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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center. And we are quite fortunate today to have Dr. Jennifer Linehan. Dr. Linehan is the Associate Professor of Urology and Urologic Oncology at St. John's Cancer Institute in Santa Monica, California. I've gotten to know Dr. Linehan over the past several years, and she is truly an expert with upper tract urothelial carcinomas and different types of treatment interventions. And so she's going to give some highlights today on topical chemotherapy interventions that we have now available for upper tract disease. So I'm going to turn it over to Jen. Thanks so much for spending some time with us.

Jennifer Linehan: Thank you. Thank you very much for having me this morning. So we're going to talk a little bit this morning about the best route of administration for UGN-101, otherwise known as Jelmyto. And when I originally did the OLYMPUS trial, there were very few of us that were giving the treatment through a nephrostomy tube. In fact, I didn't even do that during the trial. It wasn't until later that I figured out that this was a much easier mode of administration, I think both for my clinic and for the patient.

So we wrote a paper in May of 2023, and this was in the European Urology Focus Journal. And we were talking about what were the best routes of administration. And we looked at this data in 15 very large centers across the country that had collected their data. Many of them had done nephrostomies, many of them had done retrograde. We put this together to try to come up with a plan for, one, did the antegrade administration work for both renal pelvis tumors and the ureter? Because that was the real crux of whether we could use it with this instillation mode.

And then also, do you get decreased strictures if you're not going back in retrograde six times once a week that could cause strictures? So were we getting the best oncologic outcomes, and were we decreasing the strictures, were what we really wanted to answer when we looked at the data from across all these institutions.

So what were the patient characteristics? And of course, this is important for several reasons. So there were originally 136 kidneys from 132 patients, and 78 had retrograde administration, and 58% had antegrade administration. And if you broke down the groups by where the tumors were, for the antegrade group, 45 were in the pelvis. We had only had three patients that had ureter only, and then 17 had both. And if you looked at the retrograde group, you had 56 of the patients were in the renal pelvis, 12 in the ureter. So a higher proportion were in the ureter. And then 32 of the patients total had the tumors in both groups.

And most of the patients had at least one to two tumors. 9% of the patients in each of the groups, whether you were retrograde or antegrade, 9% had high-grade tumors. And even though UGN-101 is not recommended for high-grade, there still were some patients in that group that got into our registry of the patient data. And I think another important point is to look at the patients who had complete ablation prior to getting the Jelmyto because if you're doing chemoablation, which is where you're leaving the tumor, maybe half treated it, but there's still some visible disease when you left versus patients that were completely ablated, I think that that is an important point in the treatment of upper tract with the Jelmyto.

And so in this case, 56% of the patients that had antegrade were completely ablated before they got their Jelmyto treatments, and 36% were retrograde. And I'll show you in another slide here why I think that is important, because it may have somewhat changed the oncologic outcomes. Now, when we looked straight at the oncologic outcomes, again, let's talk about the chemoablation. So these were patients that there was no lasering of the tumor, there was no real treatment of the tumor, there was no resection. They basically went up, saw the tumor, and left the tumor intact. And that was 64% of the patients that had the retrograde administration and 48% that had antegrade.

And remember, the majority of these patients had one to two tumors, maybe three tumors that were about three centimeters. There was a very low proportion, about 12%, that actually had tumors that were over three centimeters in these groups. But of this group, 48% of the retrograde had a complete response, meaning we went up there, looked, there's nothing left over, and 60% in the antegrade.

Now, that's where that data I was talking about, where we looked at the patients that had complete ablation, is important, because in that group of antegrade patients, the 60% that had a complete response, was that group higher because some of them had a complete ablation? And I think that's some of the data that we're still teasing out. And that's why you're seeing a lot of papers coming out from the group because with upper tract, there are so many fine different points to look at that we're trying to gather all that data and put together I think what's most important.

But again, for this paper, we really wanted to look at, are you going to get the same response with UGN-101 from a retrograde and antegrade approach? And then of course, are you going to get decreased strictures? Now, the other thing that we're trying to look at with this data is if you're using Jelmyto you're trying to do a kidney-sparing procedure, so you're trying to preserve the kidneys. So, how many of the patients in both of these groups ended up needing a nephroureterectomy?

So in total, of the 132 patients, seven of the patients needed a nephroureterectomy. Six of those patients had grade progression, meaning they all had high grade to some degree. There were two of them that were actually T3. And there was one patient in the group that just decided they didn't want to have the UGN-101 anymore, and they proceeded to nephroureterectomy. And of those seven patients, three of them were in the antegrade group. But I don't think that in itself is statistically significant.

So now if you actually look at the clinical outcomes, and one of the reasons that I wanted to put this slide up here is that we look again at the complete response. So that was 60% in the antegrade, 48% in the retrograde. And that was almost statistically significant. But if you look at the partial response, meaning we still went back up there and there was a tumor, it was 32% in the antegrade, 28% in the retrograde. And if you look at the recurrence rates in the antegrade administration, there was 23% that had recurrence, and there was 13% that had recurrence in the retrograde.

So this data is sometimes very hard to tease out because you're looking at multiple variables among these patients that are going to make a difference: where the tumors are, how big the tumors are, what grade the tumors are, and then now our route of administration. But I think really what the paper proved to me, most importantly, is that whether you give this antegrade or retrograde, you are still getting the same level of complete response that we saw in the OLYMPUS trial that we've seen in other papers that have come out from this group. And this is a durable response because giving the treatment antegrade is really much easier for the patients, I think, in a sense, because they're not having to undergo cystoscopic procedures in the clinic. You're not having to do anesthesia with these patients.

And for a lot of these patients, if you work in private practice, it's easier to administrate antegrade because they just deliver the gel. You put it down in the nephrostomy tube and off the patients go. So I think this data signified to me that we are getting the same oncologic outcomes, whether you're giving antegrade and retrograde, perhaps a little better oncologic outcomes with a complete response of 60% versus 48%. And so that this is at least a viable administration route for most of us.

Go back. So what is the second part of this paper? The second part of this paper is, can we avoid strictures? Now, when they originally looked at the Olympus data, there was almost a 41% stricture rate. But I always tell my colleagues that that was based on data that really was very, very stringent. I mean, any patient that even had mild hydronephrosis, even if you didn't treat it, if there was anything that signified any kind of obstruction, that was considered stenosis in the trial. So when we went back and looked at the data from these 15 institutions, we tried to pull that apart more and say, "Okay, who were the patients that really, really needed intervention? Did you need to put a stent in? Did you need to put in a nephrostomy tube during when we were treating them?"

So the patients in that category, those were Grade 3, where you actually had to do intervention. And those were 21 cases that was 32% of the retrograde cases and six cases in the antegrade. So we definitely had a decreased stricture in the antegrade patients that needed intervention. And again, this data is very hard to tease out because a lot of the patients, because of the procedures that they underwent to either get the biopsy or to treat the tumor or originally may have already had a stent in place at the time that this was all done, or they may have already been obstructed. I mean, many of these patients were found because they had hydronephrosis on their initial evaluation.

So we really wanted to look at who were the patients that after they got their induction treatment, and that was again once a week for six weeks, actually needed intervention at any time point after they received their treatment. And if you look at that data that again, any time after induction that was antegrade, that was about 15 of the patients or six cases, and then again, 27% or 14 patients that actually needed stent intervention.

So I think this demonstrated to us that, one, the antegrade did have fewer strictures, and two, there was a decreased stricture rate from the original OLYMPUS trial because these were really the patients that actually needed intervention, not just those that had some evidence of obstruction. And I think that was, for me, the biggest difference. Now, I did throw this paper in here as a bonus paper because the question I get asked most about UGN-101 is, "Can I use it to treat ureteral tumors?" And doctors will call me from all over the country and be like, "Hey, have you given any antegrade administration for solely ureteral tumors?"

And I have a lot in my practice, and it does work very well. But there's actually a paper out on this right now, that you can see that demonstrates the effectiveness even in ureteral tumors. So again, they were the same, 132 patients, 136 cases, and 47 of those patients had ureteral involvement. Now, 23 of the patients had ureteral tumors and 47% had a complete response. And again, that complete response rate is in line with our data that I just presented from the antegrade administration, as well as the data from the OLYMPUS trial.

37% of those patients who had ureteral tumors already had ureteral stenosis at baseline. So again, there's already evidence of obstruction. But of those patients, only 5% of them actually needed intervention. So I think if you're looking at treating ureteral tumors with UGN-101, whether you're antegrade or retrograde, this is a viable method for that. And I think the antegrade administration does work very well for these patients.

Again, you're looking at similar complete response rates as well as decreased stricture rates. Now, they did in this paper also look at retrograde versus antegrade administration. Nine of the patients had retrograde, two of the patients had antegrade, and those are the complete responders. And again, I know the numbers are low, but we are still continuing to collect data across those 15 institutions all the time. And I think as the popularity of UGN-101 is growing, we're going to see more and more of what it can do and if we're going to be able to prevent patients from having strictures.

And if you look at their complete response rate again in this group, they had a good complete response. The typical about 20 to 30% partial response and about the 20 to 30% no response. So overall, I'm very happy with this therapy and I think the data and the results that we're seeing are showing that we can give this antegrade, we can treat ureteral tumors, and we can decrease strictures. Thanks.

Sam Chang: Yeah, that was a great overview. So, Jen, thanks so much for the highlights there on two important points. One is obviously the antegrade administration and the focus on the oncologic safety and efficacy. And we struggle with the second kind of points that you brought up regarding ureteral tumors and the ability to treat those successfully either with a retrograde or antegrade.

And let me focus on that second kind of group that you discussed. So as you do it with the antegrade, we get a measurement of the renal pelvis, we get a volume estimation, and that's the amount that we'll put. Do you do anything different for your ureteral tumors? Do you give more? Do you give less? Is it the same amount to fill the renal pelvis? That's just one kind of specific technique question.

Jennifer Linehan: Yeah, so I always just base it on what's going to fill the renal pelvis because you don't want to overfill the pelvis. I had one patient that happened to when I was doing the trial, and I actually got some administration of the gel. So I stick very stringently to what the renal pelvis can hold. And I find that you don't need more or less essentially to treat ureteral tumors.

Sam Chang: Okay, great. So along those lines of the day of administration, I would love a couple of other tips that you've learned using the antegrade administration method. These are the things that I've learned over time that are really useful on the day of administration. Anything that comes to mind?

Jennifer Linehan: So there are many things I've learned. One, when you first put the tube in, I have a lot of patients that come to me from out of town. They may be three, four hours away. They'll be like, "Can I get my nephrostomy tube placed and can I have Jelmyto the same day?" So I've done this a couple of times. My biggest comment is that it's okay to do, just make sure that the urine is not particularly bloody.

I find that the patients, when they put the nephrostomy tubes in and sometimes it's a little bloody, there's a vein or something, if they're not relatively clear, I would hold off on your administration. I feel like those patients had more pain, and I don't know if that was from obstruction or just the nephrostomy tube placement. But if the urine is clear, directly after they get the nephrostomy tube, I feel like it's okay to give the Jelmyto. In general, I would recommend at least waiting two or three days before you do the administration.

I also found some tips about when to remove the tube. So there were a couple of times that I would, okay, they've come in for the last treatment, everyone's really excited, we'd give the Jelmyto and I'm like, "Oh, I can just give the Jelmyto and remove the tube." Not the greatest idea. Mostly because I got some skin irritation. So there must have been maybe some of the UGN-101 that was left on the tube or skin, and the patients got rashes. So now, we do the sixth treatment, we wait a week, and then we take out the nephrostomy tube.

For my radiologist, I had a couple of occasions where the patients, like the collecting system, the renal pelvis, wasn't very dilated, and they were having some trouble putting in the nephrostomy tubes at times. So in a couple of patients, I would go up retrograde, do the original biopsies, and I would actually leave a small stent in, and that would help the interventionalist find the collecting system more easily. Or I could sort of guide them to where I wanted them to place the nephrostomy tube.

But honestly, for all the patients that I've treated, it didn't even matter where the nephrostomy tube was because the gel disperses throughout the collecting system, no matter where you place the tube.

Sam Chang: No, I love those tips. And you went straight to one of the points I was going to make or ask you about: the preparation work is important, the process is important. Your point regarding placing it on the same day can be safe if you're careful. And then our practice has been to leave the actual nephrostomy tube in for a week, and we've been perhaps too much on the cautionary side. We've actually done nephrostograms a week after our last treatment to make sure there was no stricture before we pulled the nephrostomy tube out. So that's why I was wondering what you do.

You wait at least a few days. If things look good, then you remove it. Okay, great.

Now those are all really important points as you go through the process of treating these patients. Are there patients that you would try to avoid? Let's take off the high grade. Let's say these are low-grade tumors. Are there particular patients where you think that perhaps UGN-101 would not be a treatment that you would advocate?

Jennifer Linehan: I mean, obviously, for me, young patients with high-grade disease are not the patients that you want to treat. I think if there are patients that have obvious invasive disease on imaging, even if I've gone up, looked up there, my cytology was low grade, my biopsies were low grade, if it looks like the tumor is invading the parenchyma of the kidney, I mean, I don't think those are the patients that are the best candidates for UGN-101.

So I definitely still use my radiologic criteria as well as what I see. I will say I have become a bit more bold about the amount of tumor as long as it looks like it's not invading the renal parenchyma. I mean, I've had some patients that do have some bulky three, four, five-centimeter tumors that are in the renal pelvis. They don't look like they're in the parenchyma, and we have treated those patients.

So I think for me, it's really the parenchymal invasion and age is also a factor. I mean, I have used Jelmyto in higher-grade patients that are over 77, in their 80s. And we've put in the nephrostomy tubes and tried to treat the patients, I think more conservatively in those cases. But I think, like I said, the CT criteria of parenchymal invasion, especially in younger patients, for me, I would not mess around with it.

Sam Chang: Yeah. Excellent point. And then the last question, Jen, is, and this is a question that we get asked about as well, what is your take on maintenance therapy? Is it something you routinely do? If yes, how long? If not, and you do it occasionally, who are the patients you recommend maintenance for? Give us your take on maintenance therapy for UGN-101.

Jennifer Linehan: So I have not, to be honest, embraced maintenance therapy yet. But I have a few patients that are younger who had more tumor burden than I think would be very good candidates for maintenance therapy. But in those patients, I will have to go back to retrograde administration because I don't think they're going to want to keep the nephrostomy tube in for a year. So it becomes a little bit more difficult in that setting. Am I able to use the nephrostomy tube? Or are you going to keep the nephrostomy tube? But I do think it's an important part of UGN-101, and I think there are many of us that have embraced the maintenance therapy, and we'll see that data come out. But I have not yet done that for myself or my patients yet.

Sam Chang: Oh, great point. Appreciate your experience and your tips, Jen, especially as we try to determine which patients would benefit the most, which route would give us the highest safety profile. And it's very reassuring to have the oncologic data that you just presented in the antegrade method. That's what we've used at Vanderbilt, and we've used that exclusively. And knock on wood, to your point, the response rates have continued to be high, and the stricture rate definitely, I think, is along the lines of, and less than, actually, what was reported in the OLYMPUS trial. So thanks again for your insights and your experience, and look forward to talking to you in the future as more data accumulates with this large registry.

Jennifer Linehan: Great. Thank you so much.