Abemaciclib is an oral selective CDK4 & 6 inhibitor dosed on a continuous schedule and has demonstrated efficacy and tolerability as monotherapy and in combination with fulvestrant in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). MONARCH 3 evaluates abemaciclib plus the non-steroidal aromatase inhibitors (NSAI) anastrozole (A) or letrozole (L) as initial therapy in HR+/HER2- ABC.
MONARCH 3 is a double-blind, Phase 3 study of abemaciclib + NSAI (A or L) vs placebo (P) + NSAI in postmenopausal women with HR+/HER2- ABC who have had no prior systemic therapy in the metastatic setting. Endocrine naïve pts or pts with disease relapse >12 months after (neo)adjuvant endocrine therapy (ET) were randomized 2:1 and stratified by metastatic site (visceral, bone only, or other) and prior ET (AI vs no ET vs other). Pts received abemaciclib/P (150 mg, twice daily continuous schedule) + 1 mg A or 2.5 mg L, daily. The primary objective was investigator-assessed progression-free survival (PFS). Secondary objectives included objective response rate (ORR) and safety. The study was powered to 80% at 1-sided α=.025 assuming a hazard ratio (HR) of 0.67 in favor of abemaciclib + NSAI, with analyses at 189 and 240 PFS events.
493 women were randomized to abemaciclib + NSAI (n = 328) or P + NSAI (n = 165). Pt characteristics were: visceral disease (52.9%), measurable disease (80.5%), prior (neo)adjuvant AI (27.4%), and de novo ABC (39.8%). At the interim analysis, 194 PFS events were observed. The PFS was significantly prolonged with a HR of 0.543 (95% CI, 0.409 to 0.723, P=.000021; median PFS: not reached in abemaciclib arm, 14.7 months in placebo arm). In pts with measurable disease, the ORR was 59% in the abemaciclib arm and 44% in the P arm (P=.004). The most frequent adverse events were (abemaciclib vs P arms) diarrhea (81.3% [grade 3: 9.5%, no grade 4] vs 29.8% [grade 3: 1.2%, no grade 4]), neutropenia (41.3% [grade 3/4: 21.1%] vs 1.9% [grade 3/4: 1.2%]), and fatigue (40.1% [grade 3: 1.8%] vs 31.7% [grade 3: 0%]).
Abemaciclib + NSAI demonstrated a tolerable safety profile and was an effective initial treatment for pts with HR+/HER2- ABC, significantly improving PFS and ORR.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company
A. Di Leo: Honoraria, consulting, and travel funds: Daichii-Sankyo, Roche, Novartis, Pfizer, AstraZeneca, Genomic Health, Eisai, Lilly, Pierre Fabre, Bayer, Celgene. Consulting and travel funds: Puma Biotechnology. Research funds: Novartis, Pfizer, AstraZeneca. M. Campone: Honoraria, Consulting/advisory, Speakers’ bureau: Novartis, Pfizer, AstraZeneca; Lilly. Travel funds: Novartis, AstraZeneca. J. Sohn: Research Funding: AstraZeneca, Eli Lilly and Company, Novartis, Genentech, Pfizer, MSD Oncology. S. Paluch-Shimon: Consulting/advisory, Speakers’ Bureau: Pfizer, Novartis, Roche, AstraZeneca. J. Huober: Honoraria, Consulting/advisory, Travel funds: Novartis, Pfizer, Roche. Honoraria, Consulting: Lilly. O. Tredan: Honoraria, Consulting/Advisory, Travel funds: Lilly, Roche, Novartis, AstraZeneca, Pfizer, Celldex. G.G. Jaliffe: Speakers’ Bureau: Roche, Amgen. T. Forrester, M. Frenzel, I.C. Smith, N. Bourayou: Employment and Stock Ownership: Eli Lilly and Company. S. Barriga: Employment: Eli Lilly and Company. M.P. Goetz: Consulting/Advisory: Eli Lilly and Company, Biotheranostics. Research funding: Eli Lilly and Company. All other authors have declared no conflicts of interest.