Chapter 16 - Crizotinib

Abstract

Crizotinib (Xalkori, Pfizer) is an aminopyridine tyrosine kinase inhibitor active against RON, as well as ALK, MET, ROS1, and some of their oncogenic variants. It was initially developed as a second-generation selective MET inhibitor through modification of a previous molecule (PHA-665,752) before the identification of EML4-ALK translocation in non–small-cell lung cancer (NSCLC), and was then found to be highly active as an anaplastic lymphoma kinase (ALK) inhibitor. The Food and Drug Administration (FDA) granted accelerated approval in 2011 for the use of crizotinib in patients with locally advanced or metastatic ALK-positive NSCLC, as detected by an FDA-approved test (FISH probe kit). The European Medicines Agency (EMA) granted conditional approval in 2012 for its use in adults with previously treated ALK-positive advanced NSCLC. Moreover, the EMA did not request a specific diagnostic test for ALK rearrangements. The safety database at approval consisted in 340 subjects who had received at least one dose of crizotinib, including 255 ALK-positive, locally advanced, or metastatic NSCLC patients treated with the standard dose of 250mg/bid, who therefore represented the core population for a detailed adverse event evaluation. By March 2015, the safety database accounted for 1200 ALK-positive NCSLC patients in continuous monotherapy at a recommended starting dose. Most common toxicities include visual, gastrointestinal, and constitutional disorders, followed by cardiovascular, respiratory, and minor neurologic dysfunctions. More concerning events include severe hepatotoxicity, interstitial lung disease/pneumonitis, bradycardia, and QT prolongation.