Pedro Barata: Hey, there. Welcome. My name is Pedro Barata. I'm a GU oncologist out of University Hospitals, Case Western Reserve University in Cleveland, Ohio. I'm very happy to be joined here during ASCO 2025 by my colleague and friend, Michael Serzan. He's a GU oncologist out of Dana-Farber in Boston. Welcome.

Michael Serzan: Pleasure to be here with you, Pedro.

Pedro Barata: Absolutely. Thanks for joining us. And we're going to be talking a little bit about immunotherapy checkpoint inhibitors, CheckMate 214, and the final OS data presented here. So maybe as a starter, can you remind us just briefly the design of the study and how do we get this to this very long follow-up and get that final OS data out?

Michael Serzan: Yeah, absolutely. So CheckMate 214, as many know, is a large randomized phase III clinical trial that was launched many, many years ago investigating induction ipilimumab plus nivolumab versus sunitinib for patients with all-risk clear cell kidney cancer who were treatment-naive.

The study was initially powered to look at response rate, PFS, and OS as co-primary endpoints. And when it was first published back in 2018, the study did meet the primary endpoint showing an OS benefit in the intermediate- and poor-risk disease groups.

Pedro Barata: That's fantastic. And I appreciate you highlighting the design. Because at that time, remember, we were actually not sure what the ideal endpoint to assess activity of an IO combo, in this case CTLA-4, PD-1 inhibition. And there were these conversations whether PFS would be the right way to go.

And at that time, the investigators, smartly, I would argue, came up with these composite endpoints actually spending more alpha, in OS to the detriment of the PFS. So those are interesting discussions around trial design in the 214. So I would argue very smart investigators in the field thought wisely. And it's a positive study. So with this much longer follow-up over eight years, where are we? Can you summarize the overall survival, your mature data, which will be the final time we'll see that being reported for this trial?

Michael Serzan: Yeah, it's really remarkable to see. I mean, again, this is one of the largest phase III trials in frontline kidney cancer, certainly with the longest follow-up. And there's a couple of things that we've seen as the data has matured over time.

We've seen that patients in that intermediate- and poor-risk group have maintained that PFS and OS benefit over that time period. And we actually see plateaus on those PFS and OS curves somewhere in the range of 20% to 30%.

Also, we've followed those patients with the favorable risk, which was a smaller number of patients but they were included on that study. And when it was first published, the OS hazard ratio was 1.45, suggesting that patients with favorable risk may actually benefit more from sunitinib than ipi/nivo.

The really intriguing part is, as we followed that data over time, we've seen those curves flip. And we see that the hazard ratio for OS in the favorable-risk group is now 0.80, suggesting that patients with favorable risk do garner long-term benefit from induction ipi/nivo at the beginning.

Pedro Barata: Right. So this is a fantastic point. So you've seen the hazard ratio assessing the difference in survival for patients with good risk, which was about 20% or so of the patients enrolled in the 214, which was not part of the ITT analysis, as you pointed out.

It's interesting the hazard ratio has been dropping now well below 1. And actually the trigger, the adoption or the inclusion of ipi/nivo as a preferred regimen in the good-risk population in NCCN guidelines that we commonly use in clinical practice to drive decisions about what to do in practice. So it's a fantastic point.

And the other aspect is, it's really important to actually wait for enough events. So what happened with the good-risk group is these patients do, fortunately, well independent of how you treat them—TKI monotherapy or, in this case, dual IO. And you've really got to wait longer than you would for more unfavorable-risk patients to really appreciate the mature difference in regards to survival. So that's a fantastic point.

So ipi/nivo is really well established as one of the preferred regimens of choice. Their use is actually common in practice, academia, community settings. How can we do better? Dual inhibition better than monotherapy PD-1 inhibition? There are fancier, novel ways to explore these checkpoint inhibitions. Can you comment a little bit on that?

Michael Serzan: Yeah. So it's really the next frontier as far as where do we go next in frontline kidney cancer. There's a number of different protocols that are being developed, some looking at triplet therapies—so looking at anti-PD-1, CTLA-4, plus LAG-3 inhibitors. There are some that are combining VEGF TKIs like we saw in the COSMIC-313 study.

There's even some earlier-phase clinical trials looking at zanzalintinib, which is a novel VEGF TKI therapy with nivolumab and relatlimab, so that LAG-3 inhibitor. So triplet therapies, I think, are certainly being developed to try to improve outcomes—not only those short-term response-rate PFS outcomes, but also some of the longer-term outcomes. What are the kind of landmark PFS and OS looking like, and how does that compare with this very well-established standard of care? So that's triplet therapies.

We're also seeing a lot of combination and sequential therapies. So there is the PDIGREE study, which was a large cooperative group study that did meet its final accrual and is at ASCO this year. We're seeing the step 1 results there. And then also looking at new checkpoint inhibitors. I thought that botensilimab is an Fc-enhanced CTLA-4 inhibitor. So combining that with a PD-1 inhibitor is thought to maybe decrease regulatory T cells and hopefully enrich the immune response in the frontline setting.

And so there are a lot of different ways that we're trying to build on this dataset. But in my mind, this is really the standard of care and the high bar that we need to meet for patients with first-line metastatic clear cell kidney cancer.

Pedro Barata: Right. No, that's a beautiful summary. It's getting busier in a good way. We learned from COSMIC-313 not always more is the answer, so getting smarter about what you’re bringing on top of the backbone IO and the timing of that addition, of that treatment—when intensification, if you will, appears to be critical.

And probably, the answer is not one size fits all and it might depend on the partners you're bringing on board and the safety or the risk that entails. And I know you and many others are involved in actively investigating these questions. You have investigator-initiated studies at Farber and great work you guys do there and many other groups. So it's an exciting time for the frontline.

And perhaps, as you said, the 20%-30% we can actually keep getting that number better and get more plateaus or tails of the curve, which means durable, long-lasting remissions—maybe some of them might be cures as the tumor never comes back. So that's what we want to see. Fantastic summary. I appreciate you taking the time during busy ASCO 2025 to be here with us. I appreciate this wonderful overview. And good luck with your investigations as well.

Michael Serzan: Absolutely. Thank you.