Tyrosine kinase inhibitor (TKI) therapy

Vandetanib. Vandetanib is an inhibitor of the RET kinase, VEGFR, and EGFR signaling. The U.S. Food and Drug Administration (FDA) approved vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable, locally advanced, or metastatic disease. The approval was based on a randomized, placebo-controlled, phase III trial that showed a marked progression-free survival (PFS) improvement for patients randomly assigned to receive vandetanib (hazard ratio, 0.35). The trial also showed an objective response rate advantage for patients receiving vandetanib (44% vs. 1% for the placebo arm).[17,18]Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only 1 had no response, and 7 had partial responses, for an objective response rate of 44%. Disease in three of those patients subsequently recurred, but 11 of 16 patients treated with vandetanib remained on therapy at the time of the report. The median duration of therapy for the entire cohort was 27 months, with a range of 2 to 52 months.[19] A long-term outcome evaluation in a cohort of 17 children and adolescents with advanced medullary thyroid carcinoma who received vandetanib reported a median PFS of 6.7 years and a 5-year OS rate of 88.2%.[20]

Cabozantinib. Cabozantinib is an inhibitor of the RET and MET kinases and VEGFR. It has also shown activity against unresectable medullary thyroid cancer (10 of 35 adult patients [29%] had partial responses).[21] A double-blind phase III trial compared cabozantinib with placebo in adults with progressive, metastatic medullary thyroid carcinoma.[22] The estimated PFS was 11.2 months for patients who received cabozantinib and 4 months for patients who received the placebo. At 1 year, 47.3% of patients who were treated with cabozantinib were alive and progression free, compared with 7.2% of patients who received the placebo. Significant adverse effects resulted in dose reductions in 79% of patients and discontinuation of cabozantinib in 16% of patients. The FDA approved cabozantinib in 2012 for the treatment of adults with metastatic medullary thyroid cancer.

Selpercatinib. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

Selpercatinib. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

For the previously treated cohort, 69% of patients had objective responses, and the median duration of response had not been reached, with a median follow-up of 14 months.

Selpercatinib. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

For the cohort of patients who were not previously treated, 73% of patients had objective responses, with a median duration of response of 22 months.

Selpercatinib. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

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. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

In a small cohort of six children with recurrent medullary thyroid carcinoma who were treated with selpercatinib, all patients had ongoing responses at a median follow-up of 13 months.[24]

Selpercatinib. Selpercatinib is a RET inhibitor. A phase I/II trial of selpercatinib therapy for patients with RET-altered cancers enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[23]

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 medullary thyroid cancer who require systemic therapy.[25]