88 Imlunestrant With or Without Abemaciclib in Advanced Breast Cancer (ABC): A Subgroup Analysis in CDK4/6 Inhibitor (CDK4/6i)-Pretreated Patients From EMBER-3

Background

Imlunestrant is a next-generation, brain-penetrant, oral SERD. The EMBER-3 trial reported significant progression-free survival (PFS) improvement with imlunestrant over standard therapy (SOC; fulvestrant or exemestane) in patients with ESR1 mutations, and with imlunestrant plus abemaciclib over imlunestrant in all patients, regardless of ESR1 mutation. There remains a need for effective and tolerable treatments available to a broad unselected population after disease progression on CDK4/6 inhibitor. Abemaciclib plus fulvestrant has shown benefit over fulvestrant in this context (postMONARCH trial). Here we present a subgroup analysis of Imlunestrant plus abemaciclib vs imlunestrant in patients with disease progression on CDK4/6 inhibitor.

Methods

A total of 874 patients with estrogen receptor–positive (ER+)/HER2-negative (HER2–) advanced breast cancer and progression on/after aromatase inhibitor with or without CDK4/6 inhibitor were randomized 1:1:1 to imlunestrant, SOC, or imlunestrant plus abemaciclib. Randomization was stratified by prior CDK4/6i treatment, presence of visceral metastases, and region. Subgroup analyses of PFS by clinico-genomic factors were performed for imlunestrant plus abemaciclib vs imlunestrant patients with prior CDK4/6i inhibitor treatment.

Results

Of 874 total patients, 426 were concurrently randomized to imlunestrant plus abemaciclib or imlunestrant (n = 213 each); the majority (n = 279, 65%) had received prior CDK4/6 inhibitor treatment. Among CDK4/6 inhibitor-pretreated patients, baseline characteristics were generally balanced; 56% had visceral metastases, 37% had ESR1-mutations, and 40% had PI3K-pathway mutations. Most patients (70%) had received prior CDK4/6 inhibitors for 12 months or more. PFS benefit of imlunestrant plus abemaciclib over imlunestrant (HR, 0.51; 95% CI, 0.38-0.68; mPFS 9.1 vs 3.7 months) showed broadly consistent effect across key clinico-genomic subgroups: ESR1 mutations (HR, 0.44; 95% CI, 0.28-0.70); PI3K-pathway mutation (HR, 0.52; 95% CI, 0.34-0.79); concurrent ESR1 mutations/PI3K-pathway mutation (HR, 0.32; 95% CI, 0.16-0.63). Benefit was observed regardless of prior CDK4/6 inhibitor duration or type, though analyses of prior abemaciclib patients were limited by a small sample size.

Conclusions

In patients with ER+/HER2– advanced breast cancer who have progressed on prior CDK4/6 inhibitors, imlunestrant plus abemaciclib showed a consistent benefit over imlunestrant, regardless of clinico-genomic factors. EMBER-3 is the first phase 3 trial to show benefit of an oral SERD plus CDK4/6 inhibitor after disease progression on prior CDK4/6 inhibitor.

Previously presented at ESMO Breast Cancer 2025.

Study is sponsored by Eli Lilly and Company.