The Newest Targeted Therapeutics for Thyroid Cancer: Development of Sorafenib and Lenvatinib

Abstract

Sorafenib was specifically developed using high-throughput screening and structure-activity relationships to target important pathogenic pathways in thyroid cancer. Initially developed to target rapidly accelerated fibrosarcoma (RAF) kinase, it was also found to inhibit several key receptor tyrosine kinases (RTKs) within the mitogen-activated protein kinase (MAPK) pathway. Preclinical and clinical studies demonstrated significant efficacy in differentiated thyroid cancer (DTC), and following the phase III DECISION trial comparing sorafenib to placebo in DTC, it received Food and Drug Administration (FDA) approval in November 2013 for treatment of advanced, radioactive iodine-refractory DTC. Sorafenib is shown to significantly improve progression free survival (PFS) an average of 10.8 months (hazard ratio [HR] 0.59, 95% CI, 0.45-0.76; P<0.0001), although an overall survival (OS) benefit has yet to be proven. An additional targeted RTK inhibitor, lenvatinib, was recently approved by the FDA in February 2015 for advanced, RAIrefractory DTC following the phase III SELECT trial. While lenvatinib has a higher average PFS of 18.3 months (HR 0.21; 99% CI, 0.14-0.31; P<0.001), as well as higher complete and partial response rates, it too has yet to prove an OS benefit. While there is clear evidence of the clinical benefit for both sorafenib and lenvatinib treatment in advanced RAI refractory patients, it is unclear which may be superior. However, each has a different side effect profile that may help guide initial treatment decisions in an individualized approach. Additionally, because lenvatinib demonstrated a similar increase in PFS for those who were previously treated with RTK inhibitors like sorafenib, lenvatinib is a powerful addition to the treatment of advanced DTC and creates another option for either initial therapy or secondary therapy following disease progression.