Pedro Barata: Hello everyone, and welcome to another UroToday video covering important data in the kidney cancer arena. Today, I'm very, very happy to be joined by the one and only Professor Brian Shuch. Dr. Shuch is a key opinion leader, a leader out of University of California, UCLA, who has been really leading the efforts around novel imaging for patients with renal cell carcinoma. Brian, thank you so much for taking the time sitting down with us.

Brian Shuch: Pedro, thanks for the invitation. Looking forward to digging into this topic.

Pedro Barata: Absolutely. And I know that we can spend an entire day talking to you about these new carbonic anhydrase 9 related radiotracer with girentuximab, and then the trial that you led, ZIRCON and further studies. And actually, I would love to sit down with you talking a little bit about your investigative study that you're doing at UCLA phase two study basically comparing, that's my take at least, ZIRCON girentuximab against conventional scans for patients who underwent nephrectomy for renal cell carcinoma. Is that correct? Can you tell us more, a little bit about the design about this IIT?

Brian Shuch: Correct. Thanks, Pedro. The ZIRCON trial established, established girentuximab with the ligand of zirconium-89 as really the the gold standard at diagnosing clear cell kidney cancer when it's in the kidney. But there's been other studies, work from Radboud in the Netherlands looking at CAIX clearly as a method to detect disease outside the kidney. We do know that distant sites of kidney cancer also expressed CAIX. We know 95% of kidney cancers have high expression. There are a couple small subset of variants that don't have CAIX expression and it's something that doesn't really evolve with the tumor. So if it's useful for detection in the kidney, it should be useful for detection out of the kidney. So when you see a patient at case, I'm sure Pedro, who has high-risk kidney cancer after surgery and you're trying to decide whether you want to put them on adjuvant therapy, restaging is recommended. All are trials looking at adjuvant, whether it's RAMPART, KEYNOTE, CheckMate, PROSPER, all patients get re-imaged after surgery to confirm that they are disease-free.

And that's a pretty important time and I'm sure in your practice if a patient clearly has disease seen, they're no longer eligible for monotherapy and monotherapy with KEYTRUDA does have some activity but not as good as combination therapies. So the purpose of our trial was to really show that at restaging, we have a better way at detecting whether disease is left over, left behind, or missed with conventional imaging, we believe. So unlike most centers which just do a PET-CT with the tracer and they do basically a CT without contrast, UCLA for many years, since they developed the PET imaging modality in the 1970s and '80s has been really advanced in their technology and they've had the ability to give IV contrast and do a diagnostic CT at the time of the PET-CT, and a lot of centers don't do that. We basically came up with a strategy where we would take all patients fitting KEYNOTE-564 eligibility, T2 grade four, T3 any grade, T4, or if they have M1 resected to NED with clear cell. Within 16 weeks of nephrectomy, they would have their first restaging scan, which would be a dual PET-CT with TLX250 with IV contrast. And the images can be directed to two different locations. You could have the nuclear medicine folks look at the PET-CT, and you can have the abdominal and chest radiology folks look at the CT with the diagnostic scan for contrast. We're basically comparing head to head what is better at lesion detection per patient and what finds more lesions.

We also are trying to look at maybe the positive predictive value if we find the lesion, we want to make sure with the composite standard of truth, is that lesion either growing without treatment, is it shrinking with treatment, or is it a positive biopsy? And obviously, you can biopsy every small lesion, so we have that composite standard of truth. We are currently at around 28 patients. We will do a pause at around 33, but to date, we have seen many patients with lesions detected more lesions with PET-CT. We've seen some patients would've had imaging that would've missed a lesion and the PET-CT has identified either small lesions or lesions like buried in the liver that were missed. Very excited about it, but we have a long way to go. And again, patients would just come to UCLA, get imaged and go back to their local center. We're always looking for people who are interested. They can always contact me.

Pedro Barata: So Brian, this is amazing. Really important, right? You're trying to basically prove whether or not novel imaging can actually overcome the conventional scans we've been using forever. This is one way to get us there. Two quick questions for you. One has to do with the thought out there that if you have the kidney mass in place, maybe the tracer will get all the way to the primary tumor and maybe you'll lose the ability for the radiotracer to find other spots. So in this setting, where you remove the primary renal mass, maybe you are more likely to find those other metastatic sites. Do you see it that way? And do you anticipate to be something like what we have with FDG-PET or where sometimes for smaller lesions you don't really see an uptake, even if they are real or more like a more like a PSMA PET where you actually see metabolic alterations even in the context of normal size organs, for example, lymph nodes. What are your thoughts about the primary tumor? How does that would impact what do you know in terms of the biology of RCC?

Brian Shuch: Yeah, I mean I don't think it's a matter of the tracer is going to be taken up completely by the tumor. There's going to be nothing to find any distant disease. I mean, on the ZIRCON trial, there were some patients who had metastatic disease identified. So I don't think it's a sink. Like the primary tumor is going to take all the tracer, just like PSMA, you have patients with very high burden of disease and you don't need to go up on the dose of the PSMA. This small molecule, it does take several days to find all the disease we image at day five routinely unlike small molecules or FDG where you can image an hour or two later. I think it gives enough time to seek and identify and bind and it gets internalized. We do have a concept where we're looking at patients with large primaries as staging as well. But in this situation, after surgery, you know that a patient has clear cell, they have probably CAIX positive if you do immunohistochemistry. So I think it could be done either way just for this purpose, we're doing it in the adjuvant or post-op setting.

Pedro Barata: Right. No, that's amazing and I am glad you highlight the properties right of these radiotracers are not the same as the others we have out there. And that might provide an advantage in relation to what you've got to see beyond the primary tumor. Another question as you're designing your study, obviously one emergent biomarker appears to be KIM-1, kidney injury molecule-1. I'm wondering if you're able to leverage any correlatives within your study, whether it's that or any other you'd like to highlight along with imaging. Are you able to leverage any of that as you enroll patients?

Brian Shuch: Well, we are prospectively banking serum and plasma. We are sending Signatera, which again, I think that ctDNA with the traditional whole exome approach is not really sensitive enough. But there's a whole genome approach. So unfortunately, halfway through the study we have half the patients who've had whole exome, the other half have now had the whole genome. We're going to adopt that approach working with Natera getting that performed. Again, I don't know whether that's going to be the answer. KIM-1, there's no real time lab assays that can do it without in a cost-effective manner. We are banking it and we are going to look at that later retrospectively to see how it impacts things. Again, I don't know what's going to be the best answer in the future. Clearly, we need to do a better job. You've done a tremendous amount of work with clusters, mRNA, profiling, working with a couple industry leaders in that area. But again, whether it's going to be transcriptomics, whether it's going to be ctDNA, circulating biomarkers, or molecular imaging, we need to do better because clearly we are overtreating a subset of patients.

Pedro Barata: Right. I mean, I couldn't say it any better. I mean that's super smart, right? You're trying to understand what actually pans out, you actually leaving the open the door open to be able to explore those in the future as you get that collection, and that's such a value. It speaks so much or speaks highly of the value of IITs, right? You are actually able to do those in real time, collecting those samples and be able to basically pick the winner, I guess in the future as they pan out. So Brian, congratulations, really important study. I'm glad the accrual is up and going. Please reach out Dr. Shuch if you have potential patients who would be willing and interested to do it. Super interesting, I would love to have it in my center so we'll wait to see what happens there at UCLA. Brian, really well done. Great job. Keep it up. Great. You're doing amazing things there in LA, and thank you for taking the time sitting down with us today.

Brian Shuch: Perfect. Thank you, Pedro.