Research Summary:
Many estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2–) breast tumors develop resistance to aromatase inhibitors (AIs) alone or in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. However, the capacity for selective ER degraders (SERDs) to induce ER alpha degradation might help overcome AI-resistant breast tumors. Fulvestrant was the first broadly approved SERD, and recent clinical trials have examined the efficacy of next-generation SERDs, such as imlunestrant, in reducing disease progression or death in patients with ER+, HER2– advanced breast cancer with disease recurrence or progression following prior treatment. The phase 3 EMBER-3 trial showed significant progression-free survival (PFS) benefit with imlunestrant combined with abemaciclib, a CDK4/6 inhibitor, vs imlunestrant monotherapy in ER+, HER2– advanced breast cancer. The phase 3 MONARCH 2 and postMONARCH trials showed that abemaciclib plus fulvestrant was superior to fulvestrant monotherapy. Jhaveri et al1 conducted an indirect treatment comparison of these 3 trials to compare the relative efficacy of imlunestrant plus abemaciclib vs fulvestrant plus abemaciclib.
The phase 3 EMBER-3 trial compared the efficacy of imlunestrant alone vs imlunestrant in combination with abemaciclib. The trial showed that imlunestrant monotherapy significantly improved PFS in patients with tumors harboring ESR1 mutations vs standard of care (SOC) endocrine therapy (ET) with fulvestrant or exemestane (5.5 months vs 3.8 months; hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.46–0.82; P<0.001). However, imlunestrant monotherapy was not associated with a significant increase in PFS in the overall population (5.6 months vs 5.5 months; HR: 0.87; 95% CI: 0.72–1.04). Imlunestrant in combination with abemaciclib demonstrated significantly improved PFS benefit vs imlunestrant alone in all patients, regardless of ESR1 mutation status (9.4 months vs 5.5 months; HR: 0.57, 95% CI: 0.44–0.73; P<0.001).
The phase 3 MONARCH 2 and postMONARCH trials both demonstrated the superiority of fulvestrant in combination with abemaciclib vs fulvestrant alone in CDK4/6 inhibitor–naïve and pretreated patients, respectively. The MONARCH 2 trial had an HR of 0.539 (95% CI: 0.449–0.647; P<0.0001), while the postMONARCH trial had an HR of 0.73 (95% CI: 0.57–0.95; P=0.017).
To compare PFS between imlunestrant plus abemaciclib and fulvestrant plus abemaciclib, Jhaveri et al utilized individually matched patient-level data from the EMBER-3, MONARCH 2, and postMONARCH trials to employ 3 different indirect treatment comparison methods: the Bucher method, matching-adjusted indirect comparison (MAIC), and propensity score matching (PSM). Due to their smaller patient populations, the MONARCH 2 and postMONARCH trials were pooled together to match the size of the EMBER-3 trial.
In the pooled population data from the MONARCH 2 and postMONARCH trials, there were 409 patients who received fulvestrant in combination with placebo and 628 patients who received fulvestrant in combination with abemaciclib. In the EMBER-3 trial, 426 patients received either SOC ET with fulvestrant or exemestane (n=213) or imlunestrant with abemaciclib (n=213).
In total, 473 patients from the pooled MONARCH 2 and postMONARCH populations (fulvestrant plus abemaciclib, n=242; fulvestrant alone, n=231) were matched in the MAIC with 426 patients from the EMBER-3 trial, and 343 patients from the EMBER-3 trial (imlunestrant plus abemaciclib, n=169; SOC ET, n=174) were propensity-score matched with 343 patients from the pooled MONARCH 2 and postMONARCH populations (fulvestrant plus abemaciclib, n=169; fulvestrant alone, n=174).
In terms of patient characteristics for MAIC, the proportion of patients with prior CDK4/6 inhibitor exposure was 65% in both the EMBER-3 and pooled MONARCH 2 and postMONARCH cohorts, and receipt of prior ET in the advanced setting was 70%. For PSM, the proportion of patients with prior CDK4/6 inhibitor exposure was 58% in the EMBER-3 cohort vs 57% in the pooled MONARCH 2 and postMONARCH cohort. Prior ET in the advanced setting was reported in 67% of patients in the EMBER-3 cohort and 66% of patients in the pooled MONARCH 2 and postMONARCH cohort.
Across the 3 indirect treatment comparison methods examined in the study (Bucher method, MAIC, PSM), imlunestrant in combination with abemaciclib showed a numerically consistent reduction in risk of disease progression or death compared to fulvestrant in combination with abemaciclib. The Bucher method produced a HR of 0.77 (95% CI: 0.58–1.04) and the MAIC analysis showed a HR of 0.77 (95% CI: 0.55–1.06), both favoring imlunestrant in combination with abemaciclib. PSM also showed a PFS trend favoring imlunestrant plus abemaciclib, with a HR of 0.83 (95% CI: 0.56–1.22).
In this indirect treatment comparison analysis, imlunestrant plus abemaciclib demonstrated favorable PFS vs fulvestrant plus abemaciclib. These findings highlight the effectiveness of imlunestrant in combination with abemaciclib for the treatment of endocrine-resistant, ER+, HER2– advanced breast cancer.
References
- Jhaveri K, Bidard FC, Kalinsky K, et al. Imlunestrant plus abemaciclib versus fulvestrant plus abemaciclib in ER-positive, HER2-negative advanced breast cancer: an indirect treatment comparison of three phase III trials. ESMO Open. 2026;11(3):106091.