Precision medicine against ALK-positive non-small cell lung cancer: beyond crizotinib

Anaplastic lymphoma kinase ( ALK ) rearrangements represent the molecular driver of a subset of non-small cell lung cancers (NSCLCs). Despite the initial response, virtually all ALK -positive patients develop an acquired resistance to the ALK inhibitor crizotinib, usually within 12 months. Several next-generation ALK inhibitors have been developed in order to overcome crizotinib limitation, providing an unprecedented survival for this subset of patients. The aim of this review to summarize the current knowledge on ALK tyrosine kinase inhibitors (TKIs) in the treatment of advanced ALK -positive NSCLC, focusing on the role of novel ALK inhibitors in this setting. In addition, we will discuss their role in the pharmacological management of ALK -positive brain metastasis. Next-generation ALK inhibitors showed an impressive clinical activity in ALK -positive NSCLC, also against the sanctuary site of CNS. Sequential therapy with ALK TKIs appears to be effective in patients who fail a first ALK TKI and translates in clinically meaningful benefit. However, these agents display different activity profiles against crizotinib resistance mutation; therefore re-genotyping the disease at progression in order to administer the right TKI to the right patient is going to be necessary to correctly tailor the treatment. To avoid repeated invasive procedure, noninvasive methods to detect and monitor ALK rearrangement are under clinical investigation.