Sam Chang: Hello, everyone. My name is Sam Chang. I am a urologist in Nashville, Tennessee, and work at Vanderbilt. And we're quite fortunate to be joined by Dr. Jonathan Coleman. Jonathan is a full member at Memorial Sloan Kettering Cancer Center, MSKCC, some people just call it MSK. He is actually also the vice chair of the Department of Surgery there, which includes the division of urology, and is a full professor at the Weill Cornell Medical Center. Dr. Coleman was actually a resident when I was a fellow at Memorial Sloan Kettering, and so we have a long history. But I think, more importantly, Jonathan has become a leader and is actually the chair of the most recent AUA guidelines, actually the new guidelines on upper tract urothelial carcinoma. And he's been doing work with upper tract disease for quite some time.

We wanted to discuss today the recent Journal of Urology article that was published in 2023, looking at, actually, an exciting option for therapeutic advances for upper tract disease, looking at photodynamic therapy. Which has been around for different types of carcinomas for some period of time, but there was a recent publication led by Dr. Coleman, and led by and actually first authored by Wesley Yip, a fellow currently at MSK.

So, Jonathan, that was a long introduction. It was worth it because I wanted to make sure everybody understood the history as well as kind of your background and your work. But thanks so much for being with us, and let's look at some of the slides going over this manuscript.

Jonathan Coleman: Well, thanks, Sam. And yeah, thanks for the introduction. And yeah, I guess it was in the days before electricity, so we somehow survived it. But yeah, thank you for the opportunity to be able to present some of the work that we've been doing in upper tract disease. And I'm just really fortunate that we're able to work in a place where we can work in rare diseases. There's not a lot of places out there where you can really develop and build a program in rare cancers, and we're just fortunate to be a place like Memorial where we can do work like this. It's been a pleasure working with Wesley Yip. He's one of our outstanding fellows, and he's going to City of Hope next year as a urologist there and I know he'll make a big impact in the field.

Sam Chang: Oh, a true win-win.

Jonathan Coleman: Yeah. So this is some of the work that he presented at the AUA this year, and I'm going to try and share my slides that he prepared and presented, just to go over some of the work that's come out of the lab.

So these are some of the slides he presented looking at this therapy, which is a new form of photodynamic therapy that we've applied to the upper tract. And many people know this drug was called TOOKAD Soluble. It was used successfully in treating patients and men with prostate cancer and has been approved for the treatment of prostate cancer in Europe and Central and South America and Israel, and now we've applied it to the use in upper tract disease.

So essentially, in looking at patients with upper tract cancer and trying to understand what we're doing in upper tract disease, one of the biggest problems that we face is that we're probably overtreating many of these patients by removing their kidneys. And there are a subset of patients that are sort of well described in the new upper tract guidelines that are amenable to forms of localized therapy, including laser-based therapies and electrocautery-based therapies, for which we can offer treatments such as localized therapy and kidney sparing options. The problem is that that's often underutilized. So overtreatment can occur in up to 90% of patients with upper tract disease, and so identifying these patients and being able to provide effective options is important.
We all know that up upper tract tumors can be superficial. And we describe these in the guidelines as being sort of the easy patients to treat, are going to be the low-grade patients, that are unifocal tumors, that don't have any evidence of obstruction or invasion in the collecting system. And so being able to treat these effectively can be somewhat challenging.

So photodynamic therapy has been around for a while. Vascular photodynamic therapy is sort of a new form of this treatment. And I would just say that vascular photodynamic therapy just means that the drug stays within the vascular system. So it doesn't get absorbed systemically, and so, therefore, it gets cleared very rapidly. And so it's been FDA approved for the treatment of endoluminal tumors within the urinary tract as well as other forms of early esophageal cancer and for biliary cancers.

And so we just really wanted to apply this new form of treatment which is called padeliporfin. It's derived from chlorophyll. So it's safe, it's something that's naturally found in the environment, but it's been slightly modified to be able to be used in humans and to use a special type of treatment modality that works on the vascular system of the blood vessels. And so when you illuminate the cells after giving the drug intravenously, you create this massive storm of reactive oxygen species that occurs within the tissues, and that leads to a form of athermal cellular necrosis, which means that you kill the cancer cells very rapidly but without using any type of heat or freezing to do it. And so, one of the advantages of this approach is that you can kill cancer cells, but you leave the normal tissue scaffolding in place. And so we've done a number of studies showing that you can leave the normal collagen in place after this type of treatment so the tissues can remodel and heal fairly effectively.

So this was a phase one study, basically, just done at our institution with about 18 patients that we treated who had upper tract cancers. These were a range of cancers. So this is a phase one trial. We took patients with either high or low grade cancers, patients who were not amenable to standard surgical therapies. Many of them had solitary kidneys, so we were doing everything we could to try and prevent them from going on to kidney removing surgery.

And basically, the treatment was done with a 10-minute infusion of drugs. So a patient's brought to the operating room, placed on the table, they get the drug for 10 minutes intravenously. And then, after the 10-minute administration of drug, we then illuminate inside the collecting system with a laser fiber for a period of 10 additional minutes. And then, after that, we remove the scope, we remove the laser fiber, and then patients are allowed to recover and go home on the same day.

And so this was a dose escalation study using three different dose levels, basically starting at a very low light level initially and then going up to higher light doses inside the collecting system. And a small number of patients were allowed re-treatment after the 30-day treatment interval that we had. So day zero was treatment, day seven was a repeat endoscopy to see what the effects looked like, and then day 30 was sort of the final follow up to see whether they had had a response or not, and then a few number of patients were retreated within the six-month interval afterwards.

As I said, this was a dose escalation trial starting off at a very low dose then going upwards. This used something that was a great design. It's called a CRT model, which is a Bayesian dose-escalation model. So that means that you start at one light dose, you don't have to go through multiple doses at the same level, you can kind of move quickly up to your dose limiting toxicity, and so it allows you to move through your dose levels a little bit more rapidly. So we went up to a maximum dose of 200 milliwatts per centimeter.

And a total of 22 patients were enrolled. 19 patients ended up being treated and were evaluable for the MTD at the end of the trial. We had one patient we had to remove for non-compliance, basically somebody who got treated initially but then was unable to follow up afterwards. Remember, a lot of this happened during Covid, so we had a hard time with dealing with some patient issues during the trial. So we had 18 patients altogether who were available for the final analysis, and that was the number of patients that we needed to treat to look for the primary endpoint of the study, which was the MTD.

So this was the age and the criteria we had. A note, that most patients had low grade cancers, but we did treat some patients with high grade. And this will play a role later when we kind of look at the outcomes, because patients with low grade tumors tended to fare a little bit better than the patients with high grade. And the tumors, some of them were very large. Almost half of them were over 15 millimeters in diameter, so we did treat some larger tumors in this trial. And many patients also had multifocal tumors, which predicts for a worse outcome.

And then we had a small number, about eight patients, who ended up getting retreated, and here are the dose levels of the patients who were treated during the trial. So we moved quickly up to the higher dose level at 200 milliwatts. And that was the MTD for the trial, so this was the actual final dose that was found to be the maximum tolerated dose for the patients. And then as far as looking at responses, we had roughly about 50% of patients had a complete response initially after just one treatment. So that's a pretty good outcome for a single therapy. Keeping in mind that if you treat patients with even just a standard laser, that the recurrence rates can be as high as 50% to 60% within the first three to six weeks after treatment. And then we had some partial responders, which is also very typical for what we see in upper tract, especially in some of the larger tumors that we see. So we thought these were very encouraging results, and this is really what, I think, led to the decision to go on to a larger phase three trial.

Just to see what the effects look like, I think these are sort of interesting slides to see, and that is that this was day zero in one patient with a low grade, fairly small tumor inside an infundibulum. These can be tough to treat because you're really trying to get just around the edge of the tumor and not go deeply in, and you also don't want to cause infundibular stenosis that can occur with standard thermal types of therapies.

But we treated by just simply placing a laser fiber in the middle of this. We came back seven days later and we saw all of this stuff that was kind of sitting around. And this turned out to be just avascular collagen. There was acellular material left here. So if you took all this out, it's just simply the leftover collagen after the tumor cells have died away. And you can see that there's really not a lot of infundibular stenosis here. This opening is roughly the same as it was before. And then this is what we saw at day 30 follow-up, and there was no residual tumor. And we biopsied all around this area, and this all came back as negative.

In the lower panel, this is a patient who had a high grade multifocal disease involving mostly the renal pelvis and some of the lower calyces as well. And so this patient we actually treated with two different laser fibers in the same setting. We put one into the lower pole and one into the middle pole and treated. And at day 30, this is what her outcome looked like radiographically, and there was no evidence of any residual disease that we saw in her. This was a solitary kidney and multifocal high grade cancer that she had. Later on, this patient ultimately did recur within six months later. But again, that's something that's fairly typical for patients with high risk or high grade upper tract disease, is that there's recurrence. And we didn't have the ability to retreat this patient on the trial unfortunately, because the trial was over after she recurred.

And then, just as far as dose limiting toxicities, we had no dose limiting toxicities at the slightly lower doses. We had a few at the higher doses, but most of those dose limiting toxicities were pain related. And one of the things that we did in the trial is we mandated that all patients should have a stent placed at the time of treatment, because we wanted to avoid any confusion that may come from patients that can sometimes have renal colic or a spasm in the ureter after just a standard ureteroscopic procedure. So the use of stents after even just standard ureteroscopy is, I wouldn't say controversial, but there are some people who stent all cases, some who stent none, and then others who stent selectively. So we just said, "Let's just take that issue off the table. We'll stent everybody and then that way it's not a factor. We don't have to worry about your renal obstruction being an issue as a possible dose limiting toxicity."

But what that ended up doing is we had a few patients who had a lot of flank pain after the procedure, which we believe was stent related. These patients all came back at seven days after treatment and we took their stents out at seven days, and all the pain that these patients were experiencing went away after we took their stents out. So we think some of these patients may have some reflux that goes up the stent after the procedure and their kidneys may be a little sensitive after the treatment, so they may have a little bit more stent colic than you'd expect. But once we removed the stents and stopped using stents, we didn't have this problem anymore.

And I'll just say anecdotally, in the trial that we're doing now, where we have a phase three trial, it's a multi-center trial being run at multiple institutions here in the US and internationally, and we don't mandate stents for that trial. And I've used no stents in that study. And I'll say that none of my patients have had the same type of renal colic pain that occurred when they had stents in place. So I wouldn't say not to stent your patients, and maybe stenting patients who get treated in the ureter would be wise because uretal treatments could be a risk for renal colic or partial obstruction afterwards. But at least in terms of what we saw in this initial phase one trial, I think a lot of the DLTs that we experienced were probably stent related.

And I see that Dr. Yip has recently joined onto the call. So maybe I can hand things over to him to go through the rest of the slides, if he'd like to jump in. Wesley, thanks for joining us.

Wesley Yip: Hey, thanks for letting me hop in here. So here we just have the overall response outcomes from one treatment specifically. So the first two lower doses, one had a complete response at 100; and then at 150, half had partial response, half had complete; and then at the highest dose, only one patient had no response, while the others had at least a partial or a complete response. So while it says that the complete response is nine of them for 50%, eight patients underwent a second treatment, and so the final complete response rate was actually 68%.

And then, splitting it between those who had high or low grade disease, you can see, the middle and the last rows show that for the high grade disease patients, one of those was no response, but then about half and half partial and complete response; and then for the low grade disease, they all had some type of response, but a little less than half had partial, and then more than half had complete response there after one treatment.

And so what we concluded from our phase one trial was mainly that this has an acceptable safety profile and a promising therapeutic effect. We did reach the MTD, and so the primary endpoint of the study was met. All the safety events were pretty much local and just pain related, as we discussed. And importantly, no strictures, obstructions, or perforations within this assessment period. So overall, systemic toxicity is pretty minimal, and there's a complete response rate of 50% after one treatment, 68% after two total. And so this has led to the creation of the phase three multi-center ENLIGHTED trial, which is currently ongoing, and we're very excited about seeing how that turns out.

Sam Chang: Well, great. Wow, that's a big group there that deserves acknowledgement. If you want to look at that, obviously a large number of surgeons, and the whole MSK oncology group, pathology group, and biostats. So I'm going to be somewhat hopefully sequential, first kind of looking at the complications. Then, even though it's a phase one, I want to also look at the efficacy data. And then the last part of the question will be, okay, where do we go next?

So in terms of complication, it looks like you obviously went up on the strength or the frequency level of your fiber that's used, but you kept the dose of the intravenous medications the same. Is that correct? So would there be... I'm just trying to think about, it's so well tolerated, maybe we can have a higher maximally tolerated dose. And maybe it's a higher strength, either the intravenous or... I mean, to me, the best combination would be shorter time, higher frequency, higher dose, but tell me kind of the rationale behind the dosing, the timing, and that maximal dose that you came up with.

Jonathan Coleman: Yeah, let me answer that one, because the original dosing studies were done early on before they even did the prostate studies. And so they used low, intermediate, and high doses of the drug, and they found that it was actually really well tolerated even up to very high doses, even four or five times higher than what we used in this trial. But the effect really didn't get any better as you got to higher dosing levels, so more drug really didn't lead to better outcomes. And also, the more drug you pump in, then the longer the half-life. So then, not that there's a phototoxicity issue, but patients, you want them to be able to leave the hospital without having to worry about the drug washing out. So right now, the patients can leave the hospital within four to six hours after the procedure without really worrying about phototoxicity as being an issue. So that's one part of it.

And then, I agree with you on the light dosing. We could have probably gone even higher on the light dosing. We went up to 200 milliwatts. I think we probably could go higher if we needed to. So there's probably a little bit more work that could be done there, but we know that this is effective at this dosing level, and it's safe, and we're getting the efficacy, I think, that we were looking for. So the treatment efficacy not only in the renal pelvis, but also we treated in the ureter as well. And we found no toxicity in the ureter. We found no obstructions, no strictures, which I think is important as far as a take-home message for the trial.

Sam Chang: Yeah, absolutely. I think I was really struck by the fact that... It'll be great to see long term, but all the treatments that we do, the laser therapy, chemo ablative therapy, the side effects tend to occur relatively quickly. So we know early on, hey, have we caused some area of stricture or obstruction? So I think that was really telling.

Along those lines, I want to now go to efficacy, although, obviously this is a phase one, we're just looking at this in terms of gathering initial data. I would love to know personally your thoughts behind, would this treatment be effective for CIS within the ureter? I mean, I know we've got high grade and low grade, we've got papillary visible disease, CIS in the ureter, to me, is always kind of the bugaboo. I don't know exactly where it is. I don't know... Those types of things. So number one, tell me, if there was any CIS, then would it be effective? And then secondly, kind the technique of a bulkier tumor versus a smaller, multiple locations, how do you keep that 10 minutes kind of constant so all the areas of concern are really treated as effectively as any other area?

Wesley Yip: Well, I mean, in terms of the surgical approach, part of it is that everything that your treating has to be within the light that actually is kind of bathing it. So if you have multiple tumors in different calyces, then you do have to reposition the fiber per calyx, because it has to sit in one area for all of it to have contact with. And so I think that's also important thing to mention about the efficacy data, is that there was no criteria about having single tumors or solitary tumors in this. So part of those response outcomes, part of it is that there were people who had multifocal tumors. And also-

Sam Chang: You just park it in a calyx. You don't have to move it, you don't have to... Basically, the light source has to cover the area involved, correct?

Wesley Yip: Yeah. But then if you have two tumors in separate calyces, then you do have to do one calyx, then the other one.

Sam Chang: Got it.

Wesley Yip: It's not like you get the whole thing at once. And then, all of these tumors also, all the patients in the study had previously failed endoscopic management. And so that's another thing to kind of keep in mind for the efficacy portion of things.

Sam Chang: Oh, I think that's hugely important. And then what about access to the lower pole?

Jonathan Coleman: So maybe I can share just a brief video here. So this is a case that I treated, so this should be a pretty brief video. This is a multifocal high-grade tumor that we found. Here's the fiber placed just in the mid-pole calyx here, but, do you see, there's tumors sort of in the renal pelvis anteriorly and posteriorly.

Sam Chang: Yes.

Jonathan Coleman: This is the fiber. And the drug is given, and then afterwards you turn the light on. And this is one of the unfortunate, I think, parts of it, is that you kind of lose some of your visualization during the procedure, but you just leave the light on during this 10-minute period of time.

Sam Chang: Okay.

Jonathan Coleman: And I promise the video's not 10 minutes long. It's shorter than that.

Sam Chang: No, and, Jonathan, this is like a three French fiber that you put in through the ureteroscope, or 1.9, what-

Jonathan Coleman: No, actually, it's like a 200 micron fiber. So it's exactly the same size as [inaudible 00:20:51], so it fits right through your port

Sam Chang: Wow. Okay. Great. Okay.

Jonathan Coleman: And then this is what you see at the end, is that it illuminates outwards from this area. So it will touch kind of all these areas of tumor. And if you kind of go back, maybe to the very beginning, and see this is what the initial tumor looks like. And then, you're not going to see a lot of difference toward the end here, but there is some blanching. These vessels have definitely closed. And so, when you come back at the seven days later, you'll see what I showed you before, and that is just pure collagen is left.

And let me just show you briefly. You asked about CIS. That first patient we treated, this was CIS. So this was his stage, this is what we first saw. And you can barely see the CIS in his upper tract, but it's kind of everywhere. So we biopsied all this and it came back as CIS

Sam Chang: Okay.

Jonathan Coleman: And this was seven days later. So it actually treated, and this was actually at the lowest dose setting that we had. And basically, all of this tissue, we biopsied multiple different areas, all this sloughed urothelium is all just avascular collagen. So it worked really well. But again, this was our very first patient that we treated. He was actually, his cytologies converted to negative and his biopsies all converted to negative, but, of course, he recurred again at two months out. And that's the problem with CIS, is it's kind of all over the place.

But this was just from a single fiber and a single treatment. I think in refining this therapy going forward, it's going to be... And we've heard from the Jelmyto team that they're now doing... There's a recent paper looking at the adjuvant use of Jelmyto suggesting that maybe it's better in the adjuvant setting. You treat first, ablate everything first, kill everything first with standard therapy, and then come in with a therapy like Jelmyto; that's good for an adjuvant treatment, not necessarily as a great primary treatment, is what I was reading off of those papers. So this could be something you could think of as maybe this is your primary therapy, ablate everything, kill everything, and then come in with some adjuvant therapy, whether it's Jelmyto or the TORUS stent or something like that, that could be used as an adjuvant afterwards. But yeah, I think there's a lot more that we have to think about in upper track that's complementary with other therapies that are out there.

Sam Chang: Well, I had been impressed with the manuscript and kind of the findings, but then you see the video and you see kind of the possibilities. I'm going to leave you with this last question. We're obviously very excited about the phase three trial, the ENLIGHTED trial, but what I didn't know was when you led off, the first slide... Wes, we gave you great credit for the slides, wonderful presentation regarding that. But what I had no idea was that this is FDA approved for urothelial cancer, correct? Can I start using this now? Or, where are we at in terms of commercial availability? Because this is a very attractive treatment. You can see that you don't have to be as attentive of getting a holmium laser to hit every spot, it's just where the light covers. So where are we in terms of, hey, we can actually start using this in patients.

Wesley Yip: The slide is that photodynamic therapy is FDA approved, right? Not necessarily vascular-targeted photodynamic therapy.

Sam Chang: Right. Ah. Thank you for the clarification. Okay. All right.

Jonathan Coleman: Yeah, that's a good clarification. Yeah, so PDT in general has been approved for urothelial cancer and esophageal and for biliary cancers, but this specific therapy is still waiting approval for those types of indications. However, as you go through this FDA approval process, there is a 510(k) sort of pathway, which is basically, look, it's the same type of therapy, it's just a new formulation.

And so the problem with this though is that, and this is sort of the problem that the company ran into when they were trying to get approval for their prostate indication, is that, because it's a drug and a device, it falls under a different part of the FDA than just device approval.

Sam Chang: Prostate.

Jonathan Coleman: So it's a harder pathway, but it's something that I think we all embrace. We need better therapies in upper tract cancer. And so, it's a hard road to go down, but I think you go down those roads easier as a team.

Sam Chang: Right.

Jonathan Coleman: That's the important part of putting this type of stuff together.

Sam Chang: Okay, last question. I said last question before, but I always do this. Provocative question. People historically, my age and older, people used to do radiographic blind basketing of stones. Then we learned, because we were smart or whatever, that you should do it under direct visualization and you should never do it blind. I can actually see where this could be a technique where you could do this under fluoroscopy perhaps of, hey, this is a calyx. We know the fiber becomes radiopaque. And I mean, I'm just a pure conjecture, off label, etc., but is this technique something that could be considered along those lines? Is it that, I don't want to say easy, but something that could be at least considered down the line?

Jonathan Coleman: Clearly, Wes hit that one, but, yeah, I think so. I mean, there's certainly refinement that's needed. Right now, I think the short answer is yes. It can go there.

Sam Chang: Okay.

Jonathan Coleman: So that definitely is on everyone's mind in terms of a way to go. For right now, I think we just want to make sure that we're getting the fiber in the right place, and we're getting the best treatment effect that we can, and we're following the same process that we use for endoscopic management. But, Sam, you're absolutely correct. I mean, that's the direction I think that this will probably go in down the line, if it gets there.

Sam Chang: Yeah, I mean, because I just think of my post cystectomy patients that are difficult, and, yes, you perc or... But I mean, just different scenarios. But the attention that you all have paid in terms of studying, evaluating, and initiating trials for upper tract disease at Sloan Kettering has really been exemplary and has really helped, I think, jumpstart a lot of the recent interest. And then, again, Wesley, you missed this, but I wanted to really give kudos to Jonathan as he led the AUA guidelines in upper tract disease, which has garnered a lot of attention and rightfully so.

So thanks to both of you guys for spending some time with us. Good luck to Wesley as he moves out to the left coast. And, Jonathan, as always, good talking to you again, and look forward to talking again soon about other advances in upper tract disease.

Jonathan Coleman: Thanks, Sam, appreciate it.

Wesley Yip: Thank you guys so much. Really appreciate it.