Tyrosine kinase inhibitors (TKIs)

Sorafenib. Sorafenib is a VEGFR, PDGFR, and RAS kinase inhibitor. In a randomized phase III trial, sorafenib improved PFS when compared with placebo (10.8 months vs. 5.8 months) in adult patients with radioactive iodine–refractory locally advanced or metastatic differentiated thyroid cancer.[50] The U.S. Food and Drug Administration (FDA) approved sorafenib in 2013 for the treatment of adults with late-stage, metastatic differentiated thyroid carcinoma. Pediatric-specific data are limited. However, in one case report, sorafenib produced a radiographic response in a patient aged 8 years with metastatic papillary thyroid carcinoma.[51]

Lenvatinib. Lenvatinib is an oral VEGFR, FGFR, PDGFR, RET, and KIT inhibitor. In a phase III randomized study of adults with 131I-refractory differentiated thyroid cancer, lenvatinib was associated with a significant improvement in PFS and response rate when compared with a placebo.[52] The FDA approved lenvatinib in 2015 for the treatment of adults with progressive, radioactive iodine–refractory differentiated thyroid carcinoma.Three children with papillary thyroid carcinoma who were refractory to radioactive iodine had a clinical response to lenvatinib.[53]

Vemurafenib and dabrafenib (BRAF inhibitors). An open-label, nonrandomized, phase II study of vemurafenib was conducted in adult patients with papillary thyroid carcinoma that was 131I-refractory, metastatic or unresectable, and BRAF V600E variant positive. No participant had been previously treated with a TKI. A response rate of 38.5% was documented.[54] For patients with metastatic or advanced BRAF V600E–altered anaplastic thyroid carcinoma, the combination of dabrafenib with the MEK inhibitor trametinib showed a response rate of 69%.[55]

Larotrectinib and entrectinib (NTRK inhibitors). Larotrectinib has been used to treat patients with TRK fusion–positive thyroid carcinoma. In one study, all five patients with TRK fusion–positive thyroid carcinomas who received larotrectinib therapy achieved partial or complete responses.[56] Responses to entrectinib have also been reported.[57] The FDA approved larotrectinib and entrectinib for the treatment of adults and children (restricted to patients older than 12 years for entrectinib) with solid tumors that include all of the following characteristics:[58]

Larotrectinib and entrectinib (NTRK inhibitors). Larotrectinib has been used to treat patients with TRK fusion–positive thyroid carcinoma. In one study, all five patients with TRK fusion–positive thyroid carcinomas who received larotrectinib therapy achieved partial or complete responses.[56] Responses to entrectinib have also been reported.[57] The FDA approved larotrectinib and entrectinib for the treatment of adults and children (restricted to patients older than 12 years for entrectinib) with solid tumors that include all of the following characteristics:[58]

Have an NTRK gene fusion without a known acquired resistance variant.

Larotrectinib and entrectinib (NTRK inhibitors). Larotrectinib has been used to treat patients with TRK fusion–positive thyroid carcinoma. In one study, all five patients with TRK fusion–positive thyroid carcinomas who received larotrectinib therapy achieved partial or complete responses.[56] Responses to entrectinib have also been reported.[57] The FDA approved larotrectinib and entrectinib for the treatment of adults and children (restricted to patients older than 12 years for entrectinib) with solid tumors that include all of the following characteristics:[58]

Are metastatic or for which surgical resection is likely to result in severe morbidity.

Larotrectinib and entrectinib (NTRK inhibitors). Larotrectinib has been used to treat patients with TRK fusion–positive thyroid carcinoma. In one study, all five patients with TRK fusion–positive thyroid carcinomas who received larotrectinib therapy achieved partial or complete responses.[56] Responses to entrectinib have also been reported.[57] The FDA approved larotrectinib and entrectinib for the treatment of adults and children (restricted to patients older than 12 years for entrectinib) with solid tumors that include all of the following characteristics:[58]

Have no satisfactory alternative treatments or that have progressed following treatment.

Selpercatinib (a RET inhibitor). In a phase I/II trial of selpercatinib therapy for patients (age range, 25–88 years) with RET-altered cancers, 19 patients with RET fusion–positive, previously treated thyroid cancers were enrolled.[59]

Selpercatinib (a RET inhibitor). In a phase I/II trial of selpercatinib therapy for patients (age range, 25–88 years) with RET-altered cancers, 19 patients with RET fusion–positive, previously treated thyroid cancers were enrolled.[59]

Fifteen of 19 patients (79%) achieved objective responses (1 complete response and 14 partial responses), and the median duration of response was 18.4 months.

Selpercatinib (a RET inhibitor). In a phase I/II trial of selpercatinib therapy for patients (age range, 25–88 years) with RET-altered cancers, 19 patients with RET fusion–positive, previously treated thyroid cancers were enrolled.[59]

The most common grades 3 to 4 treatment-related adverse events were hypertension (12%), increased alanine aminotransferase (10%) and aspartate aminotransferase (7%), diarrhea (3%), and prolonged QT interval (2%).

Selpercatinib (a RET inhibitor). In a phase I/II trial of selpercatinib therapy for patients (age range, 25–88 years) with RET-altered cancers, 19 patients with RET fusion–positive, previously treated thyroid cancers were enrolled.[59]

In 2024, the FDA granted full approval to selpercatinib for the treatment of adult and pediatric patients aged 2 years and older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and who are radioactive iodine–refractory (if radioactive iodine is appropriate).[60]

Cabozantinib (a VEGFR and RET inhibitor). Cabozantinib and placebo were compared in a double-blind, phase III, randomized trial (COSMIC-311 [NCT03690388]) in adult patients (age range, 55–72 years). These patients had received at least one VEGFR-targeted TKI for differentiated thyroid carcinoma, and their disease was deemed progressive and radioactive iodine–refractory. An effective response was noted in 10 of 67 patients who received cabozantinib, compared with zero responses in the placebo group. The PFS was 11 months (95% CI, 7.4–13.8) in the cabozantinib arm, compared with 1.9 months (95% CI, 1.9–3.7) in the placebo arm, with an HR of 0.22 (95% CI, 0.14–0.31).[61] Based on these data, the FDA approved cabozantinib in this population.[62]