title: Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology.
abstract: Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK- and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK-rearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular-defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.
authors.affiliation: Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, California 92868, USA. ignatius.ou@uci.edu
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.forename: Cynthia Huang
authors.initials: CH
authors.lastname: Bartlett
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Jean
authors.initials: J
authors.lastname: Cui
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D004347:Drug Interactions; D005260:Female; D015321:Gene Rearrangement; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
chemical_list: D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases