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Sam Chang: Good day, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we are very fortunate today to have an expert in the area of upper tract disease, and actually, ablative therapy for upper tract disease. So this is Dr. Hristos Kaimakliotis from Indiana University. He's an associate professor there, focusing on urologic oncology. I've had the pleasure of knowing him for several years. And he was recently the first author of, actually, a multi-institutional review, looking at real-world practices with Jelmyto. So Hristos, first of all, thank you so much for spending some time with us, and I think he has some slides to go over.

Hristos Kaimakliotis: Thank you, Sam, for the kind introduction, and for the opportunity to be here, wonderful program. What I will do here is do a brief overview of the publication, and touch on some highlights here.

So essentially, this was a real-world experience on the use of mitomycin reverse thermal gel titled, "The Ablative Effect of Mitomycin Reverse Thermal Gel, and Expanding the Role of Nephron Sparing Preservation Therapy in Low Grade Upper Tract Urothelial Cancer."

And just as a background here, UGN-101, the mitomycin containing thermal gel, has been recently approved for the use of upper tract urothelial cancer and low-grade disease. The way the OLYMPUS trial was conducted, patients had to have tumors that were anywhere from 5 to 15 millimeters in size, meaning if they were larger, they had to be mechanically ablated down to 15 millimeters, and that may have required a couple of trips to the operating room.

And the efficacy in those patients was about 60% complete ablation, with a durability of response of 80% at one year. So the thought process here, since mitomycin has been used for a long time in bladder cancer, using it in the reverse thermal gel has an ablative effect shown through the OLYMPUS trial, that we could possibly obviate the need to downsize these tumors, or some tumors, and avoid mechanical ablation in the operating room. And sometimes that might be more than just one trip. Partial responders with the chemo ablative effect of this novel agent, if they had small disease leftover, could also be mechanically ablated, and considered or rendered disease-free at the end of the first ureteroscopy after UGN-101 treatment.

So the aim here, as mentioned earlier, was to assess UGN-101 efficacy in patients with larger tumors, or with all the tumors. Some patients could be biopsied only if they had a one-centimeter tumor, others were one to three, and some were larger than three centimeters. And we did this by comparing patients across three cohorts. Some patients had a complete ablation, meaning the mitomycin polymer was used as an adjuvant treatment, a six-course induction treatment, or adjuvant use in the upper tract. Some patients had a partial ablation. Even though we may think that we do a complete ablation, I think some of us are fooling ourselves if we think we did such a great job. There's no cells or tiny little tumors that are left over, and sort of the debris that gets created with ureteroscopy and ablation. And then patients who just had a quick biopsy. Go up their ureteroscopically, cold cut biopsy, your method of choice, basket, BIGopsy, and then we go on to treatment.

Part of the primary outcome was patients who had a complete response. And again, rendered disease-free was complete responders, and adding up patients who had minimal ablation if they had a partial response.

A secondary analysis was looking at the size of the tumor to see if that matters. Complete responders were had a zero tumor, zero-centimeter tumor at the time of UGN, then one centimeter, one to three, and greater than three.

This is a quick flow chart showing that of the entire cohort of patients from all 15 centers that contributed to this initial real-world experience, some patients were actually treated for imperative indications, meaning they had high risk, they had high-grade tumors, and unable to tolerate surgery. Those patients were excluded. To get down to a total cohort of about 112 patients that we thought were truly low-grade patients.

Of those 50 patients had a complete ablation, 42 patients had a partial ablation, and 20 patients had a biopsy only. This is the demographics table. I know it's a little busy, but the big point here, there's not any significant differences in the patient cohorts, or the way they were treated for this retrospective review.

This table is the main results section, essentially breaking down the cohort from complete responders. Among patients who had a complete ablation, 76% of those patients had a complete response, which is higher than those who had a partial ablation at 40%, and a biopsy only at 53%. But when you look at rare disease-free rates, the response rates are quite similar, 78% incomplete ablation, meaning that if they had a small recurrence and you can mechanically ablate that either with laser or fulguration, that number goes up to 78, and partial ablation goes up to 57%, and 66% in the biopsy only.

When you break this down by size, it did not really make a difference in terms of response rates. Again, rendered disease-free response rates, 78%. The complete ablations, 87% for tumors that were less than a centimeter, and 52% for one to three, and 66% for patients that were greater than three centimeters. Among the patients that were greater than three centimeters, 16 total, we had data on 12 of them, eight of those patients were rendered disease-free. Seven patients had a biopsy. Five of them were low grade, one of them was actually a negative biopsy but able to be rendered disease-free otherwise. And two of them were high grade. And some of the other patients that had biopsies during this initial surveillance were also noted to be high grade. And I'll touch upon that a little later on.

In terms of stricture rates, there was really no obvious difference in terms of whether patients were completely ablated, or based on size, or biopsy only, or partial ablation.

So to summarize the results from this retrospective review on some real-world early data of a novel therapeutic, the response rates on whether we biopsy only or partially ablate or completely ablate are very similar, when we consider the ability to render these patients disease-free and spare that renal unit.


Stricture rates are very similar. But the thought process here was that, if you have to go into the kidney repeatedly to completely ablate, or downstage or downsize that initial tumor, we can cause a compounding stricture effect from an iatrogenic cause to the already stenotic effect that Myogel can induce.

And the incidence of high-grade disease, from this review and this article, in bulky tumors can be slightly higher. So this can be sort of a litmus test in these patients with bulky tumors. If truly this medication can ablate low-grade disease, it can bring to the surface the small focus of high-grade disease or a larger focus for that matter. We're only as good as the biopsy that we can take. And we all know how difficult it is to perform these biopsies, so it can reveal some high-grade disease when we think it's truly low grade, and treat accordingly at that point.

With that, I'll pass it on to you, Sam, for any questions.

Sam Chang: Hristos, thanks so much for that review of the article. From a realistic clinical standpoint, just some questions. First, were these patients, given the reverse thermal mitomycin C, were they given it via retrograde through ureteral catheters, or antegrade, or a combination?

Hristos Kaimakliotis: So it was about 50/50, actually. I personally give it via a retrograde approach, and I'll leave the stent in after my treatments. There was another publication that came through this group of 15 centers, showing that there was no difference. Patients tolerated that very well. And so, about 50% of doctors are now using it in that manner. And patients, I think it's about expectations, and able to facilitate that in some clinics in a faster manner.

Sam Chang: Yeah. No, that sounds good. And then, in terms of your current practice now, is your preference a single setting? Or tell me your algorithm now. Is it, hey, I'm going to biopsy treat single setting, because I don't know if it's high grade, low grade. And if it's low grade, I'm going to proceed next, or I'm going to try to ablate again. Kind of tell me your thought process after going through this data that you all help put together.

Hristos Kaimakliotis: So personally, when I perform the ureteroscopy, or a patient gets referred to me, even if they have a diagnosis of low grade, I like to get a lay of the land myself. So I'll go up, do the ureteroscopy. If it is a small tumor, and small for me, I'd say less than a centimeter. And if I think I can ablate it, I think that patient might benefit from complete ablation. And the medication can have a smaller burden of disease to have an effect on.

If it is a larger tumor, and I think that there is going to be disease left behind, I will do a quick biopsy, and if it's truly low grade, I'll come back and treat. I don't treat in the same session. I think there's some trauma that we induce with ureteroscopy. No matter how good we think we are at ureteroscopy with better tools nowadays, there's still some trauma, and any mucosal defect, or tearing, or injury, can lead to a stenosis. Not necessarily a stricture, a mild stenosis, because of the chemo desiccant effect of mitomycin has on these tissues.

Sam Chang: Yeah. No, I think that's a really important point regarding the use of this therapy, because obviously, you don't want to do harm, number one. Number two, you want to choose a therapy that's going to be hopefully beneficial. And so, by trying to do that all at once, I think, just like you said, you're only asking for a higher chance for possible sequela down the line here.

When you have patients with large volume then, determined to have low-grade disease, at least by biopsy, how many ureteroscopies do you do to try to clear it? Or do you say, "The biopsies we did were low grade, I was able to ablate some." Do you go back, or do you now, with this data say, "Let's give this a chance." For number one, treatment, to try to get a complete response. But then secondly, just as you said, if there's residual disease, that might be actually, like you phrased, a litmus test for proving high-grade disease. Kind of tell me your thought process now, now based upon this data.

Hristos Kaimakliotis: So you're only as good as your pathology report, and your pathologist at your institution. And I personally, I have faith in that. If it's low grade, I don't think I'm that good that I'm going to clear all the disease burden. And the OLYMPUS trial show this, that there is a chemo ablative effect. So I will give it the benefit of the doubt, and the chance and the opportunity to do what it's advertised to do. And I'm a believer. I've had some very large tumors, bulky tumors, that had a complete response. And some of them have residual disease, and I will just cut back my first ureteroscopy and ablate that if possible.

Sam Chang: Right.

Hristos Kaimakliotis: From there on, I will take that patient to a monthly maintenance treatment. If a patient has a partial response that's really not rendered disease-free, I'll biopsy it again, make sure it's not high grade, and either offer, at least in talking with all the people who are doing this from the 15th centers and sharing a lot of experience, either offer a second induction course, or move on from there if the patient wants to have a nephroureterectomy. But if you're able to get a disease-free patient, then I think a monthly maintenance, or even a break, or holiday from these treatments, is very reasonable.

I think this is all very early data. We don't know the exact correct protocol, and this is offering some insight into all these treatments.


Sam Chang: No, absolutely. That's why I think you and all the authors of this group, that's really put together, honestly, the largest series of ongoing real-world data with this, are providing insight. Just as you stated regarding, hey, there are clearly a group of patients that do respond, but you have to be careful about strictures. You have to consider not missing high-grade disease. These are all parts of the algorithm to determine who's best fit to proceed with therapy, maintenance therapy, or switch over to something more invasive, such as nephroureterectomy.

So I want to thank you for spending time with this. But honestly, thank you so much for you and this whole cohort, in terms of trying to get more information of real-world experience. Because that really, I think, helps guide clinicians as they start doing this. Or at least start considering this in their armamentarium.

So Hristos, it's always great to see you, appreciate your efforts. Look forward to seeing you at upcoming meetings, and thanks once again.

Hristos Kaimakliotis: Thank you. And thank you for the invitation.