Tivozanib Shows Promise Over Sorafenib in Patients With Advanced, Treatment-Refractory RCC

Brian Rini, MD, Professor of Medicine and Leader of the GU Program at Cleveland Clinic Taussig Cancer Center, Ohio, talks about the findings of the TIVO-3 clinical trial, which compared the use of tivozanib with sorafenib in patients with advanced, treatment-refractory renal cell carcinoma (RCC).

Transcript

This is Brian Rini, I'm a Professor of Medicine and Leader of the GU program at Cleveland Clinic Taussig Cancer Center.

I'm going to talk today about the evolving options in advanced RCC, as well as some exciting findings that came out of the recent GU Symposium.

Kidney cancer has changed dramatically since I got involved almost 20 years ago, from very primitive immune therapies and drugs that didn't work much, transitioning to VEGF-targeted therapies which have taken over and become the cornerstone of treatment over the last decade or so, and now rapidly transitioning to immunotherapy-based regimens.

This has resulted in greater median survival for patients, from about 1 year when I started to 2 or 3 years in the targeted therapy era. Now, I think we're going to see survival over 4 years when some of these immunotherapy trials mature.

We've also seen increases in response rate, increases in complete response rates and longer progression-free survival (PFS). The treatment options have expanded dramatically, from the high-dose IL-2 approval in 1992 now to over a dozen drugs approved and more regimens coming.

I presented data regarding a study called TIVO-3. TIVO-3 was a study of a potent selective VEGF receptor inhibitor called tivozanib, that has sort of a story development history in metastatic kidney cancer. This drug was developed a little later than some of the other VEGF-targeted therapies in RCC.

Its first trial, called TIVO-1, was against sorafenib in a front-line setting, and demonstrated great response rate and PFS advantages, and was very well-tolerated. The problem with that study is it was done in parts of the world where no secondary treatment existed.

Patients on the sorafenib arm could cross over and get tivozanib, which was active in that second-line setting, but the opposite wasn't true—tivozanib patients could not crossover. At least in part due to that reason, the overall survival nonsignificantly favored sorafenib, so the drug was not approved in the US. It was later approved in Europe in 2017, but there was still work to do to show that it was a safe and effective drug. That was the basic impetus for the TIVO-3 trial.

So TIVO-3 was the same randomization, tivozanib versus sorafenib, but this time in very refractory patients, patients who had failed 2 to 3 prior treatments, including at least 1 VEGF receptor inhibitor, and about a quarter of patients who had received prior immune-oncology (or IO) agents, as is now common, as I alluded to.

What this trial showed was, again, both a PFS and a response rate advantage of about 6 versus 4 months for PFS, and 18% versus 8% for a response rate. The survival data was immature. The hazard ratio was above 1 (it was 1.12) but nonsignificant, and again, immature data that I will await further follow-up, probably later this year, in 2019.

As we discuss the combinations involving these VGEF TKIs in immunotherapy, I think one of the defining features is going to be TKIs that are well-tolerated. TKIs that are very toxic are going to be much harder to combine and tolerate on a long-term basis, and so it may be that one of the great advantages of tivozanib (if it can get over its regulatory hurdle) is to be a backbone of combination for some of these emerging VGEF IO combinations.

The applications of the findings from TIVO-3, I think they're really supportive of what we already knew about the drug, and hopefully, the ultimate end point is to lead to regulatory approval both in the US and in Europe, so that it can be used initially in refractory patients, but as mentioned, potentially move to the front-line where it can be used in combination with immunotherapy.