Trend for improved overall survival with abemaciclib plus aromatase inhibitor in advanced breast cancer

In the MONARCH-3 trial, the addition of abemaciclib to a non-steroidal aromatase inhibitor (NSAI) previously demonstrated to significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Results from a pre-specified second interim analysis of this trial now show that the addition of abemaciclib also resulted in a 12.6-month increase in median overall survival (mOS) in this population.

Abemaciclib is an oral, potent, cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor with greater selectivity for CDK4 than CDK6, which allows continuous dosing due to less myelosuppression. Abemaciclib is the first and only CDK4/6 inhibitor approved as monotherapy in advanced breast cancer (ABC) and in combination with endocrine therapy (ET) for the adjuvant treatment of high-risk, HR+, HER2- early breast cancer (EBC). MONARCH-2 already demonstrated a significant improvement in overall survival (OS) for the combination of abemaciclib with fulvestrant compared to fulvestrant alone as second-line therapy for ABC. MONARCH-3 investigated abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in the first-line setting in post-menopausal patients with HR+, HER2- ABC.

Study design

MONARCH-3 is a double-blind, randomised phase III study of abemaciclib or placebo plus a NSAI in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily, continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival (PFS). OS is a key secondary endpoint and this prespecified second OS interim analysis (IA2) (data cut-off 2 July 2021) was scheduled after 252 events in the ITT population (80% of planned events for final OS analysis), using a stratified log-rank test and applying a pre-defined error spending strategy to assess significance in both the ITT and the subgroup with visceral disease (sVD).

Results

In total, 493 patients were randomised to receive NSAI + abemaciclib (N= 328) or placebo (N= 165). At IA2, with 70.2 months median follow-up, in the ITT the median OS was 67.1 months for abemaciclib + NSAI vs. 54.5 months for placebo + NSAI (HR[95%CI]: 0.754[0.584-0.974], 2-sided p= 0.0301). Of note, 31.5% of patients in the control arm and 10.1% of patients in the abemaciclib arm received a subsequent CDK4/6 inhibitor. A consistent trend was observed across pre-specified subgroups. In sVD, the median OS was 65.1 months in the abemaciclib arm vs. 48.8 months in the placebo arm (HR[95%CI]: 0.708[0.508-0.985], 2-sided p= 0.0392). According to the alpha spending procedure, the critical boundaries for declaring significance in both groups were not met for IA2. Follow-up is ongoing for final OS analysis (expected 2023). With a median follow-up of 5.8 years (additional 3.6 years from final PFS analysis), the PFS treatment effect is persistent (median PFS 29.0 vs. 14.8 months, HR[95%CI]: 0.518[0.415-0.648], nominal p< 0.0001). Furthermore, the addition of abemaciclib to NSAI deferred the initiation of chemotherapy by 16.1 months (46.7 vs. 30.6 months). No new safety signals were observed with long-term use of abemaciclib.

Conclusion

At the second interim OS analysis, a numerically favourable OS difference was observed in both the ITT population and sVD, although neither met the threshold for statistical significance according to the alpha spending procedure. Abemaciclib delayed subsequent receipt of chemotherapy and no new safety concerns were reported with prolonged exposure to abemaciclib. Follow-up is ongoing with final OS data expected next year.

Reference

Goetz M, et al. MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC). Presented at ESMO 2022; Abstract LBA15.