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Brian Shuch: I'm going to switch gears before we kick it off with the last talk next about kidney cancer. This is about CA-IX imaging. So in our world, I'm a urologist focused on kidney cancer, practice mostly small renal masses and advanced kidney cancer, there's a large number of cases that we're seeing now just due to the incidental detection. And there's been a tremendous stage migration. We treat more kidney cancers today than ever before. And a lot of patients have unnecessary complications.

So we do know that we have 20 different types of kidney cancers, but we have really three major types that take over 90% of the cases. And clear cell is the greatest among them. And 90% of our deaths are attributed to clear cell kidney cancer. And it does behave more aggressively than the other major subtypes with more rapid rate of growth when observed, greater risk of dissemination. So the idea of identifying this is obviously important. We do have limitations of our conventional imaging. When we have a scan, a CT or MRI, we can say there's enhancement. We can call things tumors, but we can't call them cancer.

We do know that an enhancement pattern, despite our great radiologist, they may say, oh, I favor this being this subtype, they're a little bit better than a coin flip. And I will tell you that even in the REDECT trial, one of the prospective trials we'll talk about later, the specificity was pretty poor at calling something clear cell. There are some new approaches, but they still have a lot of limitations. And we have better ways with nuclear medicine to characterize tumors. And people say, oh, Why don't you just stick a needle in a biopsy like prostate cancer or lung cancer? Well, we have errors. We have lots of swing and misses.

The radiologists can't get a good piece of tissue. Sometimes pink tumors are oncocytic. There's overlap between some tumor types, chromophobe and oncocytoma. Tumor seeding is something that people are scared about, but it probably hasn't changed the overall prognosis. And we do know there's complications. So FDG is not the solution, and there's uptake and excretion. If you look at a whole kidney, the whole thing becomes bright. And we do know that even benign tumors do have some uptake. Oncocytic tumors, oncocytomas, they lose complex one and they kind of rely on glycolysis. So not something that's reliable at distinguishing kidney tumors.

So CA-IX has long been an interest at UCLA. My mentor back 22 years ago, Arie Belldegrun, had the paper looking at its prognostic value in clear cell kidney cancer. And we do know that in clear cell kidney cancer, VHL is the hallmark of the disease where you have VHL mutations, you have loss of heterozygosity, you have failure to ubiquitinate HIF, and then HIF basically translocates and CA-IX is downstream.

We do know that there's physiological hypoxia in other tumors like breast cancer or other types of pancreatic cancer. Anything growing quickly, you can have physiologic hypoxia. But in clear cell, there's diffuse expression throughout the membrane. And as opposed to some other subtypes, there might be some more focal expression. There's been a really long journey, multiple groups identified this called G250, CA-IX, MN, but basically over the past 15 years of development, it's kind of moved slowly, but now we're moving to the clinic very rapidly. But the long journey led from the first antibody that was raised to target CA-IX from Wilex to Heidelberg Pharma, and now Girentuximab with Wilex, and now small molecules being made that can target this as well.

So the one that's furthest along is Girentuximab, which, again, is an IgG, a light chain chimeric monoclonal antibody. It can bind with high affinity and gets taken up by the cell. There's lots of different payloads that can be attached. And the good thing for a urologist is it's not renally excreted, so I can look at the kidney and not have a big blur like PSA or FDG PET. And obviously, this antibody is safe. My mentor, Arie, had a large Phase 3 trial with the-- it's called the ARISER study. They gave 800 patients Girentuximab and it wasn't toxic, but it wasn't effective as an adjuvant strategy. So again, extensive safety experience.

Now what can we do for localized tumors? Again, there's no uptake in the kidney. The REDECT trial with I-124, Dr. Divgi published this about over 10 years ago. This study was looking at imaging patients before surgery. Tumors that were very large could be on this study. They anticipated a much higher rate of non–clear cell kidney cancer when they did their power calculations. And unfortunately, with dropout and the high incidence of clear cell, probably because there were larger tumors than anticipated, they didn't meet their primary endpoint, but it was very accurate. But when the adjuvant trial was negative, it shut down.

The ZIRCON trial, when TELIX got this, they launched a large Phase 3 trial. They powered it appropriately to make sure that there was no issues with-- like the REDECT study. Basically, this was a resect-and-treat study design, where basically it was powered for sensitivity and specificity to basically have three readers and have the confidence intervals be well above what you would expect with contrast-enhanced CT. And again, 332 patients. And as expected, there were a large number of non–clear cell as well. And the study, again, as expected, similar to REDECT, very accurate. The sensitivity and specificity very high, 86% and 87%. The positive predictive value is 93% for predicting if it's positive, it's clear cell.

But we will have an abstract presented pretty shortly saying that if it is positive, it's 99% kidney cancer because there are some subtypes which are hypoxic. And I would say that if it is positive, you know it's going to be a kidney cancer. And again, very few adverse events. And we published this and it was in Lancet Oncology earlier. And then this was submitted for a biological license application. Very exciting. This was in a couple of days ago where it was announced that August 27th there will be a decision whether to move forward on this. And we're all very excited. Two very promising studies, REDECT now with Zirconium-labeled that this could make a difference.

So again, the expanded access program and move forward. There's 102 patients dosed. We have about 20. We're the only site that has done the ZIRCON and this. So a lot of other sites, about 20 other sites are getting used to using this. So we hope that if it does get approved, it could be rapidly adopted. Now what about metastatic disease? Everyone says, oh, who cares about small renal masses? People don't die of small renal masses. But the metastatic disease is the next step. And the trial from Radboud, Peter Mulders and his team have done an amazing job in Europe. And this was a study looking at distant disease, patients who had metastatic disease.

Everyone got a Girentuximab scan or an FDG PET/CT or CT. And as you'd expect, this was very accurate. They detected more lesions with the Girentuximab-zirconium PET/CT, and the SUVs were well above what you'd expect from, let's say, people who say, oh, PSMA can be used. There was no-- SUVs were very high. So we have an investigator-initiated trial. Jeremie is helping us move this forward. We are basically taking patients after surgery to see if there's any disease left over. And patients, when they're making decisions for adjuvant or surveillance, I'm trying to see is this going to help us restage patients more appropriately.

Just an example. There's one patient who had a contrast-enhanced CT at the same time. This liver lesion was clearly missed. Yet, with the PET/CT we have a 3.5-centimeter lesion, this patient had Y-90 after a biopsy confirmed. And now instead of just adjuvant therapy alone, they're getting a little bit more aggressive therapy with dual therapy just to be overly aggressive. But there are other things moving forward. This is another small molecule, DP-4452; it can detect tumors as well. We're using this in the lab with Christine Mona, who's a brilliant scientist here with Johannes. And we do see a lot of gastric uptake, as you see in this, but it can detect kidney cancer.

Another small molecule as well, the PHC-102. It's an acetazolamide analogue. This is another molecule that can detect kidney cancer. There is a lot of high renal uptake, as you see here. But it looks to be very accurate at finding small lesions in the lung on this scan. I think Dr. Hofman was on this study.

Now, just in summary, I'm over time. Again, this is an exciting paradigm shift in our field. We're probably 10 years behind prostate cancer. But for a urologist involved in kidney cancer, this is really going to be a major paradigm shift for localized and metastatic kidney cancer. Thank you. And here's just a picture of our team. And Jeremie and Johannes, thanks for all the collaboration. Thank you.