Imlunestrant Plus Abemaciclib Provides Consistent Benefit Across Key Subgroups of ER+ Advanced Breast Cancer

Cristina Saura, MD, PhD

Imlunestrant (LY3484356) combined with abemaciclib (Verzenio) showcased consistent benefit over imlunestrant alone in CDK4/6 inhibitor–pretreated patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer across clinically and genomically defined subgroups, irrespective of biomarker status or prior CDK4/6 inhibitor type or duration, according to additional data from the phase 3 EMBER-3 trial (NCT04975308) presented during the 2025 ESMO Breast Congress.1

In all patients with visceral metastases who received the doublet (n = 119), the median progression-free survival (PFS) was 8.1 months (95% CI, 6.2-11.2) vs 3.7 months (95% CI, 1.9-4.9) with imlunestrant monotherapy (n = 120; HR, 0.55; 95% CI, 0.40-0.75). In CDK4/6 inhibitor–pretreated patients who received the doublet (n = 80) vs the monotherapy (n = 81), the median PFS was 7.5 months (95% CI, 5.6-11.2) and 1.9 months (95% CI, 1.8-3.6), respectively (HR, 0.39; 95% CI, 0.26-0.57).

Moreover, in all patients with bone-only metastases who received the doublet (n = 51), the median PFS was 16.4 months (95% CI, 9.3-not reached [NR]) vs 10.4 months (95% CI, 5.6-13.9) with the monotherapy (n = 46; HR, 0.55; 95% CI, 0.30-1.02). In CDK4/6 inhibitor–pretreated patients who received the doublet (n = 31) or the monotherapy (n = 30) the respective median PFS was 16.4 months (95% CI, 7.3-NR) and 9.5 months (95% CI, 5.6-NR; HR, 0.57; 95% CI, 0.27-1.22).

Those with ESR1-mutated disease who received imlunestrant plus abemaciclib (n = 67) experienced a median PFS of 11.1 months (95% CI, 7.4-13.7) vs 5.5 months (95% CI, 3.8-7.2) with imlunestrant alone (n = 92; HR, 0.53; 95% CI, 0.35-0.80). In CDK4/6 inhibitor–pretreated patients with ESR1-mutated disease who received the doublet (n = 53) vs the single agent (n = 72), the median PFS was 11.1 months (95% CI, 7.2-16.4) and 5.4 months (95% CI, 3.1-5.6), respectively (HR, 0.44; 95% CI, 0.28-0.70).

Those with a PI3K pathway mutation who received the doublet (n = 88) experienced a median PFS of 7.6 months (95% CI, 5.6-11.0) vs 3.8 months (95% CI, 3.1-5.5) with the monotherapy (n = 84; HR, 0.61; 95% CI, 0.42-0.87). In CDK4/6 inhibitor­–pretreated patients who received the combination (n = 61), the median PFS was 7.5 months (95% CI, 5.4-11.1) vs 3.7 months (95% CI, 1.9-4.9) with the monotherapy (n = 63; HR, 0.52; 95% CI, 0.34-0.79).

Lastly, in those with both an ESR1 and PI3K pathway mutation who received the doublet (n = 40) or the single agent (n = 47), the median PFS was 11.1 months (95% CI, 7.5-16.4) and 5.5 months (95% CI, 3.5-6.3), respectively (HR, 0.48; 95% CI, 0.28-0.83). In CDK4/6 inhibitor–pretreated patients who received the combination (n = 29), the median PFS was 12.9 months (95% CI, 7.5-NR) vs 3.8 months (95% CI, 2.0-5.6) with the single agent (n = 39; HR, 0.32; 95% CI, 0.16-0.63).

“EMBER-3 is the first phase 3 trial to show benefit of an oral SERD with CDK4/6 [inhibition] after disease progression on a prior CDK4/6 inhibitor, providing an effective, tolerable, and all-oral, targeted therapy option for patients with ER-positive, HER2-negative advanced breast cancer,” Cristina Saura, MD, PhD, of Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, in Barcelona, Spain, said in a presentation of the data.

Examining EMBER-3: Eligibility, Treatment, and End Points

The study enrolled men and or women with any menopausal status who had ER-positive, HER2-negative, advanced breast cancer with recurrence on or within 12 months of adjuvant treatment of an aromatase inhibitor (AI) with or without a CDK4/6 inhibitor, or progression on first-line treatment with an AI with or without CDK4/6 inhibition. Patients could not have received any other therapy for advanced breast cancer.

They were randomized 1:1:1 to receive 400 mg of imlunestrant once daily, 400 mg of imlunestrant once daily plus 150 mg of abemaciclib twice daily, or investigator’s choice of standard-of-care (SOC) endocrine therapy (ET) with fulvestrant (Faslodex) or exemestane. “The combination arm was added in a study amendment early in accrual,” Saura said. Stratification factors included prior receipt of CDK4/6 inhibition (yes vs no), presence of visceral metastases (yes vs no), and region.

The primary end points of the study overall were investigator-assessed PFS for single-agent imlunestrant vs SOC ET in those with ESR1-mutated disease, imlunestrant monotherapy vs SOC ET in all patients, the combination vs imlunestrant in all patients. For the subgroup analyses shared during the meeting, investigator-assessed PFS was evaluated for the doublet vs the monotherapy in all CDK4/6 inhibitor–pretreated patients by clinicogenomic factors.

Of the 426 total patients in these arms, “the majority, or 66%, had received prior treatment with a CDK4/6 inhibitor. Overall, demographic and baseline characteristics were generally well balanced between treatment arms,” Saura said. “Among patients pretreated with CDK4/6 inhibitor, 45% had ESR1 mutations, 45% had PI3K pathway mutations, and 58% presented with visceral metastases across the two arms. Most patients had received their CDK4/6 inhibitor treatment in the advanced setting, with palbociclib [Ibrance] being the most commonly used agent. The majority had been on CDK4/6 inhibitor therapy for at least 12 months prior to enrollment.”

Additional Efficacy Data

Previously, data published in the New England Journal of Medicine showed that imlunestrant plus abemaciclib led to a median PFS of 9.4 months (95% CI, 7.5-11.9) in all patients vs 5.5 months (95% CI, 3.8-5.6) with imlunestrant alone (HR, 0.57; 95% CI, 0.44-0.73).2 In CDK4/6 inhibitor–pretreated patients, the doublet led to a median PFS of 9.1 months (95% CI, 7.2-11.2) vs 3.7 months (95% CI, 2.1-5.5) with the monotherapy (HR, 0.51; 95% CI, 0.38-0.68).

Additional findings from the subgroup analyses showed that in all patients without visceral metastases who received the doublet (n = 94) vs the monotherapy (n = 93), the median PFS was 11.1 months (95% CI, 9.1-16.8) and 9.1 months (95% CI, 5.6-10.9), respectively (HR, 0.64; 95% CI, 0.43-0.4).1 In those without bone-only metastases who received the combination (n = 162) vs the single agent (n = 167), the median PFS was 8.1 months (95% CI, 7.3-11.1) and 3.7 months (95% CI, 2.1-5.5), respectively (HR, 0.59; 95% CI, 0.45-0.78). The median PFS with the doublet (n = 146) vs the monotherapy (n = 121) in those without ESR1-mutated disease was 9.1 months (95% CI, 7.4-14.4) vs 5.5 months (95% CI, 3.6-5.8), respectively (HR, 0.59; 95% CI, 0.43-0.81). In those without a PI3K pathway mutation, the median PFS with the combination (n = 109) vs the single agent (n = 112) was 11.4 months (95% CI, 7.6-NR) and 5.6 months (95% CI, 4.4-9.2), respectively (HR, 0.55; 95% CI, 0.39-0.79).

In CDK4/6 inhibitor–pretreated patients without visceral metastases who received the doublet (n = 59), the median PFS was 11.0 months (95% CI, 7.3-16.4) vs 5.7 months (95% CI, 5.5-9.5) with the monotherapy (n = 59), respectively (HR, 0.66; 95% CI, 0.41-1.05). In patients pretreated with CDK4/6 inhibition without bone-only metastases who received the doublet (n = 108), the median PFS was 7.4 months (95% CI, 5.6-11.1) vs 2.0 months (95% CI, 1.9-3.7) with the monotherapy (n = 110; HR, 0.46; 95% CI, 0.33-0.63). The median PFS was 7.4 months (95% CI, 5.6-11.1) in CDK4/6 inhibitor–pretreated patients without ESR1-mutated disease who received the combination (n = 86) vs 2.8 months (95% CI, 1.9-3.9) with the single agent (HR, 0.55; 95% CI, 0.37-0.82). In those who progressed on CDK4/6 inhibition who did not harbor a PI3K pathway mutation and received the combination (n = 75), the median PFS was 11.1 months (95% CI, 6.5-16.8) vs 4.4 months (95% CI, 1.9-5.6) with the single agent (n = 69; HR, 0.47; 95% CI, 0.31-0.72).

HR for PFS favored imlunestrant plus abemaciclib over imlunestrant alone irrespective of age (< 65 years: HR, 0.62; ≥65 years: HR, 0.40), region (East Asia: HR, 0.39; North America/Western Europe: HR, 0.50; Other: HR, 0.69), number of metastatic sites (1: HR, 0.39; 2: HR, 0.62; ≥3: HR, 0.46), liver metastasis (yes: HR, 0.59; no: HR, 0.38), prior CDK4/6 inhibitor indication (adjuvant: HR, 0.33; advanced: HR, 0.53), choice of prior CDK4/6 inhibitor (abemaciclib: HR, 0.93; palbociclib: HR, 0.43; and ribociclib [Kisqali]: HR, 0.57), and duration of prior CDK4/6 inhibitor (<12 months: HR, 0.31; ≥12 months: HR, 0.60; ≥18 months: HR, 0.53).

“Benefit was observed irrespective of prior duration of CDK4/6 inhibitor or choice of CDK4/6 inhibitor therapy, although analyses of prior abemaciclib patients were limited by small sample size,” Saura noted.

She concluded that follow-up for overall survival is ongoing.

Disclosures: Dr Saura serves on an advisory board or as a consultant for AstraZeneca, AX’s Consulting, Bristol Myers Squibb, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, Menarini, Genentech, Gilead, GSK, Eli Lilly and Company, Meditech, Merck, Merus, Novartis, Pfizer, Pharmalex, Philips, Pierre Fabre, Pint Pharma, Puma Biotechnology, Roche Farma, Sanofi, SeaGen, Synthon, and Zymeworks. She provides expert testimony for Boehringer Ingelheim, Innoup, and Millennium Pharmaceuticals. Research grants (institutional) have been supplied by AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytomx, Daiichi Sankyo, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, GSK, Innoup, Menarini, Merus, Novartis, Pfizer, Puma, and Sanofi. The study was sponsored by Eli Lilly and Company.

References

1. Saura C, Carey L, Curigliano G, et al. Imlunestrant (imlu) with or without abemaciclib (abeam) in advanced breast cancer (ABC): a subgroup analysis in CDK4/6 inhibitor (CDK4/6i)-pretreated patients (pts) from EMBER-3. Presented at: 2025 ESMO Breast Congress; May 14-17, 2025; Munich, Germany. Abstract 297O.
2. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. 2025;392(12):1189-1202. doi:10.1056/NEJMoa2410858