Treatment of non–small cell lung cancer with RET rearrangements

Abstract

Aberrant activation of the RET oncogene by mutations or gene fusions drives various malignancies, including 1%–2% of all non–small cell lung cancers (NSCLCs) that harbor RET gene fusions. Initial attempts to target RET fusion–positive NSCLC with poorly selective multikinase RET inhibitors were associated with significant toxicities and limited efficacy. Two highly potent and selective RET small-molecule inhibitors, selpercatinib and pralsetinib, were granted accelerated approval for advanced RET fusion–positive NSCLC by the US Food and Drug Administration, and have been shown to be highly effective both in treatment-naive and previously treated patients with NSCLC. Selpercatinib has shown superiority over chemotherapy in a phase 3 study (LIBRETTO-431) in previously untreated patients with RET fusion–positive NSCLC, which established its place as the standard of care in this patient population. This review discusses the biology and clinical characteristics of RET-rearranged NSCLC and summarizes the evolution of treatment strategies, current understanding of mechanisms of resistance, and development of new-generation agents to overcome resistance.