OK, uh, welcome everybody to the event. I'm excited to be invited to speak. I guess I'll do my talk as everybody's getting lunch, so don't drop your plates. This is very exciting. Um, so I have no disclosures, uh, so we're gonna talk about, uh, I was asked to talk about non-muscle invasive bladder cancer, and I think that when you look at what is exciting about non-Muslim uh muscle invasive bladder cancer, it's actually the high risk population, and there's been a lot that has been done in this population and a lot that is still needs to be done in this population of patients and I think that we're gonna kind of highlight in the little 150 minutes that I got to discuss a very big topic, so. When I was in residency, we kind of went on this journey right when we got these patients we took them for a TRBT and you diagnosed him with high risk muscle invasive bladder cancer. For those that don't understand what high risk muscle invasive bladder cancer. Is those patients that doesn't have invasive disease so hasn't invaded into the muscle hasn't been into the lamina propria a little bit but has high grade features. So our goal as urologists is treated to make that cancer doesn't become, don't become muscle invasive. So when you're starting the journey we call this BCG naive, and that's because BCG has been the standard of care for the treatment of this disease since the 1990s. And then you go through a bunch of definitions that are very, very confusing BCG exposed, BCG intolerant, BCG unresponsive, and that's where things get very, very confusing. But the good thing is that things are becoming a little bit simpler and we have kind of tailored down our definitions and um help us kind of strategically be able to identify the right treatment for these patients. So when we look at this road map and the thing that I put this road map for patients here is the fact that. Every time that you go to one of these phases in your care, the runway shrinks, right? So you start being diagnosed, you start with the BCG runway, you have a long runway. You get failed BCG your runway becomes shorter, and that's when patients start getting scared because the worst cystectomy starts coming into play, right? And the goal when I was in training is that you want to avoid that cystectomy and I think that we're gonna challenge a little bit that paradigm as I go on my talk today. So let's talk about BCG naive settings. So, uh, this is the first trial that has been published in the BCG naive setting in a very, very long time. If you look at everything that was BCG naive since the SWOA trial was published in 2000, this is probably the second. Biggest trial that's been published and this is the Crest trial. This is the trial that looked at BCG Wilson telizumab, which is a subdermal PD1 inhibitor, and what they were randomizing patients to was BCG with 2 years of maintenance. This is full dose BCG, full dose at maintenance versus uh BCG plus the PD one inhibitor. And I what I wanna highlight here is the fact that this patient was a very, very high risk population of patients. A significant number of patients had T1 disease and CIS. So this is not just the high grade TA patients that were cherry picked, but and it's not surprising, right? We all as urologists and medical oncologists understand the potential side effects from a PD one inhibitor. So practitioners is not surprising, we're really trying to get the patients that we're really worried that we're gonna recur or potentially have more aggressive disease to involved in this trial. And when we got the result here we found that actually the combination of BCG plus the IO agent was superior to BCG, so 82% in uh recurrence free survival for the combination versus 75% for BCG and the CIS group is what we saw a tremendous difference and this is a very, very tough group, right? All the urologists know that every single trial on BCG responsive was in this CS category, and this because this is a true challenge. This is what we call this a field defect disease getting these patients to respond is very challenging, and this gave a very strong signal that maybe the combination was really be able to help these patients with CIS disease. However, that doesn't come with a drawback, right? Um, and it's the fact that there'll be a lot more side effects, and these side effects are not just the typical side effects that we urologists are used to. Some irritation in the bladder, blood in the urine, this is like side effects that potentially can be life threatening, something that in my practice I don't deal with every very often so it's something that we have to be very careful now when this trial came around I was like, OK, well this is the first trial these trials have been running for a very, very long time. And we got the data from Oso that it was negative. I'm like, oh my, this is gonna be like the adjuvant data for kidney cancer. There's gonna be one trial that shows a signal and no other trial shows any signal at all, but in ESO, like they've been saying. Potomac got uh presented and Potomac is also showing a signal. So this is BCG plus DA and in this trial I'm not, I don't have enough time to break it down, but there was they had 3 arms right there was the BCG plus maintenance. There was a BCG induction alone plus DRA maintenance and that was the BCG plus DRA maintenance and again a very high risk population, a lot more CIS patients here. Same amount of T1 high grade patients and again we see the same things again uh. Superior, um, uh, disease free survival for patients in the combination arm versus the BCG arm with um maintenance therapy and again what is surprising, what is interesting here is that. Like in the Crest trial, it seems like the young patients are the ones that really benefit from this so both of these trials are looking like young patients are the ones that truly benefit in the subgroup analysis, but in this trial, the CIS population really didn't see a benefit. So now we have a conflict that we. Have a trial that shows that very good for patients with CIS and showing this trial is showing that maybe the the best benefit is in the high grade and that would be for us admissions to argue a noxiom about why that happened and it probably isn't the fact that CIS was a little bit underrepresented in the Crest trial. What I really wanna point out here. Which is very, very important is the fact of how good BCG is are keeping these patients disease free, right? This is 3 years, 77% and going back 75% of the patients were disease free if you give them adequate BCG. That's a very, very high number, and I think that that's for us to know because again we haven't seen these numbers in contemporary management. The numbers that we quote patients is the 60% from the SWOA trial. We didn't do pre-staging to RBTs. We didn't have the advances in imaging where we're finding these patients that. Actually have muscle invasive disease, so these are contemporary patients and we're talking about high 70s that if you give them adequate DCG therapy that they're actually gonna have a a complete response at 3 years and actually still speaks about the effectiveness of BCG in this in this topic. Now the problem that we're having is that BCG is hard to get and that's because, um, Sanobi Pasteur closed their plan back in 2017 and that has created havoc in our practices, I mean. Every time since then we go through this, this ebbs and flows of having BCG not having BCG and trying to then find ways for us to be able to give BCG to these patients and the data that I discussed was full dose maintenance. Full dose induction full dose maintenance. I'm not giving full dose induction full dose maintenance in my practice. There'll be not be enough PCG for me to treat all my patients and so we have to start getting creative, right? And so when this happens, Gendosi came to the rescue some of practices, right? This is data that came in from the group of Iowa, and it showed that Gendosi does have an effectiveness and in this retrospective analysis it showed that was better than BCG, but I mean. These were patients getting inadequate BCG, but this is the numbers that I quote the patients that are, when we have these discussions that we don't have BCG, right? I don't have BCG to give you. What can I give you? I can give you genosi, and the data is not too bad. It's not as good as the data in the clinical trial, but we know that clinical trial patients always do look better than real real real real world data. So this is real world data, but GC GMoy does work in this patient population. So at Fox Chase we started using this biomarker, right? We don't have enough BCG to go around. We know that BCG doesn't work in about 30 to 40% of patients. So what can we do and how can we save the BCG for the patients that truly can benefit from this? And this is the that's the lab from Baler Labs, and they do, um, they have a proprietary algorithm looking at the patient's slides. So it's not a fancy test, it's not a blood test, not a urine test. We just send the slides to the lab. And they tell us is biomarker positive biomarker negative, and if the biomarker positive, then the patient is not gonna be a good candidate for BCG. And in our practice has told this slides from Alex, but it has really allowed us to actually optimize our utilization of BCG by 50%. So when we don't have enough ECG, this test has allowed us to reprioritize the patients, and we'll talk a little bit about the unresponsive side when we have to give BCG with some of the agents like Antiva, be able to start supporting that program to some degree. So I think that this is gonna be the future. Once the BRIC trial reports and hopefully reports that yosi is equal to BCG, I think that this test is gonna be very important level to select patients when BCG continues to be something that we struggle with. So now that we talk about BCG naive, let's talk about when BCG fails, right? And it's gonna be very confusing once Gendosi comes into play and then Gendosi fails. Let's talk about BCG when things are simple and everything is about definitions, right? So we have to define patient populations properly in order for us to really understand what we're dealing with. So the first thing that we have to define is what is adequate BCG. So Article VCG is a combination of 5 out of 6 inductions and 2 additional doses, either 2 out of 6 inductions or 2 out of 3 maintenances. If you don't get this, you don't get inadequate BCG, you don't qualify to be called BCG unresponsive, and we know that all the fancy agents that we saw up in the. And, and by the exhibitors are for BCG on responsive disease. And then we have BCG unresponsive, which is patients that have progression of disease. So anyone that has T1 high grade at 3 months is considered BCG unresponsive or anybody has persistent disease of 6 months that is high grade in nature is also considered BCG unresponsive. Anybody else is called coti BCG exposed, so either the patient didn't get is just after induction. They still have a little bit of CIS. That's considered BCG exposed. A patient that got not adequate BCG, that's considered BCG exposed. A patient that finished 1 year maintenance, that that's all we can give these days and then failed 12 months later, that's BCG exposed, and that definition matters because a lot of patients get treated for BCG responsive when they're BCG exposed and our and our and our role as urologists is to be able to extend on that wrong way, right? And so I think it's very, very important for us to be able to define that properly. So I'm gonna focus on BCG on responses before I go to BCG exposed because I wanna kind of set about how good or not so good these agents are at keeping patients free of disease, but right now we have 4 FDA approved agents Mendosi, which has been the workhorse that we have used for the last 10 years, and this is kind of the way that they've been, uh, they're given. I'm not gonna go through them because I'm already about time, but we have primpolisimab, which is an, uh, systemic infusion. We have naroharidine which is a siledrine. Which we give uh every 3, every 3 months for uh 4 doses we have, I'm not gonna pronounce that I'm sorry for the GME committee that's unpronounceable andtiva and BCG and you give a weekly installation, uh, once, um, for, um, just kind of following the BCG pathway and then you have TAR 200 which is the gymado beam pretzel. So all each of them have their pros and cons. I'm not gonna go through them here just because it's down of time, but they're available. They're out there in the world and we can use them. Now this is where kind of the rubber meets the road. How good are they? And I mean some are better than others, but when you look at the 24 at the 24 months you are they I mean they're not BCG, right? We're not talking about 77%, right? We're talking about 30s, high 20s, maybe 40s, right? So again that runway is getting, getting shorter and this agents. Are getting very expensive, right? So as our treatments are getting more effective they're also getting a little bit more expensive. So part of our conclusions in these talks are gonna be the fact that optimizing how what the patient gets in the front line is very, very important because these agents in the BCG responsive setting I cannot comment on how they're doing the BCG naive setting because there's no data for that now in the future there will be, but right now they're good. They allowed some patients to be able to keep their bladders, but the reality is, is that you're playing kind of the. Um, musical chairs game one agent versus the other and the process potentially hurting the patient's bladder. So as I said before, BCG exposes a very heterogeneous cohort, and our guidelines, both the AUA and the EAU recommend that we reinduce these patients with BCG. The reality is that we reinduce them with BCG. Only about 50% of those patients are gonna respond, so 50% of those patients are gonna go down to that BCG in responsive cascade, and we know that those agents, while they have some activity, they're not gonna give us a long runway to keep these patients disease free. So there it comes about managing BCG exposed. So this is a trial that was led by the group at Memorial. This is Juan PCA. He trained at Penn, and this was the phase two, phase one, phase two trial looking at a combination of gymsarabine and BCG, and the data is actually remarkably good. I mean, at 12 months we have 85% at 18 months, 76%, and these are patients with BCG alone should only be responding 50% of the time. And again these are not very expensive. BCG is cheap. Gymcitabine is cheap. We use it all the time in the clinic. It's a cocktail that we can easily, uh, adopt into our clinical preferences, and this is kind of a call in arms that there's a trial now. There's the game trial that we are activating the Fox Chase hopefully this week that is run by alliance that is looking at this patient population specifically. So for those out there that have patients that are BCG exposed that are thinking about reinducing them or thinking about grieving another BCG induction. Police centers our way. We'll be happy to enroll them in this trial and see if we can prolong the runways so they don't have to go to that BCG on responsive setting. So when we talk about our options here and this is an homage to David Chen, he talks about turtles, hares, and, and birds all the time, but we have patients that go through this runway or this trip in different ways, right? We have our turtles, we have our rabbits, and we have our birds that probably should never have been in this, in this, in this runway altogether, and I think that our job is to be able to identify these bears but as urologists try to make everybody as much as turtle as possible. Now when I was in training this is the patient and position perception uh intravesicle therapy was what you wanted. It was happy times. Getting a cystectomy was very sad times. If you were told you had a cystectomy, you're getting kicked out of the room, right? No, I don't want my bladder out. I'm coming to you because I don't want my bladder out. I'm keeping my bladder, right? And the reality is, is that the cysto trial really changed the paradigm. This is a trial that was an observational study that looked at patients that have failed BCG and they said, hey, we're gonna watch you to see how you do. We're gonna send you a bunch of, uh, quality of life surveys Fox Chase under David's guidance was, uh, the contributor for this trial, and it showed that most of the patients that actually had an early cystectomy actually were happier than the patients actually went to intravesicle therapy. So this was a surprise. So actually cystectomy is not the bad wolf that everybody thinks it is. Actually, patients do well, and I can tell you that that actually mimics my practice. Every single one of my patients that is in the BCG on responsive cycle knows every single wawa that is from their house to my office, and that's because they're peeing every 10 minutes. And so I think that when we look at how we manage this patient population, I think that it's a very dynamic journey and what I do in my practice is that I balance cancer control with bladder function, right? And that's the reality. As patients, how is your bladder working? Is your bladder actually doing bladder things? Is your bladder is not really working like a bladder? Why are we keeping your bladder for? And we have the cysto trial data to support the cystectomy actually is not gonna make you as unhappy as you think you're gonna be. Adequate treatment selection when the patient presents with high grade disease is essential. That's gonna be really tee off your patient to be able to keep their bladder the longest. And that be BCG gym Dosy, but with, with BCG you really need to give them adequate therapy. Intravesical therapy effectiveness decreases substantially the more you fail the treatments and paradoxically it actually increases in cost of the health care system so I think that our job as physicians should be to try to be able to extend how much we can actually keep those patients from going down into that cycle, and I do discuss cystectomy early and often with my patients. I think that the preconceptions of what this does to patients in the quality of life is a little bit overinflated. And I think this is trials has helped. So with that I conclude and thank you very much for your time and sorry for running a little bit longer.
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