Third Line TKI After 2 TKIs in Patients With mRCC (Tokio Study)

Advanced RCC presents poor prognosis, because his pathogenesis is not clearly understood. Additionally, the Von Hippel Lindau (VHL) gene is mutated in the majority of sporadic and familial clear cell renal cancer. The mechanism by which VHL mutation leads to RCC development and progression is postulate to be in part thought production of the protein VEGF (Vascular Endothelial Grow Factor). VEGF over-expression may be pertinent in RCC via multiple mechanism in addition to angiogenesis, including effects on dendritic cells and inhibition of apoptosis through preservation of cyclin dependent kinase inhibitors. VEGF expression could represented an independent prognostic factors for survival possibly linking expression of this protein with clinical outcome. Sunitinib and pazopanib are the standard therapy as first line in mRCC. At sunitinib failure a second line with axitinib or everolimus or sorafenib should be considered to improve the clinical outcome of the disease. Up to now there is not a clear evidence of superiority in favour of an agent versus the others available. At pazopanib failure no evidences are available to support physicians in the decision making in the everyday clinical practice. Moreover no data are available in third line with a TKi after two previous lines of therapy with TKIs. This study was designed to evaluate prospectively the efficacy of two different sequences of TKis in third line: The first (group A) to evaluate the efficacy of sorafenib after two previous lines of TKIs with sunitinib followed by axitinib The second (group B) to evaluate the efficacy of sunitinib after two previous lines of TKIs with pazopanib followed by sorafenib. 400 mg bid is the standard approved dose for sorafenib in the treatment of mRCC while 50 mg for 4 consecutive weeks every six weeks is the standard dose for sunitinb