Chapters Transcript Video The Future of High Grade NMIBC is BCG-Based Combination Eugene Pietzak, MD All right, I guess, uh, we can start. So, uh, good morning, everyone. It's an honor to introduce Doctor, uh, Eugene Peter. He's, um, an attending, uh, surgeon at Memorial Sun Catering and a leading figure in bladder and upper tract othelial carcinoma research. Uh, his, uh, work has shaped our understanding, uh, about the molecular subtypes of bladder cancer in both non-muscle invasive and muscle invasive space. He's a principal investigator on several national and institutional, uh, trials, including. Novel intraversical therapies for BCG are responsive, uh, bladder cancer disease and targeted strategies for upper tract disease. He's also a recipient of, uh, many, uh, awards including the SCO Young Investigator Award and Young Neurologic oncologist Research Scholar Award. Uh, without further ado, please join me in welcoming Doctor Eugenezak. Hey, thanks, Ellie. Thanks for the invitation and um happy to speak with you all today. Um, so, uh, let's see, so my disclosures, I'm gonna talk about two investigator initiated funding, uh, uh, two investigator initiated trials. One of them is funded by Merck, so just disclosing that up front and otherwise these are, these are my uh potential conflicts of interest and and funders. Uh, so I think as probably the vast majority of you on this call know, with regards to nonmal invasive bladder cancer, it is very common, it is very costly both to patients because of the frequency of recurrences and need for surveillance cystoscopies, as well as very costly to the health care system because of those risks of recurrence and the need for lifelong surveillances. Um, and for some patients it can potentially be lethal. Uh, obviously there's a lot of heterogeneity in the disease itself, um, but, uh, many patients who are presenting with high grade non-muscle invasive bladder cancer, if not treated properly, are at a very high risk of progressing, and even those that are properly treated, unfortunately, sometimes the tumor biology can be quite aggressive. Um, and I find it particularly interesting because this is sort of, uh, in the, the wheelhouse of the urologist, although, uh, as, uh, my presentation, um, will go into this is becoming more and more of a potentially multidisciplinary managed disease. It is still, you know, sort of the the quarterback of the team is the urologist, uh, which I find particularly interesting from a therapeutic standpoint. So BCG, as again, the majority probably know, it is a live but attenuated bacteria, uh, first reported for the use in urothelial cancer in 1976, so we have over 50 years of clinical experience. Uh, it is a non-specific immunotherapy. It's actually quite fascinating the way that it works and leveraging some of the knowledge that have been gained from understanding immune checkpoint blockade. And now applying it to this decade old um um cancer immunotherapy is quite interesting. And I, I just like to highlight this, this publication that was in the New England Journal of Medicine in 1991 where they actually allude to this long tail of the Kaplan-meyer curves that's so well now described for immune checkpoint blockade, but it was again described decades earlier for BCG. Um, treatment paradigm, again, as you're probably all familiar with, uh, is, uh, endoscopic resection and then giving BCG typically adjuvantly, um, and then, uh, the need for sort of a lifelong surveillance cystoscopies for these patients with high grade disease and over someone's lifetime, there's a 40 to 50% chance that they will have a recurrence. And so there's, there's a lot of room for improvement in this care. Uh, but the, the focus of my talk today will be on trying to enhance the effectiveness of BCG through rational combinations for the right patient. Of course, the elephant in the room, as you're probably all familiar with and probably experiencing, we're certainly experiencing it, is the BCG shortage. There's multiple reasons for why this occurs, but I, I like to always emphasize it is not because BCG is ineffective. The biggest issue with. ECG is actually it's too inexpensive and there's not a large enough profit margin for firms companies to be invested in it. So unfortunately, the United States Merck is the only company that's currently uh producing it, and there's there's not a large incentive for others to be involved. Um, this is kind of the timeline. Uh, uh, prior, um, previously, uh, the can strain was actually the most commonly used strain. Uh, but there was a mold outbreak in their Toronto factory in 2012, and Sanofi eventually closed that factory, making Merck the sole producer of BCG and um we've been experiencing uh periodic shortages. We are actually in a pretty major one right now, uh, but you may be asking why I'm talking about BCG based combinations and why I think it's the future. I, uh, you know, I think there's an end in sight for the BCG shortage. Fortunately, first off, there's this recombinant BCG strain that's now becoming available through the FDA expanded access program by Immunity BIO. The SWAGR study, which is trying to introduce the Tokyo strain into the United States, is set to read out in about 5 months. Uh, and hopefully that will allow the Tokyo strain to then come into the US market, and then Merck is building a new factory in Durham, or has been building it for the last 5-6 years, and that's set to be open and fully operational, um, you know, within the next 6 to 12 months or so, and that's a picture of the facility in North Carolina. So. Uh, hopefully by this time next year, according to the folks I talked to that Merck, the BCG shortage is quote going to be a thing of the past, uh, so they're pretty optimistic that they'll be able to keep up with, with the demand side of things. Um, and if you look at the NCCN guidelines in terms of the management of patients, uh, with high grade disease, it is, is very much BCG based, um, and I just highlighting two areas of where I'm gonna talk, uh, in the NCCN guidelines, they, they reference BCG naive, newly diagnosed patients, and then BCG unresponsive patients, uh, those that we think BCG has failed, um. And it's not worth giving additional BCG, but there's, there's this gap in between them that's sort of left out by the NCCN, um, and that's these patients what is often now referred to as BCG exposed non-muscle invasive bladder cancer, where these patients are typically retreated with additional BCG either maintenance or another induction course, uh, with about a 50% chance of uh response. So I'm gonna Uh, highlight a, uh, a trial here where we're trying to enhance the effectiveness of this additional course of BCG, uh, cause I think, you know, just trying the same thing over again and hoping for better, better results is, is sort of a missed opportunity to do better for our patients. Um, so I will discuss that, uh, shortly, uh, but I just wanted to go back and focus. On, on these BCG naive patients first, where if you look at the NCCN guidelines, um, when you look for patients who have very high risk features, and this is defined a little bit differently from the NCCN to the AUA or the European neurology guidelines, uh, but basically these are patients with uh the type of, um, Uh, clinical pathologic variables where you're concerned that BCG is going to be ineffective and you recommend upfront cystectomy. It's the preferred option. So if they have prosthetic urethral involvement, uh, histiologic subtypes, lymphovascular invasion, the AUA guidelines include patients with um high grade T1 with uh diffuse or multifocal CIS. Um, as well as, you know, larger, bulkier tumors, multifocality, persistent disease on a staging 2 RBT which go on a subsequent slide. Those are all very high risk features for potential progression. Um, and then according to the NCCAM guidelines, if there is no high risk features, then, uh, BCG is the preferred option. And then the only other option represented for these patients is actually cystectomy, which I'll, I'll briefly discuss as well. Uh, but there, there's obvious room for improvement because when you, you're dealing with the situation where you can either treat them with ECG or uh you know, radical cystectomy, it's quite dramatic and I think, you know, there's a need for some, some middle ground paths for some of these patients with very high risk features which we'll discuss. There was an attempt by James Kato in the United Kingdom to run a randomized trial, um, between these two and as you can imagine. Patients weren't very enthusiastic between being randomized to either BCG or cystectomy, but what was identified in that trial at least is somewhere between 10 to 20% of patients potentially will progress with BCG, uh, where somewhere around 50 to 60% of patients you could argue would be overtreated with radical cystectomy. So, um, definitely some room for improvement there which I will uh talk about in some subsequent slides. Uh, but I, I like to make, um, predictions and as to, you know, what the future will entail. And so what I think we're going to eventually head towards is for patients with very high risk features, we'll be looking at BCG with immune checkpoint blockade, and again, I'll talk about that in a couple of slides. Uh, but I just did want to briefly discuss for the, the cohort of newly diagnosed patients with no very high risk features. I, I, I think there's an opportunity to potentially, uh, de-intensify treatment for these patients and that may be potentially through chemotherapy, intravascular chemotherapy options. Um, that's not the focus of the talk here, but I just wanted to sort of plug the, the, the bridge trial which actually is just now fully accrued. Uh, it's gonna accrue over 900 patients closing at about 10 days or so and this is um um led by Max Gates, and this was randomizing patients to either BCG or gemci to being in Docetaxel with the idea that uh gem Dosy would have. Less side effects to be better tolerated and produce similar results in terms of uh high grade recurrence for survival. Uh, so this is a non-inferiority study that's being uh hopefully reported out in the next 2 or 3 years or so. Uh. Uh, and then just, you know, sort of, um, highlight sometimes this comes up with one of the trials I'll discussed in our own experience, and this is data being put together by Al Zhang, who was a Cleveland Clinic resident and is now working with us. Um, as our fellow, one of our fellows here at MSK, when we look at our experience of gemcitabine plus docetaxel versus gemcitabine alone, we're, we're not really seeing that much difference with docetaxol being added. Uh, most of the heavy lifting seems to be done by gem cytabine. Um, and as you may or may not be familiar with, Jansen, um, has this drug eluding device, uh, it's called the TAR 200, also known as the pretzel, uh, that's a more sustained delivery device of gemci being over the course of a week. Uh, they have, uh, they have actually several trials looking at it in muscle invasive, including BCG unresponsive disease. This is their BCG naive study, uh, of looking at the TAR 200 plus their PD1 inhibitor immune checkpoint blockade. Um, this will probably read out in another 2-3 years as well. Uh, what's interesting to overcome the BCG shortage. They've been using the Danish strain, uh, we're in the United States, we only have access to the high strain, so this is mostly a global study, um, but we'll, we'll see when this reports out as well, um. But you know, the TAR 200 system with the sustained release, you just have to keep in mind that, you know, it's an assumption that the 7 day delivery of gemcitabine will be better than the once a week of 6 weeks of standard gemcitabine that's currently given. And you know, I just emphasize that there's actually no head to head comparison with gemcitabine that has been performed or as planned. They do have some um randomized comparison studies, but it's it's dealer's choice of mitomycin, which is not actually optimized or Gem cytabine, uh, so it's not a true head to head comparison where, you know, you would think if you had a specialized drug delivery system, you would want to randomize it against the drug that's, you know, being delivered essentially, but that that's not being mandated by the FDA or required. Uh, it also requires cystoscopies every 3 weeks to remove and exchange. So, at least in our practice, it's a bit of a logistical nightmare where, you know, cystos are typically uh booked out, you know, several months in advance, and it's, it's likely going to be extremely costly. Uh, both the drug, the, the system, as well as the additional cystoscopies, and there's a big question of where it fits in with, with the utilization of gemcitabine slash docetaxol and whether cost resistance, but it's definitely an exciting time and there there's more options that are emerging. Um, but I certainly, you know, I take every opportunity to sort of just comment on the current space of BCG unresponsive disease. Again, not the focus of this talk here, but, uh, this is Richard Feynman, for those of you not familiar with it, and I think, you know, this quote from him about trying to not fool ourselves, um, and I think, you know, the issues we have with the BCG unresponsive space, as you guys may or may have seen. Um, can be very problematic. So there are several FDA approved drugs already. There's several that are likely going to be FDA approved, including TAR 200, and there's a lot of off-label use of chemotherapy, gemcitabine with or without dose of Taxol being probably the most common at academic sites. Um, and probably every time you go to the AUA or the SUO you're going to be bombarded with charts like this where we are kind of making these comparisons across the single armed non-randomized trials, um, and we really should not be doing it, but we, we cannot help ourselves. We, we, we all do it, uh, but they're, they're widely inappropriate and the reason that is, and I won't go into this, but there's a lot of factors that are involved when you're doing a non-randomized trial, including the quality of The TURBT, the urologist that's involved, the treatment that occurred beforehand, the pathologists that are involved, there's a lot of data suggesting that one pathologist will call something CIS and the other pathologist will call it dysplasia, and that could certainly affect response rates, uh, in a single arm study, and there's a lot of differences in the tumor biology between them, and there's a lot of differences actually in the trial methodology that's used in the definition of end points and whether Uh, biopsies are utilized. So, you know, I just always uh highlight that that, you know, the, the non-most invasive space is becoming very interesting, but at the same time, it's also becoming very confusing and uh there's a lot of need for more rigor uh and evaluation. Um, and just to discuss one of the treatments that is FDA approved, which is a super agonist BCG plus an aisle 15 super agonist since the focus is on BCG combinations. So pembrolizumab is FDA approved, the complete response rate is less than 20% at 12 months. Nayeraggine also FDA approved, the 12 month complete response rate is 24%. Um, and then if you look at the, uh, the BCG plus I 15s agonist, which is also FDA approved, if you exclude the patients who were retreated, uh, the 12 month complete response rate is only 33%. Um, and as I'll show you in the next couple of slides, the IL-15s agonist is very expensive and does not uh have any single agent activity. So I certainly have concerns here. Uh, but this is, this is kind of how it works. It's an IL-15 agonist, essentially, and it, uh, activates and engages natural killer cells and T cells, but supposedly not T. regs, um, and it is given very much like swag cell BCG with induction and maintenance, so, uh, a lot of treatments involved. Uh, this is the sort of the FDA registration trial. It's a singlear non-randomized trial and BCG unresponsive disease. Uh, and this is kind of the reported out data, uh, that you may have seen and, you know, this trial allowed retreatment, uh, so it appears to be better than Pembro or Ed Stillari, but if you exclude retreatment, it's only 33%. Again, emphasizing cross trial comparisons are very problematic. Um, but there was a cohort where they gave the super agonist alone, aisle 15 alone without BCG, and it closed due to uh futility as only 20%, 2 out of 10 patients had responded at 3 months, and there are a few examples in all of oncology where there's a. drug that has very poor single agent activity, contributing much to uh combination. And so I actually think a lot of this heavy lifting is being done by the BCG itself, uh, and you know, BCG unresponsive disease is based off of expert opinion. Um, and we do know that some patients with quote unquote BCG unresponsive disease certainly do respond to additional BCG. And so the question that remains is how much of this is from this IL-15 super agonist and how much is from the BCG or the TURBT. There is an ongoing randomized trial in the BCG naive space, which I think is an incredibly important study, uh, that we are considering opening here at MSK now that the bridge study is closed. Uh, and I think it's important because, uh, we really need to know what how much this IL-15 super agonist is contributing. Because it is costing over a half a million dollars to treat a single patient with this combination compared to a year's worth of BCG which is about $2000. So it's substantially costly and so we really need to know, you know, whether or not it's worth that additional benefit, and I will be talking about another intrarescal based combination, uh which is jump said to me in BCG and just to sort of get it out there up front. Uh, that combination for a year's worth of treatment is $6000 which is, uh, you know, slightly more than the BCG but substantially less than, you know, the more than $5 million to treat a single patient with, um, with bladder cancer. Um, So just shifting to some other BCG based combinations and focus back on that cohort that I discussed beginning with those with very high risk features, cystectomy, those facing BCG versus cystectomy, uh, these are patients with I, I think should be reserved for patients with T1 bladder cancer. And so stage one bladder cancer is interesting because not only do you have that risk of treatment resistance, like you do for BCG uh for noninvasive tumors, CIS and and high grade TA. But these tumors also have the biological machinery already present, where if they recur, they're at increased risk for progression into muscle invasive disease. There's also that uh uh added element that some of these patients may be clinically unders staged and that's why patients with multifocality or larger tumors are often recommended. For radical cystectomy upfront or if they have deep, you know, T1B tumors that risk of understaging, and then in a subset of these patients, there's a risk of them having micro metastatic disease and so there may be a potential benefit for adding a systemic immune checkpoint inhibitor, at least in a small subset of these patients. Um, there's a lot, there, there is rationale for combining a PD1 PDL one immune checkpoint inhibit with BCG. Uh, this has been shown by several using, uh, uh, IHC immuno histochemical standing studies. Uh, it tends to be a little bit up regulated and non-responders, and it gets up regulated post BCG, especially the macrophages, uh, although I, I, I do emphasize that it is a very imperfect biomarker that cannot be used for treatment selection. Uh, and there's been a couple of pre-clinical studies suggesting that there could potentially be some synergy between uh PD1 PDL1 plus BCG. Um, based off this, there, there's actually 4 large randomized trials, uh, the 3 industry sponsored ones I'm highlighting here. There's also the Albin study, which is a European cooperative group study, uh, that's that's smaller, it's about 5 or 600 patients or so, which hasn't reported out. Um, as you may have, uh, sorry, um, and so these are all focused in the BCG naive space, which I personally think is not the best strategy or the not the best, uh, placement for these patients with all comers with non-muscle invasive bladder cancer as the progression rate with BCG alone for patients with BCG naive disease, it is 92%. It's, I think that's actually quite good. Um, and our particular area of focus has been in these, these patients with very high risk T1 disease where, you know, some studies suggest they could have more than a 40% chance of progression, uh, within 5 years with BCG alone. Uh, but the Crest trial reported out, this is Sanzuzumab, this is a PD one inhibitor from Pfizer. It's a subcutaneous injection. uh, Pfizer's thinking that because it's subcutaneous, more urologists would be interested in using it cause you don't need to use a, um, you don't need to have an infusion suite. Uh, this was reported out at this year's AUA as well as ASCO, um, you know, the, the relative reduction in recurrences was about 33%, but the absolute reduction is really only about 7%. And most of these studies, I should have emphasized, looked at the checkpoint inhibitor plus BCG with maintenance, and there were almost all of them also had a cohort where it's their checkpoint inhibitor plus BCG induction only without maintenance, uh, and then RMC, which is, you know, swag style induction plus maintenance, and the Crest study in the Potomac, which we'll talk about in a second. Um, like, you need to give maintenance BCG with these checkpoint inhibitors, otherwise, um, you know, they're no no better than just BCG alone. So there's, there's a component that needs to be maintenance, and just because you're gonna have a checkpoint inhibitor does not mean that you cannot give the maintenance. Uh, but these are the event free survival rates, and then when you look at their supplemental table as to what events were prevented, they were predominantly noninvasive recurrences. Uh, it did not reduce the risk of progression or invasion in this cohort, but I'll show you in a subsequent slide, um, that, um, You know, like this is a relatively lower risk cohort, um, which, you know, I'm of the mindset and we'll talk about this in a second, that the risk of these serious immune related adverse events, uh, is not worth it. So it, it basically reduces the risk in this cohort of about 7% uh total of mostly non-invasive recurrences. Uh, at the cost of nearly a 16% increased risk of serious immune-related adverse events. Uh, what do those look like? Sorry, this, uh, I messed this up a little bit. This is the Potomac trial, uh, which looked at valumab plus BCG. This is AstraZeneca study. Uh, it also reached, uh, it's a press release. We haven't seen the data yet, but the data looks like it's going to be quite similar to what I just showed you for the Crest study with Sanzuzumab, um, and it's basically be, you know, the addition probably incrementally improves. Uh, but at the cost of serious immune-related adverse events, if you have not seen a patient experience these, uh, they can be quite profound, quite traumatic, uh, and can be quite scary, and I think as a urologist that's, that's something I certainly don't want to deal with or manage, um. And uh fortunate to have a lot of good uh GU medical oncologists and, you know, I think at least personally, I I'm very comfortable managing complications from cystectomy, but, you know, the, a lot of these autoimmune side effects were unfortunately, folks are ending up potentially in the ICU, etc. uh, they, they do worry me a lot. Uh, and I just wanna sort of highlight this was in the press release and I found this very interesting. Uh, so, AstraZeneca for the Potomac trial, the trial was not statistically powered to formally test overall survival. However, descriptive analysis demonstrated no detriment in their overall survival. So to me that suggests that there's probably a non-statistically significant increase in the number of patients. Who died receiving the immune checkpoint inhibitor, and that's because unfortunately somewhere around 1% or lower, um, have an immune-related adverse event that is lethal. And so it is very possible that more patients over time may die from their treatment for non-muscle invasive bladder cancer than actually dying from their bladder cancer, which is, uh, you know, again, it's a low rate. But it is, it is a real risk. And so if, you know, obviously these are, are the differences between medical complications with an immune checkpoint blockade versus surgical complications with cystectomy itself, um. But you know, if you look at them sort of head to head, they're different, but they can be just as severe and that's why I would argue that, you know, the immune checkpoint blockade um needs to be restricted to patients with higher risk disease that are really are at risk for progression. Um, and so we had initiated a, uh, clinical trial and investigator initiated study looking at uh pembrolizumab plus BCG that's, that's Merck's, um, PD one inhibitor. Uh, and if you look at our inclusion criteria, all patients needed T1 disease plus carcinoma situ with at least one additional adverse risk factor. Uh, for why, you know, urologists would recommend cystectomy. And so that's a stage one tumor re-staging 2 RBT, multifocal T1, T1B, extensive and deep invasion into the laminar propria. We allowed for lymphascular invasion, but actually did not see it when when we were looking at for patients. There were several patients who had Suspicion for lymphaster invasion, but, uh, we actually did not see any T1 tumors with LVI present. Uh, Hikma Alammadi, who's one of the pathologists that I collaborate with closely, is going to look to see, you know, what exactly is the rate that we see in our overall patients with T1 disease, but that seems to, seems to not really be present even in these more aggressive tumors. Um, and then those with large bulkier tumors, uh, that are T1, those with variant histology. Um, those with multiple T1 recurrences and those with a T1 tumor with some urethral carcinoma, um, of the prosthetic urethra were included. Uh, this is a 37 patient study. It was basically looking to see, you know, does adding pembrolizumab to these patients where you would typically recommend cystectomy, and they say, you know, we, I want to try my chances with BCG kind of potentially enhance it, um. This is what our study, our our population looks like. We just finished enrollment like at this point 2-3 weeks ago. We, we just fortunately finished the 37th patient enrollment, uh, but as you could see, you know, this is a very high risk cohort of patients, uh, but I think it needs to be to add immune checkpoint blockade, and so we see that over 70% of patients had not just T1 disease with CIS, but they had multiple adverse risk factors. Um, and you know, everyone has a CIS component, but about 70% of them had either diffuse, meaning completely endoscopically unresectable disease or multifocality where, you know, multiple areas had CIS, um, but in the opinion of the the surgeon could potentially be endoscopically resected, so. Uh, certainly a, a very high risk cohort of patients, um, and if you compare our cohort to the Crest study that's reported out, Tomic hasn't reported out yet, in the Crest study. Only 7% of their patients had high grade T1 with CIS, um, and, uh, that resulted in only 26 patients receiving their PD1 plus BCG, um, histologic subtypes only 4%, and they excluded patients with prosthetic urethral involvement, uh, compared to our, our very high risk cohort where, as you can see here, Um, and so, you know, I think sometimes these industry sponsored trials aren't designed with the patient population that's most likely to benefit from them in mind, and I think this is exactly why in the Crest study, they did not see any improvements. in progression or reducing the risk of recurrence and then uh reducing the risk of progression, and that's because they had a relatively lower risk cohort of patients, um, and so it's a little bit unclear to me uh how this interpret this data. Um, but that's been a problem with pretty much all the industry sponsored trials that have added immune checkpoint blockades. So these are BCG unresponsive studies, but if you look at them in my, in my opinion at least, you need to have these adverse risk factors. To really start to uh add in an immune checkpoint inhibitor. And so very few patients have T1 with CIS, you know, and even fewer have variant histology. Again, they're probably being appropriately selected for cystectomy, um. But you know, the these real world situations where we see folks with prosthetic urethral involvements who are refusing cystectomy, you know, these patients are not being excluded and so, you know, in these BCG unresponsive single arm non-randomized trials, I would argue that almost 90% of them are at low risk for progression. These are carefully selected patients. And in my opinion, a lot of these patients, even with BCG responsive disease are better off getting uh an intravesical based approach before even considering an immune checkpoint blockade-based approach. Um, with regards to our data, as I mentioned, the, the trial just fully accrued, uh, 2-3 weeks ago. So hopefully we'll have data that's available for like the SUO. Um, I could tell you that the, the preliminary results so far look really good. It seems to be very active, um, a very active combination. Uh, but the toxicity is real, and as I sort of alluded to, you know, I had a patient who had diabetes, um, you know, type one diabetes, who was like on an insulin drip, and, uh, it's, it's, it's concerning sometimes when, when you see these side effects. And, you know, these are all patients, I feel a little bit more comfortable because they're all patients that certainly Well I, I strongly recommended a cystectomy, and they strongly declined a cystectomy, so they understood the risks involved with this, but I, I can't imagine giving an immune checkpoint inhibitor to someone with a high grade TA tumor with without CIS or or or something like that and, and thinking it's, it's worth the the the chances of some of these side effects. Um, so just shifting for the final segments, uh, talking more about enhancing the effectiveness of retreatment with BCG using an intravescically based approach to avoid these immune-related adverse events, um, and in that population I sort of alluded to those with BCG exposed disease, those that have been treated with BCG previously and their cancer has come back. And we would typically recommend trying BCG again, uh, because they do not meet the criteria for BCG on responsive disease. And so the idea is really just trying to prevent them from developing BCG on responsive disease. This ends up being actually a fairly large uh population, um. And so it's, I used to call it BCG relapsing disease. I, uh, more recently, it's sort of been codified as this BCG exposed space for, for clinical trial purposes, um, as I sort of alluded to the uh AUA and the European neurology guidelines recommend retreatment with BCG alone. However, I think they all acknowledged that about 50% of patients will derive clinical benefit from retreat with BCG alone, um. And I think increasingly gemcitabine and docetaxol is being used for these patient populations rather than trying BCG again. This is data from John Gore and Angie Smith, basically just demonstrating using the Cysto registry, demonstrating that Gem Dosy is becoming increasingly popular as the years go by, uh, but this is data from the University of Iowa group that basically demonstrates that Gem. is no better than BCG with plus interferon in in this study, and this is data that was provided to me by Roger Lee at Moffett, uh, that basically further demonstrates that gemcitabine and docetaxol on this red curve over here is no better than retreatment with BCG um alone. So kind of makes the argument that, um, maybe there's there's a benefit and potentially combining. Um, both the chemotherapy, like gemcitabine with BCG is a chemo immunotherapy strategy. Um, I kind of already covered the BCG plus checkpoint inhibitor. I didn't really allude to, but it's also more expensive and I, I think unacceptable toxicity. We also talked about the BCG IL 15 super agonist, which is certainly has less toxicity as an intravesical therapy, but I think it's crazy expensive and I, I'm not convinced the aisle 15 super agonist is adding much to the BCG alone. There has been numerous studies, numerous studies over the years looking at BCG plus intravesical chemotherapy, um, so the idea, the concept is not novel or new. I think one of the major issues is, uh, the chemotherapy of choice has typically beenitomycin or epiubicin. Which are vesicants, they're blistering agents. There's a lot of side effects to them. But if you look at meta-analysis and you look at individualized randomized trials, all quite consistently, uh, BCG plus typically a Mitomycin-based chemotherapy, uh, combination outperforms, uh, BCG alone in terms of reducing the risk of recurrence as seen in this European study over here, um. And this Italian study over here as well, BCG and Mitomycin reduces the risk of recurrence here. And this is an Australian study that looked at mitomycin and BCG again in their higher risk cohort with uh T1 or any CIS, as you can sort of see from these Kalaya curves. The overall study was negative when you factored in the high grade TA patients. There wasn't much of a difference. But when you look at the subset that have higher risk features, um, you know, the combination of BCG plus uh chemotherapy does better than BCG alone. The issue, as I sort of alluded to, these are vesicants, blistering agents as you guys may have experienced with Mitomycin. There tends to be a lot of urinary. Side effects and that that really has limited its clinical use and and none of this has been translated. This is not something that is used in routine practice. Some centers in Europe will will use a combination of BCG plus uh chemotherapy, but I do not know anyone in the United States doing this, um. But when you look at comparisons between Mitomycin and gemcitabine, uh, there's been randomized studies that basically show that gem cytabine is more effective and it's also better tolerated. Um, you know, it's also, uh, less expensive as well, although when, when you start talking about the half a million dollars, uh, you know, it's kind of a joke when you start to consider, uh, the, the costs that that I'm sort of alluding to over here. Uh, but again, just making the argument that gemcitamine is better than Mitomycin potentially, and there's a lot of potential, um, suggestion that there could be at least an additive benefit or potentially synergy between the two. A gem cytabine is the backbone for numerous different disease states, low grade non-muscle invasive bladder cancer, high grade BCG failure, also used a muscle invasive upper tract. As well as metastatic urothelial cancer, so it has single agent activity. It also has direct cytotoxicity against bladder cancer, uh, but there's also a lot of studies suggesting that gem cytidine has some immune enhancing benefits as well by selectively reducing Tregs and my pressure cells and enhancing T cell function, um, and there are some pre-clinical modeling as well. Um, if you look at mechanisms of resistance to BCG, they tend to be that the pre-treatment tumor microenvironment is more immunosuppressed, and BCG cannot overcome that. It's almost like the pre uh pre-treatment tumor micro environment is predetermined, uh, which would, you know, make the argument that maybe adding gem cytabine to um sort of wash out so the myeloid cells could potentially improve. Um, the effects of BCG, and so that's exactly what we did. We conducted a phase one slash phase 2 study. It was modeled after one of the more successful mitomycin studies you see down here. Uh, this was run by Chris Gaffney when he was a fellow with us, and now he's on faculty, he's a prostate cancer focused surgeon now at MSK. Great, great to have him. Um, and we started with gemcitabine on week one with the idea that we would wash out some of those, uh, immunosuppressive cells, and then, uh, everyone ended up getting uh BCG 6. So these are patients who have a high grade recurrence within 2 years of their prior BCG exposures without meeting the definition of unresponsive disease. So this BCG exposed uh definition. Uh, and the phase one study of 25, 25 patients using a Bayesian. Uh, continuous reassessment methods, so the majority of patients were all treated at the highest dose level, 17 patients were treated at the highest dose level, um, demonstrated that this combination is very well tolerated. If you look at this lollipop plot over here, we saw no treatment related, uh, grade 3 adverse events, and almost all the side effects, or the majority, I should say the majority of the side effects were seen on weeks that BCG was given. And they're all the typical, you know, grade 1, grade 2 that you expect to see with BCG alone. So it was actually quite comparable, it's very well tolerated, you know, we then proceeded to a phase two study, uh, in collaboration with Hertford Hospital. Um, you know, ultimately 44 patients were enrolled, but this is the 1st 43 patients, and so about 74% of them had CIS with or without papillary disease. Uh, several of them had received higher gem cytabine or gem dosy before enrolling, uh, but it's fairly representative of, um, of, of patients with BCG exposed disease, and the, um, uh, preliminary data for the phase two was reported out at this year's uh SUO by Gal Lord, who's one of the Cornell urology residents who did their research here with me, um, and so the data looks actually quite promising. Um, so the complete response rate in the with gemcitabine and BCG in the CIS BCG exposed cohort, uh, at 6 months was 97% in the 1st 29 patients. Uh, and just to place this into context, when you ask sort of uh expert panel of bladder cancer experts what the expected response rate for BCG alone would be at 6 months in these BCG exposed patients. It is 50%. So we saw 97% compared to what would be expected with BCG alone, 50%. So that looks obviously very promising. These are some of the published 3-month response rates in the CIS population BCG exposed, we saw 100% response rate. With uh hypothermic mitomycin, it was 30% with BCG or mitomycin 47%, and this recombinant BCG that's now being made available by immunity bio uh was only 56% to 100%. And then our longer term data is certainly maturing, but um it's uh at 18 months, our high grade recurrence free survival rate for this combination was 7 76%. And then when you make that comparison to, you know, both BCG as well as gem Dosy in different combinations, their 18 month high grade recurrence free survival rate is only somewhere between 35 to 55%, so certainly seems better. Again, all the caveats of like cross trial comparisons are present. Ours is a single arm study. Um, so, you know, it's just, uh, I guess the point I'm trying to make is it looks like a very promising combination. We did a bunch of uh correlative studies as well. The one that I, I like to highlight is our hypothesis is that adding gemcitabine will reduce myelori pressor cells and regulatory cells in the tumor microenvironment. As reflected by changes in in the urine, immune cells, and cytokines, uh, so we had serial collected, um, urine as well as blood, and when we look at the urinary proteomic studies looking at cytokines and chemokines, that, that's exactly what we saw. We saw an increase in the chemokines that are associated with T cell trafficking from gemci and BCG. So, um, you know, this is typically seen with BCG alone as well. We, we see that T cells do traffic in, but what is seen with the addition of gem cytabine and is typically not noted with BCG alone is that we see a Reduction in the cytokines and chemokines associated with immunosuppressive changes. So IL 6 being the most notable one, and as you can see, there's a nice decline in that over treatment period of times. Usually when you get BCG alone, you actually see an increase in aisle 6 and aisle 8 and these other immunosuppressive cytokines. So it's kind of very much consistent with our hypothesis, um, as well I like showing it. Um, and you know, at least the way that we try to teach our fellows when you're designing a phase one or phase 2 study, you need to have a plan of what you're going to do with that data, what would be the next step, and obviously because both BCG and Gem say to a dirt cheap, there's no interest in, you know, pharmaceutical companies being involved, etc. uh, there's fortunately an opportunity in the cooperative group space, um. Where uh we were able to um get approval from the NCI to, to launch a study that could test our hypothesis about whether or not adding gemcytamine to BCG is beneficial, and that study just opened about 3 weeks ago. Uh, this is, this is what it looks like, uh, the, the combination of gemcitamine and BCG. Uh, versus BCG alone over here, and this is sort of the scheme uh, I'll, I'll put this back up at the end if there's any questions, cause obviously we would love to have you guys involved if you're interested. Um, and just going back to kind of like again the elephant in the room with the BCG shortage. So the gain trial just opened, um, just a couple of weeks ago. The recombinant BCG strain is available and is OK to be used in the gain study. The, the swag prime studies said. To read out, um, and that Tokyo strain should hopefully become available as well, and that would be OK to use in the gain study as well, um, and really just uh waiting for Merck to, to finish their factory. So Merck is not supplying BCG for this trial. Uh, because they feel very confident that the BCG shortage will be resolved with their factory, and so they they kind of, uh, did not think it made any sense for them to go through all the contracting with the National Cancer Institute just to supply BCG for a six month period of time. Um, and so this is kind of an update on their timeline where they, uh, I, I talked to them periodically. They, they're, um, they report that they're on, on schedule on the timeline it should be opening in December of this year, and it will take about 6 months for it to ramp up and be fully functional, uh, but they do expect some BCG to start trickling out before then, um. So hopefully the BCG shortage will be resolved and then uh the, the BCG based combinations I think will become uh more important. Uh, so very excited about this trial. One of the caveats I just always emphasize is there's, uh, you know, there is a biopsy that we perform at the week 13. We're trying to increase the rigor of this, and actually there are patient advocates that really like the idea of doing a post-treatment biopsy and that's because these are all BCG exposed patients. And so we want to know whether or not they have persistent disease after their induction course because then those patients, if they do have the uh potential opportunity to then switch to a different treatment earlier on, um, and potentially benefit from either another clinical trial or another treatment. But uh this is my last slide, um. And I guess I'm more than happy to take any questions, or I could also leave this slide up if there's any questions particularly about the trial itself, but uh just let me know what you would like. Hey Gene, that, that was an awesome talk. Thanks a lot for uh giving this. It's really interesting and congrats on opening the trial. Thanks much appreciated. Yeah, I, uh, I was wondering, so I know you do a lot of work also on kind of biomarkers and those things and As it relates to gemcitabine and these trials, are you looking to identify and potentially based on biomarkers which patients may respond? I mean, you talked a little bit about the tumor microenvironment and BCG, but as far as gem cytabine is concerned, Is there a subset of patients you think that do better with chemo than than others based on other biomarkers like you studied AID1A and a couple of other ones. Yeah, yeah, yeah, no thanks, Chad, great question. Yeah, so in, in the context of the bridge study, which is now fully approved, I, I don't know if you guys participated in it or not. Um, but there was a, so each cooperative group runs a little bit differently, so the gain study is through the Alliance for Clinical Trials and Oncology, what I'm showing right now, there's plenty of funds for biobanking, but they won't support quality of life surveys or patient reported outcomes because in their opinion, there won't be much of a difference, which is like kind of, you know. I we, we, we tried to fight back, but it was like a losing battle, but there was plenty of money for doing biobanking for the bridge study, um, I'm the correlative uh co-chair or the correlative scientific chair, uh, for it. There was not funding for biobanking by ECOC, but there was funding for, for. Burrows, uh, which was kind of interesting. So we had to work with Verisite, the cipher, to try to get biobanking done for that. And it took almost 2.5 years, almost 3 years. So Bridge fully accrued by the time the contract for uh, for Bridge, like the, uh, Uh, relatives is signed and executed. So for Bridge, we're now going to retrospectively go back and collect all the tissue. Um, and the plans for that are, are basically to do holoome sequencing and RNA seek, um, and obviously, although it's not as good as if we were able to prospectively collect the, the patients, at least, you know, within the context of randomized trial. So we'll be looking at all sort of the uh predictive potentially prognostic biomarkers for BCG with within the the that gem dosy population. Uh, and, um, you know, for this trial, the game study, as well as the phase one, phase two, we're certainly looking at things as well, as you sort of alluded to, our group and others have suggested that arid 1A may be a uh predictive biomarker for poor response to BCG alone, and there's actually some. Literature to suggest that arid1A may be sensitizing to gem cytabine. Uh, so that's kind of what we're looking at in particular in this study, whether or not that could identify a subset of patients to do that. Uh, and there's also some studies that suggest that of MD Anderson and others that aired when a, um, May, may be associated with a favorable response to immune checkpoint blockade. So we're certainly looking at that. Uh, A1A is certainly of interest uh to our group as well as I'm sure many others because it occurs in about 25% of high grade, uh, bladder tumors, both non-muscle invasive and muscle invasive. We, we have tried to study this in the lab, um, uh, through the David Salt lab and and uh Mike Glickman labs. Um, when you do knockout of arid 1A, uh, in at least the MB49, uh, mouse model, they, they basically become very immunogenic and grow slower. So it's been hard to do BCG studies in the MB 49 line, um. So, but as you sort of alluded to, at least in human samples and clinical samples from our own group, from the Dana Farber group and um Alex Wyatt's group in Vancouver, and I think there's one other European study all suggested that A1A may be associated with with resistance to BCG, um, so you are absolutely correct, uh. You know, there's there's a lot of ongoing biomarker work that is being done. um, ANA would be the DNA angle, but I think from an RNA transcriptomic angle as well, there, there's certainly a lot of um uh potential biomarkers for, for gem cytabine response without a doubt, uh, but that, that will show up more on the the transcriptomic studies that we have planned with the cipher. Awesome. Thank you very much. Great job. Thank you. Hi Jean, this is uh Bruno Nahar here, fantastic talk. Um, I have a quick question for you. So, um, You know, there's so many drugs available for these BCG refractory patients, right? And how do you sequence, I mean, most of these patients want to do something before they go straight for a cystectomy, right? So how do you sequence these drugs in your own practice? So you start with the BCG alone and then if they fail, you add intravascular chemotherapy for these patients plus BCG, or how do you do that? And when do you stop all these bladder sparing therapies and say, listen, this is enough, let's get your bladder removed. Yeah, I think that that is a very good question. It's very challenging, obviously it's like individualized based off, you know, how sick the patient is and their their tumor factors as well, but generally for patients with noninvasive recurrences, I, I always try to do my best to do bladder sparing, uh, for sure, depending on how, you know, how, how well their, their, their bladder is functioning, etc. Uh, so we always try to have like clinical trial options for, for the patients as well and try to get them on, on various trials. But yeah, I mean, we start with BCG we had the BCG Pembrose study which is now fully approved, so the high risk patients would go on that, you know, we would try to enroll as many patients as possible on the the bridge study, uh, to support that, but when someone got BCG and they recur. You know, if they're BCG exposed, we've been putting them on the gem BCG study now the the phase three will definitely prioritize, um, for those that aren't either trial candidates or or or don't want to, um, you know, we, we, we have some BCGM responsive trials that will we'll try to get them on, and for those that like aren't candidates again or don't want to go on the BCG uh unresponsible and we always have a discussion about Jem Dosy. Um, but we, we recently started a, um, a single institution, but we'll be opening to others, uh, looking at a clinically integrated cluster randomized study, uh, in collaboration with Andrew Vickers, who's one of the statisticians here at MSK and who has like, you know, put a lot of thought in clinical trial methodology. And it's basically the clinician gets randomized on 3 month blocks for patients where you're uncertain what their their next line of treatment should be. And so we're currently looking at nanohaaggine, we just got it on our formulary maybe like 3 months ago. The trial just opened. We're trying to treat all the patients with nanoharaine on protocol. Um, and then, uh, the other comparison is, is best usual practice, it was the arm, like what would you give if this nanohagen wasn't on the formulary. Um, and so for the most part that's gem Dosy. We, we've been giving a lot of gem Dosy, um, you know, probably like 40 patients a year or so are receiving it in like the BCG failure space, um. We have not added um Antifa, the BCG IL 15 super agonist again cause my, my our our thoughts that it's not that beneficial, uh, but we're Um, excited for the TAR 200 and Creusteaggene likely to get approved, and that's when we're the the trial I had alluded to, the clinically integrated study which we call Compare it, um, it's like, um, you know, a ongoing randomized phase three, it's just a different. approach. Um, we're, we're planning on making that at like a multi-arm multicenter, multi-stage comparison. And in that, in once we expand to that portion, and we have multiple centers, we're going to use Gem Dosy as, as the comparator rather than what we're using right now is best usual pair. Um. And so, you know, I just, I, I feel like it's very individualized. There's a lot of patients, as I'm sure you're experiencing in your own practice who are adamant that they will refuse cystectomy, and I think I, I just spend a lot of time talking to them about the quality of light data. I think the CISA study. From John Gore and Angie Smith is incredibly helpful. I will pull up like the Euro today report on like what what they present to the AUA and I will go through the quality of life benefits for cystectomy and just emphasize that for a lot of these patients. You know, their quality of life will actually improve if they undergo cystectomy. Um, and then, you know, I always highlight like the downsides with cystectomy in our own quality of life studies as well as the systo is really a sexual function and so we emphasize like, you know, the importance of doing nerve preservation, nerve sparing, or or vaginal sparing surgery for these earlier stage tumors. Um, and then, you know, talk more about like, um, continent diversions, neo bladders, etc. So, um, but even with that, we still see a lot of patients who, who, who declined cystectomy, but, uh, you know, I think what gets lost in the weeds is like, even though the approvals are for T1 tumors as well, like there's very few patients like as you saw on my slides, there's like 10-12%. Being enrolled on the nanoharaine study and of the 5 patients with high grade T1 with CIS on the nanoharaine study, 3 out of the 5 progressed to muscle invasive disease. So 60% progressed, uh, if you put it that way. So, uh, I always try to emphasize that as well. All right, I guess this concludes the session. Thank you very much, Doctor Peak. Thanks for everyone for listening. Uh, great talk. I appreciate it. Great. No, thank you very much. Thank you, really appreciate it. Mm Published July 17, 2025 Created by
