ALK inhibitors in ALK-positive NSCLC with central nervous system metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation.