Imlunestrant extends progression-free survival in ER-positive, HER2-negative breast cancer

1. In this randomized controlled trial, in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, treatment with imlunestrant significantly extended progression-free survival in those with ERS1 mutations.

2. Imlunestrant treatment was associated with lower rates of grade 3 or higher adverse events than standard therapy.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Among breast cancer subtypes, ER-positive, HER2-negative is the most common. Treatment for this cancer targets the estrogen receptor by modulating or degrading the receptors or interfering with estrogen production. However, many cancer cells develop resistance to these treatments by acquiring mutations in the gene encoding ERα (ESR1). To enhance treatment efficacy, supplementary pharmaceuticals such as abemaciclib, a CDK4/6 inhibitor, are often used in conjunction with estrogen-targeting medications. Imlunestrant has been proposed as an estrogen receptor degrader and antagonist capable of inhibiting ESR1-mutated breast cancer. This study aimed to evaluate the efficacy of imlunestrant as monotherapy and in combination with abemaciclib in patients with advanced ER-positive, HER2-negative breast cancer. The results indicated that patients with ESR1 mutations had significantly longer progression-free survival with imlunestrant compared to standard therapy (exemestane or fulvestrant). However, when analyzing all patients, regardless of ESR1 mutation status, there was no significant difference in median progression-free survival or overall survival between the groups. The study was limited by the lack of direct comparison between fulvestrant-abemaciclib and imlunestrant-abemaciclib regimens. Nonetheless, the findings suggest that ER-positive, HER2-negative breast cancer patients experience significantly longer progression-free survival with imlunestrant—whether as monotherapy or in combination with abemaciclib—compared to current standard treatments.

Click here to read the study in NEJM

Relevant Reading: Systemic Therapy for Estrogen Receptor–Positive, HER2-Negative Breast Cancer

In-Depth [randomized controlled trial]: This randomized controlled trial aimed to evaluate the efficacy of imlunestrant for the treatment of advanced ER-positive, HER2-negative breast cancer. Participants had locally confirmed advanced ER-positive, HER2-negative breast cancer, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) or non-measurable bone-only disease, and disease progression while on a CDK4/6 inhibitor, within 12 months of adjuvant treatment, or during first-line therapy. Exclusion criteria included prior treatments beyond those listed, visceral crisis, symptomatic/untreated brain metastases, or inflammatory breast cancer. Following randomization, 331 patients were assigned to the imlunestrant group, 330 to the standard therapy group, and 213 to the imlunestrant-abemaciclib group. Among patients with an ESR1 mutation, imlunestrant significantly improved median progression-free survival (5.5 months; 95% confidence interval [CI], 3.9 to 7.4) compared to standard therapy (3.8 months; 95% CI, 3.7 to 5.5; p<0.001). However, when all patients were included in the analysis, there was no significant difference observed in median progression-free survival time (hazard ratio, 0.87; 95% CI, 0.72 to 1.04; p=0.12). Overall survival was not significantly improved with imlunestrant, either in the ESR1 mutation subgroup (hazard ratio for death, 0.55; 95% CI, 0.35 to 0.86; p=0.008) or in the full cohort (hazard ratio for death, 0.69; 95% CI, 0.50 to 0.96). Treatment with imlunestrant-abemaciclib resulted in significantly longer median progression-free survival than imlunestrant monotherapy (hazard ratio for disease progression or death, 0.57; 95% CI, 0.44 to 0.73; p<0.001). However, imlunestrant-abemaciclib therapy had higher toxicity than the other treatments, with 98.1% of treated patients experiencing adverse events and 48.6% experiencing a grade three or higher adverse event. Overall, this study indicates that imlunestrant, alone or in with abemaciclib may improve progression-free survival in patients with advanced ER-positive, HER2-ngetaive breast cancer, particularly in ESR1 mutant cases.

Image: PD

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