A narrative review of the clinical development of CDK4/6 inhibitor abemaciclib in breast cancer

Abstract

Background and objective: Advanced or metastatic breast cancer (MBC) is associated with poor prognosis and presents many challenges in medical management and treatment decisions. Anticancer drugs that act on cell cycle mechanisms have shown great potential in preclinical studies. In clinical trials, abemaciclib, a reversible ATP-competitive cyclin-dependent kinase 4/6 (CDK4/6) inhibitor developed by Eli Lilly and Company, combined with endocrine therapy (ET) were associated with superior outcomes compared with ET alone in patients with advanced or metastatic hormone receptor positive (HR⁺)/human epidermal growth factor receptor 2 negative (HER2^-) breast cancer, representing a new standard-of-care in this population. Abemaciclib has been approved by the U.S. Food and Drug Administration (FDA) for use in HR⁺/HER2^- MBC. In China, abemaciclib was also approved by the National Medical Products Administration (NMPA) based on findings from the MONARCH plus trial. Recently, abemaciclib have been approved as the first and only CDK4/6 inhibitor by FDA and NMPA for use in HR⁺/HER2^-, node-positive, early breast cancer (EBC) at high risk of recurrence and Ki-67 score ≥20%. Further trials of abemaciclib are ongoing. This is an overview of the clinical development of abemaciclib in breast cancer.

Methods: We reviewed English publications in PubMed related to CDK4/6 inhibitors from 2011 to 2021.

Key content and findings: In this review, we summarized the mechanism, results of preclinical and clinical studies of abemaciclib, describing current indications for treatment, ongoing clinical trials, safety and tolerability, and future perspectives.

Conclusions: Abemaciclib is a unique CDK4/6 inhibitor with distinctive characteristics and promising data, which bring benefit to HR⁺, HER2^- breast cancer patients.

Keywords: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6 inhibitor); abemaciclib; hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer (HR+/HER2− breast cancer); metastatic breast cancer (MBC).

Figure 1

Mechanism of action of CDK4/6 inhibitors. The CDK4/6-cyclin D complex induces phosphorylation of the Rb. Free transcription factor E2F stimulates cell transition from the G1 to the S phase and cell division. CDK4/6, cyclin dependent kinase 4/6; Rb, retinoblastoma tumor suppressor protein; E2F, transcription factor family; ER, estrogen receptor; mTOR, mammalian target of rapamycin; AKT, protein kinase B; PI3K, phosphoinositide 3-kinase.

Figure 2

Chemical structure of LY2835219/abemaciclib.