Crizotinib (PF-02341066), under development by Pfizer, is an orally bioavailable,
ATP-competitive, small-molecule inhibitor of the
receptor tyrosine kinases (RTKs) c-Met (also known as
hepatocyte growth factor receptor) and
anaplastic lymphoma kinase (ALK), for the potential treatment of
cancers dependent on these oncogenic
kinases for growth and survival. Since the first published characterizations of
crizotinib only a few years ago, the
drug has been extensively validated as a highly specific inhibitor of c-Met and ALK among > 120 different RTKs surveyed. In preclinical
tumor xenograft studies,
crizotinib inhibited the growth and survival of cell lines dependent upon c-Met or ALK enzymatic activity.
Crizotinib has been particularly effective against
anaplastic large cell lymphoma and
non-small cell lung cancer (NSCLC) cell lines that harbor ALK translocations resulting in expression of oncogenic ALK fusion
proteins. During early-stage clinical testing,
crizotinib was well tolerated and produced dramatic antitumor activity in patients with ALK-rearranged NSCLC. At the time of publication, an ongoing phase III clinical trial is comparing
crizotinib with standard second-line
chemotherapy in previously treated patients with NSCLC harboring ALK rearrangement, and a phase III trial comparing
crizotinib with standard
chemotherapy in the first-line setting in non-squamous
lung cancer is planned. Thus, in the future,
crizotinib is expected to become a highly used therapeutic for the treatment of ALK-rearranged
tumors.