Milestones for development of tivozanib for kidney cancer therapy

In the May 10, 2012 issue of the Journal of Clinical Oncology, Nosov and colleagues report on a company-sponsored (AVEO), phase II randomized discontinuation trial (RDT) of tivozanib therapy for metastatic kidney cancer (1). This trial is part of a development of tivozanib seeking to expand the growing list of active medical treatment options blocking the vascular endothelial growth factor (VEGF) pathway, besides drugs with mammalian target of rapamycin (mTOR) pathway inhibition, and treatments using immune mechanisms. Among the VEGF pathway approaches, small molecule tyrosine kinase (TKI) inhibitors already approved for use in metastatic renal cell carcinoma include sunitinib, sorafenib, pazopanib, and most recently axitinib; bevacizumab is an antibody that binds plasma VEGF, so that the VEGF receptor remains without this ligand. Tivozanib is distinguished from the other small molecule VEGFR TKI by a more potent inhibition of VEGF receptors 1, 2 and 3 (half-maximal inhibition at 0.24 nmol/L or lower), and a long half-life (reported here at 87.0±27.9 hours) (1). The high potency is reflected in the relatively lower daily dose, 1.5 mg daily, versus daily doses of 10-800 mg for the others. Additionally, the relative potency for VEGFR1, VEGFR2 and VEGFR3 versus the inhibition of kinases that are not VEGF receptors is over 10 fold, which is higher than for other members of the group. This feature may decrease off-target inhibition, impacting side effects or therapeutic effects (1,2).