A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer

Abstract

Background: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates.

Scope: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; “palbociclib”, “abemaciclib”, “ribociclib”, “cyclin-dependent kinase inhibitors” and “CDK 4/6” in metastatic breast cancer (MBC). The last search was on 10 June 2017.

Findings: CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development – palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment.

Conclusion: CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.

Keywords:

• Metastatic breast cancer
• palbociclib
• abemaciclib
• ribociclib
• cyclin-dependent kinase inhibitors

Transparency

Declaration of funding

The authors have received no payment in the preparation of this manuscript.

Declaration of financial/other relationships

B.B., M.A.N.S., D.Ş.D., M.B.A. and B.Y. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.