Palbociclib—The first of a new class of cell cycle inhibitors

Abstract

During the last decades, much has been learned about with cyclin-dependent kinases (CDK) playing a pivotal role in the cell cycle regulation. CDK4/6 is the key regulator of the G1-S transition. Palbociclib (PD 0332991, Ibrance®) is the first oral CDK4/6 inhibitor showing a substantially improved median progression-free survival (PFS) in advanced estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer. This PFS prolongation was seen both with letrozole as first-line therapy (24.8 vs. 14.5 months [PALOMA 2]) and with fulvestrant in endocrine pretreated patients (9.2 vs. 3.8 months [PALOMA-3]). The main toxicity is neutropenia due to cell cycle arrest which can be easily managed with dose interruption or dose reduction leading to a favorable safety profile with delayed deterioration of global quality of life (QoL). Palbociclib is approved by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) for ER-positive/HER2-negative advanced breast cancer. Despite the well-understood mode of action of palbociclib, predictive biomarkers are not yet defined. In conclusion, inhibition of CDK4/6 using palbociclib in combination with endocrine therapy is an efficient and well-tolerated treatment option in ER-positive/HER2-negative advanced breast cancer. Ongoing clinical trials are investigating the role of palbociclib in early breast cancer as well as in other types of cancer.