Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged nonsmall cell lung cancer and beyond

Abstract

Epidermal growth factor receptor (EGFR) tyrosine inhibitors were first approved for the treatment of non-small cell lung cancer (NSCLC) in 2003 in the US. Activating EGFR mutations were subsequently discovered in 2004, and heralded the era of molecular targeted therapy in NSCLC. The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in 2007 by two independent groups not only represents the first time ALK rearrangement has been discovered in common solid tumors but also represents another important milestone in the era of molecular targeted therapy in NSCLC. Crizotinib, a mesenchymal-epithelial transition (MET)/ALK multi-targeted receptor tyrosine kinase inhibitor went into early Phase I clinical development in 2007. Using the knowledge that NSCLC patients with activating EGFR mutations benefited from EGFR tyrosine kinase inhibitors, crizotinib was rapidly and successfully developed as an inhibitor in ALK-rearranged NSCLC, based on a break apart fluorescence in situ hybridization assay, developed by two of the crizotinib Phase I sites. It cumulated in the conditional approval of crizotinib by the US Food and Drug Administration on August 26, 2011 for the treatment of ALK-rearranged NSCLC. The conditional approval was based on response rates of 50% and 61% from 255 ALK-rearranged NSCLC patients enrolled in two single-arm trials. Common adverse events of crizotinib include mild transient visual disorders, mild gastrointestinal toxicities, fatigue, rare alanine transaminase elevations, and even rarer pneumonitis (1.6%). Confirmatory trials comparing crizotinib with standard chemotherapy are ongoing. It took an unprecedented four years from the discovery of ALK rearrangement in NSCLC to the approval of crizotinib, the first ever ALK inhibitor, for the treatment of ALK-rearranged NSCLC.

Crizotinib: From Chemical Entity to Anticancer Agent

“…A steady-state concentration of crizotinib was reached after 15 days of repeated administration of crizotinib 250 mg orally twice a day, with a half-life (T 1/2 ) of around 43-51 hours. The mean steady-state trough plasma level for crizotinib 250 mg taken twice a day (the recommended Phase II dose) was 274 ng/mL or 57 nM of free drug, which exceeded the target effcacy levels predicted for the inhibition of MET (about 13 nM) and ALK (about 26 nM) based on preclinical mouse models [17,18]. Table 1 summarizes the most common-adverse events and the incidence rates the in the above-mentioned clinical trial [19].…”

“…A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C gamma, STAT3, and Akt, by crizotinib was observed at concentrations or dose levels that correlated with inhibition of NPM-ALK phosphorylation and function [14,17].…”

Diagnosis and Predictive Molecular Analysis of Non–Small-Cell Lung Cancer in the Africa-Middle East Region: Challenges and Strategies for Improvement

“…Currently there are two classes of targeted therapy approved for NSCLC patients with biomarker-positive tumours; EGFR tyrosine kinase inhibitors (TKIs) in patients with sensitizing mutations in exons 18-21 of the EGFR gene [23], and ALK TKIs for patients with transforming rearrangements in the ALK gene, which cause overexpression of ALK fusion proteins [24,25].…”

Translational Pharmacokinetic-Pharmacodynamic Modeling from Nonclinical to Clinical Development: A Case Study of Anticancer Drug, Crizotinib

“…Crizotinib phase I dose-escalation study started in 2006 in patients with solid tumors primarily as a MET inhibitor (24,25). After the discovery of ALK gene rearrangement such as echinoderm microtubule-associated protein-like 4 (EML4)-ALK in nonsmall cell lung cancer (NSCLC) in 2007 (26,27), the first ALK-positive NSCLC patient enrolled in the dose-escalation trial in 2007 followed by the second patient in 2008.…”