The recent developments in molecular diagnostics and targeted therapy demonstrate the potential for fulfilling the promise of precision medicine. An increasing number of biomarkers, diagnostic methods, and therapeutic options are adopted to optimize the patient management algorithms.

Next-generation sequencing approaches are more cost-effective and combine the high sensitivity and specificity with profiling of therapeutically actionable alterations. National Comprehensive Cancer Network Guidelines list crizotinib and entrectinib as preferred options for patients. 

A real-world evidence study comparing entrectinib with crizotinib supports this proposed approach. Entrectinib was associated with a longer median time to treatment discontinuation of 14.6 v 8.8 months and progression-free survival where the hazard ratio is 0.44. 

Also, 8% of the TKI-naive ROS1-rearranged lung cancers have shown MAPK pathway alterations, reflecting pre-existing genomic alterations causing changes in response. Molecularly directed therapy is not simply dichotomized for on-target resistance, but the bypass mechanisms of resistance are for off-target resistance to ROS1.

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Thus the mechanisms are classified into two groups: activation of a bypass pathway and acquiring a ROS1 point mutation. The combination therapy is found to be effective in preclinical models with bypass resistance. 

To treat ROS1 fusion–driven NSCLCs provided by Almquist and Ernani highlights the potential utility of molecular profiling at resistance. If the next-generation ROS1 TKIs receive mutation-specific regulatory approval, the molecularly guided strategies will warrant inclusion in standard guidelines.