Tivozanib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. In a phase III trial reported in Journal of Clinical Oncology by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC) and colleagues, tivozanib was found to improve progression-free survival but not overall survival and to exhibit a different toxicity profile when compared with sorafenib (Nexavar) as initial targeted therapy in patients with metastatic renal cell carcinoma.
In this open-label trial, 517 patients with metastatic renal cell carcinoma with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic renal cell carcinoma were randomly assigned to receive tivozanib at 1.5 mg/d for 3 weeks followed by 1 week off (n = 260) or sorafenib at 400 mg/d continuously. Prior VEGF-targeted therapy and MTOR inhibitors were not permitted. Hypertension for tivozanib and skin toxicity for sorafenib were managed according to specific guidelines. The primary endpoint was progression-free survival on independent review.
Patients in the tivozanib group and sorafenib group had a median age of 59 years and 71% and 74% were male. Other baseline characteristics were well matched except for a greater proportion of patients with better Eastern Cooperative Oncology Group (ECOG) performance status in the sorafenib group (0 in 54% vs 45%, P = .035). Seventy percent of patients in both groups had received no prior systemic treatment for metastatic disease, with the predominant therapy (> 90%) being interferon-alfa in the remaining patients. Prior adjuvant therapy had been given to 9% of patients in both groups.
Prolonged Progression-Free Survival
Patients received tivozanib for a median duration of 12.0 months and sorafenib for 9.5 months at the data cutoff. Median progression-free survival was 11.9 months in the tivozanib group vs 9.1 months in the sorafenib group (hazard ratio [HR] = 0.797, P = .042). Prespecified progression-free survival subgroup analyses based on baseline characteristics showed a consistent advantage with tivozanib treatment; significant advantages were observed among patients who were treatment naive for metastatic disease (median, 12.7 vs 9.1 months, HR = 0.756, P =.037), patients with ECOG performance status of 0 (14.8 vs 9.1 months, HR = 0.617, P =.004), and those in the MSKCC favorable prognostic group (16.7 vs 10.8, HR = 0.590, P = .018).
No Overall Survival Benefit
Overall response rates were 33.1% vs 23.3% (P = .014). A trend toward greater overall survival was observed for the sorafenib group (median, 28.8 vs 29.3 months, HR = 1.245, P = .105). A greater proportion of patients in the sorafenib group received subsequent therapy (65% vs 26%) including a next-line targeted therapy for renal cell carcinoma (63% vs 13%), with nearly all of the sorafenib patients receiving tivozanib as part of a companion protocol that allowed crossover at progression.
Adverse events of any grade that were more common with tivozanib were hypertension (44% vs34%) and dysphonia (21% vs 5%), and those more common with sorafenib were hand-foot skin reaction (54% vs 14%) and diarrhea (33% vs 23%). The most common grade 3 or 4 adverse events were hypertension (27%) and increased lipase (11%) in the tivozanib group and hypophosphatemia (26%), increased lipase (24%), hypertension (18%), and palmar-plantar erythrodysesthesia (17%) in the sorafenib group. Dose reduction due to adverse events occurred in 14% of tivozanib patients and 43% of sorafenib patients, treatment interruptions occurred in 19% and 36%, and discontinuation due to treatment-related adverse events occurred in 4% and 5%.
The investigators concluded: “Tivozanib improved [progression-free survival] compared with sorafenib in patients with metastatic [renal cell carcinoma]. Although tivozanib was characterized by higher rates of hypertension and dysphonia, it was generally well tolerated and had lower rates of certain [adverse events], including hand-foot skin reaction and diarrhea, and it required fewer dose reductions and interruptions compared with sorafenib. Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic [renal cell carcinoma].”
The study was supported by AVEO Oncology and Astellas.