Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee at Vanderbilt University. And we are privileged to have Dr. Ali Zahalka, who is completing his SUO fellowship in oncology at University of Texas at Southwestern UTSW. Dr. Zahalka will be actually presenting some important work looking at a novel therapy technique, vascular-targeted photodynamic therapy for upper tract urothelial carcinoma. So Dr. Zahalka, Thanks so much for being here, and I think you have a few slides to share.

Ali Zahalka: Yes, thank you, Dr. Chang, for having me. All right, thank you for giving the opportunity to speak about this novel technique, which is using vascular-targeted photodynamic therapy to treat low-grade upper tract urothelial carcinoma. Just a little background, upper tract disease is a minority of urothelial cancer with risk factors such as Lynch syndrome, smoking. However, about 60% of these are found in the pyelocalyceal system, whereas 40% are in the ureter. And this poses a challenge for treatment such as ablation, which the AUA guidelines recommend for low-risk favorable and some select high-risk favorable cases with low-volume disease because of the complex structure of the pyelocalyceal system. Another challenge is that with current ablative techniques is a high degree of recurrence, so this leaves an unmet need for organ sparing options. And this brings me to a little bit of background about what is vascular-targeted photodynamic therapy.

So padeliporfin, this is a photosensitizing drug that was derived from aquatic bacteria that have basically like chlorophyll. And this drug is activated by near infrared light. So the photodynamic therapy is a combination of both this bacterial chlorophyll derivative, which is light-activated, as well as near infrared laser, which activates this drug. And what's interesting is that you can give this drug through the IV and it preferentially accumulates in aberrant blood vessels such as what we see in tumors. And originally it was studied in a variety of other tumors such as skin tumors, which are very accessible to light activation. And here now there's an ongoing trial I'll talk about, which is using this light-activated drug for the treatment of upper tract cancer.

And this slide basically just showing the mechanism of action. So the drug is given IV, it is complexed in the blood, non-covalently with albumin. That's how it circulates. Then it gets stuck in the microvasculature of the tumor. And then with endoscopic illumination using a near infrared laser, it activates this photo-activated drug generating free oxygen radicals, which basically occlude the vasculature causing ischemic reperfusion injury, thus killing the tumor and releasing antigens, potentially activating the immune system.

And then here's a schema of an ongoing phase three trial. UT Southwestern is one of the sites where we're using this photo-activated drug in order to treat low-grade tumor. And this is just the maintenance phase. So basically patients come in prior to surgery, they get the infusion of the drug, takes about 10 minutes to give it, and it lasts, the half-life is about an hour. Once it's given, the patient's protected from light just as a safety precaution, given some sunglasses, brought to the OR, the lights are kept very low. And then we endoscopically go up, find where the tumor is, take a laser fiber, and using a 10-minute course, basically just illuminate the tumor which causes the ablation. And then the patient, afterwards, kind of rests in the post-operative area in the low-light region covered in blankets until the drug passes from their system.

So just some key takeaways from my talk is that this photodynamic therapy for low-grade upper tract disease is a very low-complexity procedure. Basically we just use the same techniques that we already do to find upper tract, you go in endoscopically. As soon as you find the tumor, you just need to put the laser within the region of where the tumor is and then just turn on the laser for 10 minutes. It's very simple to do. The ENLIGHTED trial, which I showed the schema, it's an ongoing phase three multi-center, multi-country study. So far it's shown safety and some evidence of efficacy, and the long-term results from this trial will hopefully provide the basis for approval. Thank you.

Sam Chang: Dr. Zahalka, that was very, very interesting. And we've heard about photodynamic therapy, honestly, for a long, long time. We've looked at it in different types of tumors. We've even looked at it in prostate cancer, long history in bladder cancer, but it's never taken off. So I'm going to start off with why now is it starting to get increased interest?

Ali Zahalka: I think that we found a very niche application where it's effective. So with prostate, you have to put... The whole idea is that you have to find an area where you can illuminate the tumor with minimal side effects on the surrounding tissue because, theoretically, every tissue takes up this molecule and you can cause destruction. And Dr. Coleman's group at MSK did some very nice studies in pigs looking at how much laser energy can you give while being safe on the surrounding urothelium. And whereas the bladder is a very large area to illuminate, the pyelocalyceal system is a very small enclosed area that is, on one hand, structurally complex, so it's difficult using a traditional laser to ablate, but while also being very contained where you can use all this light without really harming other systems and really focusing on this upper tract tumor.

Sam Chang: Mechanistically, how close does the laser have to be to the actual tumor within the pyelocalyceal system? Is it, you just place it in the renal pelvis and it goes far enough in? Or do you have to be within a centimeter, within a couple centimeters? Tell me a little bit about the mechanistic application of this technique.

Ali Zahalka: Yeah, that's a great question. So if you can't see the tumor when you illuminate it, you're probably not close enough. So you need to be able to visualize the tumor. Theoretically, could it work? I don't think that you'll have maximum ablation. So typically we go about a centimeter or so away. So you don't actually even have to touch the tumor, you just have to be in the vicinity, be able to see it on the screen, and then just leave your laser there for 10 minutes.

Sam Chang: And then 10 minutes. And so I noticed that majority, obviously these are renal pelvis, have you all tried, or within the study schema, are ureteral tumors also allowed?

Ali Zahalka: Yes. As long as they're not invasive, as long as they're less than two centimeters, and at least in our hands, we always stent afterwards just to be safe, and we haven't seen any stricture formation.

Sam Chang: Yeah, that's what I was wondering about.

Ali Zahalka: Yeah.

Sam Chang: I mean, obviously with other medications out there, the Jelmyto, the trade name of the reverse thermal hydrogel that sits in the renal pelvis and is also indicated for low-grade upper tract disease, but one that requires repeated applications. Many times now individuals are using an antegrade approach with a nephrostomy tubes. So there are pros and cons...

Ali Zahalka: For sure.

Sam Chang: ...Regarding that technique. This is a similar population of patients, correct? Low-grade upper tract.

Ali Zahalka: Mm-hmm.

Sam Chang: Within the study, are repeated treatments allowed?

Ali Zahalka: Yes, there are. So you can treat, I think up to three times in the initial phase before going into the maintenance, before a patient's considered a failure.

Sam Chang: Okay. And we've heard about this trial for a period of time, give me an update of where we sit in terms of trial recruitment, follow up, et cetera. When should we expect or at least hope for solid data coming out of this?

Ali Zahalka: Sure. So in November of 2024 we reached the halfway enrollment mark, and earlier this year at ASCO presented interim results of the study, which so far I think there was about 36 or 37 patients enrolled. There were very few Grade 3 adverse effects, mainly just some hematuria and some renal colic that resolved in a few days. And there was about an 82 overall percent response rate, which is measured 30 days after the last photodynamic treatment.

Sam Chang: And that measurement, is it radiographic or is it repeat your ureteroscopy?

Ali Zahalka: Yeah, it's a combination of cytology, visual observation, and if you take a biopsy, that the biopsy is negative.

Sam Chang: Oh, fantastic. I mean, a very exciting treatment. You can see where even a combination of treatments may be really effective for individuals as we attempt to do nephron sparing...

Ali Zahalka: Of course.

Sam Chang: For so many of these individuals that will have renal compromise or have other medical comorbidities and that type of thing. Tell me, overall, logistically, you talk about covering the patient, dimming the lights, all those types of things, how has it been in terms the actual operations of this? Obviously every study patient, we make sure we follow protocols, et cetera.

Ali Zahalka: Yeah.

Sam Chang: How difficult has it been to implement photodynamic therapy?

Ali Zahalka: It's been very straightforward. I think just the main thing now because it is a trial, because we have to follow protocol, we keep patients in the post-operative area covered for quite a period of time. I mentioned that the half-life of the drug is less than an hour, but we keep them there for several hours just to be on the safe side of things. But the actual procedure has been remarkably straightforward. It's very easy to even guide residents, junior residents through the procedure because as long as you can see the tumor, you can illuminate it.

Sam Chang: Yeah. Dr. Zahalka, thanks so much for spending some time with us. We look forward to continued updates and the long-term results as well from this exciting therapy for upper tract disease. And you can see that, from a cancer that was, one, that was somewhat orphaned, somewhat unsure of what we have now, we have many, many options. Actually, many, as you said, were outlined by the AUA guidelines that actually just a few years ago actually shed more light, at least in the United States regarding treatment, diagnosis, evaluation, surveying, and ultimately treatment goals overall for long-term preservation of renal function. So thank you so much and we look forward to having you again.

Ali Zahalka: Thank you for the invitation.