Genomics review of selective RET inhibitors sensitivity in thyroid cancer clinical trials

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.