Abemaciclib as an original inhibitor of cyclin-dependent kinase for the treatment of luminal HER2-negative disseminated breast cancer

Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, namely palbociclib, ribociclib and abemaciclib, have become a new standard of treatment of patients with hormone receptor-positive, HER2-negative disseminated or metastatic breast cancer (HR+ HER2- MBC), regardless of the line of therapy, menopause status and other individual characteristics. Short-term CDK4/6 inhibition leads to reversible arrest in the G1 phase of the cell cycle with restoration of Rb-1 phosphorylation and the complete cell cycle after termination of inhibition. The drugs have individual characteristics despite the similar mechanism of action described in the article. Abemaciclib, which differs from palbociclib and ribociclib in chemical structure, shows higher selectivity for CDK4, less myelosuppressive effect, which makes it possible to take it continuously, greater lipophilicity, and interacts more actively with ATP, resulting in its ability to interact with other kinases as well. Abemaciclib, the only one of all CDK4/6 inhibitors, has been proven effective in the treatment of refractory HR+ HER2-MBC: the proportion of patients with objective effect (OE) was 19.7%, that with disease control was 42.4%, median progression-free survival (PFS) was 5.95 months, median overall survival (OS) was 22.32 months. Abemaciclib combined with fulvestrant in the second-line therapy increases the effectiveness of treatment compared with endocrinotherapy (ET) alone: median PFS increased to 16.9 months from 9.3 (p < 0.001), OE to 35 from 16% (p < 0.001) in the ITT population, median OS to 46.7 from 37.3 months (p = 0.01) for abemaciclib in combination with fulvestrant. The use of abemaciclib in combination with nonsteroidal aromatase inhibitors (NSAIs) compared with aromatase inhibitors (AI) alone in the first-line therapy demonstrated increased median PFS from 14.76 to 28.18 months (p = 0.000002) and increased OE (from 37 to 49.7% (p = 0.005) in the ITT population. Diarrhea is the common adverse event of abemaciclib, which develops in 82–90% of patients. It does not exceed severity level 3, the frequency of the latter does not exceed 13%, diarrhea is reversible, and can be stopped by using antidiarrheal drugs. ET in combination with abemaciclib makes it possible to improve the effectiveness of treatment in the most prognostically unfavourable patient population.