ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical
C Belli1, F Penault-Llorca2, M Ladanyi3
1Division of Early Drug Development for Innovative Therapies, European Institute of Oncology IRCCS, Milan, Italy.
Abstract:
Aberrant activation of RET is a critical driver of growth and proliferation in diverse solid tumours. Multikinase inhibitors (MKIs) showing anti-RET activities have been tested in RET-altered tumours with variable results. The low target specificity with consequent increase in side-effects and off-target toxicities resulting in dose reduction and drug discontinuation are some of the major issues with MKIs. To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The results of these trials showed marked and durable antitumour activity and manageable toxicity profiles in patients with RET-altered tumours. The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations.
Insights
Selective RET inhibitors show promise for treating solid tumors driven by RET alterations. These targeted therapies offer improved efficacy and reduced toxicity compared to older multikinase inhibitors, guiding clinical detection strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Aberrant RET activation drives growth in various solid tumors.
- Multikinase inhibitors (MKIs) targeting RET have shown variable efficacy and significant toxicities.
- Limited target specificity of MKIs leads to dose reductions and treatment discontinuation.
Purpose of the Study:
- To review methods for detecting RET gene alterations.
- To establish strategies for rational detection of RET fusions and mutations.
- To provide recommendations for routine clinical detection of targetable RET alterations.
Main Methods:
- Review of available methods for RET gene alteration detection.
- Analysis of clinical trial data for selective RET inhibitors.
- Expert consensus development by the ESMO TR and PM WG.
Main Results:
- Selective RET inhibitors like pralsetinib and selpercatinib demonstrate significant antitumor activity.
- These newer agents exhibit manageable toxicity profiles.
- Selpercatinib has received FDA approval for RET-altered tumors.
Conclusions:
- Selective RET inhibitors represent a significant advancement in treating RET-driven malignancies.
- Standardized detection of RET alterations is crucial for effective patient selection.
- Recommendations are provided for implementing routine clinical detection of targetable RET rearrangements and mutations.
