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Rearranged during transfection (RET) lung cancer - Update on targeted therapies
W J Mullally1, C G O'Leary2, K J O'Byrne3
1Department of Medical Oncology, Princess Alexandra Hospital, Woolloongabba, Queensland 4102, Australia.
Abstract:
The enhanced comprehension of the molecular pathways underpinning oncogenesis in non-small cell lung cancer (NSCLC) has led to the advancement of personalized treatment for individuals with actionable mutations using targeted therapies. The rearranged during transfection (RET) proto-oncogene, is critical in the embryonic development of various tissues, including renal, neural, and neuroendocrine tissue. RET fusions have been observed in approximately 1-2% of NSCLC cases. Targeted therapies for NSCLC with RET alterations have progressed significantly over the past decade. While multikinase inhibitors (MKIs) faced limitations in efficacy and tolerability, the introduction of selective RET inhibitors (SRIs) such as selpercatininb and pralsetinib has transformed patient outcomes, resulting in deep and durable responses. Ongoing clinical trials are exploring their potential benefits in the neoadjuvant and adjuvant setting. Early phase clinical trials endeavor to demonstrate next-generation selective RET inhibitors can effectively overcome SRI resistance mechanisms, offer improved safety profiles, and enhance patient outcomes.
Insights
Targeted therapies, including selective RET inhibitors (SRIs), have transformed non-small cell lung cancer (NSCLC) treatment for patients with RET fusions. Ongoing trials explore next-generation inhibitors for improved outcomes and overcoming resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) oncogenesis involves complex molecular pathways.
- The rearranged during transfection (RET) proto-oncogene plays a role in development and is implicated in 1-2% of NSCLC cases.
- Targeted therapies have advanced personalized treatment for NSCLC with actionable mutations.
Purpose of the Study:
- To review the progress of targeted therapies for NSCLC with RET alterations.
- To highlight the efficacy and tolerability of selective RET inhibitors (SRIs) compared to multikinase inhibitors (MKIs).
- To discuss ongoing research into next-generation SRIs for overcoming resistance and improving patient outcomes.
Main Methods:
- Literature review of targeted therapies for NSCLC with RET alterations.
- Analysis of clinical trial data for selective RET inhibitors (SRIs) like selpercatinib and pralsetinib.
- Examination of emerging research on next-generation SRIs and their potential applications.
Main Results:
- Selective RET inhibitors (SRIs) have significantly improved patient outcomes in NSCLC with RET fusions, offering deep and durable responses.
- SRIs demonstrate superior efficacy and tolerability compared to older multikinase inhibitors (MKIs).
- Clinical trials are investigating the use of SRIs in neoadjuvant and adjuvant settings.
Conclusions:
- Selective RET inhibitors (SRIs) represent a major advancement in personalized medicine for NSCLC patients with RET alterations.
- Next-generation SRIs are under development to address resistance mechanisms and further enhance treatment efficacy and safety.
- Continued research in targeted therapies holds promise for improving long-term outcomes in NSCLC.
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