Sam Chang: Hello, everyone. My name's Sam Chang. I'm a urologist in Nashville at Vanderbilt University, and I have the pleasure of having Dr. Seth Lerner with us today. Seth is actually the Beth and Dave Swalm Chair of Urologic Oncology and a professor in the Scott Department of Urology at Baylor College of Medicine.

He needs no introduction. Any of you that have any background in any type of urothelial carcinoma will know what Dr. Lerner's done, and all the contributions and effort that he's put in SWOG and the SUO CTC and numerous clinical trials that have been really going on for decades. First of all, we owe a lot of gratitude to Dr. Lerner. Secondly, what I really admire about Dr. Lerner as much as anything is that he continuously looks for what is the next treatment alternative? What is the next best thing that we should do? And so recently in Lancet Oncology, there was a trial that was just published actually, when this interview is being done just less than a few weeks ago, Dr. Lerner. Seth, can you give us an overview of the Lancet Oncology article that really gives us a new treatment alternative for upper tract disease?

Seth Lerner: Thanks, Sam. So this was a clinical trial that a number of us had been working with a company called UroGen for several years. They have developed a thermoreversible gel, which is at body temperature is a semi-solid and at cold temperatures of viscous liquid that can be injected. Many of you may remember the backstop. It was used to keep stones from migrating proximately when you're doing ureteroscopy, it's the same exact principle. They just figured out the chemistry to add/mix this with a drug that we use all the time, mitomycin, in the lower urinary tract for urothelial cancer. It basically addressed the problem of drug retention in the upper urinary tract where we're doing intracavitary therapy. This gel sticks around for about four to six hours. So you have a very long exposure time for mitomycin. Mitomycin works in the concentration gradient, and therefore it can be much more effective or the hypothesis was, it might be effective to eliminate low-grade disease.

The other innovation here in terms of trial design was deliberately leaving a measurable tumor in place, even if it was resectable because this would be absolute evidence that the drug worked. In other words, if you leave a measurable tumor in place, you treat it, and you go back six weeks later and it's not there, that's a drug effect.

So we designed the trial with the FDA as a single-arm trial, single-arm because it's a rare disease and it's a huge unmet need and using this chemoablation strategy. But the idea was that patients would be treated weekly for six weeks, what we're all used to, and most of the patients were treated by putting a urethral catheter up to the renal pelvis weekly for six weeks. We screened 110 patients and registered 74, and 71 of those 74 received at least one instillation and were eligible for the primary disease evaluation, which was by ureteroscopy and six weeks after the last instillation.

Now, in order to minimize the risk that we would inadvertently enroll a patient with high-grade disease, they had to have obviously visual confirmation and measurable disease, but a biopsy showing low-grade disease, a cytology showing the absence of high-grade disease. And we felt that that was about the best that we could do. So that was the entry criteria about half the patients had so-called unresectable disease or unreachable disease, most likely in the lower pole of the kidney, because of all the difficulties we know about getting working instruments and the lower pole. The complete response rate was 59% of those 71 that were treated. And that was the same whether the tumor was resectable or not. So that's really advantageous. I'm sure many of us have done the nephrectomies for low-grade disease because we simply couldn't deal and address that lower pole of the kidney because anatomically.

So here we have a treatment where when you put the gel, then it fills the entire infundibular calyceal system. So it'll treat these tumors no matter where. And then for the patients who had a complete response, those patients could go on to get monthly maintenance out to 12 months. And we reported a sort of interim durability, which looked really good, but we will report the final durability at 12 months when all the patients have reached that endpoint. It got FDA approved on April 15th and the company should be ready to go the support to product and getting it into doctor's offices sometime early June. At least that's the last that we've heard.

Sam Chang: Seth, this is really exciting to me is cause this is a brand new treatment that gives us an alternative to removing the kidney as you mentioned, versus attempting other repeated therapies where almost 60% of tumors basically disappeared with this agent. I want to ask some questions regarding, as you went through this process of this trial because you were one of obviously the lead the investigator, but also importantly, have done this treatment. And so we want to pick your brain and learn about it. Patient selection is the first question I have, who should we consider for this? Who should we not consider for this?

Seth Lerner: I mean, the truth is, is that if you can get access to the tumor biopsy and ablate it and render that patient disease-free, that's what you should do. The drug is not, is not approved for adjuvant therapy, which is what we do in the bladder, completely resect papillary disease. For the most part, it's going to be patients with larger volume disease that you can't completely ablate, inaccessible tumors that you can see, maybe you can biopsy, but you can't laser, or patients with multifocal recurrent disease. It could be a solitary kidney. It could be two functional kidneys and you're just eager to do something beyond just going up there and periodically every three to six months in lasering tumors. And that ends up probably being a decent number of patients annually, maybe even for a busy urology practice.

Sam Chang: So along those lines, the FDA approval indication is actually very broad. It's for the adult population with low-grade disease in the upper tract. Are there at this point, would you, or can we treat tumors that are in the ureter itself as opposed renal pelvis?

Seth Lerner: Yeah. So that's obviously not an approved indication. We have a little bit of experience with that and the company will not really support this because it wasn't really part of the clinical trial and nor should they. I can call your attention to a publication in Bladder Cancer in 2019. We treated a lot of patients under compassionate use. So single patient IMDs and that's of where I cut my teeth on this. And there were a handful of patients with ureteral cancers that were treated, and many quite successfully. But I would caution people to do that now because we don't really have much experience. Quite frankly, those tumors, they're accessible, they're ablatable, you can do distally distal ureterectomies. We have other effective nephron-sparing treatments for those patients.

Sam Chang: Great. So as you have this agent, is it kept cold initially? Okay. And then brought to you, how quickly do you have to actually then inject this medication?

Seth Lerner: You have a few minutes. I learned the hard way.

Sam Chang: Okay.

Seth Lerner: It's prepared by a pharmacist. As I think most of us these days, most of this stuff we use for intravascular upper tract is prepared by pharmacy. So it comes to us cold and in an icebox. And at cold temperature to a viscous liquid. So there's a pressure injector, which urologists will recognize immediately as the same kind of device that we use to inflate a balloon for balloon dilation or percutaneous track restrictors. So it's going to be something that you're really familiar with. It comes in a syringe. You do need to measure the volume of the renal pelvis. We recommend doing that. Either under anesthesia or in the office if you have that capability. You fill with dye and measure the contrast volume, drain it, and repeat that three times and take the average.

Sam Chang: Okay.

Seth Lerner: The drug has a fixed concentration, four milligrams per cc. You want to make the patient NPO after midnight, give them bicarbonate the night before and the morning of. Two reasons: you minimize urine production during the treatment and the alkaline urine promotes the uptake of mitomycin into the soft tissues. That's data back from 2001. So what you want to do is you want to have everything ready to do the injection, whether it be through a nephrostomy tube or your ureteral catheter. Take the syringe out, hook it up to the pressure injector, hook it up to the regional catheter, and go.

Sam Chang: You do that under a fluoroscopy?

Seth Lerner: Yes. Thank you. So you want to verify the position of the ureteral catheter under fluoroscopy every time because obviously this needs to go into the renal pelvis. The other thing is that if you've got a little... I'm not recommending this, but if you happen to have a little residual contrast, what you can do is put the catheter up at the top of the infundibular calyceal system, the most superior pole calyx and inject and pull down to sort of fill everything. As you come down to the UPJ. It will form a solid gel very quickly at body temperature.

Sam Chang: At the body temperature. A question, as you're doing that is the, and if it's not, we should tell the company to do this, is the Jelmyto™ radiopaque?

Seth Lerner: No, not yet. There has been a lot of discussion about that. You're not your first person to recommend it.

Sam Chang: I'm usually years behind, but I'm just thinking as you're doing this process, cause you've calculated the possible volume, at this point as you're putting the medication in, you're under fluoroscopy, you are kind of seeing the displacement, I guess, of the contrast. You're not doing this [inaudible 00:11:24], just a thought. Do you, at each time, remeasure the volume of the renal pelvis, or you've got a good estimate from the beginning and go from there?

As you do these treatments, you give the six treatments and then the study said, then an evaluation then after these six treatments. At this point, what do you do Seth? Is it ureteroscopy and you evaluate to make sure you clear it, well then how would you follow these patients?

Seth Lerner: Yeah. So six weeks after the last administration, just like we do in the bladder, we want to do a ureteroscopy under anesthesia in verifying whether there's residual disease or not. I would recommend biopsying anything that looks like it might be residual disease, obviously do a cytology. And then if you do see something, obviously laser it. You know you can interpret the trial strictly. If you have a bonafide complete response, if you biopsy that it's negative cytology negative, then go onto the monthly treatments. Quite frankly, if you biopsy something, that's just a little tiny residual thing and you laser it, I would still put that patient on the maintenance treatment. But recognize that not all patients who have a complete response are necessarily going to want to go on to maintenance or be able to do the whole 12 months. Then in terms of followup in the protocol, we monitor them every three months.

Sam Chang: Okay. And that was with ultrasound, Seth?

Seth Lerner: Ureteroscopy. I fully appreciate that and we had to do that for the trial for the safety standpoint. But urologists may want to be comfortable stretching that out a little bit. Timeframe for an individual basis. These are elderly patients, frequent instrumentation, you kind of use your judgment there. But I wouldn't do it... Per protocol, it was every three months.

Sam Chang: Okay. So that then raises the question of your experience level is this. I'm here, perhaps even lower. There are different guesstimates of "Oh, you do a hundred robotic prostatectomies." What do you say, honestly, perhaps it's even one patient going through those six treatments, make it enough to feel comfortable with just a rough estimate of, "This is difficult to do, or this is quite doable in a short period of time."

Seth Lerner: Rather than say difficult, it's different. It's different than what we're used to. I would say that for urologists that feel really facile with upper urinary tract cancers with ureteroscopy, maybe they have some experience giving drugs up in the renal pelvis, this is absolutely a no brainer for them to bring into their clinic. I think that what's really critical is to have a lot of support for the first couple of treatments.

So for instance, I was on the phone with a colleague of mine out in the community here and he was helping me take care of a patient of mine actually, and he heard about Jelmyto™. He said, "Hey, look, I've got a patient that I'd like to treat on this." So I spent about 15 minutes on the phone walking him through. I told him when the drug was going to be available, I said when you're ready just give me a ring and I'll walk you through it.

The company will have people in the field who are there to help. All that support is really critical for patient safety, obviously. But we want the urologist to learn how to do this properly and not get frustrated. Look, mitomycin does have some toxicity. So if it gets into the soft tissues, if you get it into the soft tissues around the ureter, or you're going to have a big problem with the edema and inflammation and scarring, and we want to really minimize those risks.

Sam Chang: So what are some key points then to minimize the risk that you just said? Obviously, I think it's careful measurements of the renal pelvis, careful location of the catheter, any other tricks? I don't want to say tricks, any points that you would want to emphasize as people gain this learning curve and knowledge that you've achieved and learned.

Seth Lerner: So a couple of technical things. We've used anything from a 5 French to a 7 French ureteral catheter. The obvious benefit to the 7 French is wider caliber should be easier to get the drug up. I treated most of my patients with the 5 French and a lot of the investigators had no problem. The benefit of the 5 or 6 French, it's a smaller caliber less likely to cause injury or try to pass through a tight area. So if you have a patient with, say naturally, you know, a smaller caliber, smaller lumen ureter use a smaller catheter. There's going to be a little bit of judgment involved there. Obviously, we teach and hopefully we practice that you want to get the catheter up, you want to make sure it irrigates to and fro, you're in the right spot, confirm it radiographically.

You do have to have things coordinated with the pharmacy delivery of the drug and ice. Whoever's helping you with that in fluoro. The learning curve is I would say, short and steep. But what you shouldn't do is I wouldn't put this in the middle of a busy clinic. The first few times you do this, I would set this aside, if you can, as a standalone procedure with probably more help than you probably need and, and not something that you need to rush in and do and rush out when you're done. Do set it up and take your time. It's going to be new for your staff, it's going to be new for you. But, having said that, after the first couple of administrations, I think you'll get the hang of it.

Sam Chang: Great. Well, Seth, thank you very much. We've had the opportunity to actually learn again from Dr. Lerner about a new technology of a medicine that's been around for a long, long time, but gives an alternative therapy for patients with upper tract disease. So I want to thank Dr. Lerner again and appreciate all his contributions and for the insights for someone who's actually done this with a Jelmyto™ product. Thanks again, Seth.

Seth Lerner: Thanks, Sam, and thanks UroToday for hosting this, I really appreciate it.