99 Imlunestrant With or Without Abemaciclib in Advanced Breast Cancer: Updated Efficacy Results From the Phase 3 EMBER-3 Trial

Background

At the primary progression-free survival (PFS) analysis, the phase 3 EMBER-3 trial in patients with estrogen receptor–positive/HER2-negative (ER+/HER2–) advanced breast cancer demonstrated significant PFS benefit with imlunestrant vs standard therapy (SOC: fulvestrant or exemestane) in patients with ESR1 mutations, and with imlunestrant plus abemaciclib vs imlunestrant in all patients, regardless of ESR1 mutation status. Overall survival (OS) was immature. Here, we present updated efficacy from a prespecified interim OS analysis.

Methods

Patients with ER+/HER2– advanced breast cancer previously treated with aromatase inhibitors with or without CDK4/6 inhibitors were randomized 1:1:1 to imlunestrant, SOC, or imlunestrant plus abemaciclib. Primary end points were investigator-assessed PFS of imlunestrant vs SOC in patients with ESR1 mutations and all patients and of imlunestrant plus abemaciclib vs imlunestrant in all concurrently randomized patients. OS was a key secondary end point (tested if the corresponding PFS was statistically significant). Due to only 2 of 3 PFS end points being met, limited significance level was passed to the OS comparisons. Exploratory end points included time to chemotherapy (TTC), PFS2, and efficacy analyses of imlunestrant plus abemaciclib vs SOC.

Results

BetweenOctober 2021 and November 2023, 874 patients were randomly assigned 1:1:1 (imlunestrant, n = 331; SOC, n = 330; imlunestrant plus abemaciclib, n = 213). At data cut-off (August 18, 2025), with a median follow-up of 28.5 months, 10.1% of patients remained on treatment (imlunestrant, 10%; SOC, 5%; imlunestrant plus abemaciclib, 18%).

In patients with ESR1 mutation, the median OS (mOS) was 34.5 months for imlunestrant vs 23.1 months for SOC (HR, 0.60; 95% CI, 0.43-0.86; P = .0043, boundary for significance not achieved). In all patients regardless of ESR1 mutation, the mOS was not reached with imlunestrant plus abemaciclib vs 34.4 months with imlunestrant (HR, 0.82, 95% CI, 0.59-1.16; P = .2622). Updated PFS demonstrated sustained benefit from prior report (Table). Notably, in all patients regardless of ESR1 mutation, the mPFS of imlunestrant plus abemaciclib vs imlunestrant was 10.9 months vs 5.5 months (HR, 0.59; 95% CI, 0.47-0.74; nominal P < .0001). All pre-specified exploratory end points favored imlunestrant-based regimens. Safety profiles remain consistent with prior reports.

Conclusion

At a median follow-up of 28.5 months, a clinically meaningful improvement in OS was observed with imlunestrant vs SOC in patients with ESR1mutations (corresponding to a numeric increase in mOS of 11.4 months); however, the boundary for significance was not achieved. Also, a favorable OS trend emerged with imlunestrant plus abemaciclib vs imlunestrant in all patients, regardless of ESR1 mutation. Sustained benefit inPFS, with clinically meaningful improvement in TTC, and PFS2 further highlight the efficacy of imlunestrant-based regimens. Taken together, these updated data reinforce the potential of imlunestrant, as monotherapy or in combination with abemaciclib, as an all-oral chemotherapy-free targeted therapy option for ET-pretreated patients with ER+/HER2– advanced breast cancer.