NEW YORK (Reuters Health) – A novel VEGFR inhibitor, tivozanib, improves progression-free survival significantly in patients with metastatic renal cell carcinoma but does not improve overall survival, according to the results of a phase III trial. Nonetheless, the researchers say, “Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic RCC.” As they explain in the Journal of Clinical Oncology online September 9, sorafenib and sunitinib have become prominent in the treatment of RCC but they are broad tyrosine kinase inhibitors, which may be the reason for side effects such as myelosuppression and skin rash. Tivozanib is a selective inhibitor of VEGFR tyrosine kinase that may improve tolerability. Following encouraging results in a phase II study of tivozanib for metastatic RCC, Dr. Robert J. Motzer, at Memorial Sloan-Kettering Cancer Center in New York, and colleagues conducted a phase III randomized trial comparing tivozanib with sorafenib as first-line targeted therapy in 517 patients with metastatic RCC. Median progression-free survival (PFS), the primary end point, was significantly longer with tivozanib than sorafenib at 11.9 versus 9.1 months (hazard ratio, 0.797; p=0.042), the team reports. Rates of grade 3 or higher adverse events were similar with both drugs, but specific side effects differed. Hypertension and dysphonia were more common with tivozanib than sorafenib, whereas hand-foot syndrome and diarrhea occurred more often with sorafenib than tivozanib. However, there was a trend toward shorter overall survival (OS) with tivozanib (median 28.8 months) than with sorafenib (median 29.3 months; p=0.105), for a hazard ratio of 1.245. Dr. Motzer and colleagues suggest the lack of improvement in overall survival resulted from a study design that allowed patients who progressed to switch to next-line targeted therapies; the switch rate was 63% in the sorafenib arm versus 13% in the tivozanib group. However, in May this year, an advisory panel of the US Food and Drug administration interpreted the data to indicate a deterioration in overall survival with tivozanib, notes Dr. Marc B. Garnick in an accompanying editorial. Dr. Garnick, with Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, continues: “Other equally plausible explanations were put forth by the FDA review team, including that sorafenib may be more effective than tivozanib in improving OS, that tivozanib has greater delayed toxicity, or that tivozanib has unrecognized toxicity that contributed to the lower survival in ways that are difficult to appreciate. We will never know for sure.” He concludes, “What we do know is an inherent difficulty in bringing to market a novel therapeutic that boasts an improvement in PFS but has a study design that leads to ambiguous results for OS.” SOURCE: Preserving the Sanctity of Overall Survival for Drugs Approved on the Basis of Progression-Free Survival: Tivozanib As a Case Study SOURCE: Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial J Clin Oncol 2013.