Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: still far from a structured therapeutic algorithm

• KIs are the only medical therapy available for iodine-refractory DTC. • Only 2 agents, sorafenib and lenvatinib, achieved the phase III evaluation. • Evidence defining whether and when starting KIs administration is poor. • Many other KIs showed promising activity, but no placebo-controlled trials are available. • Emerging frontiers include iodine-redifferentiation and highly selective pharmacodynamics. The kinase-inhibitors (KIs) sorafenib and lenvatinib demonstrated efficacy in iodine-refractory DTC upon phase III studies. However, evidence allowing a punctual balance of benefits and risks is poor. Furthermore, the lack of a direct comparison hampers to establish the proper sequence of administration. However, some insights may provided: a) indirect comparison between phase III trials showed milder toxicity for sorafenib, which should be preferred in case of cardiovascular comorbidities; b) prospective evidence of efficacy in KIs pre-treated patients is available only for lenvatinib, which should be used as second-line. Promising activity was found for the majority of other tested KIs, but no placebo-controlled trials are available. Emerging, but still early, frontiers include the restoration of iodine-sensitivity and the selective activity on pathogenic mutations. In conclusion, the use of KIs in iodine-refractory DTC is far from a structured therapeutic algorithm.