Imlunestrant Plus Abemaciclib Improves Progression-Free Survival in Patients With ER+, HER2- Advanced Breast Cancer

Imlunestrant (Eli Lilly and Company) plus abemaciclib (Verzenio; Eli Lilly and Company) significantly improved progression-free survival (PFS) in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (BC) who experienced recurrence or progressed during or after aromatase inhibitor therapy. These data, from the EMBER-3 trial (NCT04975308), were published in The New England Journal of Medicine.

Breast cancer cell growth | Image Credit: © Best - stock.adobe.com

Of all cases, ER+/HER2-BC is the most prevalent subtype, accounting for roughly 70% of diagnoses. Despite that many individuals receive an early-stage diagnosis at first, about 30% will go on to develop metastatic or advanced disease. Although improvements in treatment have helped manage symptoms and delay the development of the disease, resistance to first-line medicines is still a major problem. Approximately 40% of patients undergoing second-line treatment had ESR1 mutations, which are a contributing factor to acquired resistance.

Imlunestrant is an investigational, next-generation, brain-penetrant, oral selective ER degrader that delivers continuous ER inhibition and has demonstrated significant capabilities in preventing disease progression in advanced BC. Although it is not yet FDA approved, positive data from the EMBER-3 study may support its approved indication for ER+/HER2- BC.

The randomized, open-label phase 3 study aimed to determine the efficacy of imlunestrant compared with investigator’s choice of endocrine therapy, as well as the efficacy of imlunestrant plus abemaciclib compared with imlunestrant alone. They assessed 874 patients with ER+/HER2- advanced BC that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a CDK4/6 inhibitor. The patients were randomly assigned to receive either imlunestrant (n = 331), standard therapy (n = 330), or imlunestrant plus abemaciclib (n = 256). The primary end point was investigator-assessed PFS with imlunestrant versus standard therapy among patients with ESR1 mutations (n = 256) and among all patients, as well as with imlunestrant plus abemaciclib versus imlunestrant among all patients who had undergone concurrent randomization.

Of the patients with ESR1 mutations, those treated with imlunestrant achieved a PFS of 5.5 months compared with 3.8 months for those treated with standard therapy. In the overall population, the median PFS was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio [HR] for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). When evaluating PFS in the comparison of imlunestrant plus abemaciclib with imlunestrant, the median PFS was 9.4 months and 5.5 months, respectively (HR, 0.57; 95% CI, 0.44 to 0.73; P < .001).

The investigators also reported mean survival times of 19.4 months, 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant, and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P < .001).

These findings support the potential of imlunestrant, particularly in combination with abemaciclib, as a promising treatment strategy for patients with ER+/HER2- advanced BC who have experienced disease progression on prior endocrine therapy. Continued investigation and regulatory review may pave the way for a new therapeutic option in this high-need population.

REFERENCES

1. A study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant plus abemaciclib in participants with ER+, HER2- advanced breast cancer (EMBER-3). Updated April 8, 2025. Accessed April 14, 2025. https://clinicaltrials.gov/study/NCT04975308

2. Jhaveri K, Neven P, Casalnuovo M, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N J Engl Med. December 11, 2024. doi: 10.1056/NEJMoa2410858

3. Vepdegestrant demonstrates progression-free survival in patients with ER+/HER2- metastatic breast cancer. Pharmacy Times. March 11, 2025. Accessed April 14, 2025. https://www.pharmacytimes.com/view/vepdegestrant-demonstrates-progression-free-survival-in-patients-with-er-her2--metastatic-breast-cancer