The progression free survival-plateau with vascular endothelial growth factor receptor inhibitors--is there more to come?

The field of renal cell carcinoma (RCC) treatment has changed dramatically during recent years. Sunitinib, sorafenib and pazopanib were the first generation of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) to have significant clinical activity in metastatic clear cell RCC. These TKI share inhibition of VEGFR family members, but differ in their ability to block other cellular kinases. Axitinib and tivozanib are 2nd generation TKIs, which show high specificity for VEGFR inhibition and exert a favourable toxicity profile. Both agents have succeeded in pivotal clinical trials, which were the first studies to compare two distinct TKIs. Progression free survival (PFS) shows an advantage for the 2nd generation TKIs, but also curbs enthusiasm for limitless PFS expectations with a PFS plateau of 13-14 months in 1st line treatment. More recently, novel targets have gained attention in RCC, such as the mesenchymal epithelial transition factor also known as the MET receptor and the fibroblast growth factor receptor (FGFR). These receptors are included into the inhibitory profiles of third generation TKIs such as cabozantinib or dovitinib, which showed promising activity in early clinical trials. Randomised controlled trials explore the role of these agents, and whether the expansion of targets inhibited may lead to more effective treatments in RCC.