Zachary Klaassen: Hi, my name is Zach Klaassen, urological oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Vitaly Margulis, who is a urologic oncologist at UT Southwestern in Dallas, Texas. Today, we're going to be discussing key updates from the ENLIGHTED trial, which was presented at ASCO 2025. Vitaly, thanks so much for joining us on UroToday.

Vitaly Margulis: Good to be with you, as always, Zach. Thanks for having me.

Zachary Klaassen: Awesome. Take it away.

Vitaly Margulis: Well, so the ENLIGHTED is a prospective phase III study, single arm, non-randomized. The targeted population here are folks with low-grade upper tract urothelial cancer. The premise, obviously, we're all aware upper tract is relatively rare. We know that low-grade tumors of the upper tract essentially don't kill anybody, right?

I mean, it's very rare to-- in fact, I tell patients that you're not going to die from low-grade upper tract urothelial cancer, but you may lose your kidney. This is an especially vulnerable population, because these are patients in their early 70s on average, already with baseline significant renal dysfunction. And so losing a kidney is not without downstream consequences here.

The set of tools we have-- we have some tools to manage low-grade upper tract disease, endoscopic tools, et cetera, some chemo ablative options. But the toolbox is relatively limited. And so we wanted to give urologists and others another weapon to fight this disease in such a way that we can preserve the kidney, preserve the GFR, minimize downstream consequences. So this is the impetus for the ENLIGHTED clinical trial.

The way that this works is it's a photosensitizing drug combined with a light delivery system. The drug is padeliporfin, which is essentially a chlorophyll derivative. Short half-life. It doesn't hang around too long, so you don't have to be in the dark for too long after exposure to this agent. And when activated by light from the pharma agent, essentially releases free radicals, which then destroy tumor vasculature leading to tumor necrosis. So that's the impetus behind it.

The design of the clinical trial I'll go over in a second. But the main point here, the primary endpoint is complete response after up to three treatments. So you're allowed to give patients up to three treatments spaced a month apart. And at the end of three treatments, you look and see, is there a tumor present or not. If there's something present, you can biopsy it. And then urinary cytology is mandatory to confirm lack of any disease present.

Again, we just went over the key inclusion criteria. We were very, very serious about this. It's very important for the trial to pick specifically low-grade disease. So all these patients have to have a negative cytology. And any suspicious lesions had to be biopsied. And if there's any concern for high-grade disease, these were not the candidates for clinical trial.

We also limited the tumor burden to really no more than-- no tumor could be larger than 15 millimeters and certainly no conglomerate of tumors greater than 2 centimeters. So the real deal tumor is not too large and had to be a low-grade. OK?

Here's the schema of the clinical trial. As I mentioned, there's a screening visit. And then you get up to three treatments spaced a month apart with primary endpoint assessed after up to three treatments. Of course, if during your second ureteroscopy, you visualize no tumor present, then you can assess for your clinical-- for primary endpoint at that time, but you can get up to three treatments.

Patients that had complete response up to three treatments, then go on to maintenance. And for example, if you had a small recurrence, let's just say nine months after having a complete response, you could actually be retreated during the maintenance phase of the treatment.

So that's essentially the clinical trial design. Here's the money shot, so to speak. This is a pre-planned interim analysis. 50% of evaluable patients. So 37 patients could be actually evaluated for primary endpoint. Here, you can see the complete response rate of 73%, overall response rate of close to 90%.

But the bottom line is only one patient had progressive disease. And by progression here, we mean that he actually went from low-grade to high-grade. I suspect that this probably-- this patient probably harbored mixed histology, probably had high-grade all along somewhere. Just wasn't detected. But the bottom line is that overall response rates are very high. And complete response rates are also very, very encouraging.

What is also encouraging is-- the flip side is the safety. And we have some other agents available in the space that can produce clarification and stricture, but here we saw no urinary strictures. And you can see that the grade 3 and above toxicity was less than 10%. Most of these side effects are what we are used to, patients having after ureteroscopy, some mild hematuria, flank pain, abdominal pain, vomiting, et cetera. Again, things we see after instrumentation of the upper urinary tract.

So these are the results in a nutshell. I would consider this to be-- this treatment to be so far to show very promising efficacy. I would also balance that by saying that with this efficacy, we're not seeing significant toxicity. Of course, we have to wait for the study to complete. But so far, I'm very, very encouraged by these results.

Zachary Klaassen: No, it's great. And thank you for presenting that, Vitaly. I think we've talked about ENLIGHTED a couple of times on the site together, and we've seen good results from the beginning. And now, we see the midterm results. My first question is, how does this continue to reaffirm that we're likely going to have a second option for low-grade upper tract disease very soon?

Vitaly Margulis: I certainly hope so. It's a very nuanced disease. And again, I mean, to me, it's about having your tools to treat this. I think at the end of the day, I'm hoping that this will be available widely. And again, what I want to point out, in contrast to other endoscopic options, this is very, very technically simple to do.

Basically, anesthesiologist gives an injection. And certainly, once the medicine is in, you literally just need to be able to position the fiber in the vicinity of the tumor. So there's no technical demand on you. You don't have to have a very precise skill set and maneuverability with the ureteroscope. You literally just need to be able to place a laser fiber and turn the light on.

Which again, I think makes us very appealing and hopefully applicable to vast amounts of urologists out there that treat this. The question is, of course, that are not answered is, how do we position this treatment with other treatment options available? How do you sequence things? And I think all of these questions will need to be answered.

Zachary Klaassen: Yeah. My last question-- it's a bit of a comment and a question. I think when we look at this true low-grade population, the data here plays it out. We see it in our clinical practice. We've seen it in other clinical trials too. We're not necessarily losing anything, if this doesn't work.

You said you had one patient that probably was under graded. But for the most part, if these patients are truly low-grade, we're not going to lose the cancer battle here. Just speak to that a little bit more in terms of kidney preservation and having multiple options.

Vitaly Margulis: Yeah, Zach, that's the key point here. And then, of course, when you talk to patients, they hear a cancer diagnosis, of course, they're in panic. But I think it's important for us to explain that the biology of low-grade upper tract is indolent. If you really have-- if we really have done our job and properly staged and graded those patients, nobody should ever progress or die from low-grade disease.

And yes, we should treat it, but it's not an emergency. We don't lose any ground by trying things and OK, it doesn't work when you move on to plan B, but the knee jerk reaction, unfortunately, across the country is to quickly put the kidney in the bucket. And I just don't think that's the right way to do it.

Zachary Klaassen: No, absolutely. We've got a lot of kidneys we have to take out. If we can avoid the majority of these ones, I think we'll be better off. Vitaly, always great chatting with you. Any final thoughts? Anything we haven't touched on before we wrap up?

Vitaly Margulis: No, I mean, again, I mean, I think I just want to highlight that this is a straightforward procedure, that the data so far looks exciting, and we hope that this will be available very shortly.

Zachary Klaassen: Absolutely. Always great talking to you. Thanks for taking time out of your busy day, Vitaly.

Vitaly Margulis: Thanks. Good to be with you, guy.