Crizotinib as first line therapy for advanced ALK-positive non-small cell lung cancers

The field of targeted therapeutic development has been propelled forward by remarkable advances in the understanding of driver mutations, particularly in non-small cell lung cancer (NSCLC). Our initial understanding of the importance of driver mutations developed from the discovery of somatic oncogenic epidermal growth factor receptor (EGFR) mutations, which sensitize tumors to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib (1), erlotinib (2), and afatinib (3). Anaplastic lymphoma kinase (ALK) gene rearrangements act as a distinct oncogenic driver in about 4% of NSCLC tumors (4). Testing of metastatic NSCLC adenocarcinomas to determine if they are “ALK-positive” has become the standard of care, because these tumors respond well to ALK inhibitors such as crizotinib, an orally available TKI. Crizotinib induced remarkable responses in patients with ALK positive NSCLCs in phase I and II trials (5), and appeared to improve survival of these patients in a retrospective analysis (6). A second line phase III study subsequently showed that crizotinib was superior to both pemetrexed and docetaxel as standard chemotherapy (7).