Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial

Abstract

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.

Fig 1.

CONSORT diagram based on data cutoff date of December 15, 2011. AE, adverse event; PFS, progression-free survival. (*) Includes patient deaths that occurred on study drug any time after first dose but before patient being discontinued from study drug for any reason.

Fig 2.

Kaplan-Meier plot of progression-free survival (PFS) as determined by independent radiology review. (A) Overall intent-to-treat population; (B) no prior treatment.

Fig 3.

Forest plot: subgroup hazard ratios for progression-free survival and their 95% CIs. ECOG status, Eastern Cooperative Oncology Group performance score; MSKCC, Memorial Sloan-Kettering Cancer Center.

Fig 4.

Overall survival of the intent-to-treat population.

Fig A1.

Kaplan-Meier plot of progression-free survival (PFS) as determined by investigator assessment in intent-to-treat population.