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Pedro Barata: Hi, everyone. I'm Pedro Barata, a GU oncologist at University Hospitals Seidman Cancer Center here in Cleveland. It is a true privilege to be here sitting down with Dr. Toni Choueiri. Everybody knows Toni, everybody knows you. Toni is the director of the Lank Center for GU Oncology at the Dana-Farber Cancer Institute, a world-renowned kidney cancer and GU expert. What a fantastic job, Toni, you did presenting what, to me, is really a practice-informing trial, the TiNivo-2, which basically follows the great work that you and Monty Pal led with the CONTACT-03 data.

Maybe for the audience, Toni, I would guess, if you could remind us all of the details of the design of the TiNivo-2, which I would say is not exactly the same as CONTACT-03. Do you agree, and can you remind us what you did there?

Toni Choueiri: Yeah. I mean, they’re both phase 3 trials. TiNivo-2 is a randomized phase 3 trial open at close to 200 sites. Overall, 343 patients were randomized to get tivozanib-nivolumab, the combination of TKI-tivozanib plus the PD-1 inhibitor nivolumab, or tivozanib monotherapy.

The same question we asked as with CONTACT-03 is whether rechallenging with another immune checkpoint inhibitor is of benefit. This is an important question for solid tumor oncology in general. CONTACT-03 was really a totally negative PFS-OS response rate. There was no difference. But the difference here with TiNivo-2 is, of course, it's a different TKI, but it's still a PD-1 inhibitor. It's with nivolumab, not atezolizumab like in CONTACT-03. And that's a major difference because overall frontline trials that showed an overall survival benefit were all PD-1 based, while the ones that were PD-L1 inhibitor-based, like IMmotion151 and JAVELIN Renal 101, did not show overall survival. So, this was an important question.

And another thing with TiNivo-2, different from CONTACT-03, is that we allowed patients whose last therapy before randomization was not an immune checkpoint inhibitor. So, someone could have had tumor progression on a doublet immune checkpoint inhibitor. Let's say they get cabozantinib (a TKI), then they go on the study. So, those are the major differences.

Pedro Barata: Right. No, fantastic points, Toni. So, let me get right on it. I mean, you presented the data very eloquently, and actually, I would argue you present data in a way that's very informative, in my view. One example of that is how you broke down exactly the two groups you just described, right? Folks who got on trial right after progressing on immunotherapy, which was still the majority of the trial population. But then you also had a good group of patients who had actually seen therapy, probably TKI, right before going on trial.

So, going on the data and without repeating all the data you presented, I would say these are my take-home messages, and I'm going to ask you to comment on them, criticize, and expand. One is that I was surprised that Tivo is an active TKI in this particular setting, and in some cases, this was really their first TKI exposure.

And the second is that it’s interesting to see how much more active Tivo was when patients went from progression on a checkpoint right into the trial, compared to those patients who had received a treatment in between the immunotherapy and the TKI, suggesting it’s really a TKI-driven effect. And it also suggests that with PD-1 nivolumab, there doesn’t seem to be any benefit there. Let me ask you—

Toni Choueiri: Correct, I agree.

Pedro Barata: What are your thoughts?

Toni Choueiri: Yeah, there was no benefit in the PD-1 nivolumab rechallenge. Counterintuitively and to our surprise, where we thought at least PFS would be better in both arms where the last drug was not an immune checkpoint inhibitor, or at least where the combination would work better, it did not. Both arms had a median PFS of 3.7 months.

But for the overall trial, I would say that tivozanib as a single agent had a numerically higher PFS—7.4 months versus 5.7 months—despite the response rate being the same. And there was very noticeable PFS in the patients whose immediate previous therapy was immune checkpoint; there was a noticeable progression-free survival of 9.2 months with single-agent tivozanib.

Now, slightly, the arm with the single agent rather than the experimental group was better. Not statistically significant, but at least numerically better, probably due to the dose. Tivozanib was at full dose in the tivozanib-only arm, but in the experimental arm, it was lower at 0.89 mg rather than 1.34 mg in the combination of tivozanib-nivolumab. And the reason is, when we ran this study, but also in initial patients and in the study's initial phase 1/2, there was a higher rate of grade 3/4 hypertension with the combo. So, after speaking with regulatory authorities, we dropped the dose of tivo to 0.89, and I would argue that efficacy may have been at least a bit inferior. So no difference whatsoever.

This is also a study that only included clear-cell renal cell cancer. So, I would argue that in conclusion, ICI rechallenge—at least in renal cell, and I would bet in other solid tumors, though this has not been explored much—should be discouraged in patients with advanced clear-cell RCC. Now, of course, if they came off for toxicity, never really progressed, or had a response and the patient had to stop therapy and later on progressed, that’s different.

Pedro Barata: Right. No, that’s a fantastic point, Toni. I couldn’t agree with you more, and that’s an important message for the community. One last question before letting you go. I mean, this comes after TIVO-3 established tivozanib as the standard of care, perhaps after two systemic therapies. The question now here with TiNivo is, with this data that you just quoted, for the TKI-naive population, IO-refractory TKI-naive population, you are one of the people who developed many of the standard-of-care therapies we have available, including TKI monotherapies. What are your thoughts? Is this data enough to consider tivozanib for the TKI-naive population or not yet? How do you see that, and do you think it's a reasonable option for patients out there?

Toni Choueiri: It's a reasonable option after immunotherapies, especially double immunotherapy, and it's a very reasonable option here. I’m definitely intrigued by the PFS of 9.2 months. You also have a PFS a bit over 10 months with cabozantinib from CONTACT-03, although the population is slightly different. And you also have data in patients who had one line of therapy with belzutifan as well.

So, I think these have not been compared to each other. And I hope one day we can compare these strategies, although how the field is going is more toward combination—two versus one drug. But I think this is important. I still see in my practice patients at the fourth or fifth line where the PD-1 inhibitor is kept or switched, alternating between pembrolizumab and nivolumab, back to nivolumab, back to pembrolizumab, and on and on. And the TKI is changed across therapies. And I don’t know; I mean, now we have two randomized phase 3 trials without any hint of activity. I mean, there’s a financial toxicity, and I would argue that toxicity from the immune checkpoint inhibitor can happen. You have a TKI that is oral compared to more frequent visits to get the intravenous immune checkpoint inhibitor. This is not trivial.

Pedro Barata: Right. No, absolutely. Toni, congrats. Amazing job presenting and amazing job leading these efforts. I was involved, or our site was involved, so it’s always good to make progress and move science forward, and that’s by helping accrue and offer trials to patients. So, thank you for leading those efforts. Great conversation. I really think we’re facing one of the really clinically informative data sets that we’re seeing this year in 2024. So, thank you so much. Great job. Hope to see you soon.

Toni Choueiri: Thank you very much. Beautiful meeting at ESMO Barcelona—the weather, the city, the food, the science—and hopefully, we’ll come back soon. Thank you.

Pedro Barata: Absolutely. Thanks.

Toni Choueiri: Bye. Bye.