#VisualAbstract: Imlunestrant with or without Abemaciclib in Advanced Breast Cancer

1. Median progression-free survival was 9.4 months in the imlunestrant–abemaciclib group vs 5.5 months in the imlunestrant group with HR 0.57 (significant) and 5.6 months in the imlunestrant group vs 5.5 months in the standard-therapy group with HR 0.87 (non-significant).

2. With regards to safety, adverse events grade 3 or higher occurred in 17.1% in the imlunestrant group vs 20.7% in the standard therapy group vs 48.6% in the imlunestrant–abemaciclib group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: ER-positive HER2-negative breast cancer is primarily treated with endocrine therapy, however resistance can arise via ESR1 mutations. Imlunestrant is a next-generation, brain-penetrant, oral selective ER degrader that delivers continuous ER inhibition, even in ESR1-mutated cancers. This trial evaluated the efficacy and safety of imlunestrant, alone and with abemaciclib (a potent CDK4/6 inhibitor). The primary endpoint included progression-free survival (PFS), and secondary endpoints included overall survival (OS) and safety. When comparing imlunestrant to standard endocrine therapy, it was found that in the total population, median PFS was 5.6 months in the imlunestrant group and 5.5 months in the standard therapy group, with HR 0.87 (non-significant). Among patients with ESR1 mutations, the estimated restricted mean survival time at 19.4 months was 7.9 months in the imlunestrant group vs 5.4 months in the standard therapy group (significant). Post hoc analysis found the 12-month cumulative incidence of CNS progression was 1.5% with imlunestrant vs 6.7% with standard therapy in ESR1 mutations with HR 0.18. OS at 18 months was 78.6% in the imlunestrant group and 71.8% in the standard-therapy group among all patients, with HR 0.69. OS at 18 months among patients with ESR1 mutations was 77.0%  in the imlunestrant group vs 58.6% in the standard-therapy group among patients with ESR1 mutations with HR 0.55 (non-significant). When comparing imlunestrant to imlunestrant–abemaciclib, it was found that median PFS was 9.4 months in the imlunestrant–abemaciclib group vs 5.5 months in the imlunestrant group, with HR 0.57 (significant). OS data for this comparison was immature in this analysis. Comparing imlunestrant–abemaciclib with standard therapy, HR for PFS was 0.46, and HR for OS was 0.90 at this analysis. With regards to safety, adverse events grade 3 or higher occurred in 17.1% in the imlunestrant group vs 20.7% in the standard therapy group vs 48.6% in the imlunestrant–abemaciclib group with the majority being anemia (2.1% vs 2.8% vs 7.7%), neutropenia (2.1% vs 1.9% vs 19.7%) and diarrhea (0.3% vs 0% vs 8.2%). The strength of this study was the methodology and the limitations included sample size and follow-up time. Overall this study found some improved outcomes with imlunestrant with or without abemaciclib compared to standard therapy in patients with ER-positive, HER2-negative advanced breast cancer who progressed after aromatase inhibitors or CDK4/6 inhibitors.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This multinational, open-label, phase 3 trial enrolled adults with advanced ER-positive, HER2-negative breast cancer who progressed after aromatase inhibitors or CDK4/6 inhibitors and randomized them (1:1:1) into imlunestrant alone (n=331) vs imlunestrant–abemaciclib (n=213) vs standard endocrine monotherapy (either exemestane or fulvestrant, n=330, most patients received fulvestrant). ESR1 mutations were present in the 38.7% total group. When comparing imlunestrant to standard therapy, it was found that in the total population, median PFS was 5.6 months (95%CI, 5.3-7.3) in the imlunestrant group and 5.5 months (95%CI, 4.6-5.6) in the standard therapy group, with HR 0.87 (95%CI, 0.72-1.04, p=0.12). Among patients with ESR1 mutations, the estimated restricted mean survival time at 19.4 months was 7.9 months (95%CI, 6.8-9.1) in the imlunestrant group vs 5.4 months (95%CI, 4.6-6.2) in the standard therapy group (difference, 2.6 months, 95%CI, 1.2-3.9, p<0.001). Post hoc analysis found the 12-month cumulative incidence of CNS progression was 1.5% with imlunestrant vs 6.7% with standard therapy in ESR1 mutations with HR 0.18 (95%CI, 0.04-0.90). OS at 18 months was 78.6% (95%CI, 72.6-83.5) in the imlunestrant group and 71.8% (95%CI, 65.4-77.2) in the standard-therapy group among all patients, with HR 0.69 (95%CI, 0.50-0.96). OS at 18 months among patients with ESR1 mutations was 77.0% (95%CI, 67.4-84.1) in the imlunestrant group vs 58.6% (95%CI, 47.2-68.3) in the standard-therapy group among patients with ESR1 mutations with HR 0.55 (95%CI, 0.35-0.86, p-value was above threshold). When comparing imlunestrant to imlunestrant–abemaciclib, it was found that median PFS was 9.4 months (95%CI, 7.5-11.9) in the imlunestrant–abemaciclib group vs 5.5 months (95%CI, 3.8-5.6) in the imlunestrant group, with HR 0.57 (95%CI, 0.44-0.73, p<0.001). OS data for this comparison was immature in this analysis. Comparing imlunestrant–abemaciclib with standard therapy, HR for PFS was 0.46 (95%CI, 0.36-0.60), and HR for OS was 0.90 (95%CI, 0.57-1.42) at this analysis. With regards to safety, adverse events grade 3 or higher occurred in 17.1% in the imlunestrant group vs 20.7% in the standard therapy group vs 48.6% in the imlunestrant–abemaciclib group with the majority being anemia (2.1% vs 2.8% vs 7.7%), neutropenia (2.1% vs 1.9% vs 19.7%) and diarrhea (0.3% vs 0% vs 8.2%). Overall this study found some improved outcomes with imlunestrant with or without abemaciclib compared to standard therapy in patients with ER-positive, HER2-negative advanced breast cancer who progressed after aromatase inhibitors or CDK4/6 inhibitors.

Image: PD

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