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Pedro Barata: Hello and welcome. I'm Pedro Barata. I'm a GU medical oncologist clinical trialist out of University Hospitals, Case Western Reserve University in Cleveland, Ohio. I'm super happy to be joined by Dr. Vivek Narayan, GU medical oncologist leading the clinical research program out of University of Pennsylvania. Vivek, thank you for joining us.

Vivek Narayan: Glad to be here. Thanks, Pedro.

Pedro Barata: And I'm really happy to talk to you today about your wonderful work presented at ASCO 2025. Very, very important work for a lot of reasons around the original LITESPARK data around belzutifan and renal cell carcinoma. So some of the audience might be a little bit less familiar about the story how these came up even before it was around during the process of drug development. I remember it was a Peloton codename and became what we know today as being belzutifan was initially developed for patients with VHL disease.

Vivek Narayan: That's right

Pedro Barata: So not sporadic renal cell carcinoma, but VHL-associated RCC. So instead of me talking, I'm going to ask you, can you please summarize a little bit about where this is coming from? This MOA for the treatment of RCC.

Vivek Narayan: Yeah, of course. The story is actually quite interesting as you allude to where belzutifan was really initially developed for the treatment of patients with VHL disease. And in many ways, VHL disease was the perfect scenario to test this hypothesis in.

VHL disease is a hereditary disorder, rare, that affects people, typically at an early age in life. And the mechanism of VHL disease is that it's characterized by mutations or deletions in the VHL gene, which ultimately leads to accumulation and activation of something called a HIF-2 alpha transcription factor. And ultimately, the downstream pathways of that can lead to a number of different clinical manifestations, including both benign and malignant tumors that can affect critical organs in the body. So the central nervous system the kidneys, the spinal cord, the retina, the pancreas.

And so this is, unfortunately, a disease where patients, because of these benign and malignant tumors, can be afflicted by a significant degree of morbidity because of the number of surgical interventions, radiation interventions, ablative interventions, and ultimately organ dysfunction that can result from uncontrolled growth of these tumors.

Pedro Barata: Wonderful summary. And so just going back actually these work, these efforts in the US gave a Nobel Prize, not that long ago, to the discoverer of the pathway and how you can impact it with inhibiting as a HIF-2 alpha. And as you alluded to, actually the original work comes out of these patients with VHL disease. New England pivotal paper, you were involved in that. Dr. Eric Jonasch involved in that at a few years ago and got to the approval of the therapy.

And here at ASCO 25, you present a five-year follow-up data. So the use of belzutifan for these patients, which, by the way, once daily patients take. This is oral. They take it at home. But the population is different. They don't necessarily have metastatic disease. And as you said, they have VHL-related tumors, including renal cell carcinoma, too.

So tell us a little bit about what does the clinical activity look like. And also, do you see anything from the safety perspective that's different from what we see when we use it for sporadic RCC?

Vivek Narayan: Yeah. So great question. So as you mentioned this was specifically testing it in patients with VHL disease. So they all had confirmed germline mutations leading to VHL disease. And as you also mentioned, this is patients who do not have metastatic disease. So by eligibility criterion, these patients had a primary RCC lesion, at least one that was measurable.

And they could have had other VHL disease manifestations, but the requirement was the presence of an RCC localized tumor. And we enrolled a total of 61 participants who all received belzutifan at the standard dosing of 120 milligrams daily. And really, the primary endpoint of interest was looking at the objective response rate specifically in those primary RCC tumors. But of course, we want to understand how this may affect other VHL disease-associated neoplasms as well as secondary endpoints.

And so, with this five-year follow-up data, we're showing that, ultimately, the response rate is improving across these various VHL disease neoplasms. So in the case of the primary endpoint of the RCC tumors, the response rate actually improved to 70%, so really quite striking response in this patient population. And critically, these are really durable responses as well. So now with five years of follow-up, we see the majority of patients who have had response are ultimately remaining in response at this time point, which I think is really remarkable, suggesting that we're really changing the natural history of this disease.

Pedro Barata: And by the way, just a reminder, because we always have this question. What happens to patients to remain on therapy for a long time from the safety perspective. And just a reminder, the design of this study did not plan for intermittence or holding the therapy. Is that correct? So these patients who are taking therapy and living their lives with a much fewer need for interventions. Is that fair?

Vivek Narayan: That's exactly right. I mean, I think to overall summarize the safety and tolerability profile in this patient population. This five-year follow-up data shows that it continues to be quite safe and tolerable, with the majority of patients remaining on therapy. The majority of patients not discontinuing due to treatment-related adverse events. And ultimately, they are receiving continuous therapy because that was the design of the study and what was required per protocol.

Pedro Barata: So maybe some folks, some of our colleagues in the community, might be asking, but how do I find those patients? Because it's not that we are, in general, doing germline testing for all these patients systematically speaking. We might suspect if we have a very strong family history or if they're very young patients, as you alluded to or even bilateral tumors, but not all. So two questions in one.

One is when you would recommend germline testing for when there's a suspected RCC. And second, where are these patients coming from. Like how are they identified in the community?

Vivek Narayan: Maybe take the second question first. I think one of the nice aspects of VHL disease is there is a very strong advocacy community, and there is certainly, across the United States and really around the world, certain centers of excellence that participate in the care of VHL disease patients. And these patients are followed longitudinally for long periods of time to understand the growth kinetics of the various disease manifestations.

And so there is a population of patients who exist that are now available to have access to drugs like belzutifan. And I think that is really where we're seeing the greatest impact of this disease. I think the latter aspect of that is how do we identify new potential patients who may be candidates because of hereditary mutations. And I think that is a practically much more difficult.

I mean, VHL is a very rare disease, and by and large, these patients are identified early on because most patients have some VHL disease-related manifestation, usually by 30 years of age. And so even in the late pediatric early adult population, patients presenting with retinal hemangioblastomas or CNS hemangioblastomas, really those are oftentimes the first triggers to understand clinically who may be harboring a VHL mutation.

Pedro Barata: So likely what for our community colleagues is more than likely they might get a call or a referral from one of those specialties, what the patient is admitted or found in emergency room or within a different specialty, and is asking for help when to use medical therapy in this context.

Vivek Narayan: I think that's right.

Pedro Barata: Gotcha. Well, that's super helpful. Well, Vivek, thank you so much for taking the time again. Congratulations. Very, very important data. It changed practice obviously for VHL-related RCC, but then for sporadic RCC, which we'll talk at a later time. But super important new MOA, very active therapy and sounds like patients are really benefiting from therapy in the long run.

So congrats for that data and for your presentation.

Vivek Narayan: Thanks, Pedro. Always a pleasure.