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Zach Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined for this UroToday discussion with Dr. Vitaly Margulis, who is a urologic oncologist at UT Southwestern University in Dallas, Texas. Dr. Margulis, thanks for joining us today.

Vitaly Margulis: Good to be here with you, Zach. Thanks for having me on.

Zach Klaassen: Absolutely. So we're going to talk about a trial in progress that was presented at ASCO 2024 called the ENLIGHTED Trial. It's a phase three trial, but before we get into it, maybe just discuss with our listeners a little bit about the background and unmet need for low-grade upper tract urothelial carcinoma.

Vitaly Margulis: I think the main issue with the disease is the fact that it's over-treated. We know that the biology of low-grade urothelial cancer is such that it doesn't metastasize, but the problem in the upper urinary tract is we have a limited set of tools to work with these tumors. Endoscopic management is difficult, technically demanding. The options that we do have that are approved in this space, such as Jelmyto for example, are good. It's an important part of our toolbox, but it produces limited response rates. Some of them are not durable and there are significant side effects associated with the utilization of these potentially caustic chemical agents. So the unmet need is the ability to really control the tumors reliably while limiting the downstream side effects.

Zach Klaassen: Excellent. So talk a little bit about the mechanism of VTP and maybe some of the early phase one, phase two trials and just highlight the data in those spaces.

Vitaly Margulis: Right. So the concept has been around. I think that we have heard about this technology under the name of 2-CAD where it was utilized in managing prostate cancer. And the idea is pretty simple. The agent is a pro-drug, which gets infused and gets activated by a certain wavelength of light. When it gets activated, it basically causes the release of free radicals and destruction of, preferentially, the tumor vasculature because of some of the abnormalities associated with tumor vasculature. And obviously, by destroying the vascularization, you destroy the tumor itself.

And so what's unique technically about this procedure is that when you are ablating these tumors, it's not technically demanding at all. So basically, you position your ureteroscope up next to the tumor, you visualize the tumor, the medicine gets injected for 10 minutes, and then you literally just shine the light on it. So you don't need to actively ablate it. It's not a contact enterprise so to speak. And so that makes it very accessible. I mean, anybody who can introduce a ureteroscope and find the tumor can actually treat it this way. So I think that's what makes it unique and really accessible to a wide variety of urologists with various skill sets.

Zach Klaassen: And what about some of the data that led to the design of the phase three in terms of complete response rates and whatnot?

Vitaly Margulis: Right. So we presented the early data and this was a mixed bag of patients with, most of them were heavily pretreated, a lot of them were high grade. And the complete response rate, even in this heavily pretreated population with various sorts of sizes of tumors, et cetera, was 50%.

Zach Klaassen: Good.

Vitaly Margulis: This was a complete response rate and the overall response rate was close to 90%. So we saw that we were expecting the biology of these tumors, we were cyto reducing them and this led to the development of the ENLIGHTED Trial, which is a prospective single-arm trial dedicated to managing patients only with low-grade urothelial cancer.

Zach Klaassen: Excellent. So I'm going to pull up the trial schema. As I'm pulling that up, maybe just discuss some of the inclusion criteria for the ENLIGHTED trial.

Vitaly Margulis: So the key thing to remember is we want to exclude patients with high-grade urothelial cancer. As you know, it's important to screen them properly. So you have to have a low-grade biopsy, cytology has to be obtained and if it shows high-grade disease, those patients would be excluded. Patients recently managed with muscle-based bladder cancer are excluded. Patients that are recently treated with intracavitary treatments such as BCG had to have a washout period. Interestingly, patients that could have had ablative treatments are included. Patients that were treated with Jelmyto and had recurred could be included, but basically you want to rule out concomitant high-grade disease in the upper tract. Now the size of the tumors, you could have up to two locations in the renal pelvis and calyces. The index tumor cannot be bigger than 1.5 centimeters. You could treat tumors in the ureter, but the contiguous urethral involvement could not be longer than two centimeters.

Zach Klaassen: Okay. Excellent. So this is a pretty full slide, but maybe just take our listeners through some of the highlights of the induction treatment phase and also maybe the maintenance treatment phase.

Vitaly Margulis: Yeah. So the trial has two phases. During the induction treatment phase, and this is where the primary objective of the trial, which is complete response up to the induction phase. And the induction treatments are basically three treatments separated a month apart. So patients take an operating room, they get an infusion and treatment, and then they get reassessed a month later. If there is still persistent tumor, you can give them a treatment. If there is not persistent tumor, then you basically have a complete response and then they go into the maintenance phase. So during the induction phase of the trial, you can do the treatment three times.

Now if after three treatments patients still have residual biopsy-proven low-grade cancer, then obviously they've reached the endpoint. They have not achieved a complete response. If they did reach complete response, and again, this could be after the first treatment, after the second treatment, or after the third treatment, then they go on to the maintenance phase where obviously they go under standard of care evaluation of the upper tract and if, for example, three months later you found that they have a small recurrence, they were allowed to have, and now the treatment, and they're allowed to have essentially three more treatments spaced three months apart.

Zach Klaassen: Right. Excellent. So I'm going to take this down and let's talk about a little bit, you mentioned the key objective, the complete response rate at three months. At the ASCO presentation, there was sort of a bit of a highlight of 17 patients that have already been enrolled in the trial. Maybe just talk about what you're seeing in early signals for complete response and some of the tolerability data.

Vitaly Margulis: Right. A little bit more about the trial. So remember, this is a global trial. It's international. There are 29 clinical sites in US, European Union, and Israel. The target enrollment is 100 patients. As of now, there are 27 patients have been enrolled. Now our ASCO presentation focused on 17 patients that have had complete treatment, to complete induction treatment so we could evaluate their complete response. And the data is such that we showed, and again, I mean technically not supposed to talk about the oncologic outcomes, but we saw 77% complete response rate out of the patients that were treated in the induction phase and completed their induction phase.

Now I think what really separates this data from some of the other products in this case is the fact that we essentially saw no grade three complications. So there were no urethral strictures, there is no urethral obstruction, an unexpected need for stenting, so on and so forth. There are only grade one to two complications, which were all very mild and resolved continuously. And so to me, that means that we are able to effect treatment without causing some of the dreaded long-term complications that these patients can face from scarring.

Zach Klaassen: Yeah. And I think it's an important point because in some of the other treatment regimens in this disease space, that's been some of this conversation. Depending how you describe or define your urethral obstruction, it can be as 20% or as high as 40%. So I think having zero grade three for that is really certainly encouraging, isn't it?

Vitaly Margulis: Yes. Yeah. I mean, obviously we want to temper our optimism and so far the data looks good and so far the complications look very manageable, but I mean obviously we'll have to wait for enrollment. We hope to enroll by the end of the year and to be able to share additional data with you.

Zach Klaassen: That's great. That was my next question was when do we expect enrollment? Sounds like pretty soon and then we'll get that three month complete response rate data and hopefully something next year. Does that sound about reasonable for expectations?

Vitaly Margulis: Yeah. So again, we want to finish enrollment by the end of the year. I think it will take some time to analyze it and present the data, but the trial is moving at a reasonable clip and we're enrolling the patients and I think it's good and appreciate the opportunity to get the message out there.

Zach Klaassen: Yeah.

Vitaly Margulis: This is an orphan disease and then again, I think it's universally recognized even in the SUO trade circles that a lot of these patients are probably over-treated.

Zach Klaassen: Yeah, absolutely. Great discussion. Maybe just a couple of take-home points for our listeners.

Vitaly Margulis: I think if anything, I think the main point here is that we have to think about high over-treatment rates in patients with low-grade upper tract urothelial cancer. A lot of times these tumors can be managed endoscopically. We are beginning to have some tools in our toolbox to manage this. And VTP is so far a very intriguing and so far a successful way to manage these tumors while limiting the necessity for really high-end endoscopic expertise.

Zach Klaassen: That's great. Dr. Margulis, thanks so much for your time and for getting the message out there for the ENLIGHTED Trial. We appreciate it.

Vitaly Margulis: Zach, I appreciate you having me on.