Woodson Smelser: Thank you very much, Dr. Chang. There were a lot of updates packed into the first hour, and then of course the second great bladder cancer session the following day, which I'm sure you guys will review. But I do have some highlights that we'll go over and then talk about some of the key takeaways and how this new information and data may affect our practices moving forward. So Dr. Chang, as you mentioned, we had the first bladder cancer session on Thursday of the SUO and it was extremely well attended. And so here's an overview of the program that we had. And you can see we had a great lineup of speakers. We had a couple of state-of-the-art updates, including update on the AUA Hematuria Guidelines, which were recently updated this year.
Some updates on risk stratification and intermediate-risk, non-muscle-invasive bladder cancer, and then a debate about some details within that domain. And finally, an update in trials and intermediate-risk, non-muscle-invasive bladder cancer, which I think even five or six years ago was sort of hard to conceptualize that we would need an update in that domain. But as you'll see, where there's a lot of material now. And as you said, it was a packed house. Here's a view from the podium. And if you look closely, you can see Dr. Chang, audience left there in the front row. But the real reason they were there is because this outstanding lineup of speakers that the SUO Planning Committee helped deliver. You can see really diverse representation from across the country to talk about bladder cancer. The first updates came from Dr. Yair Lotan at UT Southwestern, and that was on the updates in the microhematuria guidelines.
And just for a primer, this is an updated algorithm for the AUA Microhematuria Guidelines. And you can see, the key thing is that there's risk stratification and we have low or negligible risk, intermediate risk and high risk. And so Dr. Lotan went through some of the data updates that led to changes in this risk stratification and some additional considerations that we should think about when we are looking at these patients and working them up in clinic. First he looked at low and negligible-risk patients. And one of the key takeaways, and this is an excerpt directed from the guidelines, is that it's okay in these patients to repeat a urinalysis within six months, rather than performing immediate or reflexive cystoscopy and imaging. And I think the key takeaway here is that the likelihood, if properly risk stratified, of missing a malignancy in these patients is overall very low and probably less than 1%. But here are some factors that can make people higher risk. And you can see, these are things that the guideline update took into account. And I would point to the column on the right or the table on the right that shows some additional things like prior pelvic radiation, occupational exposures, family history of either urothelial cancer or a predisposing genetic condition like Lynch Syndrome, or a history of chronic indwelling foreign body that may make someone higher risk.
Additionally, he had some intermediate-risk stratification updates. And so, one of the key things in this new update is that for patients who are at intermediate risk, who do not want to or do not elect to undergo cystoscopy, you could consider urinary biomarkers. But if you do forego cystoscopy, you should obtain a repeat urinalysis within 12 months. And if there is persistent microscopic hematuria, then that patient should be counseled that cystoscopy is the standard of care. Dr. Lotan gave a nice overview showing the various bladder biomarkers that are often used to screen for malignant conditions in populations of patients with hematuria. And you can see, the only one that has grade A or level A evidence is the Cxbladder triage, and that has now made it into the guidelines as a potential surrogate biomarker to screen whether or not maybe cystoscopy and further workup needs to be done. And then in the high-risk domain, Dr. Lotan called attention to these conditions that are tabulated here on the left that predispose individuals to an increased genetic risk of renal tumors. And the key takeaway here is that if they have any of these conditions or Lynch Syndrome, that they should have cross-sectional imaging and not renal ultrasound in addition to cystoscopy, no matter what.
Transitioning from there to the domain of intermediate-risk bladder cancer, really I would say the key takeaway here is that we have lots of evidence now looking at non-muscle-invasive bladder cancer risk stratification for patients who are intermediate risk, but we do still have some outstanding questions. And so, as a primer, here's an excerpt from the AUA Guidelines for Non-Muscle-Invasive Bladder Cancer. And you can see what we're talking about here, is this middle table, intermediate risk. And there's a couple things that can make people intermediate risk, including timeline and recurrence, solitary versus multifocal tumors. Low-grade T1, which many of us think is a very rare, maybe non-existent entity. And then high-grade TA tumors less than or equal to three centimeters. So we had a state-of-the-art update from Dr. Wei Tan, and this is a prior publication that Dr. Tan is first author on from the International Bladder Cancer Group, or IBCG. And you can see, they actually propose an alternative risk stratification for intermediate-risk group determining how many of these various risk factors the patient has, and then have also proposed a management algorithm that may or may not use things like intravesical induction chemotherapy, or even in some patients who are at higher risk. And you can see here, that was defined as greater than three risk factors, even considering BCG. And so then Dr. Tan shared this slide, and again, this is credited to him, showing the different stratification schemes that can be used.
They all have some overlap. And you can see the goal of this IBCG risk stratification plan is to try to harmonize some of these factors and account which patients may actually be higher risk. And then that segued into a debate between Dr. Rob Svatek and Dr. Kelly Bree about whether or not any patient who has high-grade Ta NMIBC should automatically be considered high risk. Because as you know, as this prior slide had shown and prior table, in some risk stratification schemes, that person would be intermediate risk including in the AUA guidelines. And at the end of the debate when we polled the audience, I think most people still feel that despite the utility of this, we should stick with the AUA guidelines. And then of course, that segued into a nice update for emerging trials that are either accruing or recently opened in intermediate-risk, non-muscle-invasive disease. And this was summarized by Dr. Vig Packiam from Rutgers Cancer Center. And the bottom line is there has been a proliferation of trials in this space. And so over the last couple of years, we've seen many new FDA approvals in high-risk non-muscle-invasive disease, utilizing a number of different modalities and mechanism action. And we are now seeing that permeate into the intermediate-risk space.
And so, Dr. Packiam went through a series of clinical trials, and I'll show the name of those clinical trials and I'll read them on screen. So first, there's the LUV001-202 study, which is for high-risk or intermediate-risk NMIBC, non-muscle-invasive bladder cancer, and that is a study utilizing gemcitabine and docetaxel in a reverse thermal gel, comparing that at two different dosing schedules, one that's a six-week induction and then a two-year maintenance versus a 12-week induction and also a two-year maintenance. Then in the ENVISION study, they are comparing ZUSDURI, which is a reverse thermal mitomycin gel, in patients who have low- to intermediate-risk non-muscle-invasive bladder cancer. And that's being compared against a placebo or a control arm. The FORT001-102 study is for intermediate-risk non-muscle-invasive bladder cancer. This is a single-arm phase 2 trial of an FGFR3 inhibitor that's administered orally. Dr. Packiam called this a targeted trial. It's only for patients who have a genomic FGFR3 mutation. And patients on that trial are administered at a dose of 10 milligrams orally, twice a day for 12 cycles. And what they do is they look for radiographic complete response. And then finally, this RESQ132A trial is using N-803 or ALT-803 nogapendekin, which is a IL-15 super agonist. And you can see in one arm, patients are going to be given gemcitabine two grams, plus the N-803. In another arm, they'll be given the N-803 plus BCG similar to the QUILT trial, and we will follow these patients and look at complete response rates.
So I think the key takeaway here is that there's been an enormous interest or increase in management options for intermediate-risk NMIBC. And I would be remiss if I didn't mention that we also have a recently FDA-approved agent in ZUSDURI, which is a reverse thermal mitomycin gel. So we've gone from basically having just intravesical chemotherapy in the perioperative setting and maybe BCG in some select patients, to now more than five agents that are being tested.
Sam Chang: Woody, great overview of a really great session, really highlighting different areas. So let's focus on each of those areas and would love to hear your thoughts.
Woodson Smelser: Sure.
Sam Chang: The microscopic hematuria guidelines, to their credit, have continued to update to attempt to decrease the burden on those that are low risk, but yet, not miss those few patients that really would benefit from early diagnosis, et cetera. Tell me, in the new guidelines, the most important change that Dr. Lotan to you, represented in terms of, "Hey, gosh, okay, this is an important big change. I want to make sure this is passed on to the residents, remember, et cetera."
Woodson Smelser: Yeah. For me, I think all of our biggest fears is missing a high-risk condition or a life-threatening condition in a patient who may be high risk and we just missed a factor. So I think the biggest update for me is just that acknowledgement of our larger understanding of hereditary cancer syndromes like Birt-Hogg-Dubé, VHL, Lynch Syndrome, and really asking questions about risk factors other than just, "Do you have any family history of bladder cancer?" But drilling down and looking for those, because we know the prevalence of cancers in those patients is non-zero. And in some populations, it's up to 10%. A range that Dr. Lotan quoted was from about 5% to 11%, depending on the study population. And it is okay to get cross-sectional imaging in, say, a 35-year-old female in that situation because there may actually be significant findings. I mean, on the converse, on the very low-risk patients, if they truly have none of these risk factors and they're considered negligible risk, it's okay to sort of de-escalate.
Sam Chang: Yeah. No, I think really important points. The debate, which was quite a friendly one between Dr. Bree and Dr. Svatek is, everybody knows that in certain situations, both of them are quite true. I think a key takeaways that I got from that clearly was that in those patients that are higher risk, they're higher risk. But in those patients that are lower risk, they should be given the opportunity to some of these new medications, et cetera, that really clinical trials, other things they would've missed out on if they were put into different categories of higher risk. But let's talk about the new kind of medications that are being examined in this population. It's so fantastic to have options. I struggle with how do we determine which of these patients we should be giving these... Assuming they're approved, I think clinical trials are really important. But which of these medicines should we actually be utilizing? Because they may be more expensive, they may have side effects, and the risk of progression for some of these within intermediate risk really probably aren't that high. So to you, what are going to be the key components as you integrate these newer agents into your practice?
Woodson Smelser: Well, I think briefly, both cost and also just mechanism delivery are crucial. I think there is some appeal, for example, the oral FGFR3 inhibitor where a patient can be prescribed the medicine. Now, albeit they may need to have an FGFR mutation, but to not tie up infusion space or intravascular instillation space, not to tie up a procedural nurse. If that has a well-tolerated adverse effects profile, then things like that I think are winners. I think losers, unfortunately, are anything that may depend upon our existing BCG supply, as we know, that's been a now more than a decade issue in terms of logistics. And even with potential FDA approval of recombinant BCG, any mechanism or modality that's going to rely on using our existing supply, I think has serious logistical challenges. And then I think the combination agents that maybe utilize gemcitabine and docetaxel together, I think are really appealing because we've seen excellent data in the high-risk population for that. And certainly if it is in a formulation that is well tolerated and can be given in a more compressed timeline versus having to give sequential intravesical treatments, I think that's the potential winner. But I think the bottom line is it's going to come down to duration of response, overall complete response rates and then cost.
Because I think the alternative for some of these patients and the alternative arm in many of these trials is observation, which is sometimes more cost-effective. And if they are low intermediate risk and not higher intermediate risk, then if you have a recurrence that occurs six or nine months later, it may be relatively inconsequential.
Sam Chang: Yeah, I think that combination of factors you brought in, cost, effectiveness, duration, response, I think all of those are going to have to come into play, because I really think a substantial proportion of these patients will be in the arm of, "We should do surveillance." And then the other group, yes, if we can treat in a cost-effective, minimal side effects, all those things, then we have done a service. We decrease the chance of progression that's already low to very, very low. We decrease the recurrence rates, avoided future operations, et cetera. I agree with you totally. I'm going to push back on you on just one area, just one area.
Woodson Smelser: Sure.
Sam Chang: And that's when you said we have excellent data regarding gemcitabine and docetaxel being effective in the high-risk population.
Woodson Smelser: Retrospective data.
Sam Chang: Yeah, I'm going to say we have good data.
Woodson Smelser: Sure.
Sam Chang: We do. And that's why I think Dr. Kates' trial that you've mentioned in the past, that BRIDGE trial is going to be very important because it's going to give that prospective data that will really help drive practice. Because clearly, the retrospective data shows promise. There is no doubt about that. But like anything, just like promising phase-two data, sometimes it just doesn't wash out so it will be great. And then it goes back to BCG and your points about the availability, the lack of consistent supply is really in play. That's why I think we really look forward to the SWOG study led by Dr. Svatek to really determine, "Gosh, are we going to have another strain? Are we going to have actually a more effective combination with a SubQ boost?" All those things.
Woodson Smelser: Sure.
Sam Chang: So, a really exciting time. And knowing how effective and how good you've been in leading some of these initiatives within the SUO and within the AUA, I look forward to talking to you again, Woody. It's always a pleasure. And really excited about upcoming findings as these trials mature and as we open new trials.
Woodson Smelser: Yeah, I agree. Thank you very much. I think five years ago, again, it would've been hard to fathom that we would have an SUO update where we reviewed five to seven trials at intermediate risk, non-muscle-invasive bladder cancer. We had limited options even in high-risk disease, so it's truly a Renaissance era.
Sam Chang: Absolutely, who would have thought? Who would have thought? All right, Woody, thanks again.
Woodson Smelser: Thank you, Dr. Chang.