title: Crizotinib: an anaplastic lymphoma kinase inhibitor.
abstract: Crizotinib is an oral small-molecule inhibitor of ALK and c-Met tyrosine kinases that is being developed by Pfizer. ALK mutations or gene rearrangements result in growth factor-independent ALK activation. Most of the available clinical data with crizotinib are in patients with tumors that have an activated ALK, and the drug has shown very promising clinical benefit in these patients. ALK gene rearrangement occurs in approximately 3-5% of non-small-cell lung cancer patients, most of whom are never- or light smokers and have adenocarcinoma histology. In these patients, crizotinib at a dose of 250 mg twice daily demonstrated a response rate of 56% and a disease control rate of 87% in previously treated patients. The drug is generally well tolerated, with the most common adverse events being nausea, vomiting and some minor visual disturbances that are fleeting. Grade 3/4 elevations in hepatic transaminases occurred in 6% of the patients, which in most patients resolved with dose reduction. Ongoing studies will define the true utility of this drug in ALK-rearranged non-small-cell lung cancer patients and in patients with other tumors that also have ALK activation. Preliminary data suggest that the drug may also be active in tumors with an activated c-Met pathway.
authors.affiliation: Karmanos Cancer Institute, Experimental Therapeutics Program, Wayne State University, 4100 John R, Detroit, MI 48201, USA. gadgeels@karmanos.org
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases