Multikinase inhibitors in thyroid cancer: timing of targeted therapy

In the 9 years since the publication of our 2011 review of targeted treatment of thyroid cancer with multikinase inhibitors, much has changed in the landscape of this heterogeneous disease. New multikinase and selective inhibitor treatments for medullary thyroid cancer, radioiodine-refractory thyroid cancer and anaplastic thyroid cancer have completed trials and improved progression-free survival. Many physicians are concerned by dose-limiting adverse effects of these drugs and are wary to begin treatment in patients who are systemically well but have marked disease burden, which makes the timing of treatment initiation challenging. Published mechanistic data on tyrosine kinase inhibitors (TKIs) have helped guide our understanding of how to dose effectively with these drugs. A major goal in TKI therapy is to optimize inhibition of oncogenic kinase drivers while maintaining patient quality of life. Real-world data have now been published on how TKIs have fared outside the clinical trial environment. In this Review, we provide a summary of published data on the efficacy of TKIs in clinical practice, to provide clinicians with a more realistic view of how their patients will manage and respond to TKI therapy. Furthermore, we review the data on mechanisms of inhibition, outcomes and adverse effects of TKIs and provide an update on targeted treatment of thyroid cancer, focusing on optimizing the timing of treatment initiation. This Review summarizes the evidence from clinical trials for the efficacy of tyrosine kinase inhibitors in the treatment of thyroid cancer. The data from the experience with these drugs in clinical practice are also discussed, and factors that can help clinicians decide when to start or whether to continue tyrosine kinase inhibitor therapy are considered. Key points Pivotal phase III trials of multikinase inhibitors in the past decade have provided new options for treatment of radioiodine-refractory differentiated thyroid cancer and metastatic medullary thyroid cancer. Once metastatic disease develops, the driver mutation and the pathology of the tumour inform treatment options. Multikinase inhibitors exist on a scale of specificity that often reflects their ability to inhibit VEGF. VEGF inhibition is largely responsible for the effects of tyrosine kinase inhibitors in the management of metastatic thyroid cancer. Both static and dynamic predictors can assist in determining which patients will benefit most from tyrosine kinase inhibitor th