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Targeted therapy has become the standard of care for non-small cell lung cancers with a range of targetable alterations, including ALK and ROS1 kinase fusions. RET fusions drive the oncogenesis of 1-2% of NSCLCs and represent a substantial global burden of disease. Although these fusions were first identified more than thirty years ago, targeted therapy for RET fusion-positive lung cancers was only explored in the last decade. Whereas repurposed multikinase inhibitors were initially tested, selective inhibitors RET inhibitors have dramatically improved outcomes for patients whose tumors harbor these alterations. In 2020, the US Food and Drug Administration approved selpercatinib, a selective RET inhibitor, for adults with lung and thyroid cancers with RET rearrangements or mutations, making it the first targeted therapy to be approved for RET-altered cancers. While resistance to selective RET inhibition has been described, next-generation RET inhibitors are already being explored for patients who progress on prior RET kinase inhibitors.

Decade in review: a new era for RET-rearranged lung cancers