Maturation of Overall Survival in TIVO-3 with Long-Term Follow-Up - Kathryn Beckermann

June 28, 2023

Pedro Barata discusses the TIVO-3 trial with Kathryn Beckermann. The trial assessed Tivozanib, a novel tyrosine kinase inhibitor (TKI), used in the treatment of refractory clear cell RCC patients. They explain that the primary endpoint of the trial was progression-free survival (PFS), but they also delve into the complexities of considering overall survival (OS) in global trials. This leads to a discussion on a possible novel endpoint, conditional PFS. Dr. Beckermann reports an improved conditional overall survival for Tivozanib compared to Sorafenib based on a 12-month PFS condition. They also touch upon the slower uptake of new therapies in the community, possibly due to the COVID-19 pandemic, and how important studies like TIVO-3 can raise awareness about new treatment options. Finally, they highlight the favorable tolerability of Tivozanib, considering it showed better rates of treatment duration and discontinuation compared to Sorafenib.


Kathryn Beckermann, MD, PHD, Assistant Professor of Medicine, Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

Read the Full Video Transcript

Pedro Barata: Hello, and welcome again. My name is Pedro Barata. I'm a GU medical oncologist at Seidman Cancer Center, Case Western University in Cleveland, Ohio. I'm very happy today to be joined by my friend, colleague, and guru, Kathryn Beckermann. Dr. Beckermann is an Assistant Professor of Medicine in the Department of Medicine at Vanderbilt University Medical Center in Nashville. Welcome. Thank you for taking the time today.

Kathryn Beckermann: Yes, thank you Dr. Barata. It's wonderful to be here and to chat with you about this data.

Pedro Barata: Absolutely. So congratulations on your presentation. You basically were talking about TIVO-3 trial and you did present data titled Maturation of Overall Survival Interval Three with Long-Term Follow Up. And this in my opinion, is a very, very important analysis because we've been talking about this trial for a bit now. I mean it was basically leveraged the approval of Tivozanib for in the refractory clear cell RCC space, which is very important. There's a novel TKI out there, and the primary endpoint is PFS as you're going to tell us more about that. But then it's quite interesting to see the behavior of the other ratio over time. So tell us a little bit about the thought process that led to these analysis, and what were the findings?

Kathryn Beckermann: Yeah, yeah, no thanks. So I'll just kind of briefly summarize. So Dr. Rini presented the first, as you mentioned, primary endpoint here being PFS. And these are patients metastatic RCC, who've had at least one or two prior therapies. And the inclusion criteria required one of those to be a prior TKI. So really looking at sequential treatment for patients with refractory RCC and could they benefit, as you mentioned from this novel TKI. So Tivozanib was compared to Sorafenib and did meet its primary endpoint improvement in PFS. And then the question and the rationale for these kind of longer term follow up is these are patients who've been through multiple lines of prior treatment and does sequencing multiple TKIs still provide benefit? And when we think of someone who's in this late line refractory setting to look at that overall survival benefit is sometimes challenging.

And so there were some post hoc analysis looking at what we'll talk about now looking at long-term PFS, looking at overall survival and looking at conditional overall survival. And so maybe to touch on each of those, knowing that it met its primary endpoint of PFS, they took a look and at various intervals, so pretty much six-month interval going on throughout follow up and showed that long-term PFS at six-month intervals showed an improvement for Tivozanib compared to Sorafenib. And if you look at the kind of specifically look three years out, 36 month follow up that patients had a long-term PFS with an improvement of 12% over 2% in the Sorafenib arm. And so again, showing that this is even in such a refractory setting, patients who are on third or fourth line treatment showing that benefit of this TKI.

Pedro Barata: So that's amazing. Great summary of those results, Katie. And I agree, I mean I agree with you as you demonstrated that over time with more events kind of the as the hazard ratio keeps dropping. And I guess that leads to a more broader question in the RCC space because we're having more and more therapies available and then we usually take PFS as an acceptable endpoint for approval of these therapies. And a lot of us still look for overall survival, obviously. So because, but the rest can be impacted by what you do afterwards and to some extent that's very difficult to control because we run trials in different places, different patients and it's not easy. So as we move from TKIs to IO and IO TKIs and so forth, I think a lot of times getting OS every single time is not easy. Right? So do you agree with that, number one? Number two, do you feel like we have to add other endpoints of interest in addition to OS? And maybe one of that endpoints might be conditional PFS and that's maybe my excuse to ask you if you can explain to us what that really means.

Kathryn Beckermann: Yeah, no I think you've really nicely highlighted that obviously our gold standard is we want our patients to live longer, but as we conduct these trials that are worldwide and access to different medications is different after they've progressed on this therapy and what they get next or not able to get next, that impacts overall survival. And of course further on down the road with multiple treatment types, it is hard to really fully capture if later line intervention is impacting OS. So this is the idea that can you maybe try to still capture that? So looking at a conditional OS based on your time point or your condition of interest. So for example, this has been looked at another trial. So in CheckMate-214 they were able to look at a conditional OS and that was kind of some nice data. And subsequently we've done the same here from TIVO-3 to ask the question if we look at patients who at a 12 month PFS condition can we use that to stratify and look at a conditional OS?

Knowing that as you've kind of touched upon that the total overall OS hazard ratio is trending in an improved direction. So kind of 0.99 to 0.89. But could we further discern if based as I mentioned on that 12 month PFS condition, does that show any difference in a conditional OS looking at Tivozanib compared to Sorafenib? And the hazard ratio really does separate quite rapidly and nicely if you use that conditional OS with a hazard ratio there of I think 0.49 of showing Tivozanib benefit in a conditional OS compared to Sorafenib. So I think it's a novel endpoint, another way to show that this is helping patients. And of course you have to look at that in the broad context of everything else going on. But I do think it's a nice novel endpoint to kind of contextualize how patients are responding.

Pedro Barata: Right. No, I agree completely I mean my take on the data that you and the TIVO-3 group have presented. So it sounds like if you're selecting patients who have not progressed within a year, those are patients who first of all seem to be benefiting the most from novel TKI such as TIVO. And it seems like because you're benefiting more from the therapy you're on, you're more likely to live longer. Right? Whereas for patients who progress shorter than a year, I guess are probably destined enough to do great whatever therapy you try. And unfortunately they'll have those events early on. So I really like that as also a novel way to present that data. So thank you for that as well. So I know you've been using TIVO now in clinical practice, and let me then ask you the question and see if the same is happening to you because I talked to a lot of colleagues in the community and so forth and for whatever reason, I don't know if it was Covid or not, I feel like the uptake of novel therapies has not been the same as pre Covid.

In other words, I get the sense that it takes more time, longer, for people to start being aware of these novel therapies that have shown to be beneficial to patients. And perhaps Tivozanib is within that group. I would expect more people to use it because we don't have a limited number of options still. And so do you agree with that? Is that what you're seeing out there as well? Do you feel Tivozanib will probably would be used more and might likely will be used more and more overtime as we also provide more data? And how do you think that presentations like yours can help the community to, or raise awareness in the community better said, to the fact that Tivozanib is actually a very active agent out there?

Kathryn Beckermann: No, I totally agree. I think we're seeing the same in our practice that while we have recognized it as an excellent option for patients in the refractory setting, I think some of it too in the community is that maybe especially for generalists who don't see as many patients with renal cell carcinoma and then to get to third and fourth line treatment, maybe even a smaller group. And so just the recognition, getting awareness out there as you mentioned, to show the benefit so that if they do see that patient walk in the door or sequencing multiple treatments to understand that this is an option in that lineup.

Pedro Barata: Right. Awesome. And I guess final question for you before I let you go, is there anything you can share with us from these big database that TIVO-3 provided, is there any insights, any new ideas maybe correlatives, if you will, that you want to share with us as what to expect in the near future?

Kathryn Beckermann: I think I'd say that the one thing we maybe haven't touched upon that I'd want to also emphasize is that there has been publications from TIVO-3, both on both in the original publication and then subsequently showing that duration of therapy and rates of discontinuation were better on TIVO-3 than they were compared to Sorafenib. So just wanted to touch upon that, that really the tolerability of Tivozanib based on this clinical trial. So it not only showed PFS benefit but then showed that it was a tolerable agent in patients, again, who've been on multiple treatments. And so that's just kind of nice data to say, hey, tolerable, reasonable for efficacy and kind of the whole picture.

Pedro Barata: Right. No, I agree with you is interesting, right? Because the treatment exposure, which much longer for Tivozanib compared with Sorafenib, but yet all the safety endpoints like treatment discontinuations, those reductions actually is much lower than the Tivozanib, right? So despite being longer on therapy, patients remain on the standard dose that was offered to them. Yeah, that's a fantastic point as a real role point as well, right?

Kathryn Beckermann: Yes.

Pedro Barata: That's because I think what all of us are seeing in clinical practice, it matches what we've seen the trial and what we're seeing in clinical practice. Would you agree?

Kathryn Beckermann: Yes, absolutely.

Pedro Barata: Great. All right. Well this has been great. Thank you so much for taking the time. We're going to be chatting again very soon, I know that. But anyway, thank you for being generous and taking the time to sit down with us and tell us about the great analysis that you did, regarding overall survival for TIVO-3. So, thank you.

Kathryn Beckermann: Yeah, wonderful to see you.

Pedro Barata: Appreciate it. We'll see you soon.

Kathryn Beckermann: Thank you.