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Sam Chang: Hello, everyone. My name is Sam Chang. I am a Urologist at Vanderbilt University in Nashville, Tennessee. We are very fortunate to have Surena Matin, who is a tenured Professor at the MD Anderson Cancer Center. He really does not need an introduction. He has been a thought leader in upper-tract urothelial carcinoma for years and years, and we are quite fortunate to have him actually speak on endoscopic management of low-grade upper-tract disease, and so I'll turn it over. Go ahead.

Surena Matin: Thanks so much, Sam. It is always fun getting a chance to catch up with you and talk to you. Thanks for this kind invitation. What I've done here is just provide a summary in terms of our established therapies for low-grade upper-tract urothelial cancer. We always talk about the gold standard being nephroureterectomy, and the reason for that is, it is historically what we have done, but it still has some advantages. It's a single effective treatment for patients. We eliminate the risk of ipsilateral recurrence. There is a lot of talk about how it's overtreatment, and I think that is largely true. However, in a case where there is a high-volume or multifocal disease and there's a good contralateral kidney, I think it is still a very reasonable option in those settings, what I would call an elective setting. On the other hand, of all the different options we have available, it comes at the highest cost of GFR decline in most cases, and so many of these patients may present with preexisting chronic kidney disease. And so usually it's not an elective situation, but more of an imperative situation to consider renal preservation.

We have the option of a distal ureterectomy. I don't really talk about other types of segmental ureterectomy because I think it's an extremely narrow indication and not something we would typically consider in the modern age. But for this, basically, it also is a single effective treatment and it helps maintain kidney function as opposed to a nephroureterectomy. On the other hand, we do worry about the risk of ipsilateral recurrence in patients who have a little bit more intensive follow-up. And these are really highly selective cases. It has to be a unifocal disease in the distal ureter, you want to do a good ureteroscopic evaluation to make sure there is no proximal multifocality, they can not have active bladder disease, or at least have the bladder disease managed and controlled, and then we need to think ahead about viable reconstructive options.

the simplest would be a psoas hitch, then it gets escalated to a Boari flap.  If it's a really long segment and we need to consider, gosh forbid, an ileal ureter. Actually, not sure that would be a gosh forbid, sometimes that is a good option. But clearly, then it gets to be much more complicated. Those things all have to be considered ahead of time.

And then as we get less invasive and more organ-preserving, we're looking at endoscopic management, and I'll just talk about ureteroscopy because that is what most people do. Of course, it's minimally invasive, it's repeatable, it's been associated with high cancer-specific survival on retrospective single-institution studies and with meta-analyses that have been done, and it does a pretty good job of maintaining kidney function and preserving kidneys. On the other hand, it's got no great options for preventing recurrences, recurrences being as high as 90%, multiple procedures as a result, risk of strictures from these multiple procedures. Clearly, it is more invasive and creates more symptoms than a cystoscopy. Well, we rely on a stent to prevent complications, but in the process, we buy more phone calls and more deterioration of the patient's quality of life in many cases with these. I think it's a very suboptimal procedure for high-volume and multifocal diseases. And then when we are looking at having to do it more than once, which is in most cases, then we're looking at a pretty high cost.

Now more recently in regard to newer established therapies, there is a mitomycin gel that was approved by the FDA in 2020. For the interest of time, I'm not going to go over the phase III trial or show that data except to summarize it here, to show that it is in fact minimally invasive. It actually is an entirely new paradigm because we are chemoablating residual tumors. We've never really done that before. All the topical therapies we've tested out before have been for prevention and we do not rely on those for chemoablation. But this was shown to have a 59% complete response in this phase III, single-arm trial, where there were residual tumors that went away.  And we are going to, hopefully, be publishing a paper that has the 1-year follow up for these, and it shows that there is 80% durability in those who did have a complete response, suggesting that it probably does function as a preventative as well as an active treatment for the low-volume residual low-grade disease, and it maintains kidney function.

I have to say, the adoption of this has not been as enthusiastic as we have hoped, because I think a lot of people are concerned about the stricture risk.  In this trial, there was a 30-40% risk of either temporary narrowing of the ureter or permanent strictures that became very problematic. There is a cost associated with this procedure, which is not small. You still need to get access, antegrade or retrograde, in order to inject the gel. And we still do not know how efficacious it is for high-volume disease, because the trial required tumors to be 1.5 centimeters or less, and we don't know how efficacious it is for ureteral tumors either, because ureteral tumors had to be laser ablated completely before we could give them this mitomycin gel on the clinical trial. So, of course, there is interest in exploring this now that it's commercially available, but we just really do not have the data.

Now, the issue with the stricter is something that many of us who were involved with the clinical trial have been talking about. A bunch of us got together to talk about how we addressed it. It took us, several patients, after the trial was started to recognize that this was happening. And what people have done is, and we learned this from our [inaudible 00:06:28] stone experts, actually, is to prescribe steroids as soon as you think it's happening. Usually, you start seeing it happening by the third or fourth instillation. And so that is what I do. I give a Medrol dose pack and I will give a treatment holiday. I'll say, "You know what? We need to take a break for 2 or 3 weeks," because we think it's inflammation and edema at first, and so we do think it is probably reversible in those cases.

Some people do routine stenting, even during treatment. I have not done that except for cause if I see that there is some narrowing. And then the other thing that some of us are gravitating toward, and this is a completely untested territory, but this is my practice now, which is that when I'm doing that first endoscopic biopsy and I see that I can probably laser it all the way, I will do that. I'll try to laser and get total endoscopic control if I think it's reasonable to do in that one setting. And then what I'll do is give this, in a retrograde fashion, limited dosing as an adjuvant, primarily. And so we will only give those two or three doses in order to minimize the risk of any strictures forming.

On the other hand, if it's a patient with a lot of multifocality or high-volume disease that, with the laser, all I'm doing is cytoreducing and I feel like they have to get the full induction course, then I will place a nephrostomy tube because there is a thought, and there will be some papers coming out retrospectively that do suggest that the instillation through a nephrostomy tube may have lower stricture rates. So many of us are gravitating toward this type of approach. And look, all of the above, there are no restrictions in place for doing these things, they are not on-label either, and again, we don't really have any good data yet, although that data is being generated, and hopefully within the next year or two, we will have some more information.

The other thing I want to talk about in the last two slides is some very interesting clinical trials that are going on in this space, which is actually really cool. The mitomycin gel was the first registration trial specifically for upper-tract disease, and we are hoping now with these trials, that down the line, maybe there will be more level 1 data in this space.

This is a trial that I'm a PI for, it's an investigator-initiated trial here at MD Anderson, and it's using infigratinib, which is a pan-FGFR inhibitor. And we are giving these to patients who are either undergoing endoscopic management or undergoing definitive surgery with ureterectomy or nephroureterectomy. We're doing tumor mapping ureteroscopically first, and then we have to have enough tissue to do a biomarker study. However, we do not need to know for sure if they have FGFR alteration or not, because this is primarily a tolerability trial. It has never been tested in nonmetastatic patients, and that is basically what we are doing as a primary endpoint. We're going to be giving them two cycles of this drug. And then when they come back, basically by the eighth or ninth week is when we are doing surgery and then doing another tumor mapping, and using that tumor map to evaluate the response. And so we can talk a little bit more about this trial later, because total accrual is 20 and we are up to 12 patients currently in terms of accrual, with 9 patients having completed treatment.

This is the other very interesting trial that Jonathan Coleman is PI for, and it's actually a phase III registration trial. And, really, hats off to him. He did the initial animal studies, they then did a phase I trial in humans, and based on that data, this phase III was developed. It's a little bit complicated. Basically, the summary of it is that patients have to have low-volume, low-grade upper-tract disease, and you can go up and do this photodynamic therapy and then you can repeat it once a month for 3 months.  And then visit two is when we do the primary response evaluation. And if they have had a complete response, they can come back for maintenance treatments if they were to have a recurrence. And so I think we are going to try to participate in this trial as well. It's not open at our center yet, but I think this will be great data to have in a space where we have very little prospective data. So, that part of it is really exciting.

In terms of key takeaways for low-grade upper-tract urothelial cancer, if it's low-volume, again, my practice is to do maximal endoscopic laser ablation, followed by the mitomycin gel, either as adjuvant or induction, depending on how much disease is left. If it's high-volume disease and I think I'm leaving the patient with a good contralateral kidney, I think nephroureterectomy is a good option. Of course, the very select patients who are candidates for distal ureterectomy, we will do that. But it's just that it requires a bit more work up ahead of time so that you know you are selecting these patients well. The big need here is that a lot of our patients do not fit those criteria. They have high-volume or multifocal disease and they either have a single kidney or really bad chronic kidney disease and so there is a major knowledge gap and needs gap here. Hopefully, those clinical trials that are currently undergoing will be able to fill some of that need. And so this is that targeted therapy that I mentioned and also the photodynamic therapy. So, we'll stay tuned to see what interesting data comes out in the next few years.

Sam Chang: As always, Surena, everything that you present is crystallizing the key points and really is helpful for clinicians as they try to decide what to do with these patients who, honestly, as you know, do not represent a huge number, but still, are probably some of the more problematic patients we have. If you've got a few minutes, I was going to ask you probably questions on each one of these key takeaway points. So first about the mitomycin C gel, I loved the tidbits regarding helping to prevent or possibly helping to prevent, strictures with your strategies.

As I was listening to that, and again, I know this is off-label and we will identify that as off-label, have there been any investigators who have been giving it at the time of, basically, a perioperative dose like we do when we do perioperative chemotherapy within the bladder, do you know of anybody who has done that yet or has been willing to try?

Surena Matin: I don't know if anyone has tried it. I don't think so because it has to go through a whole financial...once we identify, you have to identify the patient and submit some paperwork that goes to a third-party-hub that helps the patient manage all of the insurance issues. I think this was the company's way to address the $21,000 per-dose cost to make sure that also patients can get maximal usage, I think. I'm speaking a little bit beyond my range of knowledge, but I think this was set up as a strategy to make sure a patient can get access, even though they may not have total insurance coverage for all that. It's going to be given at the time.

But also biologically, I'm not sure I would want to do that. In the same way where we used to give mitomycin post-TUR and then 3 to 6 months later you come back and you got to all those dystrophic calcifications, and then even harder to manage that in the upper tract. So if it's one thing I've learned about this is, I think there are patients who are particularly susceptible to these strictures. The patient who has a very tight distal ureter that you've got to dilate in order to get the scope up or get an access sheath up or a kinked UPJ that you are trying to manage it as gently as you can, and of course by the end of it, it's kind of dog meat.

Sam Chang: It's beaten up. Yeah, exactly.

Surena Matin: So those, I think, are the kinds of situations where they may be predisposed to these issues, and I think the key thing in those, is to give it time. And thankfully it's a low-grade disease. You don't have to rush to do it within 2 to 4 weeks, but within 4 to 6 weeks, you're okay. Let that heal and then go start doing your treatment after that. I've had to remind myself not to be too gung ho in those cases, just to let that healing process take place.

Sam Chang: Yeah. I think your experience shows through. Exactly, the points regarding anything, especially like you said in the upper tract, there's a sense of the importance of it, it's a little bit more delicate. It doesn't take a hit as easily as what we do to the bladder in time. So I think those are very, very important points.

You mentioned distal ureterectomy and I think with the advent of the robots, smaller incisions, those types of things, we definitely consider that. Tell me what you do to ensure that the upper tract, so that the ureter proximal to where you are resecting, do you require ureteroscopy? Do you repeat the ureteroscopy at the time of your distal ureterectomy? How do you evaluate proximal to the area you're going to excise for the distal ureterectomy?

Surena Matin: Yeah. If I'm considering them for a distal ureterectomy, I don't feel as strongly anymore about scoping every single patient that is referred to me. I mean, there are cases that I think we have a tissue, you have a scan, me doing another biopsy isn't really fruitful. Over the years, I've worked with people who are adamant about re-scoping everybody. I've gone away from that.

But in this case, I do, because I think you need that diligence to make absolutely sure there is nothing more proximal. I like to radiographically mark, with both the retrograde and my scope, where the upper extent of the tumor is plus maybe a little margin because I know what I'm doing in that case, that's the one thing I will stress out most about. Because to this day, we do not have a great technique of labeling where that tumor is. And then if you're doing it robotically and if there is no hydro, even more so. Trying to hem and haw. And then of course you want to save every little fraction centimeter so that you are not making the reconstruction more difficult.

So I do the ureteroscopy, I do a cystogram on the table to check their bladder capacity. If I still have concerns, if they've had longstanding BPH or something, I'll have them get urodynamics if we get concerned about that. I didn't mean to discount the role of the ileal ureter. I actually think it is probably underutilized. I have had cases where I've resorted to it and have been very happy with it, but I think that's when it is selectively to the ureter. But if it's a long segment of the ureter or something like that, I think potentially it has a good role there, especially if you really want to try to preserve kidney function.

Sam Chang: Yeah. Those are all, I think, incredibly important points, especially the careful evaluation. And just like you said, you can tell your clinical expertise, because I agree, making sure you are proximal enough, just like you said, you want to make sure you have a margin and at the same time, you want to make the reconstruction more likely not to require a bigger procedure. It's absolutely on the mark.

I want to end with two questions regarding the promising trials. To me, I applaud your efforts regarding taking the next step regarding therapy options. Now we've got a targeted oral therapy to see what we'll see. And I know you are gathering phase I data. If it appears to be safe, where do you see the next steps going with the targeted anti-FGFR therapy?

Surena Matin: Yeah, thanks for that question, Sam. We have completed therapy in 9 patients. Actually, of those 9, there were 2 who did not tolerate the full extent of the drug. And that has met, so far, our continuous monitoring criteria for safety, so we are on a good track. I will say that of those 9 patients, 4 of them had confirmed FGFR alterations and they all had dramatic responses with just those two cycles, 25-83%. So what I would call a near CR in one case where there was, we basically converted the patient from a nephro-U to kidney preservation.

Now, what we are wondering is that so far we haven't seen any CRs and maybe we're just not giving enough drugs. So assuming the phase I finishes as promising as it has been so far, we are going to go into a phase II, and we're probably going to be looking at higher doses of the drug, but screening patients so that they are on-target, meaning that we will screen them ahead of time to have the FGFR alteration, which we expect 50-80% of the time, and testing it in those patients as one arm. And then the other arm will be in those patients in whom you do...let's say you do the biopsy, but then you can just laser ablate it completely. Could there be a role for this drug as an adjuvant? And so, we're going to test that more of as a phase I at the same time, just to be opportunistic to capture that data, to see if there is any signal that you could potentially use an oral compound as an adjuvant drug. That's the future plan.

Sam Chang: Yeah, I'm getting creatively excited about it, because to be able to piggyback on that phase II, look at the response, and then following it up in the adjuvant, you can almost see, depending upon the tolerability, like you were saying gauging the response, you could almost see a stepwise type of trial, where after the first three, you see a significant response, but not yet a CR. Perhaps you build in a couple more doses and you continue, the options, I think, are incredibly exciting. To be honest, I'm more excited about that than the photodynamic therapy, but I have to give Dr. Coleman his due. Phase III, already to have it out there and available. The two-CAD photodynamic therapy, you know this, there has been a long history of attempting to do this for prostate cancer and other tumors. And so I'm incredibly excited that there is going to be a prospective evaluation with this and being able to monitor its response and get data. Is there anything else really exciting for you, Surena as you look at this photodynamic therapy trial?

Surena Matin: No, listen, I agree with you. And again, hats off to John for doing this. I have never been that excited about any sort of laser therapy for soft tissue, just because of the absorption and penetration, but for a luminal disease, it certainly makes a lot of sense.

Sam Chang: Makes sense.

Surena Matin: And the more we are learning about this, too, the more we manipulate, the more we risk additional seeding. So in many ways, this sort of no-touch technique may have promise. I think for me, thematically speaking, I want to be highly supportive of work like Jonathan is doing and others are doing, because when we get a trial like this, and I felt like this for the mitomycin trial, because if we cannot demonstrate that we can complete these trials, then we've lost all hope. And so for those of us who work in urothelial disease or upper-tract disease or whatever, and we have an opportunity for a prospective trial for a rare disease, if we believe in the importance of it, then I think we need to get fully on board, even if we have our concerns about how complex it might be because you do not really ever know, post-commercialization, how things are going to play out. And so I do think we need to keep a little bit of an open mind and be highly supportive of our colleagues' efforts in the same space.

Sam Chang: Yeah. Wise words for sure, and words that we all in academic and clinical practice really need to, I think, start walking the walk more. And I think we are doing better, but I hope we can continue doing that. Surena, thank you so much for spending some time with us and showing us your expertise, your knowledge, but also enlightening us regarding these two important trials coming up that I think really may change the landscape in terms of these treatment needs for these patients that currently we've got more options than we ever did before, but definitely excitement down the road. So, thanks again.

Surena Matin: Thank you.