Comprehensive Review of ROS1 Tyrosine Kinase Inhibitors-Classified by Structural Designs and Mutation Spectrum (Solvent Front Mutation [G2032R] and Central β-Sheet 6 [Cβ6] Mutation [L2086F])

Despite ROS1 fusion-positive NSCLC comprising roughly 1% to twoPercent of NSCLC, there’s a lengthy listing of ROS1 tyrosine kinase inhibitors (TKIs) being developed additionally to 3 approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib. Here, we categorized ROS1 TKIs by their structures (cyclic versus noncyclic) and inhibitory abilities (active against solvent front mutation G2032R or central ß-sheet #6 [Cß6] mutation L2086F) and summarized their reported clinical activity to be able to give a dashboard regarding how to begin using these ROS1 TKIs in a variety of clinical situations. Additionally, the less known Cß6 mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (repotrectinib, taletrectinib, and potentially NVL-520) that may be overcome by cabozantinib as documented in printed patient reports and potentially by certain L-formed type I ROS1 TKIs including ceritinib and gilteritinib, that is approved like a FLT3 inhibitor for relapsed refractory FLT3 acute myeloid leukemia but have printed preclinical activites against ROS1 (and ALK). Future numerous studies should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that may target ROS1 L2086F Cß6 mutation.