The increased CNS availability of vepafestinib, the superior efficacy in preclinical CNS disease models and the broad activity against RET solvent front mutations, as well as across various RET fusions regardless of N-terminal partners in NSCLC and in MTC models represent a possible effective strategy to overcome the emergence of acquired resistance to first-generation RET-selective inhibitors. The gene discussed is RET; the disease is non-small cell lung carcinoma.