ALK disease: best first or later, and do we care about variants?

The therapeutic landscape in advanced ALK⁺ non-small cell lung cancer (NSCLC) is rapidly evolving due to the increasing availability of selective and potent tyrosine-kinase inhibitors (TKI), of which three generations are already available. Compared with crizotinib, the second generation compounds ceritinib, alectinib, and brigatinib generally show improved efficacy. Alectinib and brigatinib in particular, have recently demonstrated impressive hazard ratios (HR) of 0.5 for systemic and even lower for brain progression in randomized head-to-head trials vs. crizotinib, along with better tolerability. Their higher systemic and intracranial response rates of about 80% result in median progression-free survival (PFS) intervals over 2 years and suppress the annual intracranial progression rate below 10%. On the other hand, when administered after crizotinib, both drugs show much lower efficacy, which in conjunction with the modest activity, especially in the brain, of first-line crizotinib suggests an inferior patient outcome. Therefore, although overall survival (OS) data are still immature, upfront administration of second-generation ALK inhibitors currently emerges as the preferred strategy, further encouraged by the fact that about half of these cases have also been amenable to subsequent targeted therapies after disease progression. Dissection of mechanisms underlying TKI resistance is key for further therapeutic advances, with recent data suggesting an important role of specific molecular tumor properties, especially the type of ALK fusion variant and presence of TP53 mutations. These novel insights can help refine prognostication, select patients for more aggressive monitoring and guide preclinical studies, but their utility for individualization of treatment is still unclear and an area of intense investigation.