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

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          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.

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          Author and article information

          Journal
          Drug Des Devel Ther
          Drug Design, Development and Therapy
          Dove Medical Press
          1177-8881
          2011
          23 November 2011
          : 5
          : 471-485
          Affiliations
          Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA, USA
          Author notes
          Correspondence: Sai-Hong Ignatius Ou, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA 92868, USA, Tel +1 714 456 8104, Fax +1 714 456 2242, Email ignatius.ou@ 123456uci.edu
          Article
          dddt-5-471
          10.2147/DDDT.S19045
          3232174
          22162641
          © 2011 Ou, publisher and licensee Dove Medical Press Ltd.

          This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

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