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Pedro Barata: Hi, everyone. I'm Pedro Barata, a GU oncologist from Case Western Reserve University, Cleveland, Ohio. I'm super thrilled to coming out of ASCO GU and get the chance to sit down with the one and only friend, colleague, Dr. Katy Beckermann, currently the medical director of the GU clinical research for medical oncologist out of Tennessee Oncology.Wonderful work, Katie. And really want to take the chance to chat with you a little bit about the wonderful presentation and, quite frankly, very important data—informative data—regarding KEYMAKER-U03. So you did a fantastic job. I love the discussion also around the topic.

And so hopefully, we can summarize the highlights here for our audience today. So maybe I'll suggest—so welcome, obviously. And maybe I'll suggest first, do you want to walk us through the take-home points from the trial?

Kathryn Beckermann: Yeah, that's great. Thank you so much for this invitation. It truly is my pleasure to be here. Of course, love sitting down and chatting with you, Pedro.

And then, also, just a pleasure to be part of UroToday. And so, yeah, let me just take a moment to say thanks to my colleagues. I was able to present this at GU ASCO and really, what a wonderful group of colleagues you can see here on the screen on behalf of Dr. Albiges, Dr. Suarez, and so many others. This was a global study that was conducted and supported by Merck.

And so the rationale and the reasoning behind the study—and I'll describe the study design because I really appreciate the clinical trial design for this. So we know, in the first-line setting, that we've made great strides for patients who have untreated clear-cell kidney cancer, but, unfortunately, it's still the case that most patients will ultimately go on to progress. And our current standard of care in the refractory setting is, of course, sequencing of targeted agents. And that includes our well-known tyrosine kinase inhibitors, as well as the newer mechanism of action targeting HIF-2 alpha.

And so the rationale behind this study was to ask the question, would intensifying therapy by designing novel combinations help patients in a refractory setting? And the reason that I wanted to highlight the trial design was this was a—it was, again, a large effort. It's a phase I/II. It was open label, an umbrella platform.

And so maybe I'll show you the clinical trial schema here. So there, on the right, you can see multiple study arms. The statistical analysis was not a comparison amongst the arms. And so just to point that out, but really, rather, trying to assess in an efficient and a quick way if there is any efficacy for patients in the refractory setting for these novel combinations.

So if we go to the eligibility criteria, this trial required patients to have some clear-cell component. And then I'll also highlight that they had to have both a PD-1 agent and progressed on a TKI. And that could've either been in combination or sequentially.

Patients were then allocated based on their IMDC criteria and whether or not they'd had a prior CTLA-4 and progressed on that. So the arms that I presented and are highlighted here in light colors on the right are arms B4, B5, and then a reference arm. So again, it was a phase I/II. There was a safety lead-in of about 10 patients.

And then you can see about 60 patients were enrolled in the arms that I presented. Median follow-up was approximately 17 months for this study at the time of data cutoff. And then also, just to mention that, while it's grayed out here in this box, arms B1, B2, and B3 were the ability to test some novel immunotherapy combinations.

And so here, this data was actually also simultaneously presented at GU ASCO by Dr. Suarez, looking there at novel combinations with pembro (a PD-1) plus LAG-3, a PD-1 plus CTLA-4, and here a PD-1 plus an ILT-4. So looking at the targeted combination therapy arms, which are the ones that I presented, I presented data that looked at patients who had been treated with pembrolizumab plus belzutifan; with lenvatinib plus belzutifan, there in the dark blue; and then a reference arm of pembrolizumab plus lenvatinib.

And just to call out some of the patient characteristics so that we understand the type of patients that were entered into this trial, about 2/3 of patients had IMDC intermediate risk group criteria. Most factors were balanced across these arms. Maybe I'll just highlight here that patients in the lenvatinib plus belzutifan arm had a slightly higher percentage of patients with poor risk disease there at 17% compared to about 11% in the other arms.

And then that arm of lenvatinib plus pembrolizumab, there was a slightly higher percentage of patients who had sarcomatoid features there at 18% compared to about 6% in the investigational arms. And then, as we try to put this data into context with maybe some of the other trials that we've seen in the refractory setting, what I want to emphasize here is that this patient population was really quite a refractory patient population. So about a third of patients in each of these arms had had two prior lines of therapy before coming into this trial, and almost 50% of patients actually had three or more prior lines of therapy before getting these combination treatments.

So with that said, the primary endpoint was objective response rate. And what you'll see was that in the pembrolizumab plus belzutifan arm, there was a 20% objective response rate. In the lenvatinib plus belzutifan arm, there was a 47% objective response rate. And then lastly, in that pembrolizumab plus lenvatinib arm, about a 40% objective response rate.

And the other thing that I've highlighted here that I think—I'm specifically highlighting because of the tail of the curve that we've seen with belzutifan in the refractory setting—I'm showing the duration of response, which was one of the secondary endpoints of this study. And so again, these are small numbers. For patients who did achieve a response, the duration of response in the pembro plus belzutifan was not reached, actually.

And then, in the lenvatinib plus belzutifan arm, the duration of response was approximately 22 months, while in the pembrolizumab plus lenvatinib, there it was about eight months. And another secondary endpoint that was presented was the progression-free survival. So progression-free survival, here, again, median follow-up of about 17 months across the study. But you can see there the light blue pembrolizumab plus belzutifan investigational arm—median PFS was 5.4 months, lenvatinib plus belzutifan was about 12 months, and pembro plus lenvatinib was about nine months.

And then we always, of course, want to be mindful. We've done a lot of intensification. We've gone from single-agent monotherapy TKI to dual agents in the first-line setting and even been testing triplets. And so now, to ask of our patients to be undergoing intensified therapy, of course, the goal of that is to improve efficacy, but we also want to be mindful about the AE profile to ensure that we're not causing increased toxicity or synergistic toxicity.

And so just to maybe highlight here across these arms, 100% of patients experienced any-grade AE across all arms. If we look a little bit closer at which were called treatment-related AEs, and if we look at this significant grade 3 through 5, you'll see pembro plus belzu had about 42% grade 3 through 5; lenva plus belzu, 60%; and the pembro plus lenva, about 50%. Similar discontinuation rates across these different arms and treatment types at about 10%.

So when we delve down into those side effect profiles, I think what we really saw was that the side effects were similar to what we would expect from a monotherapy with the known TKI side effects and the known HIF inhibitor on-target side effect, for example, of anemia and things like this. But we did not notice any new signals for toxicity or increased synergistic side effects. So that was good to see.

And so to sum up this study, again, a study designed to test for patients with refractory clear-cell kidney cancer novel combination therapies: in the investigational arm that tested lenvatinib plus belzutifan, there was an ORR of 47% and a PFS of about 12 months. In the investigational arm that tested pembrolizumab plus belzutifan in this refractory patient population, we saw an ORR and a PFS that was quite similar to the monotherapy arm from belzutifan alone that we could see in the phase III LITESPARK-005 study. So there maybe the pembrolizumab and that combination, maybe not adding a lot of extra benefit over the belzutifan monotherapy arm.

And then I think the lenvatinib plus pembrolizumab, again, was called a reference arm because we certainly have seen some phase II data for this combination in the refractory setting. And so, what I think it showed us was that there is still antitumor activity—again, an ORR of 40% and a PFS of nine months in a very refractory patient population. Hard to know because we only had the combination here. But I think a lot thought that maybe the TKI is driving some of this benefit, given the other data that we have from larger randomized phase III, where the I/O component has not shown to be helpful to continue, for example, from CONTACT-03.

Again, I've mentioned that the adverse events were pretty manageable, and the safety profiles were consistent with the individual profiles of each agent. And then lastly, just to highlight—because these were, I mean, certainly sizable 60-patient arms—but I think we're all very excited to see what LITESPARK-011 will show because this trial, LITESPARK-011, was already ongoing at the time that this trial was started. And so LITESPARK-011 will test the combination of lenvatinib and belzutifan in a second-line setting, so slightly earlier than those patients seen on this trial.

And it's a randomized phase III comparing to cabozantinib. So that trial, the primary endpoints are—I think it's a dual primary endpoint of both PFS and OS. So the trial has completed enrollment, but I'm hoping to see that that will report out soon.

Pedro Barata: Yeah, this is wonderful, Katy. And congrats, again, on this wonderful work. And maybe I'll tease you a little bit because, when we saw the data—first of all, big effort, as you said, proof of concept, 60, 70 patients in each cohort gives you a sense what the signal is. And that's wonderful because you can actually tackle many different questions that we have.

One of them is the one around Salvage IO. When we saw the data, I think one of the points mentioned during the discussion and from others was it appears that the efficacy has been driven mainly by the backbone pembro. On the bel pembro and the len pembro, you see activity of, really, what the HIF-2 alpha bel is with around 20% responses and a PFS of 5.4 months, very similar to what we saw on LITESPARK-005 compared to everolimus for belzutifan.

And then on the lenv pem, I mean, the 39% or 40% is actually quite interesting because, with 20 milligrams of lenvatinib, it's not really—I mean, that's really what I would expect if I were to put my money in. And to me, of the three cohorts, I really was looking forward to see the data from the lenv bel. And as a way to tease you, when we see PFS of 12.5 months, I think, responses in the 40-plus, 46% or so, and the duration almost two years.

Is that fair to say that, when we think of a cabo performing as we would expect, in the 10, maybe 11 months, it might not be enough to find a difference on the LITESPARK-011 of the combo versus cabo in the second line, assuming a lot of those patients probably were exposed to an IO TKI in the front line? Therefore, this would be kind of a second TKI. What are your thoughts on that?

Kathryn Beckermann: Yeah, so I think it will remain to be seen. And I think the big difference here, to your point, I've thought about that as well, Pedro. When we saw in CONTACT-03, cabo has that ORR of about 40% and a PFS there of 10 months. But I think the difference here, and again, we'll just have to wait for LITESPARK-011, but this patient population was quite refractory. So really the more—although, we're not supposed to do cross-trial comparisons and all that—but if we were to look at a similar patient population, I would be looking at TIVO-3 and saying, in a TIVO-3 setting or a LITESPARK-005 setting, because these are three and more prior lines of therapy, we know with subsequent TKIs—as you were just kind of alluding to—we get increased resistance mechanisms and our typical response rates. They're ranging, of course, those are from pure VEGF TKIs, but we see a more common ORR of about 20%.
So I think if we use that with this patient population, then this is a pretty big difference. And how it will perform in earlier lines of treatment? I'm not sure. And I think what I'm hopeful that it might do is what we all are concerned about—in the setting of using belzutifan as monotherapy, I think we love that it has a different side effect profile. But what I worry about is the primary progressive disease rate.

And so what I think this combination might offer patients is if we don't see a lot of increased toxicity, but we can de-risk that primary progressive disease as best response. So with that TKI component, can we get the higher ORR, initially have less patients progressing, and then ultimately have the longer tail of the curve with belzu in an earlier refractory setting, if that makes sense.

Pedro Barata: Yeah, no, it certainly does. And speaking of that, when you look at your safety signal that you just presented, it appears that the dose reductions are in the 50%, 60% range, including on the bel lenv, assuming lenv of 20 milligrams. And most of those reductions were on lenvatinib, I think. And that's using a higher dose of lenvatinib, which is also, I think, comparable to what's happening in real world.

So the other thing you mentioned—I want to make sure it doesn't go unnoticed—is the second part of this story that you presented with Cristina Suarez on that poster, where you look at the different cohorts. I mean, this is a great exercise to go after other potential combinations that make sense. I mean, there's a mab, the CTLA-4, but combined with pembro, and then the LAG-3, mab, and then the MK-4830, which is ILT-4, as you said.

When I was looking at the data—I don't know what you thought—but when I looked, it appeared the responses were the highest if you take the left pembro side, they have it for comparison there. But it appears that the combination of the CTLA-4 in these refractory group of patients were the highest at 30% for pembro/CTLA-4, although the PFS was shy of six months. But it's quite interesting because those patients were heavily treated, even though, on that cohort, I don't think they were previously exposed to CTLA-4. So it's almost like a salvage CTLA-4 with a different CTLA-4 inhibitor, looking at 30%, which perhaps is the highest we've seen when we think of the data with ipi, nivo, FRACTION, and other data sets in the refractory setting. Is that your take as well? Any other insights about where you think that might go moving forward?

Kathryn Beckermann: Yeah, I think it, again, just shows us that continuation of PD-1 is not helpful. The idea that we would try some of these novel mechanisms—which is what I loved about this trial design—is that, with new mechanisms of action, we don't know what might rescue that resistance to IO in the frontline setting. But I agree, we saw, in the PD-1 and LAG-3, some clinical benefit, but no objective response—no ORR was seen—similar in that ILT-4, which is supposed to target macrophages and some myeloid suppressive-type components. So that didn't seem to rescue the PD-1 resistance.

And I do think what's unique there is the CTLA-4. So in that arm, they specifically did not allow patients who had had prior CTLA-4 exposure. So I think that is the big thing to highlight. And, yeah, when we've seen other data—cooperative group studies, OMNIVORE, FRACTION—these types of studies where it's smaller numbers, the range has been quite large. So it's somewhere between ORR of 4% up to 20%, I think, in some of the historic studies that we've seen. So here, an ORR of 30%, I wished it had been a little bit more durable. But again, really refractory patient population, so I think we just don't know yet how to pick those patients who need CTLA-4 who respond best to IO.

Pedro Barata: So maybe a way to sum this up, Katy—so based on your data, to some extent, a lot of it is aligned with what we've learned in the last year with CONTACT-03 and [INAUDIBLE]. Maybe the story—I'm not going to say it's over, but it's a lot more skepticism to come with a salvage PD-1, PD-L1. Maybe something around a CTLA-4 for patients not being exposed to it that perhaps will figure out a way to make them last. And there are certainly other combinations that we might get updates on, such as the LITESPARK-011, as you pointed out, which to me is one of the trials to keep an eye on in the near, near future.

Maybe later this year or early next year, we'll find out about what's going to happen in the second-line space. And then, of course, looking at novel MOAs and continuing to explore different immune therapies that can maybe salvage some of these tumors, but we're not quite there yet. Is that a fair summary or did I miss any specific point you'd like to highlight?

Kathryn Beckermann: That was perfect, Pedro. This has been such a joy to discuss the data and always to bring that summary to home. I think that's perfect.

Pedro Barata: Well, wonderful. You did an amazing job. So congrats again. You generated a lot of buzz, a lot of discussion. We're looking forward to the manuscript. You're working on that, so wonderful. And yeah, it's always a pleasure to have you, and I'll see you soon.

Kathryn Beckermann: Thanks.