Chapters Transcript Video Management of BCG Unresponsive Disease Roger Li, MD Welcome. Awesome. Welcome everybody to, uh, this month's bladder cancer-themed grand rounds. Our first speaker is truly a rising star in the world of bladder cancer, Dr. Roger Lee. He comes to us from uh Moffit Cancer Center, which, as many of you know, is a center of excellence for bladder cancer, has paved the way for many, uh, bladder cancer trials and the management of, uh, bladder cancer through radical cystectomy and other modalities. Um, Roger trained at MD Anderson, and uh, he has really, you know, sort of, uh, exploded on the scene of bladder cancer with a lot of good work in a number of trials. Um, probably most recently, the, the landmark trial that he is a part, he's a part of is the COR01 trial, which is for BCG unresponsive bladder cancer using a new viral vector retosimaggen. Um, it's an exciting trial and an exciting new drug, and um, he's also a big part of the International bladder Cancer Group. So he's gonna talk to us a lot about BCG unresponsive NMIBC and some of the cutting edge work he's doing and what's going on in the field. So, without further ado, Roger, please go ahead. Thank you. Thanks so much, Chad, um, for that kind introduction, and it's really my pleasure to um Give a, a talk on this subject, um, and I, you know, look forward to working more closely with, uh, University of Miami cause I know you guys do a lot of great work down there, um, especially in, in bladder cancer with Chad, um, and others, um, so. Look forward to future collaborations. Um, so, BCR responsive NMIBC has really been a hot topic in urology over the last several years. Um, and so I thought we kind of talked today a little bit about the definition, um, some background on clinical trial design in this space, uh, some of the results for, from historic trials and then recent trial readouts. And also what the future might look like in this disease space. So we'll start off with um describing a case that we typically will see in the clinic. So, uh we have a 72 year old gentleman with hematuria on the primary resection, the patient was found to have T1 high grade bladder cancer. He then undergoes BCG induction. And um on 3 months surveillance, uh, he was found to not have any recurrence, and so he undergoes another 3 weeks of maintenance BCG at that time. But at 6 months, he was found to have recurrence and biopsy shows that he has T1 high grade disease. So at this point, uh, there were a couple of different treatment options. You could either repeat BCG induction. You could take the patient for a radical cystectomy. Or you could try some other intravesicle agents. So really, this is kind of the, the quintessential patient with BCG unresponsive disease, where they have received adequate BCG and by the definition that was put forth by the International Bladder Cancer Group back in 2016, this patient will qualify as BCGR responsive. And in this definition, Um, the group really, um, combined patients with refractory disease or those with persistent high grade disease at 6 months, despite adequate BCG, and also those with relapsing disease, or recurrence of high grade disease after achieving initially a disease-free state at 6 months following an adequate BCG together to formulate what was then called the BCGR responsive definition. And as you know, this definition has since been adopted by the FDA um and has been implemented in several of the different clinical trials that brought many of the agents that we're now familiar with, uh, that we have available in the clinic for use in patients, uh, who have recurrent disease after BCG. So traditionally, um, as you know, radical cystectomy has always been the gold standard for BCG responsive disease, and it remains so to date. Um, but this disease also occurs in patients who are frail and have many other medical comorbidities. Um, despite the advancements in surgery and post postoperative recovery protocols, many of these patients simply cannot undergo surgery. And so, you know, obviously conservative management strategies are needed in that setting, um, but in the past, this space has also played, been plagued by um an unlevel playing field where there's a lot of heterogeneous uh patient populations being enrolled into different clinical trials in the past, so, uh, the results of those clinical trials were very difficult to interpret. Um, and also, you can imagine that, uh, uh, testing, uh, novel bladder sparing agents in this space, um, uh, you can't have a control on in that setting, um, because the standard of care is radical cystectomy, making it very difficult for comparison studies. And finally, there's also a lack of consensus on the trial endpoints. So what level of efficacy actually warrants for approval of the drug? And so all of those really made it difficult for the FDA to determine what is worthy of approval um to be used in that setting. And so, because of all those issues, the FDA and the AUA had a um workshop that was um held at the 2014 um GUASCO, and uh in which they discussed a lot of the different issues that were surrounding the disease space, um, and from that workshop, emerged the BCGR responsive definition. And importantly, the FDA had accepted that single arm studies um can be used for registrational purposes. And that to inform the uh approval of the drugs in that space, that complete response rates and the duration of response were the two primary endpoints, co-primary endpoints that needs to be used to support marketing applications. And so, that, of course, uh, raises the question, what is the clinically meaningful therapeutic effect. And from that initial 2016 paper, the International Bladder Cancer Group also proposed some benchmarks uh for both CIS containing disease, as well as papillary only disease that then have somewhat been um also referenced by the FDA and others in uh for marketing purposes. And so those benchmarks include for uh carcinoma and situ 2 disease. So this is CIS that's found at the time of the diagnosis of BCGR responsive disease, that you have to have a durable response at 6 months of 50%, 12 months of 30%, and down to 25% at 18 months. Um, and similarly for papillary disease, 30% recurrence free survival at 12 months and 25% at 18 months. And so when looked at in that lens, if you look at all of the uh the historical data, Well, Valruicin was the only one that was approved um by that time, and at 6 months it approved uh it showed 21% complete response, but by 12 months, that already uh dropped down to 17%, and upon even longer follow up, uh, we all know that the complete response rates dipped even lower to below 10%. Gemcitabine was tested in the swab trial in the 2000s, and its 12 month recurrence-free survival was at 28 28% and 24 month recurrence-free survival at 21%. Abraxan um was tested in a very small clinical trial that was published in 2014, um by the Columbia Group. And in that trial, it did show that 12 months recurrence free survival surpassed the aspirational goals uh put forth by the uh the IBCG at 35.7% at 21 months, um, down to 25%. So, um, by those standards, uh, suffice it to say that all of the historical agents, um, do not really measure up. Um, and we also similarly looked at a lot of the different trials up to 2020. That were performed um in patients who have experienced BCG and had developed recurrence. And what we found was, again, um just confirming what the group at AUA uh or I'm sorry, at the uh GUAO had also um found was that there was a lot of trial heterogeneity in terms of the patient population. Uh, who was enrolled into previous different trials, um, and of course, there's also, um, a lot of heterogeneity in the, the end points that were chosen for the different clinical trials. So as a result, um, it really made the the results from these historical clinical trials very difficult to interpret. But nevertheless, we did do a meta-analysis looking at the complete response rate of carcinoma situ, containing tumors, um, and at 6 months, it appeared to be 26%, dropping down to 17% at 12 months. Um, for paploid only, it does appear to be higher, um, but The progression free survival rate um was uh relatively uh uh very favorable with overall um of 91% progression free rate. So, um, we concluded that in the past, based off of all of these different studies that bladder sparing therapy, um, had only achieved modest efficacy and that further trial and investigations were needed. So, um, what are some of the most exciting domains of therapy? Um, so we'll cover each of these by starting with intravesicle chemotherapy. And of course, we're talking about intravesicle chemotherapy, we have to start with sequential gemcitabine and docetaxel, which is a regimen that was initially uh developed at the University of Iowa um by Mike O'Donnell and colleagues. And um in a multi-institutional study that was published a few years ago, uh, this regimen had showed a 1 year recurrence free survival of 65% and 52% also at 2 years. Even in the CIS containing population, as you recall, this population um had lower response rates overall that still demonstrated to be 50%. And this, uh, as you may very well know, compared to many of the trials that have, um, reported out, uh, thus far, um, and for some of which have gained FDA approval, seems to be really high, and, um, of course, we have to take into account the fact that this is a retrospective study, um, that there are a lot of patient selection criteria, um, that may be different than those that are used in the prospective studies. Um, and again, in this study, they also found that only 7.6% of the patients have progressed to muscle invasive disease, and all of these low progression rates remind us that it may be that BCG responsive disease is not as ominous as we once thought that uh they are destined to become muscle invasive disease. And that there could be a window of opportunity in which we treat these patients with multiple salvage agents in order to help patients save their bladders. Um, the Sunrise One study is using a TAR 200 device, uh, as I'm sure many of you know, this is a pretzel-shaped device that's placed inside the bladder. And it constantly elutes um gemcitabine, um, and the device is exchanged every 3 weeks for the 1st 24 weeks, and um then after that, it's every 12 weeks through week 96 or about 2 years of treatments. Originally, the Sunrise 1 study was designed as a 3-arm study looking at TAR 200 monotherapy versus citrulimab monotherapy. Versus the combination of the two. And um when they initially reported out the results, the uh monotherapy seems to be doing even better than the uh combination, and hence they decided to close down both the uh the combination arm as well as the cireumab uh monotherapy arm. And continued only with the uh TAR 200 monotherapy on which they accrued 85 patients. And um the, the study uh primary endpoint was looking at overall complete response rate. So this was reported just recently at the AUA 2025, in which they reported that uh the complete response rate seen at 3 months was um the highest that's been reported for any uh monotherapy trials thus far. At 82.4% and 70 out of the 85 patients. And uh the responses also seem to be quite durable in a significant proportion of the patients, where 45.9%, just under 50% of the patients continue to have a complete response at 12 months. And I think this is a, a place where, you know, we can make the point. That, um, even though a lot of the trials reporting out thus far have been concentrating on the 3 month complete response rate, um, when, when we're treating patients with BCG unresponsive disease, we're really looking for a durable complete response to help maintain their bladders without disease, um, for a long period of time. And so, even the, the, the, the reason why the FDA had chosen the 3 month complete response as a primary endpoint, um, is because number one, they thought that CIS cannot be completely resected, and hence that's the Z space where single arm studies can be used to test the efficacy of a drug to treat the disease, um, even though with uh the 3 month complete response rates, um, Very few of the trials actually mandated a biopsy at that time point. Most of these trials really just used a cystoscopy with a negative cytology is being sufficient to um to prove that a patient is in complete response. But really, if you think about a patient who's coming into clinic to see you, they're not really worried about whether a drug is gonna be able to, to maintain their disease free state for only 3 months. They're worried about 1 year or even beyond. And also, um, they're worried about whether the treatment is gonna prevent them from getting muscle invasive disease. So I think going forward, we may have to focus on those two points more durable response and also progression free survival in order for us to differentiate between the different um drug regimens that may be available. So this is the swimmer plot that shows again the durable response in these patients, um, that, uh, if you were to derive a response in the 70%, 70 patients who did have a complete response at 3 months, uh, more than 50% of them were able to hold that response for up to 12 months. Um, and, uh, um, of the 11 patients who had completed 2 years of treatment, 9 of them had remained in response. So, Uh, if you were to derive a response from this treatment, seems that, uh, they're quite durable. From the safety perspective, uh, most of the safety issues as expected are related to urinary tract symptoms, um, such as, um, urgency, frequency, dysuria, urinary tract infections, um, but you'll note that there's, there was, uh, a few events, um, 11 events or 13.9, 13% of the patients. Did experience great um greater than 3, severe adverse events, meaning that uh they were, because of these adverse events, um, they needed to either have a procedure to be hospitalized. So, um, still quite, um, A significant number of patients um having grade 3 SAEs, um, and this becomes very important we're comparing this against some of the other trials. At the AUA, uh, they also reported out the results from the TAR 200 mile therapy in cohort 4, which is the papillary only disease. So, um, the, the three arms were tested in CIS containing patients. Um, they also tested it in the patients without CIS and only 52 patients, um, looking at disease-free survival at 12 months. That was the primary endpoint. And um they haven't reached that time point yet, but Um, looking at the 9 month disease-free survival, it does seem to be uh quite um impressive at 81% of the patients having durable response out to 9 months, um, with the TAR 200 device. Um, and, um, overall, only 6% of the patients uh had to undergo radical cystectomy, which is also very, um, uh, very low. Um, so, uh, similarly, looking at progression free survival and overall survival as you would expect, um, with this device inside, um, progression-free survival and overall survival, uh, both appear to be very high, um, at 95% and 98% respectively. So, um, that was kind of a, a summary of the intravesicle chemotherapy based agents, and now we move to systemic immunotherapy based agents, which is, uh, probably, um, the, the um um the mechanism of action of drugs that we have the most experience in. And of course, this starts with uh keno 57 in which um the trial tested uh patients with carcinoma in situ BCG responsive disease, uh to be treated with pembrolizumab, 200 mg every 3 weeks. Um, and again looking at complete response at 3 months. Um, uh, and also disease-free survival, um, in a cohort B patient which, uh, only had pathway only disease. A similar child design was also seen in SOA 1605, um, and this was, uh, tested in the same population with a teallizumab, which is a PDL1 um agent. The design for this study was slightly different than uh the one with Pembro in which the patients were mandated mandated to have a uh bladder mapping biopsy to be done at 6 months following trial enrollment. Um, only for those patients with CIS disease, and this was set to be the primary endpoint. Um, they had planned a, uh, sample size of 202 patients, but did an interim analysis. Um, and the long story, uh, short for this trial was that at the interim analysis, um, they didn't meet the futility standard, um, by one patient, and so hence they had to stop the trial short. Um, but nevertheless produce some study, uh, some results that we can compare against the Keno 57 study. Two additional smaller studies that were done um using PL1 agents, um, one was done here at Moffett using Duvaluab, in which we tested 17 patients using a very similar design as the SWO 1605, um, where, uh, we had biopsied patients at the 6 month time point. Um, and also another study that was led by Brent Eman, um, who was at Duke at the time testing a tizellizumab plus or minus BCG in 24 patients with BCG response to CIS. And so here are the results um from those studies, um, uh, compositely. So if you look across the 3 month CR rate for all these trial agents appear to be quite similar, um, so ranging from just under 30% to just above 40%. But you can also see that there is a steady drop off of the complete response rates, um, to about 12 months and then 18 months for some of the studies that followed their patients um for that longer period of time. So, um, in general, I would say that for these PD1, PDL one inhibitors, um, that the efficacy rate does appear to be quite modest, even compared to intravesical chemotherapy, um, and if you look at the papillary only group, Uh, so, even though the results are a little bit better than the CIS containing, so for um Pembro, uh, at 12 months instead of 20%, you're looking at 43.5%, looking at 49% for a Tzo in the swab trial. So a little bit better than the CIS containing, but not um as good as some of the other uh agents that we've seen, um, thus far. And um if you look at the progression rates, so, uh, as we mentioned before, sorry, let me go back. Oh shoot. So, um, looking at the patients who uh had gone on to muscle invasive and meta metastatic urothelial carcinoma in the CIS containing group, um, it was quite similar. So the keynote 57 trial had 9% of the patients progress on to muscle invasion or metastatic disease versus 12% in the swab study. But if you look at the pappiar only, uh, for some reason, the um keno 57 had a higher percentage of patients developing uh disease progression than the Atizo group, um, perhaps due to longer follow up, um, but, you know, this suggests that there is still a significant number of these patients, um, who may progress on to muscle invasion. Um, but most importantly, I think, is, uh, the, the different toxicity profile that we're seeing in these systemic agents. Um, and even though these systemic agents, uh, have been used throughout for several different disease, um, you know, and also for metastatic bladder cancer. Um, and the toxicity profile that we're seeing in this population weren't that different than what was seen before, but nevertheless, we have to also take into consideration that, um, in the BCG unresponsive setting, um, the patients may not be as tolerant for the level of toxicity that you're seeing with these agents as, say, a patient with metastatic disease after failing multiple lines of treatment. Um, and who are getting these, uh, PDL one, agents in desperation. So, um, put in that light, the total grade 3 or 4, severe, uh, SAEs seem to be 13% in the Pembroke trial and also similarly, um, there was 14% SAE that was seen in the uh Tizo trial, um, and importantly, there were uh several deaths that happened, um, in the Tizo trial as well. That just points to the danger of using these drugs for very treatable disease. Um, so you have to keep in mind that, uh, uh, ultimately, we're comparing these results to what we would be able to alternatively provide the patient with radical cystectomy. And as we all know that, um, even though radical cystectomy does uh carry with it a uh morbidity and uh mortality rate. But if you, um, you know, compare that against the 2%, One would make the argument that if you were to have a radical cystectomy done um at a high volume tertiary referral center, um, that we may actually, um, you know, have death rates that are, that may be even lower than what's seen on the, on the teasel trial. So, um, a couple of years ago at the IBCG retreat, uh, there was a, um, manuscript that was generated looking at sequencing of these drugs, and, um, from the discussion, um, long story short, we basically Um, um, had formed the consensus that because of the toxicity profile of these systemic immune agents, that they should be used as the the the treatment of last resort if the patient really were ineligible or declined radical cystectomy. Um, and that future child development using these agents were possible, but they were most likely to be, um, combined with other agents because of their additive or synergistic mechanism of action, um, to enhance the efficacy that you're seeing with other agents. All right, so that was the systemic immunotherapy. What about uh immunotherapy that we can ad administer through the bladder? So maybe we can reduce the toxicity using that. And the first one, to mark it was at Stillon or in Stilloron at the time of um the the phase one and two studies. So, what this is is an adenoviral vector, um, uh, that knocks in an interferon, uh type one interferon gene to either the tumor cell or the urothelial cells. And so after being infected by this virus, the urothelial cell essentially gets turned into a interferon producing factory. Um, and this works with a 30 day, uh, cycle, so that, uh, uh, the nice thing, one of the nice things about this drug is that, um, the dosing only happens once every 30 days, uh, uh, I'm sorry, once every, um, uh, 90 days for the patients to be coming back, um, once every 3 months. And so, in the phase two trial, um, what was found was the complete response rate was 44%, um, with a 12 month recurrence free survival overall of 35%. They tested out two different dosing levels and eventually went with the 3 times 10 to the 11th viral particle level, um, because of the higher efficacy. Um, and so at the phase two time point, they, they did see that, uh, these, um, uh, complete response rates did meet the IBCG benchmarks that were proposed a few years ago. And this was taken to a phase 3 study in which 157 patients overall um were enrolled, about 100 in the CI's containing group and the rest in the papillary only that were treated with 3 times 10 to 11 uh viral particles. Um, and on this trial, unlike Pembro, um, they did mandate a, uh, 12 month biopsy, uh, mapping biopsy to make sure that, uh, uh, All of the disease um were assessed. And so from the uh CIS containing group, um, 3 month complete response rate was seen at 53.4% compared to the 41% in uh keno 57, um, down to 24% at 12 months. And, um, similarly as the previous trials, you see that there is higher efficacy rates in the papon group, um, from 72% initially to 43.8% at 12 months. Um, so the progression, the muscle invasive, uh, was, uh, very low, so, um, only 55 patients in the, um, CIS containing group had progressed on to muscle invasive or metastatic disease, um, and overall, only 5% of the patients, um, were found to have, uh, progression. And finally, um, this was the differentiator between at Stilloron versus Pembro, which was that the safety profile was strictly limited to bladder related issues, um, very few, um, um, systemic, uh, issues such as fatigue and chills. Um, and then, uh, the second one that was approved by the FDA was N803, um, and this was an IL-15 super agonist. Um, that, uh, um, you know, essentially is, uh, is thought to stimulate both T cell and NK cell activity. And so it's thought that when used in combination with BCG, um, BCG actually provides, uh, what's called trained immunity by activating the myeloid cells, uh, within the bone marrow, so that that, those myeloid cells can then And migrate to the tumor microenvironment and act as an antigen presenting cell um by taking up tumor associated antigens and um also BCG for priming. And in addition to that, you have the NAO3 agent that uh um additionally activates the NK and the T cells, and the two together can act as a 1-2 punch, um, to eliminate the tumor. So, similarly, as the atstilorin and also the keynote studies, they had two different cohorts of patients, um, uh, one with CIS containing, the other one papillary only, uh, for a total of 160 patients, again, looking at a complete response, either at the 3 or 6 month uh time point for the CIS containing group, and it's important to point out, um, that, uh, in this trial, Um, they did accept that for patients with, uh, persistent CIS or TA high grade disease at month 3, that they're eligible for reinduction using NAO3 plus BCG, um, unlike in keno 57 or attire, um, prior to it. Um, In the pabla only cohort, they looked at disease-free survival at 12 months, and um this was initially presented at uh GUAO 2022, um where they reported out complete response initially at 71%, and this is combining those patients with either a complete response at 3 months, or those who had uh uh persistent disease at 3 months, but then went on to have reinduction. And we're able to derive a response at 6 months. So combining the two together, you have 71%. Um, and overall, um, the 12 month uh complete response seen, um, it was not uh uh reported out here, um, was around 50% or so. And um the efficacy in the papillary only, uh, again was um a little bit higher than what was seen in the CIS containing. So, um, disease-free survival at 12 months with 57%. And very importantly, um, and this is something that they had uh uh um. Uh, touted, uh, repeatedly that there was no grade 3 SAEs seen in, um, in this trial at all, and that most of the the complications associated with this trial were all bladder related symptoms. And then finally we have um reimagine grenay repvec, which is an alkalytic adenolvirus. Um, so this uh adenovirus has a E2F promoter with a GMCSF transgene, and this has been covered extensively in um other uh. Medical conferences. So, um, I'll just kind of briefly go through uh where it's designed to um attack those cancer cells with a defective RB pathway in which uh E2F1 um protein is, is elevated. And because you have elevated levels of E2F, these proteins then bind to the promoter that's causing acolytic um uh viral replication. And in addition to that, the GM-CSF gene is uh transcribed as part of the viral replication, and that potentiates the um uh immune activity of the unloaded virus. And so, the BON 3 study um was presented by Mark Tyson at the recent AUA and um we're hopefully gonna be able to put together the manuscript for this soon. Um, this was tested in 110 patients with CIs containing Um, BCG unresponsive disease, uh, where the alkalic virus was given, um, as an induction course of 6 doses, um, with an option again of a reinduction at 3 months if the patient were to be found with persistent CIS or TA high grade with maintenance courses given at 69, 12, and 18 months. Um, Sorry, so, uh, the results from those actually showed that there was about a 75% complete response at 3 months and out to 12 months, also just a hair under 50%, and the toxicity profile for this was also very well tolerated. Um, um, in these patients, uh, with mainly bladder-related symptoms, and again, no grade 3 SAEs, um, and, uh, as a result of this study, the, uh, application for registration is, um, is gonna be submitted later on this year, and we're we're hoping to bring this as a monotherapy agent to the market for BCR responsive patients. In addition to that, as mentioned by Chad earlier, um, I've led a study that looked at the combination of CG0070 increased imaging with um Pembro in the BCGRR responsive setting. Um, and so the hypothesis behind that was the unloid virus can um cause viral lysis and um uh cause GM-CSF to Trigger these antigen presenting cells to come in and take up the uh the tumor associated antigens, um, and elicit an anti-tumor response, but in turn causes um immune uh exhaustion. And um the, in turn, if you add the pembrolizumab, then you can reinvigorate the exhausted T cells in the microenvironment um to further eliminate the tumor cells. So they may have synergistic, uh, activity. And so we tested this hypothesis in 35 patients with um CIS containing BCR responsive disease where we gave uh pembrolizumab for up to 2 years and um Cretasteagine was given uh in the same regimen as it was delivered in BON 3. Um, and for the primary endpoint, we looked at complete response at 12 months, um, and it calculate the statistical power was calculated according to, um, the hypothesis that the combination was going to um be superior than, uh, what was seen from the keno 57 trial with Pembrolizumab alone at that time. And so here's the um swimmer plot where we observed a complete response of um 85% um with the combination, and out to 12 months, you're seeing 68%, and this is including those patients who were taken off trial um for unrelated, uh, for reasons that were unrelated to disease progression. Um, and of course, we saw, uh, some immune-related activities that as you would expect from Pemblezumab, um, but I think, um, You know, comparing the the efficacy rates from this trial versus keno 57. Um, I think the toxicity that we're seeing from the Pembro, uh, was not much higher than what was seen from keno 57. So in other words, there weren't any synergistic toxicity that was seen by adding the two agents together, and with the efficacy rates that we see from the combination, um, I do think that there is an argument to be made by, uh, for using the two agents together to achieve a complete response in higher number of patients. Um, I should also mention that, uh, there were no patients that progressed to muscle invasive disease or metastatic disease, um, following at least 2 years of follow-up. And finally, we'll just wrap it up with uh targeted agents. Um, so, um, fibroblast growth factor receptor, which is a receptor that's um probably familiar to you all, um, very commonly found in non-muscle invasive bladder cancer. Um, so this is uh uh thyrosine kinase signaling pathway that is um involved in several different, um, Cellular processes, um, causing cancer cell proliferation, migration, angiogenesis, and survival. Um, and this, uh, receptor has been targeted by several different agents, um, and sourdainib, uh, which is owned by J&J, is an oral selective pan FGFR tyrosine kinase inhibitor. Um, and as, uh, uh, a result of the Ford study, it had already been approved uh to use in locally advanced or metastatic. Uothelial cancer patients who have seen at least one line of systemic agent and, you know, testing the 41 study that was tested after the use of cisplatin containing chemotherapy, in which um erinnib demonstrated to have a survival benefit as compared to um other uh uh chemotherapeutic agents. And so this uh urini oral urda was also tested in the TOR2 study, um, looking at uh patients with high risks NMIBC with CIS, um, after BCG treatment, um, and in this study, uh, It was actually shown to have uh quite a bit of efficacy. So, um, in very few patients uh that was tested, um, uh, the complete response was seen in, um, all the patients, um, and, um, with a duration of response that was seen in some of the patients up to, uh, just over a year. Um, but the problem with that trial was that the, the adverse events were deemed to be, uh, too significant in this population. Um, and, um, even though the toxicity level again from the Thor 2 study weren't too different than, uh, the Thor 1 study, and in fact in Thor 2, they actually used the lower dose of the urofinib compared to Thor 1. Um, there was still a very high discontinuation rate, um, so you, you can see here, um, that, uh, there were several, uh, serious TEAEs and many of the adverse events leading to discontinuation, dose reduction, or interruption and uh essentially all of the patients, um, that were enrolled into the study. And because of this, it was thought that oral urdo uh did not have a pathway forward um in this disease space. But the good news is, um, the company also formulated uh another Taurus um product called a TAR 210, which loots out er ayib, um, instead of gemcitabine. And um at the most recent AUA, um, in the trial in progress, uh, the concept of Moonrise 3 was also um presented in which patients with pap only high grade NMIBC after BCG treatments. Um, uh, or intolerance of BCG, uh, can be randomized to receive, uh, TAR-210 for 2 years versus, um, investigator choice of single agents intravascular chemotherapy. So this, uh, study is ongoing and it's, um, um, testing out the efficacy of TARP 210 in the post-BCG setting for FGFR altered tumors. And finally, in Fortumabvidotin, as we all know, had great success in the metastatic setting. It is also being tested in the neoadjuvant setting um for uh urothelial cancer in general, um, and the way that this drug works is it targets nectin 4, that's expressed, um, um, uh, on urothelial carcinoma. Um, extensively and uh with a payload of um MMAE. And um in addition to all of the systemic agents, EB 104 tested uh uh formulating this drug in an intravesicle formulation, um, and this was initially reported, um, out a few years ago at, uh, um, ASCO, um, with a few patients tested with a complete response seen in some of the patients, um, but still very early results and we're still waiting for, uh, for the follow-up from that study. So that was kind of an overview of the entire landscape of all of the drug uh agents that um are being tested and um are ongoing at the moment. Um, so some of the unanswered questions that are still in this BCR responsive space. So, as mentioned before, you know, I do think that uh we're understanding a lot more about the disease and that Not everybody who develops recurrence of high grade disease after BCG or destined to develop muscle invasion. And so that gives us this window of safety for um for some of these patients, maybe a, a long window of safety in which we can repeatedly uh treat these patients with salvage agents, um, and not necessarily have to worry about uh them developing progressive disease. And with so many different agents that are now available and also being tested right now, um, the question of sequencing of the different treatments obviously comes to mind. So, do we lead off with one agent versus the other, um, You know, do we also treat everybody with BCG necessarily, or are there other agents that may be even more effective than BCG as the frontline treatments? And then, of course, um, other, uh, certain biomarkers that we can use uh to help select patients for Different types of treatments. And um I have to uh admit that up till now, I don't think that there's really great um biomarker work done, um, in, uh, as correlatives to many of the um trials that have reported out thus far. Um, monitoring for CIS also comes up, as you all know, um, you know, we do have the cysview, uh, or blue light cystoscopy that enhances the detection of CIS, but nevertheless, um, doesn't really tell us. What the burden of disease is at the time of treatment starts. And also, um, when we're monitoring patients for disease recurrence, we're usually resorting back to white light cystoscopy and not necessarily picking up on all of the disease that there is, um, and since the monitoring is so subjective, you know, using white light cystoscopy. Um, can we actually, you know, still treat, uh, the results of one, study equally as the other? And then, um, the role of immune checkpoint blockade, as we mentioned before, um, I, I do not think that it, um, has a role as a monotherapy in NMIBC setting, but nevertheless, when you compare, um, or you combine it with uh an intravesicle agent, it may add additional efficacy, but more importantly, uh, may add durability to the response. So with that, I'd like to thank you for your attention and uh be happy to take some questions in the next 10 minutes. Roger, that was so much fun. fantastic, really. This is Bruce Cava. Um, I, I think, you know, one of the things that I find fascinating is really this whole change that um You know, in the past, when, when, when I first started doing this 60 to 80% of patients who were not controlled with CIS in the bladder were thought to progress within 2 years to muscle invasive disease. And this whole change in, in the, this, this window of opportunity that we have that it's no longer that. I mean, we're, you're showing data showing less than 10% of patients will actually progress to an invasive disease, which is how, how do you account for that? Do you think that the, the imaging, the, the way that we staged patients that, is there something that we missed years ago that that has changed over time? You know, I, I think, um, it's a great question. Um, so I think certainly the technology that we're using nowadays to detect disease and also a lot of the procedures that we're implementing, right? So the, the uh mandated VTUR, um, and, and, uh, um, so, you know, just the extent to which that we make sure that the patients do not have more invasive disease, um, at the start of treatment, I think. is a significant reason why we're, we're seeing less progression to muscle invasive disease. Whereas I think in the past, probably a lot of the patients who progressed the hunted disease probably were underdiagnosed in the very beginning. Um, so, in addition to that, I think, um, also the, uh, I just think overall, people are adhering to the swap protocol a lot better than before, um, where, um, you know, we're not only giving the induction, um, but also the maintenance. As you know, you know, for the longest time, there has been this thought that, uh, as long as you give the induction, then, um, you know, you're not gonna gain too much by providing maintenance. And I think the tide has really turned. Um, you know, uh, even given the crest data that was recently presented. So I think it's, uh, a combination of all of those different things, but nevertheless, I do think that there is, um, still a lot of work to be done to identify those patients who are at risk for progression. Uh, and if we can identify those patients up front, that would be perfect. But even if we're able to use, say, recurrent tissue samples as they develop recurrence, cause as you know, you know, most of these patients who develop progression don't necessarily just all of a sudden go to muscle invasive disease. They'll actually have sequential recurrences, non-muscle invasive disease prior to developing progression. So I think there's a lot more work to be done to understand that process. Yeah, that's interesting. And there are plenty, there are a lot of clinicians and experts in this area on, on the line right now. And I, I know from my own personal experience, just from facing a patient with non-response to BCG I'm always feeling if I don't offer that, if I don't get that radical cystectomy done in a, in a short window, I'm, I'm, I feel like I'm, I'm really worried and, and so. You know, offering them something at the time Valrubison and then later, you know, all these other, you know, areas that the other treatments, offering them something like that. I always felt like we were giving them second, you know, not quite standard of care when, when you compare it to radical systems. and you always felt like on the clock, you know, if you didn't get it in quickly, you didn't restage them, we didn't check that they were cured, you know, that they had a response very quickly you were worried that they, they'd already developed, you know, advanced and more advanced disease at that point. So great, great. Thank you, appreciate it. Thanks so much, Roger. It's a fantastic talk and uh kind of following up to, to Bruce's points, I was curious cause, you know, we've been talking a lot internally about using things like Signaera um in these cases of heavily pretreated and just like Bruce is saying, you know, you worry about missing this window of do we have an aggressive tumor or even some of these patients. With plasma cytoid variant or these aggressive bad actors. I was just curious, are you using Signature at all to help you decide about like early cystectomy? I know that the folks at Cleveland Clinic recently published something and John Sakanos, uh, has done some work in this space. Is, is that something you guys are, are looking at as well, like circulating to my DNA? No, thanks for that question, Chad. I think, um, you know, in, in theory, definitely there is a role in plasma circulating tumor DNA to detect muscle invasive disease, right? And that's been shown in the adjuvant setting, um, but, you know, in my opinion, I think if you're dealing with non-muscle invasive disease, the prevalence of CTDNA in the plasma is really, really low. And I think the yield for that is really low as well. So, um, you know, the Uh, from the Niagara trial, they took CTDNA in a lot of the patients that, um, uh, prior to the onset of systemic therapy, and what they found was that up to 50% of the patients, um, prior to, uh, prior to the onset of systemic therapy with muscle invasive disease even didn't have detectable CTDNA for the uh Nterra platform. And so I think You know, um, finding a high risk disease in the NMIVC setting, especially with plasma CTDNA is probably a pipe dream. I think the, the answer is gonna be from the urine. And so we are um looking at, um, using the urine circulating tumor DNA in a very similar way that Na terror is uh looking at it, using a tumor informed uh way. To see whether we can detect those disease, um, you know, as a first step, but also to use the granular data from the specific mutations, um, to differentiate those patients with higher risk disease than those that are unlikely to progress. So, um, hopefully more to come on that soon. Yeah, no, that, I, I totally agree. I mean, that's the concern we have too is whether the yield will be enough to really make a difference. Um, and then, as a follow up, what about tissue? I mean, are you guys doing molecular profiling? Do you ever send a tissue for like next gen sequencing again, not many actionable mutations for non-muscle invasive, but I was just curious if you've ever used it. Yeah, so I, I think um there were some hints from the Euromo group in looking at uh RNA sequencing profiling of NMIBC to see which ones are more aggressive than others. Um, so the uromo uh groups 2A and 2B. Um, even though, you know, that's also not very applicable, um, there's, as you mentioned, there's not really any, um, actionable mutations that can be used other than, you know, FGFR 3 now, um, in the, in the low risk group for uh treatment with TARP 210. But, um, to answer your question, I, we haven't really been Um, doing a lot of genomic sequencing, um, for our clinical practice, um, but for research purposes, I do think that there may be a role, um, in the future looking at, uh, you know, DNA, um, RNA, and, and kind of combining the two together to understand the biology of the disease. Awesome. Thank you very much. Published July 10, 2025 Created by
