RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape

Abstract

The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world’ studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting.

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“…Generally, the response rates with these drugs were under 30% and median PFS was <6 months. 61 Due to the ability of these drugs to inhibit multiple kinases, these drugs can be associated with more toxicities. The role of these drugs following treatment with RET selective inhibitors is unclear.…”

“…RET gene rearrangements are identified in 1%-2% of NSCLCs. 61 Clinical characteristics of RET -rearranged NSCLC patients include predominantly adenocarcinoma histology, about 50% are never smokers, and 30%-40% of patients develop central nervous metastases during their lifetime. 61,62 The most common fusion partners are KIF5B (70%-80%) followed by CCDC6.…”

“…61 Clinical characteristics of RET -rearranged NSCLC patients include predominantly adenocarcinoma histology, about 50% are never smokers, and 30%-40% of patients develop central nervous metastases during their lifetime. 61,62 The most common fusion partners are KIF5B (70%-80%) followed by CCDC6. Two selective RET inhibitors are currently approved for the treatment of RET -rearranged NSCLC.…”

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“…Both agents, however, elicit off‐target effects on the VEGF signaling pathway, possibly influencing wound healing and blood pressure [70] . These agents have gained regulatory approval, with selpercatinib preferred for first‐line therapy in RET fusion‐positive metastatic NSCLC and pralsetinib recommended for subsequent treatment, although direct comparative trials are requisite [71] …”

“…[70] These agents have gained regulatory approval, with selpercatinib preferred for first-line therapy in RET fusion-positive metastatic NSCLC and pralsetinib recommended for subsequent treatment, although direct comparative trials are requisite. [71] Primary mechanisms of RET-dependent drug resistance encompass gatekeeper mutations, particularly at the V804 position, sustaining kinase activity due to inhibitor depletion. [72] In contrast, non-gatekeeper mutations, such as RET G810S/R/C, disrupt inhibitor binding by occupying the solvent front of the ATP-binding site, conferring resistance to selective RET inhibitors like selpercatinib and pralsetinib.…”