Updates in systemic therapy for refractory thyroid carcinoma – targeted agents, immunotherapy, and chemotherapy

PURPOSE OF REVIEW: Systemic therapy for refractory thyroid carcinoma has moved from chemotherapy and broad multikinase inhibitors towards molecularly targeted treatment. This review summarizes recent practice-changing developments in radioiodine-refractory differentiated thyroid carcinoma, with brief updates on medullary and anaplastic thyroid carcinoma. RECENT FINDINGS: Recent guidelines and clinical studies emphasize early molecular testing, and careful selection of patients for personalized systemic therapy. Lenvatinib remains the preferred first-line multikinase inhibitor for most progressive radioiodine-refractory differentiated thyroid cancers without actionable alterations, while cabozantinib is the best-supported option after lenvatinib. Selective Rearranged during transfection (RET), Neurotrophic Tropomyosin Receptor Kinase (NTRK), and Anaplastic Lymphoma Kinase (ALK) inhibitors have reshaped treatment for fusion-positive disease, and MAPK inhibition can restore radioiodine avidity in selected tumours. In anaplastic thyroid carcinoma, BRAF/MEK-directed treatment and emerging immunotherapy-targeted therapy combinations have prolonged survival and in select instances also enabled resection. SUMMARY: Contemporary management of refractory thyroid carcinoma relies heavily on early molecular testing and utilizing genotype-directed targeted therapy options.