MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer

Abstract

At the MONARCH 3 interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (AI) significantly improved progression-free survival (PFS) and objective response rate (ORR) with a tolerable safety profile as initial treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). MONARCH 3 is a randomized, phase III, double-blind study of abemaciclib/placebo (150 mg twice daily, continuous) plus nonsteroidal AI (1 mg anastrozole or 2.5 mg letrozole, daily). A total of 493 postmenopausal women with HR+, HER2− ABC with no prior systemic therapy in this setting were enrolled. The primary endpoint was investigator-assessed PFS (final analysis after 240 events); other endpoints included response and safety evaluations. Here we analyze the final PFS data and update secondary endpoints. The abemaciclib arm had a significantly longer median PFS than the placebo arm (28.18 versus 14.76 months; hazard ratio [95% confidence interval], 0.540 [0.418–0.698]; p = .000002). The ORR was 61.0% in the abemaciclib arm versus 45.5% in the placebo arm (measurable disease, p = .003). The median duration of response was longer in the abemaciclib arm (27.39 months) compared to the placebo arm (17.46 months). The safety profile was consistent with previous reports. The most frequent grade ≥ 3 adverse events in the abemaciclib versus placebo arms were neutropenia (23.9% versus 1.2%), diarrhea (9.5% versus 1.2%), and leukopenia (8.6% versus 0.6%). Abemaciclib plus a nonsteroidal AI was an effective initial treatment with an acceptable safety profile for HR+, HER2− ABC.

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

“…The patients were randomized 2:1 to receive abemaciclib with anastrozole or letrozole compared to placebo plus anastrozole or letrozole. The results showed that the abemaciclib arm had better median PFS than the placebo arm (28.18 versus 14.76 months) [149], which also led to the FDA approving abemaciclib (Verzenio) in combination with aromatase therapy in HR+/HER2− M/ABC patients as first-line therapy in February 2018. In addition, other ongoing studies with abemaciclib in BC were carried out, such as the neoMONARCH (NCT02441946) phase II clinical trial to compare the biological effects of abemaciclib combination with anastrozole to those of abemaciclib monotherapy and anastrozole monotherapy for two weeks, as well as to evaluate the activity and safety of abemaciclib with anastrozole in a subsequent 14 weeks with HR+/HER2− ABC [150].…”

Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment

“…Three CDK 4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are used in the treatment of metastatic HR+, HER2 negative BC. CDK 4/6 inhibitors are indicated only in combination with endocrine therapy (AI or fulvestrant) [64][65][66][67]. Laezza et al showed that anandamide analogue (Met-F-AEA) induces S-phase cell cycle arrest and decreases the percentage of cells in G2/M phase in the MDA-MB-231 line.…”

Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer

“…Inhibition of CDK4/6 with a small molecule prevents cell-cycle progression through G 1 and arrests tumor growth. Abemaciclib is one of three currently approved selective small-molecule inhibitor of CDK4/6 for treatment of HR þ /HER2 À metastatic breast cancer, the other two being palbociclib and ribociclib (8)(9)(10)(11)(12)(13)(14). In preclinical studies, short-term inhibition caused temporary G 1 arrest in vitro and in vivo (9,13).…”