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Pedro Barata: Hi, welcome. My name is Pedro Barata. I'm a GU Oncologist and the Director of the Clinical Research GU Program here at Seidman Cancer Center in Cleveland, Ohio.

And I'm very, very happy to be joined today by Dr. Brian Shuch. Dr. Shuch is the Director of the Kidney Cancer Program and Endowed Chair in Kidney Cancer Research at UCLA. Brian, welcome. Thank you for taking the time.

Brian Shuch: Pedro, thanks for having me. I appreciate you highlighting our work.

Pedro Barata: Absolutely. I mean, we were chatting here today about your outstanding, and in my opinion, practice changing data. You just presented at ASCO GU. For those in the audience less familiar with it, it was a podium at ASCO GU. It's probably one of the highlight in kidney cancer, I would argue.

And you did a fantastic job, you delivered nicely as always. But also the data that you presented is quite important. So hopefully we'll chat a few minutes about the ZIRCON trial that you help leading, and how important is that for our kidney cancer patients.

So maybe first things first, Brian, can you remind us... Of course the press release is out, a lot of people are familiar at this point. But just remind us briefly the design of the ZIRCON phase three trial for us?

Brian Shuch: So this was an international study. It was a great team of investigators at 36 sites in nine countries. Facilitated by the Telix company, which sponsored the trial and coordinated with a lot of different logistical teams for shipping.

But this was basically a cohort of patients who had a T1 renal mass, which means seven centimeters or less, that was scheduled for a partial or radical nephrectomy that did not have a prior biopsy. And patients who consented were to have the dosing of the imaging agent, which is desferrioxamine-zirconium-girentuximab, which is, we'll talk about it, a chelated zirconium labeled antibody. They got that infused. And then they had imaging about three to seven days later. And then within 90 days they had partial nephrectomy. And you had imaging centrally reviewed and you had the pathology centrally reviewed.

Pedro Barata: Got it. No, that's very helpful. So of course we've been talking all these days about how sensitive the molecule is, the compound is. And maybe I'll ask first, why the carbonic anhydrase IX as the target? And then can you summarize a little bit for us, what were the take home points when you scanned those patients with these fancy scans, compared with conventional scans? Tell us a little bit about what were the highlights of the data.

Brian Shuch: Yeah. So first of all, carbonic anhydrase IX, this has been a 20-year journey since the discovery in the 1980s that it is highly expressed in kidney cancer, and then finding ways to exploit it. Our team, led by Arie Belldegrun and Allan Pantuck, have been working in this space for a long time.

But there's long been a very specific antibody called girentuximab, which binds CA9. And CA9 is upregulated, it's one of the hypoxia-inducible genes. So if you have true hypoxia, meaning the cell is starved of oxygen, or you actually lose the VHL protein due to a VHL mutation, which is the hallmark of clear cell kidney cancer, you have dysregulated HIF, hypoxia-inducible factor, which leads to upregulation of CA9.

And CA9 is a cell surface marker or a transmembrane protein, which is not expressed in normal cells. So it's upregulated really specifically in the tumor, which makes it an ideal target for imaging, and we'll discuss later maybe therapeutics.

Pedro Barata: Got it. And so you did that... I'm going to call it Telix250, just because it's easier for me. It's a big name. So what happened to the patients as far as the endpoint of your trial?

Brian Shuch: So this is a phase three trial, and everyone is used to oncology as a phase three trial randomizing patients between one drug versus another drug. Well, this was a single arm study and it was designed with a very, very narrow confidence interval to be measured around specificity and sensitivity. Really looking at the confidence interval to beat a threshold value, which was considered relevant by the FDA.

So basically 300 patients got dosed and looking at the three central reviewers for imaging, and then the final pathology, were able to come up with a specificity and sensitivity of the overall cohort, which was 300 patients. And then secondary endpoints was really looking at the performance sensitivity, specificity, positive predictive value, negative predictive value in the T1a cohort. For every T1b, you probably have three or four T1a, meaning there's a lot more smaller tumors out there than larger tumors.

And then obviously looking at safety data, wanted to make sure this imaging agent was safe, without any harmful side effects.

Pedro Barata: Got it. So to summarize, you have no safety concerns at all, and then very high sensitive in specificity. I guess allow me to pick your brain a little bit on another point, or another endpoint of interest to some of us, which actually is the number of false positives. Because it's actually a relevant point that you make around that. Can you tell us a little bit about that with this Telix250?

Brian Shuch: Yeah. So clearly the ability to pick up clear cell kidney cancer is important, it's the most common subtype and it's what most patients die of. Again, for small tumors occasionally theres some bad actors in there, collecting duct or medullary, but those are very, very rare. So for most small renal masses, we're going to find clear cell, papillary, chromophobe oncocytoma.

So this positive predictive value is about 94%. And you might say, "Oh, well what about those other patients? Are they still resecting benign tumors unnecessarily?" Well, there were about 11 false positives, and right now the data which we're looking at is 10 of those 11 were actually papillary renal cancers.

Papillary kidney cancer, when it's aggressive, it can be hypoxic and there could be focal CA9 expression. So I would say the positive predictive value to detect a cancer is clearly like 99%, which we have nothing like that.

So I, again, view it 94% is to pick up just clear cell. But again, this is not an agent that focuses only on CA9 from VHO loss, it can pick up the CA9 expression from true hypoxia. Which is why there are other studies ongoing, looking at breast cancer imaging, bladder cancer imaging, any cancers that have true hypoxia. So yes, 94% positive predictive value, but 99% probably for looking at cancer in general of the kidney.

Pedro Barata: Right. That's so important. Because, to your point, yes, we were talking about clear cell as the main focus, but the ability for this tracer to detect cancer goes beyond those 94%, to your point, right? That's so relevant.

Okay. So great data. I mean, I would be very surprised if the regulatory agency, after you guys met the threshold necessary, I think it will be approved and available to us.

The question is, based on your experience in the field, we've seen this story happening in prostate cancer, for example, with different tracers for PSMA, for example, in prostate cancer. Can you walk us through what do you think is going to happen if the regulatory agents approves it? Or when it approves it, how long are we going to wait to have these available? Is that easily available to all of us? It might take some time? How do you see the field playing out from that perspective?

Brian Shuch: Well, I mean, I'm hopeful. The data is very strong. However, there was a trial before with I-124 girentuximab, and the trial was about 175 patients. And it did not get approved because the confidence intervals were very wide. So this is a much cleaner agent, it's renally excreted, and the confidence intervals are much more narrow.

So if it does get approved, I see this following the PSMA story very similarly. One, the company, Telix, does have a PSMA product and they do have theranostics. And this agent has been shipped already for this trial to nine countries. It's fairly stable, it's half life is about four days. So you could ship it. And there's been studies showing that it can be useful imaging up to 10 days. So it is possible to get this, and the company is operationalizing getting it all over the world.

So I do think it's not so hard to read, it's not like looking at a prostate MRI where you need extensive training. Really there's not looking... Either these are very hot, with high SUVs of 30 to 40, or cold. And we're not really trying to characterize it as SUV 20 or 30 or 40, it's either it's considered hot or cold. And there was very high agreement between reviewers.

So it's a matter of logistics getting it out there. This will work on a standard PET scanner. And the radiologists really don't need much training, or nuclear medicine doctors, to say, "Does it look hot or cold?" These are not like equivocal.

Pedro Barata: Got it. No, that's very helpful. And that's actually great news for the treating physician out there. And then Brian, again, I know you're very well involved and you have a good sense of where the field is moving, right? To me, it makes a lot of sense that you start in those smaller, I guess, renal masses, localized disease. But to me, I would say, "Oh, it makes a lot of sense." You would explore these scanning ability in other settings, right? Rule out metastatic disease even in the metastatic setting. I mean, do you agree with that? Where do you think the field is going?

Brian Shuch: So this agent has shown... In this trial there were 40 patients or so that actually had full body scans and there were some lesions picked up. I think first you need to show that it detects clear cell kidney cancer, and then we need to start moving into bigger, more advanced settings. So we have an IIT, investigator initiative trial, where we're going to be looking at post-op patients who have high risk disease that will fit the adjuvant pembro KEYNOTE kind of criteria. We know they're clear cell or CA9 positive, and they'll have side by side conventional staging versus PET CT staging.

And I think it'll be the Will Rogers effect, where you have some patients who are going to have small disease, which is probably going to do worse, and those who have no disease are going to do better. So we're going to be shifting some patients into different baskets of true metastatic disease or true localized disease.

I see it as really trying to select patients. I think adjuvant therapy is going to under-treat a lot of patients who actually have real disease. So if you're putting a patient on monotherapy pembro, yes, there are some responses, but it doesn't compare to what you're going to get when you treat a patient with len-pembro, or cabo-nivo, or axi-pembro, or ipi-nivo. So I think we're probably under-treating a subset of patients.

And I think also it'll be very useful in the metastatic setting. I know you, Pedro, you have some patients who do so well and they have really deep responses. When do you stop therapy? Well, maybe if we imaged those distal sites and they're actually now CA9 negative, if they revert, maybe you would probably can talk to a patient about maybe going off therapy and potentially observing.

Pedro Barata: Yeah. No, those are fantastic points, Brian. I mean, I completely agree with you. Again, I mean, I would stay all day here chatting with you about this. It's really huge, important data. I'm actually looking forward for this data to be published in a high impact factor journal. I really think it's practice changing. And I just have to congratulate you for that. Keep up the great job. I mean that IAT just speaks for itself. It's really brilliant, it's really what we need to see. And so again, congrats. Thank you for taking the time. And I'm sure we're going to be talking soon of more developments about this Telix250 and your work. Thank you.

Brian Shuch: It's my pleasure. Appreciate it. I know we can put our heads together and come up with some even more exciting concepts.

Pedro Barata: There you go. Thanks.