A roundtable discussion, moderated by Brian Rini, MD, addressed considerations for clear versus nonclear cell kidney cancer, as well as recent data from ESMO 2023. Dr. Rini was joined by Tian Zhang, MD; David McDermott, MD; and Hans Hammers, MD.
In the next segment of the roundtable series, the panel discussed the results of the LITESPARK-005 trial, which assessed belzutifan versus everolimus in the refractory RCC setting, as well as the role of biomarkers in kidney cancer.
Dr. Rini: Let’s turn to the more refractory space. ESMO was just recently probably the biggest set of data was around belzutifan. There was some monotherapy data from the phase 3 and then also some combination data, so maybe I’ll ask you each to comment. Tian, talk about light LITESPARK-005, belzutifan versus everolimus in a refractory setting, mostly third- and fourth-line largely, but a typical refractory kidney cancer population. What was your initial take on the data?
Dr. Zhang: Positive trial. This was a registration trial for belzutifan monotherapy in the refractory setting. It improved progression-free survival (PFS) compared with everolimus. Do I wish it was compared against a different control? Probably, but I think that has certainly activity in refractory settings. To me, we have to be somewhat selective about the patient population. I would want to see a patient who is a little bit more indolently progressing and seems more angiogenic driven to select them for belzutifan monotherapy.
Dr. Rini: In all the trials, belzutifan, the responses have been a little bit delayed, more delayed than a TKI [tyrosine kinase inhibitor]. I don’t know that that trial reported median time to response and, I have a 3.6 months number in my head from a different trial of belzutifan, something in that range, which is probably a little more than TKIs. When you say angiogenic driven, how do you know that?
Dr. Zhang: Hard to tell, right? I don’t know that we know. Maybe you’ll tell us. The gold standard would be to send transcriptome data, but we don’t set that for everybody. But it’s the clinical gestalt of slowly progressing; maybe they’ve had responses to prior IO [immunotherapy]/TKIs or TKI monotherapies in the past and they’re now slowly progressing. But I do think of all the data that was at LITESPARK-005, it is a very well tolerated agent, and patients do have good quality of life on it. I think it’s an easy treatment to give.
Dr. Rini: Especially for that more indolent patient that hopefully could be on it for a while. If we’re not curing patients, then tolerability is important. David, what did you think of the LITESPARK data?
Dr. McDermott: Once again, I agree with everything Tian said.
Dr. Rini: You need to disagree more.
Dr. McDermott: She’s usually right. Building on what she said, I think it’s proof of principle that HIF-2 is an important target and that was debated 10 years ago whether that was a target. But when you think about the number of patients who carry a VHL mutation and the response rates with belzutifan, there’s a gap between those 2, which I think is somewhat exciting. Tian mentioned one of those opportunities, which is with selecting patients better, you might be able to improve outcomes. That’s what the early studies showed.
A PFS of 14 months in the trials that we did in phase 1, those are better selected patients by definition. We need to find out how to do that. I think we can based on tumor-directed markers, because this is the first exciting tumor-directed therapy. We need to come up with the EGF marker or the BRAF marker for this. There is potential; there’s at least potential there. We have to insist on that research because half the patients didn’t get much benefit at all from the drug. The other thing I think we could do is potentially once we have a marker is bring the drug up earlier. Because as Tian said, it’s a pretty nontoxic drug. Patients like being on it when they switch from TKI. It’s like…
Dr. Rini: Water.
Dr. McDermott: Well yes, hypoxic water. But yes. That’s exciting. But also trying to fill that gap between the 80% of patients who carry a mutation and 20% response rate; what can we add to belzutifan or other HIF inhibitors to increase the response rate? Those targets may exist and we should pursue them.
Dr. Rini: Before, and Hans I’ll get to you one second, so you mentioned combination. There was also data at ESMO, belzutifan/cabozantinib in a refractory setting, 31% response rate and in a frontline setting, a 70% response rate. Select patients, small numbers, all the caveats. You were part of at least 1 of those cohorts. What did you think? Are they surprising, exciting? 30% in a refractory setting isn’t that great, right? Belzutifan alone is 23%; cabozantinib alone is probably in the 20%, so it doesn’t even appear additive. What do you think?
Dr. McDermott: I think if you do that combination in a VEGF-naïve population, you’re going to see exciting response results. But you need to do the randomized trial to figure out what’s…
Dr. Rini: We’ve been burned before by single-arm response rates that are nice and shiny. We’ve all been down that road.
Dr. McDermott: Right, so do the trial is what I would say. Is it worth doing? Absolutely. If that trial was positive, 1 of the LITESPARK trials, I forget the number, it would be an incremental improvement for patients, which is good. But what I’m talking about is bringing HIF inhibition upfront as a single agent, not as a combination. You have a drug that’s active, relatively clean. I would prefer not to dirty it up with something that causes lots of side effects, because then it loses, to Tian’s point, one of its better components, which is it’s clean.
Dr. Rini: You think there could be a role for belzutifan or other HIF inhibition monotherapy in select frontline kidney cancer patients? Not to put words in your mouth.
Dr. McDermott: Not frontline, VEGF-naïve.
Dr. Rini: So in your ipilimumab/nivolumab failures.
Dr. McDermott: Correct or PD-1 adjuvant failures. Yes. In the right genetic background, building on Tian’s point. VHL mutated, PBRM mutated.
Dr. Rini: Hans, what do you think? The LITESPARK data as it stands and then the future…
Dr. Hammers: I’m glad it’s here, quite frankly. When it works for patients, it’s unique. It’s a real game-changer, especially for patients who are washed out from TKIs. The quality of life for a targeted therapy is unmatched. Yes, some patients with some structural lung disease, for example, may have hypoxia risk, anemia. Again, all of these are very easy to manage coming to. Take a step back. I’m sometimes a little bit of a biomarker skeptic so to say, but finding a biomarker for belzutifan will have one of the biggest impacts I think for patients and their quality of life. I think it’s critical to do that because the drug either works or it doesn’t work.
PD [progressive disease] rate is very high. There’s very little overlap. Who are the patients? I think patients who are probably very close to the VHL pathway. For example, I had a VHL patient, numerous kidney lesions. She was on belzutifan; there was 1 breakout lesion and so we had that resected. The lesions around it that were shrinking on belzutifan, they were all beautifully differentiated low-grade tumors. The one that actually continued growing was a high-grade, fully differentiated. I think it’s going to be somewhere in that realm of the better differentiated closer to the VHL biology leaning tumors, and the question is how do we identify those?
There were, by the way, HIF-2 positive tumors. It wasn’t like they weren’t having HIF-2 inhibitors. It’s a tantalizing compound, I think. It’s not curative but palliative. But coming back to David’s point, I have a patient who had the chance to go on a belzutifan trial right after failure of nivolumab/ipilimumab. He’s not 3 years on it, in fact did a CR [complete response], and he’s happy collecting honey from his bees without any side effects.
Dr. McDermott: I was just going to say building on that, 2 things. One, the HIF-2 story is real, so Bill Galen, MD, doesn’t need to give back his Nobel prize, which is great. But people didn’t think this target could be drugged. That’s a really exciting story for drug development, not just in kidney cancer but in other tumors. I don’t think people realize, and Lisa Pickering, PhD, gave an excellent discussion driving this home; this is not a TKI, this is targeting a transcription factor. People said we couldn’t do it. The UT Southwestern team figured out how to drug the pocket and you have activity.
Dr. Rini: Do you think belzutifan can replace TKIs? Will we be sitting here in 10 years, if we’re not retired, and we’re going to say, “How silly; we gave people TKIs. Those things were toxic and not really well targeted.” Hans?
Dr. Hammers: I actually don’t think so. Coming back to what works, what doesn’t work, and maybe leaning toward that these VEGF-producing tumors, I actually don’t think we are going to find that. For example, I don’t see typically dramatic decreases in enhancement on the scan. It’s not really like devascularizing tumors clinically. I had some patients who did well on TKI before, they got the opportunity to go on belzutifan, it did nothing, and they went back on a TKI, beautiful responding. I don’t think it’s going to be that.
Dr. Rini: They’re different.
Dr. Hammers: They’re different. I think we really need to invest in how to identify those patients. I think that will be very impactful work that needs to be funded either by industry or government.
Dr. McDermott: The last thing I would say is the endpoints are cool too. The endpoints on that trial are long-term endpoints. We’re going to have discussions about duration of response, landmark PFS, hopefully long-term survival. That’s also good for our field, is our patients living longer. We have to keep measuring their outcomes, not just efficacy but quality of life and toxicity because the improvements in quality of life were one of the best parts of that LITESPARK-005 study, I think.
Dr. Zhang: What a great story from bench to bedside as you’ve highlighted. Our scientists at UT Southwestern from 10 years ago now to actually affecting patient care and getting into our patients with kidney cancer; it’s a tremendous just bench to bedside.
Dr. Rini: The story we talk about all the time but so rarely happens.
Dr. McDermott: Because so many people said it couldn’t be done, pharma didn’t want to invest until Peloton, which is also a Dallas operation, showed it could do it. Hopefully that’ll have impacts for other transcription factors.
Dr. Rini: There are other companies obviously that make HIF inhibitors and they make different pharmacodynamics and different this and different that. It’s like the first TKI; it’s the sorafenib of TKIs.
Dr. McDermott: I don’t think they want to go with that.
Dr. Rini: Maybe last thoughts on belzutifan, there wasn’t a survival signal. The medians were different, but there was no survival. It was a pretty mature, I think there was 50%, 60% of events. Does that matter? Does it just not matter because PFS and well tolerated? Does it not matter because we all think it’s going to be used earlier anyway? Do you care about the survival in LITESPARK-005?
Dr. Zhang: I think it’s a step. Obviously, we care if agents are able to help our patients live longer. But having something to delay progression, and to your point earlier, if it’s a palliative therapy on later lines and well tolerated, then that’s a win.
Dr. Rini: David, were you…?
Dr. McDermott: I think it’s the reason we have to insist on selection as a group, as a community. We have to say you got to do better than this. We get OS [overall survival]. I think it might impact not just approvals, potentially reimbursement, particularly outside of the United States. If you can’t get OS with belzutifan in the later line, what does that say for your second line, your first line and your adjuvant approaches?
Dr. Rini: You think it’d be more likely in a refractory setting and less likely as you move earlier?
Dr. McDermott: You could argue with that both ways, but I think OS is harder to get earlier, because there’s so much other salvage that can be applied at that point. For example, if you look at what’s the LITESPARK-012 study where belzutifan is being looked at I think in the triplet combination, it could add to PFS and not OS let’s say. Then what? That might have significant impact on how those triplets get used.
Dr. Rini: Yeah, agreed.
Dr. Hammers: I think LITESPARK-005, it would’ve been difficult, to be honest with you, to show an OS benefit for a patient population that is so selectively benefiting from it. There’s much over-bleed. You don’t move the majority of the population. It’s not like immunotherapy that gives a little bit of benefit to everyone.
Dr. McDermott: Everyone?
Dr. Hammers: Well, the median was more than CheckMate-025. The response rate of 20-something percent. Long-term you may see a little differentiation of the curves; you won’t see it now. Knowing that the responses can be quite durable, I wouldn’t be surprised eventually you will see something on these curves. It may not be the measure that we normally apply to OS curves, but I do think there’s undoubtedly a patient population that will live longer because they’re doing well on belzutifan.
Dr. Rini: Yeah, sure.