Genomics Review of Selective RET Inhibitors Sensitivity in Thyroid Cancer Clinical Trials
Sara Gil-Bernabé1,2, Lucía García-DeLaFuente1, Alejandro García-Álvarez3
1Pathology Department, Faculty of Medicine, Valladolid University, Valladoli, Spain.
Abstract:
RET gene is a driver of thyroid cancer (TC) tumorigenesis. The incidence of TC has increased worldwide in the last few decades, both in medullary and follicular-derived subtypes. Several drugs, including multikinase and selective inhibitors, have been explored. Selpercatinib and pralsetinib are selective RET inhibitors that have shown clear clinical benefits for patients in the LIBRETTO and ARROW trials, respectively. Currently, their development and application in clinical practice are ongoing. However, its efficacy in different RET pathogenic variants has not yet been well established. Although selpercatinib and pralsetinib achieved a high ORR, no data are available regarding the differences in tumor responses of both TC groups according to RET pathogenic variants. Clinical trials and literature have analyzed the efficacy of selective RET inhibitors with a special interest in the most common variants. A review of LIBRETTO and ARROW trials was made regarding the change in tumor size depending on the pathogenic variants. M918T pathogenic variant resulted in a higher complete response rate. Patients who underwent fusion had the highest ORR (objective response rate). MKi-treated patients did not exhibit significant differences from untreated patients. Different RET pathogenic variants are not biomarkers of RETi response in TC. Selpercatinib showed a tendency to achieve a complete response. All patients with RET pathogenic variants should receive treatment with selpercatinib or pralsetinib at any moment of the therapeutic schedule owing to off-target inhibition and toxicity. Therefore, new targets for drug sensitivity and resistance should be explored.
Insights
Selective RET inhibitors like selpercatinib and pralsetinib show promise for thyroid cancer (TC). However, their effectiveness varies across different RET gene variants, necessitating further research into drug resistance and sensitivity.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Thyroid cancer (TC) incidence is rising globally, affecting both medullary and follicular-derived subtypes.
- The RET gene is a known driver of TC tumorigenesis.
- Selective RET inhibitors (RETis) like selpercatinib and pralsetinib offer clinical benefits but their efficacy across diverse RET pathogenic variants requires further elucidation.
Purpose of the Study:
- To evaluate the efficacy of selpercatinib and pralsetinib in thyroid cancer patients with different RET pathogenic variants.
- To compare tumor responses based on specific RET alterations and treatment regimens.
- To identify potential biomarkers for predicting response to RET inhibitors in TC.
Main Methods:
- Review of clinical trials (LIBRETTO and ARROW) and literature data.
- Analysis of tumor response rates (complete response and objective response rate) stratified by RET pathogenic variants.
- Comparison of responses between RETi-treated patients and those treated with multikinase inhibitors (MKis) or no treatment.
Main Results:
- The M918T pathogenic variant showed a higher complete response rate.
- Patients with RET fusions exhibited the highest objective response rate (ORR).
- Multikinase inhibitor (MKi)-treated patients did not show significant differences compared to untreated patients, suggesting RET-specific inhibitors are crucial.
Conclusions:
- RET pathogenic variants are not definitive biomarkers for predicting response to RET inhibitors in TC.
- Selpercatinib demonstrated a trend towards achieving complete responses.
- All patients with RET pathogenic variants should be considered for treatment with selpercatinib or pralsetinib due to potential off-target effects and toxicity of other treatments, highlighting the need for new therapeutic targets.
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