Key Points
• Conclusion/Relevance: “The development of the RET-selective TKIs [tyrosine-kinase inhibitors] selpercatinib and pralsetinib offers patients with RET fusion-positive NSCLC a preferred treatment option with improved clinical efficacy and tolerability. However, the downstream development of acquired resistance is expected, and molecular profiling should guide the choice of subsequent therapy..
• Even though TKIs have proven effective at treating NSCLCs, the authors pointed out that RET-selective inhibition is still an issue. Indeed, researchers have noted both acquired RET mutations and off-target, RET-independent mechanisms. Of note, acquired mutations seem less frequent. Moreover, experts hypothesize cross-resistance between selpercatinib and pralsetinib.
• “RET-independent resistance mechanisms include MET and KRAS amplification, raising interest in potent yet specific multi-target inhibition when these alterations are identified,” the authors wrote. “Importantly, genetic profiling at the time of progressive disease can identify mutational signatures with the potential to guide therapy and is therefore critical for pragmatic selection of subsequent treatment.”
• Although driver alterations including RET fusions are usually considered mutually exclusive, case series have demonstrated occasional coexistence of multiple driver mutations as a possible mechanism of primary or acquired resistance to targeted therapies. The existence of multifarious driver mutations opens the door to combination targeted therapy, per the authors.