**4.8 Selpercatinib**

Selpercatinib is a receptor tyrosine kinase RET (rearranged during transfection) inhibitor developed for the treatment of cancers harboring RET alterations [22]. Selpercatinib was approved by the FDA for the treatment of RET fusion-positive nonsmall cell lung cancer, RET fusion-positive thyroid.

#### **4.9 Larotrectinib**

Larotrectinib is a selective and specific inhibitor of tropomyosin receptor kinase A (TRKA), TRKB, and TRKC approved for use in Europe and the USA, which is used in the therapy of solid tumors harboring NTRK gene fusions. NTRK gene fusions involving either NTRK1, NTRK2, or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB, and TRKC, respectively) are oncogenic drivers of various adult and pediatric tumor types. It has been applied in thyroid tumors thought to harbor NTRK gene fusions [91] and has been approved by the FDA for tumor agnostic indications.

#### **4.10 Entrectinib**

Entrectinib is another inhibitor of TRKA, TRKB, and TRKC. It has been applied in the treatment of NTRK fusion-positive cancers, including thyroid cancer [92]. Thyroid cancer-specific data are not yet available for entrectinib.

#### **4.11 Vemurafenib**

Vemurafenib was developed as a low-molecular-weight molecule for the inhibition of the mutated serine-threonine kinase BRAF, and it selectively binds to the ATPbinding site of BRAFv600E kinase and inhibits its activity [93]. It has potential to be applied in papillary thyroid carcinoma, which harbors a BRAF mutation.

### **5. Mutational testing in thyroid cancer**

Most thyroid cancer cases carry a good prognosis. However, 15% of differentiated thyroid cancer cases present with locally advanced disease, and in radioiodine refractory thyroid cancer 10-year survival drops below 50%. Patients with advanced thyroid cancer and radioiodine refractory thyroid cancer should undergo somatic mutational screening [94], as novel drugs are available to treat them. These drugs are the novel multiple kinase and angiogenetic factor inhibitors, which have offered patients and physicians a new option for the treatment of advanced thyroid cancer and have revolutionized the treatment of advanced thyroid cancer patients.
