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Updated: May 16, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Treatment of non-small cell lung cancer with RET rearrangements
Hui Jing Hoe1, Benjamin J Solomon1,2
1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
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.
Insights
Targeting RET fusions in non-small cell lung cancer (NSCLC) has evolved. Selective inhibitors like selpercatinib offer superior efficacy and established standard of care for RET fusion-positive NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Aberrant RET oncogene activation via mutations or fusions drives malignancies, including 1-2% of non-small cell lung cancers (NSCLCs).
- Early RET inhibitors showed limited efficacy and significant toxicities in RET fusion-positive NSCLC.
- Recent advancements include highly potent and selective RET inhibitors, selpercatinib and pralsetinib.
Purpose of the Study:
- To review the biology and clinical characteristics of RET-rearranged NSCLC.
- To summarize the evolution of treatment strategies for this patient population.
- To discuss resistance mechanisms and next-generation agents.
Main Methods:
- Literature review of studies on RET fusion-positive NSCLC.
- Analysis of clinical trial data for selective RET inhibitors.
- Examination of resistance mechanisms and emerging therapies.
Main Results:
- Selpercatinib and pralsetinib demonstrated high efficacy in advanced RET fusion-positive NSCLC.
- Selpercatinib showed superiority over chemotherapy in treatment-naive patients (LIBRETTO-431 study).
- These agents are now standard of care for previously untreated RET fusion-positive NSCLC.
Conclusions:
- Selective RET inhibitors represent a significant advancement in treating RET fusion-positive NSCLC.
- Understanding resistance mechanisms is crucial for developing future therapeutic strategies.
- Ongoing research focuses on novel agents to overcome treatment resistance.
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