Ashish Kamat: Welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat from MD Anderson Cancer Center in Houston, Texas. And it's my distinct pleasure to be joined by Dr. Seth Lerner, who is Professor of Urology and the Beth and Dave Swalm Chair in Urologic Oncology at the Scott Department of Urology at Baylor College of Medicine, right across the street, right here in Houston, Texas. Thank you so much for joining us today, Seth.

Seth Lerner: Thank you, Ashish. Happy to be here.

Ashish Kamat: So Seth, we chatted about this topic, I guess, about six months ago, and that's before the actual FDA approval of the agent. Since then, obviously, stuff has changed. We're now facing COVID. It's a completely different situation, but I thought it'd be a good opportunity to circle back with you, and have you present to our audience, again, primary chemo ablation for the treatment of low-grade upper tract urothelial carcinoma. So Seth, take it away.

Seth Lerner: Great. Thank you so much. As you mentioned, this drug, and I'll go into some of the details, is now FDA approved for the treatment of low-grade cancers in the upper urinary tract, primarily the renal pelvis. We'll just walk through some of the rationale for the study and then some of the details, which are now published in Lancet Oncology, as of the end of April.

I think that we're all aware that low-grade upper tract disease, generally, is considered a rare disease and not a whole lot of treatment options, in terms of kidney-sparing surgery. We obviously have all the endoscopic tools available to us, but the efficacy of intracavitary chemotherapy or immunotherapy with BCG has some limitations and often requires repetitive interventions. The tumors are often multi-focal and as every urologist knows, that there are regions of the collecting system, particularly in the lower pole, which don't lend themselves always to complete ablation.

And so it ends up, a lot of these patients end up needing a nephroureterectomy for a disease, which otherwise, has generally a low, or virtually no, metastatic potential. And then patients for whom a nephrectomy would necessitate going on dialysis, they have even fewer options. We treated about 20 patients on a compassionate use program that was supported by UroGen and we published that, and that really gave a lot of us the confidence to go ahead with the clinical trial, which I'll describe next.

It's important to understand the chemistry. This is an admixture of the thermoreversible gel and mitomycin, such that, in the figures on the right it's a viscous liquid at cold temperature, which can be injected through the ureteral catheter, and at body temperature, it turns into a semi-solid. And this, essentially, gets over the limitations of intracavitary therapy with drug retention.

So in fact, you get the release of mitomycin for a range of about four to six hours, when it can really work, it can get into the submucosa. And the idea is to do chemoablation. In other words, tumors that are existing in place. The study design is a single-arm, prospective Phase III trial. Again, the target population is low-grade upper urinary tract cancer. The primary endpoint was complete response, at the primary disease evaluation, which we referred to as PDE, which followed within four to six weeks of six once-weekly installations. And then we also looked at the durability of response at 12 months, in patients who achieved a complete response at the PDE visit.

We worked very closely with the FDA to limit the risk that we'd inadvertently be treating patients with high-grade disease. So they required biopsy confirmation of low-grade and a cytology that was negative for high-grade. They had to have at least one measurable papillary low-grade tumor between five and 15 millimeters. For patients who had larger disease burden or multifocal disease, a partial resection was permitted as long as they could get the target lesion down to 15 millimeters or less. And this only applies to patients who have renal pelvic tumors. We did not include any patients with ureteral tumors. The target population was 74 patients and gave us 90% power to demonstrate that an observed complete response rate was better than 15%. Some might argue that that's a pretty low bar, but that's what the FDA actually negotiated collaboratively with the company, again, highlighting the unmet need for this patient population.

Of the 74 eligible patients, 71 received at least one treatment. And then those who had a complete response, which was 41 patients, could go into the maintenance phase. And I've outlined this as part of the concert diagram, which is in the Lancet Oncology publication. And I think the take-home message here is that we don't have a complete set of data on all patients, and we'll report that separately. So this is the final cohort, 71 patients who completed the primary disease evaluation, fairly typical mix of gender, age. And what's, I think, really important is about half the patients had multiple tumors and about half had unreachable tumors. And again, most of those were in the lower pole. This is the take-home message that 59% of patients had a complete response, which was defined as no visible disease. If there was any residual visible disease, it had to be biopsy negative. And of course, a cytology negative. And what's interesting is that the complete response was essentially identical in those patients who are deemed to be unresectable or resectable.

And one thing to remember is that the gel is distributed throughout the collecting system, so it's particularly valuable for those patients with unresectable disease, oftentimes in the lower pole. I know we'll get into talking about adverse events, but this was generally well-tolerated. But there was a higher than expected normal of ureteric stenosis, hydronephrosis, and some of this is likely due to repeated instrumentation, but it's quite possible that the mitomycin may have compounded this to a degree. We know that mitomycin is a desiccant, and if it gets into the submucosa or even penetrates through the wall of the ureter, you can get a fair amount of edema, inflammation, and that can lead to stenosis. And a lot of these patients were able to be managed with stinting, some had to be dilated, and we can get into this in a bit more detail after the presentation.

So this single-arm trial demonstrated that a chemoablation strategy for low-grade upper tract tumors is both feasible, safe, and effective, with a complete response rate of 59%. It's FDA approved. The company's working very hard to make this available to urologists and their patients. The complete response rate was similar in patients who have unresectable disease. And the early interim data on durability suggests that with maintenance installations, you can maintain the complete response, and the adverse event profile was acceptable. I just want to shout out to the patients, the families, and their caregivers and this amazing group of investigators, and a special recognition to Nir Kleinmann from Israel who put 10 patients on the study. Thanks so much.

Ashish Kamat: Thank you. Thank you so much, Seth. Now that the agent is actually approved and people will hopefully start using it, could you share with us, some of your tips and tricks and how someone actually goes about using this, instilling it, making sure it's at the right consistency, et cetera?

Seth Lerner: Yes. And all the investigators who have experience with this, are very happy to help those who don't have the experience when they have a patient they think would be good for treatment. So we have this mixed by a specialty pharmacy close by the medical center, and it came to us in a styrofoam cooler. So at cold temperature, it's in a syringe, and then you hook it up with a pressure injector, much like you would for balloon dilation of the percutaneous tract or ureter, so urologists are going to be quite comfortable with this. You can inject it through, as small as a 5 French ureteral catheter, but we also used 6 and 7 French catheters. Obviously, bigger is a little bit better, but there's some concern that the larger profile catheter may cause a bit more ureteral trauma.

And so, what we do in our office, and I realize not everybody has the setup, is I would scope the patient, just put a ureteral catheter up over a wire, take them over to fluoro, which is just a couple of doors down, also in our clinic. Confirm the position of the catheter. You do need to take three-volume measurements with contrast and take the average of volume for your instillation. Again, the concentration's four milligrams of mitomycin per CC. And then when you're happy that the catheter's in a good position, you take the syringe out of the icebox, hook it up to the injector. It's pretty easy to inject, and the key is to not have it sit out at room temperature for very long because it will get into this semi-solid state and make it very difficult to inject. If that happens, just put it back in the cooler until it cools off again. So that's one thing.

A number of urologists had used a short course of steroids to try to reduce and manage these ureteral lesions with some success, and we'll be putting out an SOP for how and when to use that. And those are a couple of tricks of the trade, so to speak.

Ashish Kamat: Okay, great. You also mentioned that as part of the trial, that there could be ablation or partial resection of tumors if the tumors were larger than 1.5 centimeters. In clinical practice, would you recommend trying to ablate as much as you could before starting this? Or if a tumor is less than say 1.5 centimeters, are you okay with just using a Jelmyto™ right away?

Seth Lerner: Yeah. I actually think that both scenarios are appropriate. I think that, if your access is good, your visibility is good and you can maximally ablate, that seems to a lot of sense to me. But it's perfectly fine to use the entry criteria of the trial to leave a small tumor in place. I'll just give one example, as a patient of mine that I'm taking care of now. I've tried a couple of times to clean out his lower pole. Access is not a problem, but it just gets bloody, and I can't see. So he would be a perfect candidate for this. And just lay the ureteral catheter in and make sure I can exchange that out. The drug is also approved for administration through a nephrostomy tube, so that gets at the difficult access issues that sometimes these patients have.

But I think that the one thing, we don't really consider this as adjuvant therapy. In other words, if you can completely ablate a patient, right, then why not? If at the end of your ureteroscopy, you've got it completely, the patient's disease-free, that's going to be a good thing. And then, if you go back, say three months later, and there's a regrown tumor, then that would be a good time to use Jelmyto™.

Ashish Kamat: Right, right. And obviously, as part of the trial, you had to be strict in your response criteria and follow-up, but what about a situation where you have this tumor you ablate or resect as much as you can, and you use Jelmyto™. And you evaluate the patient, and there's not a complete response or not complete disappearance of the tumor. In the real world, in clinical practice, would you consider repeat dosing this patient or trying to ablate more, and then going back in with Jelmyto™? Any data in the real world off-trial to talk to that?

Seth Lerner: Well, obviously we don't have any data on that, per se. Let me rephrase that. If you go to the compassionate use paper, which was published in Bladder Cancer, there were a few patients, one of mine included, that got more than one treatment. And of course, those were N of 1, essentially experiments, approved by the FDA individual IMDs. And so, I think the best thing moving forward is, when you have patients with low-grade disease that you've confirmed, that don't necessarily meet the strict entry criteria, is to have a conversation with the sponsor, UroGen, one of us who were on the study, and see if it makes sense. But I think the scenario that you're describing would be akin to what we do in the bladder. Right? You get a sense that, gee, my patient seemed to respond. It just didn't quite have a complete response. And I'm going to go back in and try it again because I think the drug's working. And I think the same thing's going to be true in the upper urinary tract.

Ashish Kamat: So Seth, you've worked in bladder cancer and upper tract cancer for decades. You have a lot of experience. And clearly, this was not a randomized trial with a control arm, but how would you compare and contrast these results to what we and you have seen historically when using say mitomycin or BCG, either via stent or Percodan® is trickling down. What's your sense as to, how much better is this over the other therapies that we have?

Seth Lerner: Yeah. Well, as you point out, because it's a single-arm trial, the strict answer to that is, I don't know. But this is also a different strategy of chemoablation. In other words, we haven't been used to doing this in the upper urinary tract or quite frankly, in the bladder, for that matter. But I think it suffices to say, that a 59% complete eradication of tumor with six instillations, is likely to be better than anything that we've been able to achieve, particularly in those that are unresectable. And I think that we should be on the lookout for the durability data, because obviously that's really important, with and without maintenance therapy. But, I think that this is, for some patients who otherwise would have to go on to get a nephrectomy, I think that this could be a game-changer. Now, how long they benefit from that, if they do get a complete response, will obviously remain to be seen.

The other thing, too, I think I've said this a few times in different scenarios, where I got soured a little bit on intracavitary therapy, because of lack of durability. And so my experience through the compassionate use program and working with the investigators on this clinical trial, we're not only comfortable doing this through a ureteral catheter and the patients that were on the trial. I've treated a bunch of patients with BCG this way. And I'm back doing this, when it's appropriate, with a high degree of comfort. And so I think it's taught a lot of us how to apply this, not just with Jelmyto™, but in multiple scenarios, low-grade, high-grade disease.

Ashish Kamat: Those are great points that you bring up. Would you, again, in the absence of an actual clinical trial or data, would you consider using in the appropriate patient that has a tumor in the ureter, for example?

Seth Lerner: We have, obviously, it's not in the FDA label. So it would be an off-label use, and I think that if you could get it approved and paid for, I think it would be a reasonable approach. We have a couple of these patients in the compassionate use study, that had complete responses in the ureter. I think you got to be a bit careful, because of the risk of certainly transient obstruction, and I think with taking all of the precautions, verifying sterile urine, et cetera, it, it likely can be done safely for the patient, who can be managed short of doing, I'd say, just a ureterectomy. So it's possible, but we, we haven't really studied that patient population in a clinical trial. Yeah.

Ashish Kamat: Right, right, right. So Seth, we're running short of time. We could obviously chat about this forever, but any closing thoughts that you want to share with our audience?

Seth Lerner: Yeah. This is really an exciting step forward to have an FDA approved product for this, often difficult to treat, patient population. I would just invite urologists who have patients that they think would be eligible, to reach out to anyone of us that are investigators in the clinical trial, if there's someone in their neighborhood. The company is really gearing up to support patients and urologists. And I think this should be ready for distribution pretty soon if it's not already.

Ashish Kamat: Right. Thank you again, Seth, for taking the time to be part of this important educational activity. It's crazy times here in Houston, so stay safe, and hopefully, we'll see each other in person sometime.

Seth Lerner: Yeah, you too. Thanks for the invitation.

Ashish Kamat: Anytime.

Seth Lerner: Always happy to talk about this. Take care.