Molecular targeted therapy for thyroid cancer in Japan: Current status and future perspectives

Since the introduction of sorafenib in 2014 and lenvatinib in 2015, multikinase inhibitors (MKIs) have substantially advanced systemic therapy for patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) in Japan. More recently, the clinical introduction of molecularly targeted agents, including BRAF/MEK inhibitors, selective RET inhibitors, and TRK inhibitors, has shifted therapeutic strategies from predominantly histology-based treatment toward molecularly guided precision medicine. However, because most driver alterations in thyroid cancer are mutually exclusive, only a limited subset of patients is eligible for each targeted agent. Therefore, in addition to appropriate molecular testing for treatment selection, optimizing the selection and sequencing of MKIs and genotype-directed therapies has become an important challenge in improving clinical outcomes. This review summarizes the current evidence supporting targeted therapies available in Japan, the roles of companion diagnostics and comprehensive genomic profiling (CGP), and treatment strategies based on actionable driver alterations. We further discuss emerging therapeutic approaches, including redifferentiation therapy, neoadjuvant therapy, and conversion surgery, as well as the remaining challenges and future directions of precision medicine for thyroid cancer.