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Pedro Barata: Hello. I'm Pedro Barata. I'm a GU oncologist and clinical trialist at University Hospital, Seidman Cancer Center at Case Western Reserve University in Cleveland, Ohio. Today I'm very, very happy to be joined by Dr. Naomi Haas, a key opinion leader in GU field, medical oncologist, Professor of Medicine at University of Pennsylvania, and actually leader of many studies in the kidney cancer arena, including the adjuvant setting.

We're here around ASCO 2025, and important data has been presented around key pivotal trial with adjuvant pembrolizumab, KEYNOTE-564 for patients in the context of adjuvant setting with clear cell renal cell carcinoma. So. Dr. Haas, thank you for joining us today and taking the time.

Naomi Balzer-Haas: Sure. My pleasure.

Pedro Barata: So, wonderful job presenting updated data from that important trial that was one of the first to actually show-- to demonstrate not only disease free survival prolongation, but also an overall survival benefit with the addition of one year of pembrolizumab compared to placebo. Can you please remind the audience quickly the design of that study?

Naomi Balzer-Haas: Sure. So KEYNOTE-564 was a nearly 1,000-patient study where patients were randomized 1 to 1 to receive one year of adjuvant pembrolizumab or one year of placebo. The eligibility criteria included patients with pT2 high grade disease, pT3, pT4, disease, node-positive disease, and a small number of patients who had had a metastasectomy of their kidney cancer as long as it was within a year of resection of their primary. And for the metastasectomy population, patients were stratified by US versus non-US site, and also by ECOG performance status.

Pedro Barata: So your role has been really important in establishing new standard of care in the adjuvant setting. You help developing data with target therapies, particularly anti-VEGF. And now with immunotherapy of many immunotherapy studies. By the way, you play a pivotal role in the co-operative group, ECOG-ACRIN. And that's actually a big effort from the cooperative groups around adjuvant studies, which has been a setting where the corporate groups have been successfully enrolling. I'm thinking of PROSPER, et cetera.

But to that end, it's interesting on this presentation that you gave, you gave us reassuring data, to me at least, regarding the survival signal. But also, you really dedicate a time to look at patients who end up having recurrent disease. And actually, what happened to those patients as far as local therapy as well as medical therapies-- systemic therapies they receive. I would love to hear your thoughts beyond the presentation, if you will. What are your insights as you walk us through that data?

Naomi Balzer-Haas: So I think one thing that's important is this presentation was of patients-- all of the patients are now five years beyond treatment. And so it was really a landmark analysis of nearly six years of data in this population. And what we found was that the safety signal really didn't change at all compared to the last three years. The major side effects that patients experience-- the most common was, believe it or not, hypertension. And then the second most common was transaminitis, and the third was diarrhea.

But what was interesting, and I think because of some of the comments that we had gotten in previous presentations, this one highlighted two things. One was that the overall survival remained very stable. The curves remain separated. There's no dilution effect as the numbers of patients are followed.

And in the patients particularly that had recurred, there were 171 patients, I think, who had received adjuvant pembrolizumab. And I think it was 227 or 217 patients who had previously received placebo. So we tried to be as transparent and look at that population. What we found was about 40% of patients in either arm of the study got systemic therapy at the time of progression.
There were another group of patients that got combination of systemic and local therapy, local therapy being either surgery or radiation. And then there was another group of patients that just got local therapy. About the proportion of patients that got a VEGF inhibitor, which was by and far the most common salvage regimen, was-- the percentage was essentially identical in both groups.

And more patients who had relapsed after placebo received a PD-1 inhibitor. And if you look at the number of patients who-- the percentage of patients where there was additional data that was not reported-- so some of those patients were simply observed, and other patients the data was missing. But if you look at the proportion in both arms of the study, it's essentially very similar to one another.

Pedro Barata: No, it's a very thoughtful breakdown. And that data is really needed. I mean, that was the feedback that's been having. Actually, it's quite interesting. We put together an analysis looking at access to immunotherapy when we have randomized studies where patients are allocated to a non-IO approach. And actually, this seems-- this amount of patients receiving IO is aligned with all the other IO-based studies in randomized, confirmatory phase III trials, even beyond kidney cancer world.

And to me, the way you describe it to me reminds us of how different the biology of these patients who end up recurring. Some will actually safely be observed. Others are getting systemic therapy, whether it's a TKI monotherapy. Perhaps some will be getting a combo. There was a few IO's being offered to some patients on the pembro arm as well, if I recall correctly from the data.

Naomi Balzer-Haas: Yeah, about 20%.

Pedro Barata: Exactly. It was lower than the placebo, as expected. And then you have the third group that got a combination of local therapy and systemic therapy. So to me, it reminds us of how patients are coming, unfortunately, with recurrent disease. But they are presenting in a different way.

I guess one question-- and I think there's always this hot topic-- is, so we're trying to cure patients. We are not able to do that in every single patient, and end up getting adjuvant pembrolizumab. And then the question is always what to do next? versus holding tight. And upon progression, offer an IO-based combo. I'm wondering what progress can we make since pembro is established based on disease free survival and overall survival, which is the gold standard that we want to see-- how can we do better moving forward to get those curves of recurrence getting even better?

Naomi Balzer-Haas: So I think it's really important to understand what is it in the biology of the patients who are never going to recur? And also to look at that group of patients who had the metastasectomy. Are we under-treating those patients? Are we over-treating the patients? And how do we figure out who's never going to relapse?

I think that right now, the best devices that we have are nomograms. And people are working very hard on biomarkers. There's a lot of excitement about kidney injury-1 molecule and about some of the T-cell signatures. But all of these need to be validated both retrospectively and prospectively. These are not things that-- and the assays vary. There are several different KIM-1 assays.

And so really, what we don't want to do is have people deciding to do one of those assays on their own and then deciding whether a patient should get adjuvant therapy or not. And it really is a shared decision between the provider and the patient. There are going to be patients that don't want to have adjuvant therapy no matter what. They're going to be patients that are not good candidates for adjuvant therapy based on underlying health conditions. And then there are going to be patients that can't sleep at night because they absolutely want to do something.

And so, I think that what I do with my own patients is to really go over all of the adjuvant and perioperative immune trial results, and what were the results. And there were three that didn't show benefit and one that did. What are some of the differences? And really try to explain it to patients, and then to see where they are as far as what they want to do. But I think being open and educating patients is the most important thing.

Pedro Barata: I fully agree with you. And you remind us all that there are free calculators, nomograms that are put together derived from different data sets, including trial data sets, as you were part of. ASSURE is just an example of that. I actually use it in clinical practice.

And one thing that I usually bring up with patients, to your point, is number one, at least half of the patients might be cured, and we just don't know who they are. And the second point is, when you run the different nomograms, you can end up with some variance of the probability of recurrence. And it's interesting. You're using ASSURE versus CLA versus other scores. You can find some variance.

So actually, I use more than one when I'm running a number to explain the patient that he's not a number. For him, it either recurs or he doesn't. It's either 0% or 100%. But if you think of a thousand people, here are what the numbers would look like. But there can be variations in that number. And in my experience, when I show that, to your point to as well, for some people, a risk recurrence of 25% at five years-- they are willing to take the risk and not want to embark on adjuvant immunotherapy. Or for someone else, that 25% does not let them sleep well at night.

So the same data in a different patient means different things. And so, I couldn't agree with you more. I'm glad you brought it up. Giving the best information along with, here's what the different IO's perform in this space is probably the best way to have this really well educated, shared decision process.

Naomi Balzer-Haas: Yeah. And I think the thing that's scary or gives people pause about immune checkpoint inhibitor therapy is, some of the side effects can be permanent. And we did show an update of the duration of side effects. And I would say that the permanent side effect rate is pretty much equivalent to what you see in advanced disease. But the majority of the most common severe side effects were things that were reversible, such as hypertension and transaminitis and diarrhea.

Pedro Barata: Which is--

Naomi Balzer-Haas: We can fix that.

Pedro Barata: --better to fix it. Exactly. I guess I just want to highlight again your work in this space. It's really pivotal and relevant and important. I'm curious to see what happens with another cooperative group study, STRIKE. We're adding a shorter duration of the TKI, in this case, tivozanib, on top of pembrolizumab. Randomization 1 to 1 to either that combo or pembro alone. And it's an Alliance study, but I know he has an active participation. It's SWOG that I'm part of but also ECOG-ACRIN. And so, thank you for your leadership role in those kind of endeavors.

Naomi Balzer-Haas: And ECOG is planning to do-- actually look at the role of adjuvant pembrolizumab in non-clear cell histology as well. So there's a lot to learn with kidney cancer in general, and with early disease and risk and the role of immune checkpoint inhibitors.

Pedro Barata: Definitely. For sure. And we're definitely going to have the opportunity to sit down again and talk about those advances in the near future. Thank you so much for taking the time and joining us today.

Naomi Balzer-Haas: My pleasure.