median PFS was 11.1 months vs 5.5 months, respectively (HR, 0.53).

“If you look specifically at the ESR1 mutant tumors with prior CDK4/6 inhibitor therapy, we see the longest medium progression-free survival ever reported here in the second-line setting,” said invited discussant, Rupert Bartsch, MD, with Medical University of Vienna in Vienna, Austria.

Saura also explained that the benefit of the imlunestrant plus abemaciclib combination was evident irrespective of prior duration of CDK4/6 inhibitor therapy or choice of CDK4/6 agent, though overall survival analyses are ongoing. 

Clearly, prior CDK4/6 inhibitor therapy “does not compromise activity of combination therapy,” Bartsch agreed. 

“There is consistent benefit of abemaciclib and imlunestrant across the different biological and clinical subsets,” he said. The results of this analysis are “clinically relevant and can guide our clinical decision making once [imlunestrant] is clinically available.”

The study was sponsored by Eli Lilly and Company. Saura and Bartsch disclosed having relationships with Eli Lilly and other pharmaceutical companies.