Phase III Safety Data for Tivozanib in Renal Cell Carcinoma

Ben Leach
Published Online: December 3, 2012
Robert J. Motzer, MD

Robert J. Motzer, MD

Patients with advanced/metastatic renal cell carcinoma (RCC) in the first-line setting who were treated with tivozanib experienced fewer Grade 3 or higher adverse events, stayed on treatment longer, and required fewer dose reductions and interruptions as compared with patients treated with sorafenib, according to results of a phase III trial presented at the European Society for Medical Oncology (ESMO) 2012 Congress.

The data were from TIVO-1, a global, randomized trial comparing the safety and tolerability of tivozanib and sorafenib in patients with advanced RCC. In results from the trial presented at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting in June, tivozanib increased progression-free survival and objective response rate compared with sorafenib.

Tivozanib, an oral tyrosine kinase inhibitor, targets vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, which have been known to promote angiogenesis and tumor progression.

“This study demonstrated that a more potent selective VEGF-R inhibitor with a long half-life achieved superior efficacy combined with decreased off-target toxicities,” said Robert J. Motzer, MD, attending physician, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center in New York City and professor of Medicine, Weill Medical College at Cornell University, in the presentation at ASCO. “Tivozanib should be considered as a first-line treatment option for metastatic renal cell carcinoma.”

In the phase III trial, 517 patients with advanced RCC were randomized to receive either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week of rest (n = 260), or 400 mg of sorafenib twice daily continuously in a 4-week cycle (n = 257). Patients were either treatment-naïve or received no more than one prior systemic therapy for metastatic disease. No patients in the study received any prior VEGF- or mTOR-targeted therapy. The primary endpoint for the study was PFS.

Hypertension was the most frequent adverse event related to treatment with tivozanib (for grade 3 or higher, 23.6% in the tivozanib group vs 15.2% in the sorafenib group). Hypertension is an established on-target effect of angiogenesis inhibitors; in this study it was easily managed with standard anti- hypertensives.

As compared with the sorafenib arm, patients in the tivozanib arm also experienced more dysphonia, but less diarrhea, hand-foot syndrome, and alopecia.

Dose reductions were needed in 11.6% of the tivozanib group versus 42.8% of the sorafenib group (P<.001); interruptions occurred in 17.8% of the tivozanib group versus 35.4% of the sorafenib group (P<.001); and discontinuations occurred in 4.2% of the tivozanib group versus 5.4% of the sorafenib group. Overall, there were fewer drug-related adverse events in the tivozanib arm: 67.6% versus 83.3%.

“Minimizing toxicities associated with anti-VEGF therapy is a vital consideration in RCC. Adverse events have been shown to contribute to dose reductions, interruptions and discontinuations of anti-VEGF therapy,” said Timothy Eisen, PhD, FRCP, study investigator, Cambridge University Health Partners, in a press release. “The data from TIVO-1 show that treatment with tivozanib led to fewer side effects and lower rates of dose modifications than with sorafenib. This suggests that it is easier to maintain full dose therapy with tivozanib.”

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