Zach Klaassen: Hi, my name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined by a good friend of UroToday, Dr. Sam Chang, urologic oncologist at Vanderbilt University. Sam, thanks so much for joining us today on UroToday.

Sam Chang: Zach, it's really an honor and pleasure to get to speak to you and have a conversation with you, looking at actually new imaging modalities for renal cell carcinoma. But I just want to also express my thanks to all of us who follow all your updates at the different meetings. You really get kind of, from different outlets, really the true snippets of things that are important, different meetings throughout the US and actually internationally. So I want to express my thanks.

Zach Klaassen: Yeah, thanks, Sam. I appreciate that. And the UroToday platform, not just these videos, but the conference updates are super important just for us keeping up-to-date. Because there's so much going on, not only in kidney cancer but prostate and bladder cancer, too. So thank you for the kind words.

And we're going to talk today about the ZIRCON data, really what's going to be a game-changer in imaging small renal masses. So I'd love for you to walk us through that data. And then we'll go through some clinical scenarios for the application of that data.

Sam Chang: Great Thanks very much, Zach. I'll pull up my talk.

So this paper out of Lancet Oncology, Zach, looks at a new imaging modality focusing on PET-CT capabilities for a specific antigen and target. And this is a prospective, open-label, multi-institutional trial. So what this looked at was actually focusing on adults with renal masses that were less than 7 centimeters, but had some suspicion or some concern for a clear cell carcinoma. And this was actually a single dose of this agent, with then surgery planned afterwards. So this is truly a pathologic confirmation of what was considered to be suspicious at the time in preoperative evaluation.

So what does it really look like? Well, this is some examples of what this is. This is actually a target looking at specifically the agent carbonic anhydrase 9, CA9. And so zirconium is actually linked to this. And you have then an antibody targeted imaging utilizing PET-CT capabilities.

So these are examples of imaging where it actually works. The top slide shows actually a positive scan. You can see the arrow. You can see the bright red spot on the right-hand side. You see the small lesion of concern on the diagnostic CT on the left-hand side. And you can see it's bright red on the right-hand side.

Just as importantly as we are concerned about both, obviously, those images that are positive but also those that are negative, if you look at the bottom set of images, here's an example of a negative scan. You've got a lesion here on the left kidney that's kind of multicystic. Has those septations. I can't even tell you how many of these images we see in our office that are concerning, sometimes growing, sometimes staying the same. What do we do with them? And then this is an example with the PET-CT combination of the ZIRCON imaging showing a benign and confirming that it's a benign lesion.

Now, this is not a perfect test. Our examples of where it didn't work. This is actually an example of a papillary renal neoplasm. And as you know, Zach, we have the predominance of malignant neoplasms being clear cell, but we have a whole host of those that are not clear cell. And this is an example of a renal neoplasm that's papillary renal neoplasm. And this was negative.

Importantly, though, actually of 11 different cases of papillary renal cell carcinoma, eight of them were in fact positive. So it's not that they miss all papillary renal neoplasms. It just doesn't seem to be as accurate and as able to find those lesions that are papillary in nature.

Another example where it didn't work. This is a clear cell carcinoma. Again, one of those cystic lesions where there really wasn't positive imaging, and they came back negative. But this was an example of a false negative.

So it's not a perfect test. But when we look at the overall results and the diagnostic criteria, you can see that, first, there's a little bit of variation between the different readers. So this is the case with all of our nuclear medicine imaging that does take some experience. It does take some know how, and there are some slight variation. But overall, you can see the variance isn't very great between the different readers that read all these.

And if you look at the overall sensitivity and specificity, you have a significant actual ability to find lesions with both a high positive predictive value and a relatively high negative predictive value with an accuracy of 86%. Now, that does tend to get better in lesions that are a little bit larger. So as we get larger, we're a little bit more able to identify those lesions actually in an effective manner. But it does show actually the ability of this particular scan to be able to differentiate between benign versus malignant lesions.

With any new kind of imaging modality, be it different types of PET scans, be it different types of contrast imaging, you always worry about are there any safety concerns. There were no treatment-related deaths. The most common, actually, side effects were those that were actually quite minimal with hemorrhage and urinary retention. We don't even know if those are specifically related to the contrast agent, but you had overall a high diagnostic accuracy with pretty good inter-reader agreement, as you could see from that previous results slide.

So in conclusion, high sensitivity and specificity for clear cell renal cell carcinoma. A safety profile with actually no real signals of concern. And the hope that we can potentially reduce unnecessary interventions, be it biopsy, be it surgery, and decrease the concerns associated with different types of lesions over time.

Zach Klaassen: Sam, thanks so much for that overview of the ZIRCON study. And you and I could spend the next 30 to 60 minutes talking about clinical implications, but I want to maybe hone in on a couple that we'll see in the clinic over the next several months. And so the first scenario is positive image, let's say, a 4.0 to 4.5 centimeter mass, so maybe a big T1a, small T1b.

Let's say you have a co-morbid patient, elderly. You really want to do surveillance on that patient, but it's a positive PET scan. How are you counseling that patient?

Sam Chang: Yeah, no, I think that's a really important scenario. And to me, the way I would use this test is to help confirm or reaffirm your initial plans. So if you have someone who's already to the point where you are not going to proceed with treatment, either diagnostic or with surgery, honestly, I probably wouldn't get the scan. I wouldn't want to know.

Zach Klaassen: Yep.

Sam Chang: But it's in that scenario where, hey, that patient's on the edge. This lesion is enlarging. We think we should do something. OK, we get the scan. It's positive. OK, that's enough to push us forward.

Similarly, that patient we think we can operate, but it's negative. OK, then that makes us feel much more comfortable to say, let's back off. Let's re-image in six months, see if symptoms change, et cetera. So I think the initial fork in the road is, would we really do something if there is a positive test? Oh, we would. Would we want to? No. But we would.

Zach Klaassen: Sure.

Sam Chang: And this test confirms that. And so it obviates the need for a biopsy. It puts everyone, I think, much more at ease of, hey, we need to intervene. We think this is a cancer.

And I think, importantly, although treatment has changed significantly for kidney cancer, we still understand that we don't have really that cure, that cure safety net. And we've got lots of great measures and interventions, but we don't have that cure. So I think that's important at that point.

Zach Klaassen: Yeah, a great point. And so I think you kind of led into this a little bit. So you've got a younger patient. They're undecided on treatment options. They have a 4.0 to 4.5 centimeter mass. That's positive. How do you use that to maybe counsel them towards an intervention, such as a partial nephrectomy and the confidence that, hey, we know what this is for the most part, 85% to 90%?

Sam Chang: Right. I think, in that scenario, it puts everyone at ease of intervention is necessary. Let's, again, bypass a biopsy. Let's focus on curative measures.

And it's in those patients where everyone feels, OK, hey, we need to do this. We'll proceed with the metastatic evaluation. Let's act.

And so I think it's also quite helpful-- say in that same scenario where there might be something of concern on the other side, a cystic, multi-cystic, whatever, just another kind of affirmation of, hey, this is something we need to do. We go from there.

Zach Klaassen: Absolutely. And let's flip the script a little bit. So that same 4.0 to 4.5 centimeter mass, negative imaging. And you kind of alluded to it a little bit earlier. Again, that gives you the confidence in that elderly patient. You said you may not even get it, but you get it. It's negative. That really cements the fact that, hey, we're gonna just keep watching this.

Sam Chang: And I think it's difficult to measure, but you can't deny the psychologic benefit of that.

Zach Klaassen: Yes.

Sam Chang: On the flip side, you have to be prepared for the fact that, hey, it is positive. Then what do you do? So it's in those scenarios that I think it becomes more difficult, but it really will help you in the decision making analysis.

Zach Klaassen: Last sort of scenario. And I think this could go a number of different ways. So that same 4.0 to 4.5 centimeter mass, negative imaging, 52-year-old healthy, kind of wants treatment. Is this a patient you're going to counsel let's just go ahead and operate, knowing that there's a percentage chance that it's negative? Or would you think about an MRI or a biopsy in this patient?

Sam Chang: Oh, that's a tough one, Zach, because it's not perfect. You saw there are some false negatives. And I think in that scenario, I, personally, in a healthier patient with a suspicious mass, I'd take the next step.

Zach Klaassen: Yeah.

Sam Chang: And that probably would be biopsy.

Zach Klaassen: Yeah.

Sam Chang: But if you look at the percentages of this non-invasive test, it's not too far off from biopsy accuracy. And I tell our folks, just as a rough figure, whenever patients come in, it's about a 90% plus with biopsy. It's not 100%. But I probably, in that scenario, I would take the next step of let's do a biopsy. Let's be assured.

And unfortunately, if that biopsy comes back negative, those patients, and we talk about this actually in our conference, we still continue imaging those patients.

Zach Klaassen: Sure.

Sam Chang: Because nothing is perfect at this time, other than the pathologic specimen.

Zach Klaassen: That's right. No, I appreciate you obliging those clinical scenarios. I want to ask you, you and I see a lot of small renal masses in our clinic. As we fast forward, and let's assume there's FDA approval down the road for this imaging modality, in your opinion, where's the top three sort of clinical scenarios that you would see this working in your clinic?

Sam Chang: Yeah, I'm glad you only go to three because once I get to past three, I start losing clarity. I think in looking at the different scenarios and how patients come in, this is kind of a transition from we just had CT scan. We're not so sure. Oh, we have biopsy.

The number of biopsies that we have done here at Vanderbilt has increased exponentially over the past 10 years. It gives us clarity. And I think now this is a noninvasive test to give us clarity.

And so, for me, it's two kind of scenarios of reaffirmation-- a smaller lesion, even though that actually goes down a little bit. 2.0 to 3.0 centimeters that you really don't want to biopsy. You really don't want to do anything about.

Zach Klaassen: Yeah.

Sam Chang: And if you do find something, yeah, you could treat it. You probably could treat it noninvasively. But you really don't want to. You don't want to do surgery for sure.

In that scenario, I'd say, hey, let's get this. Oh, it's negative. OK, we feel better. Would we image? We probably would continue to image, but we would decrease not every six months, or we'd start stretching out, et cetera, especially in that patient with comorbidities that you first mentioned. It's like, let's wipe it off the table. Let's stop.

Zach Klaassen: Yeah.

Sam Chang: In a similar scenario, in a patient with not necessarily comorbidities, but multiple lesions in the same kidney or synchronous lesions in both kidneys, I think it would give us some idea of what's the most obviously suspicious or concerning. Where do we go? Help us define that scenario of treatment algorithms in those patients with these awkward situations where you don't really know which kidney to intervene in, which lesion to intervene on, I think, would be really helpful.

Zach Klaassen: No, that's great. And I think you're right. I mean, this is another data point for shared decision making, right? I mean--

Sam Chang: Oh, absolutely. Absolutely.

Zach Klaassen: I think when I really think about this and where we're going to be in the clinic, noninvasive. It's not perfect, but it's pretty good. It's really good, actually. And the fact that we can have this discussion with the patient with another data point that's really just a glorified CT scan with some fancy injections is fantastic. And I think that's where we're going to work it into that clinic. Would you agree with that?

Sam Chang: Oh, I totally agree. And I think that to me would be the take-home message of now we've got another piece of diagnostic information that's noninvasive that's pretty darn an accurate. And as a result, it can add to the information that we share with our patients as we try to decide the next steps.

And importantly, you talk about a test that it's one injection. It's done within a five-day window. It's uptake is so strong that it can last that long. So background isn't really as much of an issue and without any safety concerns.

I think adds to that diagnostic armamentarium. We haven't I think always accurate information gives us more structure to figure out, hey, what are our next best steps.

Zach Klaassen: Absolutely. Sam, great overview of the ZIRCON data. Thank you for the clinical scenarios. I know those are helpful as listeners start to work through when and how they're going to use this new imaging modality. As always, thanks for your time and expertise on your UroToday.

Sam Chang: Oh, thank you, Zach, very much for the opportunity and appreciate the time.

Zach Klaassen: Thank you.