TiNivo-2 Efficacy: Breaking Down the Data on TKI and Immunotherapy in RCC Treatment

In part two of this roundtable, the panelists analyze the recently published results of the TiNivo-2 study, which examined the efficacy of tivozanib with or without nivolumab in patients with renal cell carcinoma. The panel explores key findings, including the role of TKIs post-IO therapy, the implications for sequential treatment strategies, and how these results compare to CONTACT-03. They also provide insights into the evolving landscape of renal cell carcinoma management and informs decision-making for advanced RCC treatment.

Watch the third segment of this series: Navigating Treatment Sequencing and Toxicity in RCC: Insights From TiNivo-2

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Dr. Beckermann:
This study was just recently presented and published in the Lancet. Congratulations. Everyone on the call here was certainly involved in that. And so maybe, Dr. Barata, if you wanted to start us off on what you thought of the overall highlights of the efficacy of this trial.

Dr. Barata:
TiNivo-2. So yeah, so as Toni alluded to and Monty before him, a super-important study. The difference of TKI is relevant. I think when we look at the breakdown, one thing that I really like and I think was very clear to the readers is to see, first of all, really. An absence of benefit of bringing nivolumab on top of tivozanib. And number two, the activity of tivozanib on the combo seems to be inferior to the TIVO, let’s call it, approved standard dose of 1.34.

So I think we can drive the conclusion that really, the activity in the post-IO setting is really TKI-driven. And I think that’s an important one. The second aspect, I think, is when we look specifically at the patients who received, as to Toni’s point, a therapy that was not an IO, because you did not require a progression IO right away as immediately prior therapy, you can see that activity is actually much shorter compared to tivozanib in patients who got it as the first TKI. Which also speaks to when do you take the most benefit of the TKI is actually the first time you use it.

So you do have TKI-naive population in there. Actually, I would argue tivozanib really performed well if we want to think of this a second line post-IO. If you think of patients treated, for example, a dual-IO regimen in frontline with ipi/nivo, over nine months of PFS with tivozanib there, you can definitely see activity of tivozanib, which I think established tivozanib as another good option to have among the active options for advanced RCC these days. So it’s really practice-informative in my mind. When we put the story, it really makes sense when we get them together.

Actually, I was in the wrong side of the biological reasons. I actually thought TiNivo could be positive. And obviously, the trial showed me clearly wrong. Because I really think there was some sort of rejecting the system, the immune system. You give them a break and come back with an IO later on, and that doesn’t seem to play out.

And so I think the take-home message is, until we generate that data that salvage immunotherapy is a good idea right now, we really are more clear on that point that with the therapies we have available, PD-1, PD-L1s, and even, I would argue, with CTLA-4 inhibitors, right now the standard should not be offering a standard approach with another immune checkpoint inhibitor. Should be offering a TKI that’s shown activity after progression of prior TKIs, which, again, confirms our practice of the current management of RCC, if you will. So from that perspective, I think TiNivo is really informative. Is really important that was conducted.

Dr. Beckermann:
That’s great. I think we may have to consider in our NCCN Guidelines, we go from “preferred,” and then “next” and “possible,” we might have to include a column that says, “Recommended against,” and have our continuing IO agents there, or something like this.

Dr. Hammers, maybe a question to you, then. I think one of the highlights that Dr. Choueiri pointed out, unlike CONTACT-03 where CABO was at full dose in both arms, I guess I wonder what your take is on TiNivo-2, seeing the differences in the overall population with the median PFS in the combo arm, where TiNivo was dosed at 0.89, that median PFS being lower at the five month-ish mark compared to the overall, where TiNivo monotherapy dosed at the full dose, 1.34, came in at a median PFS there in the overall population of about, I think, 7.4 months. And so I wonder, when you’re thinking about choosing a TKI and choosing dosage, if this was practice-informing for you.

Dr. Hammers:
Yeah, no, absolutely. So both studies were incredibly important for the field. And kudos to Dr. Pal and Dr. Choueiri for leading these efforts. Really clarifying. To me, to be honest with you, I was never a big fan of continuing PD-1 after PD-1 progression. Immunologically, it never really made sense. If you want to think about immunotherapy, you have to think about different targets. Then it can make sense in selected patients.

But for the TKIs, clearly, there’s a dose response. So there was no surprise here. In fact, I would say most of us were dismayed by the demand of the FDA, quite frankly, to insist on the 0.89, because it makes it hard to compare. There will always be some question marks. But the truth is we just learned, again, as we all well know, there’s clearly a dose efficacy relationship for the VEGF-TKI. So we had to demonstrate it again. I wish it wouldn’t have happened. And as Dr. Choueiri pointed out, blood pressure is not necessarily one of the side effects we are too scared of. I think we have a lot of experience with it.

So besides that, I think we’ve got a really important data set, as Dr. Barata indicated, for now the second-line use. So for example, for myself, I have a lot of patients who worked with dual immune checkpoint inhibition. And when they progress, I want to have options. I don’t want to necessarily always go to cabozantinib or one of the big guns there. There could be clearly a space for more selective agents with a lower tumor burden.

And tivozanib is uniquely well-tolerated, I think, among the TKIs. I think the side effect profile is great, outside of hypertension. You really don’t have the more frequent high-grade diarrhea or the more frequent high-grade hand-foot syndrome that you observe with cabozantinib or lenvatinib. So I do think this was an extremely helpful study. It really informed the field, and it gives me now options. I do hope that insurance payers will look at the data set, and the NCCN and our European colleagues can give us some guidance. But I think kudos. Again, this was a great study, an important study. It enriches our armamentarium, and just prove some points that were important to convince ourselves of again, I guess.

Dr. Beckermann:
Yeah. I think another, just to add to that as well, one thing that both CONTACT-03 did and TiNivo-2 was to give us these contemporary data sets where now that the frontline treatment has changed, where it’s a PD-1 backbone, we can now understand what to expect out of a sequential TKI treatment in that refractory setting. Truly proving that patients are still benefiting from TKI following a PD-1 backbone combination therapy in that frontline setting. So I think that’s also been really informative, both from CONTACT-03 and TiNivo-2, just to see the median PFSes really improving even after that IO combination in the frontline.