Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center and a guest of Georgia. As always, delighted to be joined on UroToday by Dr. Vitaly Margulis, who is a urologic oncologist at UT Southwestern in Dallas, Texas. Vitaly, thanks very much and always for your time on UroToday.

Vitaly Margulis: Thanks for having me, Zach, and I think it's really exciting time in kidney cancer and the rest of urologic oncology, especially as we will talk about the molecular imaging in kidney cancer. We're getting into that era.

Finally, we have some sort of molecular imaging tool as we have in prostate cancer that we can leverage in our kidney cancer patients. So that's exciting. Thanks.

Zachary Klaassen: It's very exciting. I think all aspects of urologic oncology are just so exciting, and now we're seeing kidney coming into the game with imaging. Before we get into the molecular imaging, in terms of Girentuximab PET-CT, let's talk about 2025 where we stand right now. How are you imaging? How are you working up all these small renal masses that we're seeing in the clinic?

Vitaly Margulis: I'm sure your practice and my practice is similarly inundated with those people, with folks. As we know, and the data's pretty clear on this, a vast majority of these small renal masses defined as mass, I guess, four centimeters or smaller, most of these are indolent. I think in most of the cases you can make an argument, at least for initial attempt at active surveillance followed by reassessment and going from there. Of course, it's a very nuanced field. You have to factor in patient factors, patient goals of care, access to medical care, longevity, comorbidities, so on and so forth.

But to answer your question, how do we characterize renal mass? Cross-sectional imaging without contrast, I think this would be a standard, right? A lot of these patients would show up with, for example, a quote, unquote "tumor" on a non-con CT that was ordered for kidney stones, and it's important to get cross-sectional imaging with or without contrast, whether it be MRI with or without contrast. And for some folks that can have iodine contrast can have an MRI. I think ultrasound with contrasted ultrasound is another kind of an important tool to have in your toolbox for these rare patients that can have either.

Zachary Klaassen: Yeah, absolutely. And I think to move into molecular imaging, the ZIRCON trial presented several years ago now, published last year in Lancet Oncology, really looked at a population that was planned to undergo nephrectomy, renal masses less than seven centimeters. They all got Zirconium Girentuximab PET-CT scan.

And we're sort of pending approval for this, and I think as we sit in September 2025, by the time people listen to this, it may be approved, but just tell us about the molecular targeting and the molecular mechanism that really lends itself to clear cell for this agent.

Vitaly Margulis: So we have known for quite a while now, I mean some of the initial trials have been done decades ago, that kidney cancer, especially clear cell renal cell cancer, are expressed as CAIX, carbonic anhydrase-IX on their surface. It's a surface molecule, so easily targetable with small molecule or antibody.

In this case, Girentuximab molecule targets that, and it's coupled to Zirconium, photo emitting element so that you can, in theory at least, specifically look at clear cell renal cell cancers in the body.

Zachary Klaassen: Yeah, absolutely. And I think this trial really showed great sensitivity specificity over 85% for both for the clear cell entity. Now, getting into patient selection, that's sort of our goal tonight, and we opened with active surveillance. Let's say pending approval, everything else, you have this agent in your clinic, which patients will you consider a Girentuximab PET-CT scan for their management?

Vitaly Margulis: Exactly, I think it's a million-dollar question. I think when we get these new tools, just 'cause you have a hammer and everything is a nail. So as we get these new tools, I think we kind of refine our practices and rethink where we would deploy this technology. I don't think it needs to be done in everybody with small renal mass, but the way that I think about it... And we've had this actually as part of our expanded access program, and so we've been kind of struggling with these questions. Some of that is already driven by the patients, by the way. So you may have patients showing up on your doorstep asking, "What's this PET scan?"

But the question is your routine small renal mass that you're considering for active surveillance, who should get it? And I'm not entirely clear. I think the way that I think about it is perhaps I think about this as an image biopsy, non-invasive image-based biopsy. So if there are patients that you're thinking, "Okay, I need to try to figure out what this is," and those patients, we would routinely order a percutaneous biopsy, perhaps this would be the tool to replace that.

It's complicated. I don't think everybody needs it. I think we need to remember also that there's some logistical issues. So with this scan, you get an injection followed by an actual scan five days later. So unlike where there are PSMA scans where patients kind of get injected and injected and get imaged one hour later, this is more complicated. If you have patients that are driving for a second opinion from far away, this may be difficult.

Zachary Klaassen: Yeah, no, it's good. That's a fair answer. And I think let's shift now to the patients. You're planning an intervention, whether it be a partial nephrectomy for a four centimeter renal mass or an ablation. Is there a role or where do you see a role potentially for pre-op imaging in these patients with, say, that three and a half, four centimeter renal mass?

Vitaly Margulis: To be honest with you, again, I think if I'm going to manage a small renal mass, I'm going to go under the assumption that this is most likely kidney cancer. Depending on your patient population, 20% are benign. But the problem with this agent is that 20% of the time with a scan is negative. It doesn't mean you don't have cancer. It just doesn't mean you don't have clear cell renal cancer, right?

So, you're still kind of stuck with that sort of uncertainty to some degree. Yes, we know that other entities are less biologically aggressive, but it doesn't rule out kidney cancer when the scan is negative. I think it's very sort of reassuring that if the scan is positive that you have clear cell renal cell cancer. But if when I offer somebody active surveillance, I offer it under assumption that I'm dealing with a small indolent clear cell renal cell carcinoma.

So in most cases, having that scan, having that confirmation probably would not change my management. There are nuanced scenarios, kind of sacred patients with enlarging, rapidly, or maybe not rapidly, but a growing tumor, and you need to kind of want to know, "Okay, what's the biology of that?"

Typically, I would do a biopsy. Here, you can make an argument, "All right, well this is enlarging faster than I like. Let's see what this is and get the scan." So yeah, it's not as straightforward as I would like to be. Again, I don't think this needs to be done in everybody. And maybe in these select cases where there's some questions that maybe these borderline cases you're not sure what to do, this could be useful.

Zachary Klaassen: And let's move a little more to the world that we live in, the locally advanced, big, nasty kidney tumors. I think about this when we're planning a 15 centimeter nephrectomy, maybe there's a renal vein thrombus or a level two, obviously, thrombus.

And I think in my practice, could there be utility for identifying lymph nodes? Maybe this will light up a couple of the perihilar lymph nodes. Do you think this could guide us in staging these patients or even preoperative planning of how we go about these bigger nephrectomies?

Vitaly Margulis: Yeah, I think to me this is the most interesting application of this technology. We all see these huge renal masses with borderline mediastinal lymphadenopathy, some shoddy lymph nodes out of place, you don't know what they are. Certainly, proper characterization, identification with the metastatic disease early would probably lead to early systemic therapy.

And I think we are for these really large, aggressive tumors, I think we're probably shifting into obviously multimodal treatment with the KEYNOTE, et cetera, and perhaps into pre-surgical treatment mode. And traditionally, before I could give somebody pre-surgical, and we have several clinical trials in the space, pre-surgical therapy, you have to have a biopsy.

So here, I could imagine doing the scan and showing, "Here, this lights up, this is going to be clear cell renal cell cancer." So this is kind of where I think a lot of advantages will be, this borderline. Do I need this scan to tell me that four centimeter lung nodule or multiple, multiple large cannonball size lung nodules or lymph nodes are metastasis? Probably not. Could it be useful in these borderline cases where you're not sure? I think probably yes.

Zachary Klaassen: Yeah. No, that's fair. I think just to dovetail into the working through the spectrum from active surveillance to metastatic disease, it's distinct. We're going to have an imaging agent at some point, like this agent that's going to be FDA approved. Moving it to potential radioligand therapy, where do you see this maybe fitting in as you move into the real metastatic setting where this may be able to help with our metastatic patients?

Vitaly Margulis: Right. I think this obviously would be a natural extension as what we've seen happen in prostate cancer. And I think the known Pluvicto-type therapies in prostate cancer have been a home run. I think it's practice changing. Certainly, for patients with metastatic kidney cancer, this will be another mechanism of action that you can leverage, right?

There's only so much you can get with TKI immunotherapy and various permutations of combinations. Essentially, at some point, you run out of treatments. And so to have a radioligand-based treatment that targets specifically a known target that's expressed very specifically in kidney cancer, with what I would expect to be relatively low off target toxicity is very exciting. And I think that would be a natural extension of this technology.

Zachary Klaassen: Yeah, absolutely. Vitaly, always good catching up with you. Always a high-level efficient conversation. Any take home messages, concluding statements, anything we didn't hit on?

Vitaly Margulis: Yeah, I think again, I think as urologic oncologists, we need to be careful how extensively and whom we utilize this technology. It's good for patients to ask, but we have to be careful. And it may be one of those situations when once you open the toothpaste, you're not going to be able to put it back in, that situation. So we have to be careful, and I think we all have to think prospectively who and when we want to use this technology on, just for healthcare costs, patient anxiety, et cetera, et cetera.

Zachary Klaassen: Yeah, absolutely. Vitaly, thanks as always for your time.

Vitaly Margulis: Thanks, Zach.