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Sam Chang: Hi everyone, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and we're very fortunate to have Dr. Joseph Jacob, who's the director of urologic oncology and an associate professor at Upstate Medical Center in Syracuse, New York. He is actually going to be giving us an update on a registry trial that's looking at the effectiveness of Jelmyto or UGN-101 in the treatment of ureteral tumors. A diagnostic and treatment area that I think all of us struggle with in terms of what we need to do. We don't want to be too dangerous, and yet I know we want to be nephron-sparing. So, I want to thank Joe for spending some time with us, and I know he's got a nice presentation going over some of the data that's been accumulated.

So, first of all, thanks so much, Joe. I appreciate it very much.

Joseph Jacob: Thank you, Dr. Chang. Appreciate having the opportunity to be here. All right, so I'm Joe Jacob from Upstate Medical Center. I'm very honored to be here with Dr. Chang. I'm going to talk just briefly on the treatment of ureteral tumors with Jelmyto. It's a tricky subject, but I'll try to cover it here. So real quick, we're going to just talk about the patient population that was studied. We're going to try to understand the heterogeneous treatment patterns all over the country, and we'll review some outcomes. So, just to give you background on where this data came from, after the OLYMPUS trial was published in about 2020, there were a lot of people that started using Jelmyto in various ways. As you all know, probably when you look at the OLYMPUS trial, this was a very selected cohort of patients. They were only renal pelvis tumors of a certain size, and they were studying the ablative efficacy of Jelmyto.

So what we did is, we pulled together 15 of the highest-volume academic and community centers in the US, and it was actually a great collaboration. Everybody sort of shared their data, and everybody was very collegial. And we sort of tried to answer some questions. One thing we found is that Jelmyto was used for many different clinical scenarios, much more broad than we expected and more broad than the OLYMPUS trial allowed. This was a patient population that was treated between 2020 and 2022. And what we wanted to do was ask the question, is anybody treating ureteral tumors with Jelmyto, and how are they doing it? And does it work, or is there even a signal there? And so, that's what we'll focus the presentation on.

So one thing that, again, we understood was, everyone was doing things a little differently. We had groups that were doing retrograde administration of Jelmyto. We had groups that were putting neph tubes in and doing antegrade administration. People were using it in the adjuvant setting, so they were using laser or fulguration, or whatever they were using, and completely ablating these tumors and then using it in the adjuvant setting. And then some people were using it in the ablative setting, meaning that there was still tumor there that needed to be treated. And then some people were using six weeks of induction. Some people were doing induction plus maintenance, and then sort of a spectrum in between. And what we did find is... It was actually a significant number of patients with ureteral tumors that were treated. And this was a patient population that had never really been described before because these patients were excluded from the OLYMPUS trial.

So this is sort of how we came up with our 23 patients. I know 23 patients sounds like a very small number of patients, but this is the largest cohort described. And as you know, it's a rare disease, and there aren't that many of these tumors across the country. So what we did was, we pulled the whole cohort together. At that time, it was about 140 patients, and then we looked at the patients that were completely ablated, and we wanted to get rid of those. We wanted to see if there was actually an ablative, if the Jelmyto had a treatment signal. So, we wanted to look at ureteral tumors that weren't completely lasered or ablated. We wanted to see if Jelmyto actually had an efficacy signal. So, we got rid of all the ureteral tumors that were completely treated. And we only looked at those 23 patients that had disease in the ureter at the time of Jelmyto treatment.

Your typical patient population, I mean, most of these patients were white men that smoked, with various different patient factors. So a handful of these patients had recurrent disease. Some of these patients had solitary kidneys. And you can see that there was a small percentage of patients that had high-grade pathology in this cohort and various stages. Most of these were stage TA on biopsy and then a heterogeneous group of tumors. So the number of tumors was anywhere from one to more than three. And if you see like that, the ureteral tumors were more often associated with multiple tumors because a lot of these patients had renal pelvis tumors. And then, I think, with seeding, they developed ureteral tumors as well. And various sizes too, anywhere from less than a centimeter to over three centimeters. And about 30% of patients had big tumors over three centimeters. And like I talked about before, a handful had retrogrades in the OR. A handful had retrogrades in the clinic, and then some had an antegrade with a nephrostomy tube. Antegrade treatment with Jelmyto.

And by the way, just so everybody knows, people always ask this, Jelmyto was administered into the renal pelvis. So no Jelmyto was administered in the ureter. Anyway, so these are the results. Out of these 23 patients, about 50% of patients had a complete response. I mean, they started with a tumor in the ureter, and at post-induction, whenever the treatment team decided to look inside, 50% of these tumors completely melted away. 26% of these tumors showed a partial response, and then 26% had no response. And this was all based on whoever the surgeon was and whatever their assessment was on their operative note. And one thing we wanted to look at as well was safety. We found that about 5% of patients developed new ureteral stenosis, and we defined that as something significant where it would require some kind of intervention. It really was up to the administering physician to decide if this was a significant ureteral stenosis that required intervention.

One thing that was important is, a lot of these patients presented with hydro and presented with ureteral stenosis just because of the nature of the disease. But if you look at the patients that developed new ureteral stenosis, it was about 5%. Obviously, there are a lot of limitations. And we want to be completely upfront with this. I mean, this is a heterogeneous patient population, sort of all over the country. There wasn't a set defined... this was retrospective data. There wasn't a set defined treatment algorithm or treatment approaches. This was a very small patient population. It was 23 patients, and with relatively short-term follow-up, most of these patients had about a year's worth of follow-up. And there was heterogeneous surveillance, I mean most people were doing post-induction ureteroscopy, but some people were doing CT scans, some people MR urogram, sometimes CT urograms. So it was a heterogeneous population. So, I don't want to make grand assumptions based on this heterogeneous, small patient population.

So, I just wanted to be completely upfront with that. But that being said, I do think that there appears to be an efficacy signal there that's worth thinking about. And this is sort of the first time that we're talking about treating ureteral tumors by giving a chemotherapy gel in the renal pelvis. I think it's worth sort of, at least, studying further and thinking about, and it looks like it's safe. It was only about 5% of the patients that developed new ureteral stenosis.

Thank you very much for letting me be here. It's an honor to be here with Dr. Chang.

Sam Chang: Joe, that was fantastic. I want to talk a little bit about the success and then talk about that stenosis, and then kind of the follow-up surveillance question. Those are three areas I want to focus on. When you look at that, I mean, I think everybody's impressed with the 50% CR rate, which is fantastic. I know with small numbers it's hard to say, are distal tumors just as likely to respond as proximal? Did you find that out? And then, I guess, importantly, with these many times we do biopsies, many times we'll do lasering, some lasering, not a lot. Sometimes we just biopsy and find out what we've got. Tell me kind of the success of distal and then whether or not there was some laser ablation or if that was hard to track.

Joseph Jacob: Sure, yeah. Great questions. So it was small numbers when we did try to tease out proximal versus distal, but you're talking about numbers in the tens, and it didn't look like there was a big difference in efficacy there. So it seems to be effective, but again, with the caveat of very small numbers, everyone sort of sees, when you give Jelmyto, that you start seeing discoloration of the urine. And so, you assume that this is starting in the renal pelvis and then coating the ureter, and then makes its way down to the bladder. So, from a theoretical standpoint, I can't see why we couldn't treat distal tumors. So that, hopefully, is an okay answer to your first question. Your second question, so there was a heterogeneous group, and that's one of the reasons why we wanted to get rid of all the patients that were ablated. So there were a bunch of patients that were completely ablated with laser or fulgurated in the ureter, and we got rid of those patients.

We could maybe talk about those patients at a different time or different paper. But we got rid of those patients because we wanted to see if Jelmyto actually had an effect on active, present ureteral tumor.

Sam Chang: Oh, fantastic. I think everyone has a concern about the ureteral stenosis. So that new stenosis rate of 5%, I think, again, caveat small numbers, but it's encouraging, especially when considering or thinking that, "Boy, you've got a much smaller kind of possible variability with that ureter tube as opposed to the renal pelvis." With those 5%, obviously, that's a small one or two patients, basically. Was it long-term? Again, caveat small numbers, but I'm just trying to figure out... I think people will accept transient stenosis, narrowing, etc., short-term stent, etc. It's the long-term kind of stenosis that people worry about. And I don't know where that 5% is probably a single patient. Did they have long-term issues, or you didn't find that?

Joseph Jacob: If you look at the whole cohort, there were a small number of patients that had long-term issues. Most of the patients that had ureteral stenosis you could treat... a lot of the centers would treat with steroids, temporary stent, and then it would resolve. And it's a great question, and I don't know what happened to that one or two patients. I could find out. But if you look at the whole cohort, a very small number actually developed long-term ureteral stenosis.

Sam Chang: Encouraging to hear. And then the last point, which I think everyone... and I'm sure that's why you get this heterogeneous... so I would love to know your follow-up kind of regimen at Upstate for these patients with ureteral tumors. And you don't have to say specifically about Jelmyto. Is your kind of practice to do an initial three or four-month ureteroscopy? Is it imaging? Tell us what you do personally with these patients.

Joseph Jacob: I will do ureteroscopy at three to six months, and I'll mix in an MR urogram or CT urogram every six to 12 months. But I really do think it's important to do ureteroscopy. I think we miss a lot of small tumors on the urograms.

Sam Chang: I totally agree. I guess the thought process, and I struggle with this is, if that initial one is clean, then I tend to get CT or MR urogram. And honestly, if that continues to be clean, I tend not to do a repeat. There are others at one year or later on who will take another look. And I guess it's case by case, but I think the fact that you have early CRs and if you look at the Jelmyto data for the renal pelvis tumors, a significant number even without maintenance, definitely tend to have a long-term response. So it'll be very interesting to see the longer-term kind of follow-up for these patients that had a CR, at least a partial response, and go from there. So, Joe, what's next? What are you guys going to be looking at examining anything prospectively, or what else are you going to be looking at in this large multi-institutional database?

Joseph Jacob: Yeah, I appreciate it. So right now, UroGen is putting together a prospective registry, and it's very similar, basically the same sites, but we're just going to start following people more prospectively. So, I think it'll be cleaner. I think we'll be able to ask more questions. I think a lot of... The others in the group have been asking some of these questions, like, "Do you do maintenance? Do you ablate? Do you do adjuvant?" And so, I think it's a lot of interesting questions. And one thing that's sort of cool about this cool data is, if you're seeing sort of what everybody does across the country, it's real-world data. So it's kind of nice to see what everybody else is doing.

Sam Chang: Oh, absolutely. And learn from each other, for sure. I think those are the best parts of these collaborations. So, Joe, thank you so much for spending some time with us, and we look forward to the next iterations, the prospective files of larger data, longer follow-up, and we look forward to having you again soon.

Joseph Jacob: Thanks, Sam. Appreciate it.