Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor, which specifically inhibits the activities of the cyclin D-dependent kinases CDK4 and CDK6. During the cell-division cycle, abemaciclib arrests progression through the G1 phase and thereby promotes transient cell-cycle withdrawal into a quiescent state (G0) or into a permanent proliferation inhibition (senescence). As a result, DNA synthesis is supressed and cancer cell growth stopped. Abemaciclib has been approved by the US Food and Drug Administration (FDA) in September 2017 for the following two indications: abemaciclib as monotherapy for patients with hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced breast cancer (ABC) who have received prior endocrine therapy (ET), and abemaciclib in combination with fulvestrant in women with HR-positive, HER2-negative ABC who had disease progression following ET. Currently, abemaciclib is not approved in Europe.

The safety and efficacy of abemaciclib in combination with fulvestrant in patients with hormone-receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced breast cancer (ABC), who have progressed while receiving endocrine therapy (ET), were assessed in the MONARCH 2 trial, a randomised, double-blind, global, placebo-controlled phase III study. 669 patients were randomly assigned in a 2:1 ratio to receive either abemaciclib plus fulvestrant (n=446) or placebo plus fulvestrant (n=223). The stratification of randomisation was based on the metastatic site (visceral, bone only, or other) and ET resistance (primary or secondary). At a median follow-up of 19.5 months, the primary endpoint progression-free survival (PFS) showed a statistically significant increase of 7.1 months (median) in the intention-to-treat (ITT) population of the abemaciclib arm. In addition, the improvement of the overall response rate (ORR) in the ITT population of the abemaciclib arm (+19.1%) was statistically significant. However, at the time of data cut-off (February 2017), overall survival (OS) results were not mature and quality of life (QoL) outcomes were not reported. The most frequent adverse events (AEs) of any grade were diarrhoea, neutropenia, nausea, fatigue, and abdominal pain. Grade ≥3 AEs were observed more commonly in the abemaciclib group (60.5%) than in the placebo group (22.8%).

In conclusion, the treatment with abemaciclib offers a statistically significant improvement in PFS (+7.1 months) and ORR (+19.1%) with an inferior safety profile at high costs. Due to the immature OS data and the missing QoL results, there is a need for long-term data to avoid a systematic overestimation of the treatment effect of abemaciclib. In the future, the identification of a robust predictive biomarker to identify the most suitable patients will be crucial for the class of CDK4/6 inhibitors. Finally, direct comparisons of abemaciclib to palbociclib and ribociclib are essential to investigate which treatment option is most beneficial for HR-positive, HER2-negative ABC patients.