Alicia Morgans: Hi, I'm so excited to be joined today by Dr. Pedro Barata, who's an Associate Professor at University Hospital Seidman Cancer Center at Case Western University in Cleveland, Ohio. Thank you so much for being here with me today, Dr. Barata.

Pedro Barata: Thank you for having me. Pleasure to be here. Excited to talk about the data.

Alicia Morgans: Great. An exciting time to talk to you, too. I'm excited to talk with you today though, about the work that you and your team have done on tivozanib. And that specific investigation and analysis that you've presented, looking at the non-clear cell RCC population. Can you tell me a little bit about it, please?

Pedro Barata: Absolutely. And thank you again for the opportunity. So, tivozanib is a selective androgenic therapy. It's FDA approved for patients with advanced renal cell carcinoma, in the refractory setting. So, it's actually a therapy we've been using more and more in clinics, and we know to be active. However, the data that we have to support its use, is mainly derived from clear cell RCC cases. So really, the question was, we're trying to put up data together, in the non-clear cell histologies, as you and I know, Alicia, is less common. We have the papillary, unclassified translocation, et cetera. So, what we did, we went back to this Phase II trial, that has a very particular design, that was conducted several years ago, in patients who were not previously exposed to VEGF therapies, and tested tivozanib in this discontinuation trial of tivozanib.

So, at that time, when the trial was designed and conducted, patients with advanced RCC, again not previously exposed to VEGF therapies, were randomized, or located to a better set, to one of the arms depending on the tumor shrinkage. If they had tumor growth, they end up stopping treatment and pursuing another systemic therapy. If they had more than 25% or more tumor shrinkage, they continue on tivozanib, open label for three months, I should say. And then, if you had responses that were between 25% tumor shrinkage and 25% tumor growth, so a little bit different from our current definition of response, the patients were randomized to either tivozanib for 12 weeks, three months, or a placebo. And it was double blind, and randomized in this portion of the study.

This study enrolled over 270 patients. Again, a lot of them had clear cell, and in this effort here, we put together the data for the non-clear cell population. And we're really talking about over 45 patients representation, that mixed and classified histology followed by papillary. And we had a couple of patients with chromophobe and collecting duct in here. So really, the goal was to report on the activity, but also really, on the safety profile of tivozanib, in this setting.

Alicia Morgans: Wonderful. So, thank you for talking us through that. Now, I imagine there were very few patients with collecting duct and similar type tumors. Can you tell us a little bit about the breakdown? Who were the majority of these non-clear cell patients?

Pedro Barata: Yeah, absolutely. This is a great question, because a lot of times, when we think about non-clear cell, it depends on what kind of patients are able to be included in this kind study. So I think, we had over 30% of mixed or unclassified histology. Then we have another 11% with papillary RCC, and then, two patients had chromophobe, two collecting ducts. So you have representation of different subtypes in here, and we were able to collect data for those patients. Again, the data we have on efficacy and safety, it's a little bit different from the one we are currently reporting these days, because at the time, we didn't have the expert consensus about exactly what the percentage of tumor shrinkage would be. So by design, we've got to put it into context. But nonetheless, that was the representation, about the patients who were able to enroll in this particular Phase II trial.

Alicia Morgans: Great. So, in terms of the efficacy analysis, were you guys looking at a radiographic progression-free survival endpoint, or what kind of measures were you assessing?

Pedro Barata: Yeah, that's a great question. What we're looking at, basically, we were looking for responses. And here again, the response rate at the beginning of the study was defined, as I said, to 25%. But then, we used the conventional response rate afterwards, at 16 weeks. So, the response rate at 16 weeks, at the time of randomization, to either tivo for three months or placebo, was about 15%. So, that means 15% of the patients had an overall response rate of four months on therapy. Now, we know responses can happen afterwards, but that was enough to check, to get the randomization going. And then, at any point, the response rate for patients with non-clear cell RCC, who actually continue on tivozanib, was confirmed, 21%; unconfirmed, 31%. And so, those numbers, really put this into perspective, are in line with other TKI data out there, like cabozantinib, I'm thinking, and others. And so, that's really in line with what we would expect to see.

And then, the other perspective that was important, that we were chatting about a little bit earlier today, has to do with the disease control rate. Of course, some of these groups of patients had really small representation. For example, the collecting duct, we had one patient there, two patients with chromophobe. But in general, those numbers were very, very high. You range somewhere from 66% to a 100%. So, in other words, the majority of patients, while on trial, were able to be on therapy without progressive disease, as best response. Which is good news, because it means that, you do see activity of tivozanib in this patient population. And if I may add one other efficacy point here, we also were able to check the radiographic progression-free survival. And for patients on tivozanib, the radiographic PFS was a little bit over six months. To be precise, 6.7 months, which again, it goes really well, or compares really well with other data from very effective TKIs, such as cabozantinib in non-clear cell subtypes. And so, when we put this efficacy data together, it's reassuring to think that tivozanib can be, potentially, an option to be considered for patients with non-clear cell RCC.

Alicia Morgans: I agree. But the other side of that excitement is, of course, just making sure that the drug is tolerable. Can you share with us some details about that?

Pedro Barata: Yeah, it's a great question, because in these particular settings, a lot of times, we're looking for tumor control. Unfortunately, we cannot talk about cure. And so, tivozanib is very selective. You don't have a lot of off-target effects. And actually, we're able to see that in this particular subgroup analysis, if you will. The most common treatment related adverse events were mainly minor ones. So, we didn't see many Grade 3s and higher. There were no Grade 5s, by the way. And the only Grade 4s documented, were two events, if you will. So, most side effects were minor, which is really concordant for this therapy. I guess, the most common side effect, again, which can be seen as an effect of the on-target effect of tivozanib, has to do with high blood pressure. High blood pressure is relatively common, in about almost half of the patients, percentage wise, developed some degree of high blood pressure. Which, for the most part, is well controlled. So, I would argue that the safety profile is actually very similar to what we saw, for example, in Phase III trials with tivozanib, in others such as TIVO-3. The same favorable safety profile, suggesting that tivozanib continues to have a very good profile. Is really well tolerated, in patients who end up getting it.

Alicia Morgans: That's great. So, what would your main message be? Or the message to listeners, as a take home?

Pedro Barata: Sure. So, I think of course, as you know, we've got to take this data with limitations; in a grain of salt, in a sense, that we don't have a very large core. That's, in general, the challenge with conducting studies in non-clear cell. It's very difficult for us to find a very large group of patients. And so, that's that. This is a subgroup analysis. Nonetheless, or with that said, I think it's fair to say that tivozanib seems to be active in the non-clear cell subgroups. There's limited options for patients with non-clear cell, beyond papillary RCC. And I really think that tivozanib is another agent that can be considered in those patients, in the right circumstances. So, for folks out there, as they're thinking about other therapies, I think tivozanib is a good option for those patients.

Alicia Morgans: Well, it's always important to expand our options. So, I really appreciate you taking the time, to certainly do this work, in the non-clear cell RCC population, but also then, of course, to share your findings, including both efficacy and safety, just to help us have such a clear picture. So thank you so much for your time and for your expertise.

Pedro Barata: Thank you so much for having me, and I'll see you soon. Thank you.