Abstract
Genetic assessment is crucial to address the correct treatment for advanced medullary thyroid cancer (MTC). Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.