Current treatment and future challenges in ROS1- and ALK-rearranged advanced non-small cell lung cancer.

Non─small cell lung cancer (NSCLC) presents different druggable genetic abnormalities, including ROS1 and ALK rearrangements, which share relevant clinical features and therapeutic strategies. The homology between the tyrosine kinase domains of ROS1 and ALK defines unique subsets of patients highly sensitive to targeted tyrosine kinase inhibitors (TKIs). Genomic profiling in advanced NSCLC is standard, immunohistochemistry and fluorescence in situ hybridization being the main techniques used to detect genomic rearrangements. Personalized treatment with TKIs in ROS1- and ALK-positive NSCLC patients has dramatically improved patients' outcomes. Crizotinib has been the first-line standard of care treatment in ALK-rearranged NSCLC patients for a long time, while crizotinib still represents the best upfront therapeutic option in ROS1-positive NSCLC patients, followed by next-generation TKIs at the time of disease progression. However, the improved intracranial efficacy of next-generation TKIs has led to these drugs becoming first-line options, widening treatment opportunities for these patients. Since all patients will develop disease progression under TKI therapy, understanding the mechanisms of acquired resistance is crucial to define the optimal sequential therapeutic strategy. Despite the positive correlation between personalized treatment and patients' outcome, access to next-generation TKIs and genomic profiling at the time of disease progression are major challenges to achieving this goal. In this review, we present updated evidence on ROS1- and ALK-rearranged NSCLC regarding epidemiology and diagnostics, current therapies and the most suitable sequential treatment approaches, as well as mechanisms of acquired resistance and strategies to overcome them.