Indirect Treatment Comparison Evaluates Imlunestrant Plus Abemaciclib Against Fulvestrant Combination Therapy

The landscape of treatment for estrogen receptor-positive (ER+), HER2- advanced breast cancer is continually evolving, but gaps often exist when comparing the efficacy of new drug combinations head-to-head. A recent study utilized an indirect treatment comparison (ITC) to evaluate the relative efficacy of imlunestrant (Inluriyo; Lilly) combined with abemaciclib (Verzenio; Lilly) against fulvestrant (Faslodex; AstraZeneca) combined with abemaciclib, addressing a comparison for which direct trial data are currently unavailable.¹

Background and Necessity

The ITC study sought to compare the efficacy of imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib by analyzing data from 3 pivotal clinical trials: EMBER-3 (NCT04975308), MONARCH 2 (NCT02107703), and postMONARCH (NCT05169567).¹

The EMBER-3 trial established the progression-free survival (PFS) benefit of imlunestrant plus abemaciclib compared to imlunestrant alone in patients with ER+, HER2- advanced breast cancer who had experienced disease progression following prior therapy with an aromatase inhibitor, either alone or in combination with a CDK 4/6 inhibitor. Conversely, the MONARCH 2 and postMONARCH trials demonstrated the superiority of fulvestrant plus abemaciclib versus fulvestrant alone, specifically in patients who were CDK 4/6 inhibitor-naïve (MONARCH 2) and those who were pretreated (postMONARCH). Given the lack of a direct head-to-head trial comparing imlunestrant plus abemaciclib and fulvestrant plus abemaciclib, the ITC was leveraged to provide essential comparative efficacy data.^1-4

Methods of Comparison

The study focused on investigator-assessed PFS, employing 3 distinct ITC methods to compare the treatment arms. These methods included the Bucher method, the matching-adjusted indirect comparison (MAIC), and propensity score matching (PSM).

The Bucher method is a standard ITC approach that does not involve population adjustment. In contrast, MAIC and PSM are sophisticated, population-adjusted methods designed to account for differences in baseline characteristics across the study populations.

For this comparison, 10 specific prognostic and predictive factors were selected as baseline covariates for adjustment, including age, race, menopausal status, prior CDK 4/6 inhibitor use, prior endocrine therapy in the advanced setting, region, Eastern Cooperative Oncology Group Performance Status (ECOG PS), number of metastatic sites, visceral metastasis, and measurable disease.¹

The MAIC approach adjusted the pooled population data from MONARCH 2 and postMONARCH to align with the population characteristics of the EMBER-3 trial. The effective sample sizes varied across the analyses; for example, in the Bucher and MAIC methods, the EMBER-3 population size was 426, whereas the pooled MONARCH-2 and postMONARCH populations were 1037 and 473, respectively.¹

Key Findings

Following population adjustment via MAIC and PSM, the baseline characteristics were generally found to be balanced. Across all 3 ITC methods employed, the comparison of PFS consistently favored imlunestrant plus abemaciclib over the fulvestrant combination.¹

The resulting hazard ratios (HRs) for imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib ranged from 0.77 to 0.83. The specific results for each method demonstrated consistent trends:

1. Bucher: HR 0.77 (95% confidence interval [CI]: 0.58, 1.04)
2. MAIC: HR 0.77 (95% CI: 0.55, 1.06)
3. PSM: HR 0.83 (95% CI: 0.56, 1.22)

Although the findings consistently suggested a PFS advantage for imlunestrant plus abemaciclib, it is crucial to note that the study was not powered for formal hypothesis testing. Nonetheless, these results, derived through robust, population-adjusted statistical methods, provide valuable insight into the comparative efficacy of these combination therapies in treating ER+, HER2- advanced breast cancer patients who have progressed on prior aromatase inhibitor therapy.¹

REFERENCES

1. Bidard FC, Jhaveri KL, Kalinsky KM, et al. Imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib in estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC): an indirect treatment comparison (ITC) of three phase 3 trials. Presented at: European Society of Medical Oncology 2025 Congress. Berlin, Germany. October 20, 2025.

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; NCT04975308). Clinicaltrials.gov. Updated July 11, 2025. Accessed December 10, 2025. https://www.clinicaltrials.gov/study/NCT04975308

3. A study of abemaciclib (LY2835219) combined with fulvestrant in women with hormone receptor positive HER2 negative breast cancer (MONARCH 2; NCT02107703). Clinicaltrials.gov. Updated October 21, 2025. Accessed December 10 2025. https://clinicaltrials.gov/study/NCT02107703

4. Abemaciclib (LY2835219) plus fulvestrant compared to placebo plus fulvestrant in previously treated breast cancer (postMONARCH; NCT05169567). Clinicaltrials.gov. Updated April 18, 2025. Accessed December 10, 2025. https://www.clinicaltrials.gov/study/NCT05169567