Further Evaluation of Tivozanib Shows Promise for Relapsed, Refractory Renal Cell Carcinoma

Results from the phase III TIVO-3 trial of tivozanib (Fotivda) demonstrated a statistically significant improvement in median progression-free survival (PFS) compared with sorafenib (Sutent), as well as favorable tolerability, in patients with relapsed or refractory renal cell carcinoma (RCC).

These agents were previously evaluated in the frontline setting of this patient population in the phase III TIVO-1 trial, which showed a slight advantage in PFS and response rates for tivozanib; however, overall survival benefit was in favor of sorafenib. In a recent interview with Brian Rini, MD, from Vanderbilt-Ingram Cancer Center, he explained the one-way crossover design of the study was a flaw.

In the phase III TIVO-3 trial – designed to evaluate tivozanib versus sorafenib in patients who had received 2 or 3 prior lines of therapy – the vascular endothelial growth factor tyrosine kinase inhibitor demonstrated a statistically significant improvement in median PFS compared with sorafenib, at 5.6 months versus 3.9 months, respectively. Moreover, 2-year PFS rates were 18% versus 5% in favor of tivozanib.

In addition, response rates were higher and the agent induced durable responses with favorable tolerability.

Rini spoke to Urology Times about the two trials, and why results from the phase III TIVO-3 trial are key in demonstrating another treatment option for patients with advanced RCC.

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TIVO-1, which was done many years ago, was also versus sorafenib. It was a frontline study that showed progression-free survival advantages to tivozanib over sorafenib. It was positive from that sense with a pretty clear progression-free survival advantage, good tolerability. That was all good. Where the problem was is that this study was conducted largely in the Russian Ukraine, and the study design, which was fatally flawed, had a one-way crossover, meaning patients who failed sorafenib could cross over and receive tivozanib. Most of those patients did, and they did quite well, not surprisingly, on tivozanib in that setting. Patients on tivozanib who progressed did not cross over to anything, and in those countries, very little else was available. In essence, it became a study of two sequential TKIs versus just one. While it wasn’t significant, there was a numerical advantage in survival in patients who got the sorafenib-tivozanib sequence. Because of that, the FDA was hesitant to approve the drug and did not approve the drug. Hence, the need for TIVO-3.

There are two main differences (between the trials). One is that TIVO-3 was done in a third- and fourth-line setting, whereas TIVO01 was frontline. Otherwise, the comparator was the same – sorafenib. The results showed a progression-free survival advantage. The absolute numbers are lower, of course, because it’s in a more refractory setting, but similar PFS advantage. There is not a difference in survival. So, there is not a numerical or statistical difference one way or the other. I think this really reaffirms that TIVO-1 was flawed because of that crossover, and when you give patients equal access to subsequent therapies. There was no crossover in either arm in TIVO-3, so patients could go on and get whatever therapy was available, or multiple therapies, in their country. I don’t know the number of patients who had subsequent therapy offhand, but the survival is basically overlapping, which is what we’ve seen in the major trials of VEGF versus VEGF in this refractory setting.