Abstract
RET alterations are recognized as key oncogenic drivers in different cancer types, including non-small cell lung cancer (NSCLC). Multikinase inhibitors (MKIs) with anti-RET activities resulted in variable efficacy with significant toxicities because of low target specificity. Selective RET kinase inhibitors, such as pralsetinib and selepercatinib, demonstrated high efficacy and favorable tolerability in advanced RET-rearranged NSCLC patients, leading to their introduction in the clinical setting. Among the different approaches available for the identification of RET rearrangements, next-generation sequencing (NGS) assays present substantial advantages in terms of turnaround time and diagnostic accuracy, even if potentially limited by accessibility issues. The recent advent of novel effective targeted therapies raises several questions regarding the emergence of resistance mechanisms and the potential ways to prevent/overcome them. In this review, we discuss molecular testing and treatment strategies to manage RET fusion positive NSCLC patients with a focus on resistance mechanisms and future perspectives in this rapidly evolving scenario.
Highlights
In recent years, the advent of personalized medicine combined with comprehensive genomic profiling has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC), leading to the development of targeted therapies that radically changed cancer care in molecular selected patients [1]
Initial reports showed that to other oncogene drivers, REarranged during Trasfections (RET) fusions were typically associated with younger age, female gender, non-smoker status, Asian ethnicity, advanced stage, and adenocarcinoma subtype
ROS1, adenocarcinomas are the most frequent histology to carry out RET rearrangements, followed by adeno-squamous, squamous cell, and neuroendocrine cancers [27]
Summary
The advent of personalized medicine combined with comprehensive genomic profiling has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC), leading to the development of targeted therapies that radically changed cancer care in molecular selected patients [1]. A retrospective analysis showed the presence of concomitant genomic alterations in 4 of the 12 patients with RET-rearranged NSCLC analyzed, harboring EGFR, MAP2K1, CTNNB1, and AKT1 mutations [7]. 2 (VEGFR2) and EGFR, they were, characterized by limited efficacy with significant off-target adverse events and negative impact on health related quality of life, leading to high rates of high grade toxicities and dose reductions in NSCLC patients [9]. These disappointing results have contributed to the further development of selective RET kinase inhibitors, characterized by promising activities and more favorable tolerability. RET fusion positive NSCLC patients, summarizing the available therapeutic options, with a focus on resistance mechanisms and future perspectives
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