Imlunestrant Both as Monotherapy and in Combination Shows Promising Survival Benefits for ER-Positive, HER2-Negative Advanced Breast Cancer

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The novel agent imlunestrant, administered both as a monotherapy and in combination with Verzenio (abemaciclib), was found to significantly improve survival compared to standard therapy in the treatment of ESR1-mutated estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, according to findings from the Phase III EMBER-3 trial (NCT04975308) published by The New England Journal of Medicine.^1-3 According to the trial investigators, these results show the promise of imlunestrant as an oral targeted therapy option following progression on endocrine therapy.

"The median progression-free survival (PFS) observed in EMBER-3 is among the most compelling we've seen in CDK4/6 pre-treated ER-positive, HER2-negative advanced breast cancer patients and indicates a potential shift in the therapy options we provide for these patients, which are currently very limited," trial co-principal investigator Komal Jhaveri, MD, section head, endocrine therapy research and clinical director, early drug development at Memorial Sloan Kettering Cancer Center, said in a press release. "The benefit and safety profile of the imlunestrant and abemaciclib combination signal a potential new all-oral option for patients."¹

Imlunestrant is an investigational, brain-penetrant, oral selective ER degrader that has been shown to provide continuous ER inhibition, including for ESR1-mutant cancers. The drug is currently under evaluation in multiple clinical trials for advanced breast cancer and as an adjuvant treatment for early breast cancer.

“In the phase 1 EMBER study, imlunestrant, as monotherapy and in combination with abemaciclib, showed mainly low-grade toxic effects, favorable pharmacokinetics, and encouraging antitumor activity in patients with ER-positive, HER2-negative advanced breast cancer,” the study authors wrote.³

Trial Design

The randomized, open-label EMBER-3 trial compared imlunestrant monotherapy, investigator's choice of endocrine therapy, and imlunestrant in combination with Verzenio in patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease recurred or progressed during or after treatment with aromatase inhibitor therapy with or without a CDK 4/6 inhibitor.

Investigators enrolled 874 adult patients who were randomly assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant plus Verzenio. The trial’s primary endpoints were investigator-assessed PFS with imlunestrant compared to standard therapy among patients with ESR1 mutations and among all patients, and compared imlunestrant plus Verzenio vs. imlunestrant monotherapy among all patients who underwent randomization concurrently. A total of 32% of patients were enrolled from the adjuvant setting into first-line treatment for advanced breast cancer and 64% as second-line treatment after progressing on initial therapy for advanced breast cancer.

Among 256 patients with ESR1 mutations, median PFS was 5.5 months with imlunestrant compared to 3.8 months with standard therapy. At 19.4 months months, the estimated restricted mean survival time was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) among patients administered imlunestrant compared to 5.4 months (95% CI, 4.6 to 6.2) among patients administered standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001).

For the overall patient population, median PFS was 5.6 months for those administered imlunestrant compared to 5.5 months for those given standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P=0.12).

In the comparison of imlunestrant plus Verzenio vs. imlunestrant monotherapy, among 426 patients, median PFS was 9.4 months in the combination cohort compared to 5.5 months in the monotherapy cohort (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). In terms of safety, incidence of grade 3 or higher adverse events was 17.1% in the imlunestrant monotherapy cohort, 20.7% in the standard therapy cohort, and 48.6% in the imlunestrant plus Verzenio cohort.

“This phase 3 trial involving patients with ER-positive, HER2-negative advanced breast cancer that had progressed during or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor showed significant prolongation of progression-free survival with imlunestrant over standard therapy among patients with ESR1 mutations, as well as with imlunestrant–abemaciclib over imlunestrant in all patients,” the study authors wrote. “Imlunestrant showed mainly low-grade toxic effects as monotherapy and in combination with abemaciclib. Imlunestrant, as monotherapy or in combination with abemaciclib, provides an oral targeted-therapy option after progression during endocrine therapy in patients with ER-positive, HER2-negative advanced breast cancer.”³

References

1. Lilly's Imlunestrant, an Oral SERD, Significantly Improved Progression-Free Survival as Monotherapy and in Combination with Verzenio® (abemaciclib) in Patients with ER+, HER2- Advanced Breast Cancer. News release. Eli Lilly. December 11, 2024. Accessed December 18, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-imlunestrant-oral-serd-significantly-improved-progression

2. A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3). ClinicalTrials.gov. Updated December 11, 2024. Accessed December 18, 2024. https://clinicaltrials.gov/study/NCT04975308

3. Jhaveri k., et al. Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. N Engl J Med 2024. DOI: 10.1056/NEJMoa2410858.