Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important 
molecular subgroups of advanced non-small cell lung cancer (NSCLC). The 
identification of these genetic driver alterations created new potential for 
highly active therapeutic interventions. After discovery of ALK rearrangements 
in NSCLC, it was recognized that these confer sensitivity to ALK inhibition. 
Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was 
initially approved as second-line treatment of ALK-positive advanced NSCLC but 
after this, it was firmly established as the standard first-line therapy for 
advanced ALK-positive NSCLC. After initial response to crizotinib, tumors 
inevitably relapse. Next-generation ALK inhibitors, more potent and 
brain-penetrable than crizotinib, may be effective in re-inducing remissions 
when cancers are still addicted to ALK. Ceritinib and alectinib are approved for 
metastatic ALK positive NSCLC patients, while brigatinib received granted 
accelerated approval by the United States Food and Drug Administration. 
Regarding ROS1 rearrangement, to date crizotinib is the only ALK-tyrosine kinase 
inhibitor receiving indication as treatment of ROS1 positive advanced NSCLC. 
Expert commentary: Although novel ALK-inhibitors are under clinical 
investigation compared to crizotinib as front-line treatment for ALK-positive 
NSCLC, nowadays the current standard first-line therapy for these patients is 
crizotinib. Further research will clarify the best management of ALK-positive 
NSCLC, above all who progress on first-line crizotinib.