Abemaciclib + Fulvestrant: PFS Improvement in ABC Progression

The standard first-line treatment for individuals with HR+, HER2- advanced breast cancer (ABC) involves the combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET). Despite this regimen, almost all patients experience disease progression. The ideal treatment for those who progress on CDK4/6i + ET remains uncertain.

Real-world evidence indicates that abemaciclib use after disease progression on a prior CDK4/6i prolongs progression-free survival (PFS) in ABC. However, Phase 2 trials with other CDK4/6i have produced varied outcomes.

Kevin Kalinsky and the team outlined the primary outcome analysis of the Phase 3 postMONARCH trial (NCT05169567), evaluating fulvestrant + abemaciclib or placebo in HR+, HER2- ABC patients post-progression on prior CDK4/6i + ET.

The postMONARCH study was a global, double-blind, placebo-controlled trial where patients were randomized 1:1 to receive abemaciclib + fulvestrant or placebo + fulvestrant. Eligible individuals had experienced disease progression on a CDK4/6i + AI as initial therapy for advanced breast cancer or relapse following a CDK4/6i + ET as adjuvant therapy for early breast cancer, with no prior treatment for advanced breast cancer allowed.

The primary endpoint was investigator-assessed progression-free survival (PFS), with secondary endpoints including PFS by blinded independent central review (BICR), overall survival (OS), objective response rate (ORR), and safety. Assuming HR of 0.7, the study had approximately 80% power to detect superiority for abemaciclib, with a cumulative two-sided type I error of 0.05. The Kaplan-Meier method was used to estimate PFS curves, and the treatment effect was estimated using a stratified Cox proportional hazard model.

About 368 patients were randomized, with 182 receiving abemaciclib + fulvestrant and 186 receiving placebo + fulvestrant. Nearly all patients (99%) were enrolled immediately after CDK4/6i + ET as initial therapy for advanced breast cancer. Among those with prior CDK4/6i treatment, 59% received palbociclib, 33% received ribociclib, and 8% received abemaciclib.

At the interim analysis, the study met pre-specified criteria, showing significantly improved investigator-assessed PFS with abemaciclib + fulvestrant compared to placebo + fulvestrant (169 events, HR = 0.66; 95% CI 0.48 – 0.91; P= 0.01). At primary analysis (258 events), the HR was 0.73 (95% CI 0.57 – 0.95), with PFS rates at 6 months of 50% vs 37% for the abemaciclib and placebo arms, respectively.

Consistent effects were observed across major clinical and genomic subgroups, including patients with baseline ESR1 or PIK3CA mutations. ORR was higher with abemaciclib compared to placebo (17% vs 7%, respectively, in patients with measurable disease). PFS, according to blinded independent central review (BICR), also showed improvement with HR = 0.55 (95% CI 0.39 – 0.77). OS data remain immature (20.9% event rate). Safety findings were consistent with the known profile of abemaciclib.

The conclusion drawn from the study indicated that in patients with advanced breast cancer who experienced progression on prior CDK4/6i-containing therapy, the combination of abemaciclib + fulvestrant led to a statistically significant improvement in progression-free survival.

The trial was sponsored by the Eli Lilly and Company.

Source: https://meetings.asco.org/abstracts-presentations/231580

Clinical Trial: https://clinicaltrials.gov/study/NCT05169567

Kalinsky K, Bianchini G, Hamilton EP, et al. (2024). “Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial.” Presented at ASCO 2024, J Clin Oncol 42, 2024 (suppl 17; abstr LBA1001), DOI: 10.1200/JCO.2024.42.17_suppl.LBA1001 (LBA1001)