LAUSR

Abstract Treatment of differentiated thyroid cancer (DTC) is multidisciplinary and begins with surgical intervention. Often, radioactive iodine is used as the prototype targeted therapy to ablate any residual thyroid tissue or metastatic deposits. While these initial therapeutic modalities are often curative with no need for further treatment, many patients develop radioactive-iodine refractory (RAIR) disease. When patients present with progressive RAIR disease, they often require systemic therapy. Several multikinase inhibitors have been approved for treatment of DTC, with sorafenib and lenvatinib employed in frontline treatment settings since approvals in 2013 and 2015, respectively. While patients have benefited from such treatment, progression is inevitable, and until recently, there were no established second-line options. Cabozantinib was recently approved for treatment of patients with DTC who have progressed on either frontline sorafenib or lenvatinib. Molecular testing for driver mutations or gene fusions, such as BRAF V600E or RET or NTRK fusions, has become standard recommendations for RAIR DTC patients due to excellent treatment options with highly selective targeted therapies, most RAIR DTC patients do not harbor such aberrations or have so-called “undruggable” mutations, making rendering cabozantinib an attractive and feasible treatment option for many patients.