Imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib in ER-positive, HER2-negative advanced breast cancer: an indirect treatment comparison of three phase III trials

BACKGROUND: The EMBER-3 trial demonstrated significant progression-free survival (PFS) benefit for imlunestrant + abemaciclib versus imlunestrant alone in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) with disease recurrence/progression during prior aromatase inhibitor ± cyclin-dependent kinase 4/6 inhibitor (AI ± CDK4/6i) treatment. The phase III MONARCH 2 and postMONARCH trials demonstrated the superiority of fulvestrant + abemaciclib versus fulvestrant in CDK4/6i-naïve and pretreated patients, respectively. The efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib has not been directly evaluated in randomized controlled trials. In the absence of head-to-head trial data, indirect treatment comparison (ITC) analyses allow fair evaluation of between-trial efficacy. This study aimed to determine the relative efficacy of imlunestrant + abemaciclib versus fulvestrant + abemaciclib through ITC of the EMBER-3, MONARCH 2, and postMONARCH trials. MATERIALS AND METHODS: To compare investigator-assessed PFS between imlunestrant + abemaciclib and fulvestrant + abemaciclib, three ITC methods-Bucher, matching-adjusted indirect comparison (MAIC), and propensity score matching (PSM)-were employed using individually matched patient-level data from the EMBER-3, MONARCH 2, and postMONARCH trials. Ten prognostic and predictive factors were selected as baseline covariates. The standard Bucher method had no population adjustment, whereas PSM and MAIC were population-adjusted. The MAIC analysis adjusted the pooled MONARCH 2/postMONARCH population to match the EMBER-3 population. The PSM matched the propensity score between the EMBER-3 and pooled MONARCH 2/postMONARCH populations. RESULTS: Baseline characteristics were well balanced across adjusted populations by MAIC and PSM. Though not powered for formal hypothesis testing, PFS favored imlunestrant + abemaciclib versus fulvestrant + abemaciclib across all three ITC methods. Hazard ratios (95% confidence intervals) for Bucher, MAIC, and PSM were 0.77 (0.58-1.04), 0.77 (0.55-1.06), and 0.83 (0.56-1.22), respectively. CONCLUSION: In this ITC analysis of patient-level data from three phase III trials, although not powered for formal hypothesis testing, the all-oral targeted combination therapy imlunestrant + abemaciclib showed a consistent numerical reduction in the risk of disease progression or death compared with fulvestrant + abemaciclib in patients with ER-positive/HER2-negative ABC previously treated with endocrine therapy ± CDK4/6i.