PURPOSE: Tivozanib is a potent and selective tyrosine kinase inhibitor of 
vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase 
III trial compared tivozanib with sorafenib as initial targeted therapy in 
patients with metastatic renal cell carcinoma (RCC).
PATIENTS AND METHODS: Patients with metastatic RCC, with a clear cell component, 
prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic 
RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted 
therapy and mammalian target of rapamycin inhibitor were not permitted. The 
primary end point was progression-free survival (PFS) by independent review.
RESULTS: A total of 517 patients were randomly assigned to tivozanib (n = 260) 
or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the 
overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 
0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed 
on sorafenib crossed over to receive tivozanib. The final overall survival (OS) 
analysis showed a trend toward longer survival on the sorafenib arm than on the 
tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P 
= .105). Adverse events (AEs) more common with tivozanib than with sorafenib 
were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with 
sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and 
diarrhea (33% v 23%).
CONCLUSION: Tivozanib demonstrated improved PFS, but not OS, and a 
differentiated safety profile, compared with sorafenib, as initial targeted 
therapy for metastatic RCC.