Episode 486: ctDNA and utDNA Data in Peri-operative Urothelial cancer

[MUSIC] >> Welcome everyone, you're listening to a year ago's podcast, Tom and I are joined by Mikhail Vanderhiden. We're going to talk about CTDNA and UTDNA in the perioperative space in bladder cancer. This is a very large and evolving topic. There are some data that ask of you. The last few major meetings, there's been various pieces of data. We're going to try and string those together, hopefully into a coherent whole. We're going to take this in parts. Tom, I'm going to turn it over to you first to talk about CTDNA, circulating tumor DNA from your Envigor O11 efforts. >> Brian, we're going to try and make it simple if I can. That's my ambition. But do you must let me know how successful I'm being in this? >> I will gladly let you know. >> Okay, so I need feedback, Mikhail. I need feedback from you too. So Envigor 11 is a daughter of Envigor 10. Envigor 10 showed that CTDNA, after surgery in Muslim-Vase of bladder cancer, about 40% of the peri-risk patients are CTDNA positive, and about 60% are negative. The positive patients, almost all of those patients, relapse. A Tesselizmab is associated with a reduction in the risk of death in that subgroup of patients. Remember, none of the unselected adjuvant trials ever achieve the noble survival signal. So we achieve it with a Tesselizmab by the first part time, by sifting out those positive patients. And then when we looked at the negative patients, the 60%, there was no survival advantage with a Tesselizmab number one. The treatment was a sociable life-changing toxicity in about 20%, and the relapse rate was much, much lower at about 25%. And so when you pull that together, you can see that treating those at risk-based sense and sparing those that don't need therapy is attractive. Vigor 11 had one modification in it in that we tracked patients CTDNA. So if you were negative of the came positive, which was about half of those patients that we talked about. So if you're negative and became positive, those patients were then randomized with Tesselizmab to sleep others away. And those patients also achieve that benefit associated with a Tesselizmab. And so essentially, in Vigor 11 was a trial which was positive, overall survival in those patients that receive a Tesselizmab and receive old. And those patients that were negative and remain negative might one of those patients died, maybe about five of those patients died at two years of bladder cancer. The issue within Vigor 11 was that we define patient as positive and negative. And CTDNA is more nuanced than that. And the nuance is that you can get various levels of CTDNA. The positive is defining two clones and tracking those two clones with time. But you can get MTM levels, the basic going from zero, which is nothing, is 0.1, all the way up to 10 or 15. And when you get levels above about three, then those patients, that's relatively high levels. And what we did in this analysis at ASCOGU this year is we looked at the relevance of the levels. In the same way as one might look at PSA, you might say PSA above five is positive, so less than five negative, above five positive. But we know you can get PSAs up to 2,000 or 3,000. The same sort of thing applies with CTDNA. And actually the parallels are quite similar. Higher levels are associated with worse outcome, number one. Number two, any measurable level is associated with worse outcome. So the negative patients, the ones you can't detect it in, they do quite well, they do really well. Even if you have low levels of CTDNA, inevitably almost all of those patients relapse. A teznalism app appears to work well, irrespective of whether you have lower or higher levels. And then the last bit that then we moved on to and shot him did this beautifully was we then looked at CTDNA clearance and again, all the same rules sort of apply. So CTDNA clearance occurred in about 30% of patients, but there was also CTDNA reduction. So you can have reduction in the levels of your MGM. And that was also associated with better outcome. Yes, clearance had the best outcome, but reducting your MGM level was associated with a better outcome. And no change, your increase in your MGM level was associated with a poor outcome. Tom, can I ask you a question about that? Yeah, you can follow. So if you on a teznal, you reduce your mutation number, right? But you don't completely clear it. Yeah, your level. And you don't completely clear it. Are all those patients going to relapse? Or I mean progress is the better word here? Yeah, so from a dear disease-free survival perspective, on those patients that clear their CTDNA, they don't reach a median disease-free survival. All of the other groups do reach. But those with a two-fold decrease, their median disease-free survival is about 15 months. Whereas those patients that have a two-fold or any increase, theirs is less than six months. So there is a more different, and actually, it's a graded difference between clearance, a two-fold reduction, and a two-fold increase. You know, a real big difference between-- I'm going to tell you, first of all, excellent concise summary out of character for you, but well done. You've got a great class of cool one. Are you being my one out? Almost fell out of my chair, so concise. So do you think-- I know some of the thresholds in the O11 analysis presented at ASCO. Do you, though, what came presented? Those weren't obviously predefined. You just sort of picked some thresholds that you just described. So my question to you is, do you think there'll be further work as has been done in prostate cancer with the PSA analogy of looking-- you know, we look at PSA 90, PSA 50, and those are arbitrary, too. But it's sort of an industry standard, if you will, that when you're reporting the activity of a novel prostate drug, you're going to report those PSA thresholds. Do you think we're heading there with CTDNA in your otheoleal cancer? I think that I haven't talked about something that was a bit confusing on purpose. But there-- And I'm going to talk about it in a second. I think that MTM levels are important, but it's very clear that if you have-- providing you have relatively high levels at baseline or measurable levels at baseline, that the clearance is really important. And failure to clear is less good in having clear-- I mean, that all of those patients end up doing poorly in the end. So a lot of it is about clearance. The having any CTDNA there is bad news now. That's what I was going to ask. So clearing is good. Obviously, more clearing might be better, but unless you actually clear, you're still in trouble. You're in trouble. And so when you're monitoring treatment in the future, it's great to monitor that at the MTM level. You could do an advanced disease, and you could watch it come down. And you wouldn't want to stop if it was coming down, because you could clear. And just to expand on that point, clearance at week 6 for a Teslaism app was only 25%, and that went up to 37% on further time points. So just because you haven't cleared in the first sample doesn't mean you won't subsequently clear. That's number one. And the other slightly complicating fact is there was CTDNA clearance in the placebo arm. And the reason why that was the case is it's still the case that you have a proportion of patients where the calls are quite marginal. So you can show very low levels of detection, one or two clones. And there probably is some false positivity there still. There's still a balance between low level of detection and defining positivity. And there is clearly a cut point that one needs to set to define positivity. We say two clones or more define positivity. If you define that as four clones or more, you would then become much more specific. But you would lose a lot of those negative patients, a lot more of those would relax. Presumably these false positives aren't high levels. No, they're all super low levels. Yeah. So if you get a patient and you've had surgery, they come back as positive. And their MTM level is close to 0, 0.1, where average is more like between 0.5 and 2. So you've got to see super low levels. You're like, okay, why don't we do another test in six weeks and see where we are? Exactly like PSA, right? After a definitive local therapy, right? You can get little PSA. Radiation has, you know, the Nader+2 definition. So that's where all this came from is because you don't want to overreact to low levels. So the strength of this analysis is it's very robust and it's teaching us a huge amount about monitoring. It's teaching us about clearance. It's teaching us about accuracy. I think it has able to save those patients, you know, we never, I'll repeat it again. We never previously achieved global survival. We have for the first time by picking a group by definition, if you pick a group where you achieve survival and in the trial that originally was negative and didn't, those other groups can't be benefiting. That's just common sense. And so therefore those negative patients who have a very low low, low chance of risk of death are and by the way, immune therapy as a single Asian, we know even the positives is only clearing in 25%. So in those negative patients, much no risk, immune therapy doesn't help everyone. And of course, life changing toxicity in those negative patients, the risk benefit ratio still exists. There's always going to be risk, but much, much favors not giving therapy rather than giving therapy and the other way around the positive patients. But this doesn't apply in the neo-aggibment setting because in the neo-aggibment setting, we're giving treatment up front. And the Niagara study, I'm going to summarize that for you in two seconds right now. The Niagara trial was the next step in this. And what we did there is we looked at CTDNA before neo-aggement chemotherapy and Juvalumab followed by surgery and then adjuvant Juvalumab. And what we showed is the following. At baseline, pre-surgery and post-surgery, presence of CTDNA was strongly prognostic. And it got more and more prognostic as time went by. And what that means is at baseline, about 60% of patients were positive. And the hazard ratio of death of being positive was about three or four. Then only 20% of patients were positive pre-surgery, which means about 60% of patients cleared their CTDNA with the neo-aggibment chemotherapy. But then the hazard ratio jumps up to about seven. So being positive pre-surgery, that means your chemotherapy's failed. So that's very, very bad. And then it drops down even further to only 10% post-surgery. And at that time point, your hazard ratio goes to about 10. So as time goes by and your treatments are unable to clear your CTDNA, your outcome is getting worse and worse. You said hazard ratio. Do you mean risk of death? Yeah. So the hazard ratio can make you create a hazard ratio from the positive and the negative patients. And so yeah, it's your risk of death essentially. And so that leads us to the next step, which is, Mikael, I'm going to hand over to you because I've given the background of CTDNA in the adjuvant setting, the MTM and the PSA analogy. And then we talked about the switch to the neo-aggibment setting where more patients are positive. There is CTD clearance both with neo-aggibment chemotherapy, plus duvalumab and surgery. It's strongly prognostic, but you did a lovely study at ASCO to you. Do you just describe that study? Yeah. So it's the end of the blade study. So this study builds on our previous work with Ipleemop and Nevolumop. So the Nabukos study, which showed that in high risk, and I think this is often missed at the patients that were treated in Nabukos, where we're really high risk stage three. There was half of patients had, where no positive. And in this very high risk group of patients we found that about half of the patients had a path CR on Ipleemop, plus neo-aggibment. So that made us think that these types of very active systemic therapies, induction therapies. And now of course we have an even more active induction therapy, presumably with EV plus Pempleemop. But we worked with epineval, could also broaden the population of patients who could receive bladder sparing therapy. So in the end of the blade, we treated 50 patients with epineval. And then we did a response assessment. And if patients didn't progress, so you didn't have to have a very strictly defined clinical complete response, you just need to be a non-progressor. Patients could continue with chemoreadyo therapy. So 90% of our patients actually continue with chemoreadyo therapy. And the end point of the study was bladder intact event free survival for the full cohort for all 50 patients. And we included patients of T2 to T4, but also N1 or even N2 if the nodes were very close to the bladder and could be incorporated into the radiation field in the end. So given that we had a broader population and usual for organ preservation, a bit higher risk population, we said that we would at least want to exclude 50% with this trial. And we made that target by reaching a bladder intact event free survival at two years of 78%. And also very high at this very early stage, very high two year overall survival of 96%. So what you got so far is you've done neo-adjuvant therapy with ipinivo. You've got an exceptionally good result, but intriguingly in Niagara, the baseline CTNA positive rate was 57%. In your neo-adjuvant trial where you did surgery, you had much higher rates of positivity. Your positivity rates here were much lower. And that gave quite accurate information that this overalls a lower risk group and that lower risk correlated with better outcomes. And so are we beginning to see signals that CTNA rather than T stage baseline is a better way by identifying patients at risk. And what's do you take on that statement? Well, I think these are different ways to enroll patients. So in terms of stage, the way they were stage beforehand, I think there was not much of a difference with Niagara. We had just like Niagara, we had 40% T2. We also had 14% of node positive. I think that was almost the same percentages in Niagara for N1. And then we had some T3. I think T3, I think what the difference was that these patients needed to be eventually amenable to chemoreduotherapy. So if you have disease that is very bulky, then you wouldn't, you know, that would not be an appropriate patient for this trial and you would anyway want to have surgery in the end. So I think there was some selection. On the other hand, this study was done in a relatively short period of time in three centers in the Netherlands. So in two years, we recruited 50 patients. So we could, we were also not super selective in the patients we recruited. Baseline positivity. But baseline indeed, where slumposivity was lower than in Niagara. And one of the reasons is probably that we included less bulky disease. Another possible explanation is I don't think everywhere in the world a complete T2R is done for diagnosis. We do that always in the Netherlands could be a bit in that at some of the patients in Niagara. I didn't have as complete of a T2R as that we have, but that's a theory. Probably multiple reasons. Yeah, and I think this also is what is seen in other bladder preservation studies that indeed CTDNA at baseline is a bit lower. So we do selects for patients who have at least less tumor volume. I'm going to talk a bit about your CTA dynamics because you showed that there was quite a lot of clearance with epinevo. And you also showed some clearance with radiation therapy, but most of it was epinevo. And you showed that was really strongly problematic term of an outcome. Yeah, so basically for CTDNA, we saw very similar results as you would see with chemotherapy. So we actually had also done CTDNA in the book. So the other epinevo study where we had a much higher percentage indeed of baseline positivity. And we see that patients after three cycles. So basically after about six weeks, six to eight weeks can already clear their CTDNA on the immunotherapy. We saw that in quite a few, of course, the numbers are much lower than a study like Niagara. And we saw that basically everybody who had an event had at some point the positive CTDNA assessed. We also saw from the few patients that still had CTDNA before chemotherapy. That too, I think out of those four or five patients, clear CTDNA by chemotherapy, which is something we also observed in Niagara. of course that patients can have their CTDNA from invasive residual disease which can be cleared by cystectomy but apparently also by chemotherapy. You also showed your hazard ratio at baseline was 4 and then your hazard ratio post treatment was 8 for being CGA positive. Very similar to those values I gave you for Niagara. There are quite strong parallels. It doesn't seem to matter too much what the intervention is. It's all about whether you're achieving this clearance. Yeah absolutely and we've seen several studies now and sometimes they, you know, if it's a smaller study sometimes they end up a bit higher but I think this is the number that is pretty much correct and it doesn't matter that much what the matter is. Did anybody questions from the count? I was just going to say it's reassuring that the biomarker in this case CTDNA has similar performance across trials, across modalities of systemic therapy, or types of systemic therapy modalities like surgery or chemo radiation. Right? I mean we would expect that of a good biomarker that it's not dependent on necessarily the type of therapy that the patient got. It might differ. They might have different baselines. It might clear more with therapy versus therapy B but being persistently positive at these various time points clearly is a bad thing. Yeah so I think Tom has presented, I don't know if it eventually got published somewhere on Kino 361 where it seemed to be that clearance by chemotherapy is less strongly prognostic than clearance by immunotherapy so less patients get cleared by immunotherapy but if they get cleared. Are you following my work closely enough? I apologize Tom, I apologize, there's so many publications and purists cannot follow them all. So we're going to talk about that in a second but I think clearance with immune therapy seems to be more relevant than clearance of chemotherapy. In the metastatic setting appears transient where clearance with immune therapy appears more prominent. So it looks like your baseline level is important. It looks like achieving clearance is important but not all clearances mean the same and it's drug dependent. I suspect EV by itself clearance with EV would be less significant than clearance with EV plus Pembro but we just don't know the odds that yet. I expect EV Pembro to have very high clearance rates. I would assume so, yes. Yes, and what you said. So there was another presentation at this meeting called Retain 2 and that study Neoijivand ostensed back plus Neuvolumab, those patients doing well not having surgery, those patients not doing well, those patients not going into clinical CR having an intervention. But I think what that showed was really interesting. Everything around that analysis showed pretty much exactly the same as what we've talked about so far. Levels at baseline positive, they were about 60% as well. Because there was evidence of really good clearance as you would expect similar to Neiagra. And then those patients that didn't have surgery because they've cleared already, many of them, their CT DNA, you remain clear. But there was one complication Brian and I was paying attention and what it showed was that the CT DNA wasn't super good at identifying non-muscle invasive relapse. So a number of local diseases came back and the socistoscopy remained an important role there because you can have local recurrence but not be CT DNA positive. And so I think it's fair to say at the moment that CT DNA is good at identifying bulky local disease. Remember, even in Neiagra, 40% of patients were CTD negative at baseline despite having muscle invasive bladder cancer. That dropped down to maybe only 30% being positive at baseline in the radiotherapy trials. And that's partly because of better patient risk and maybe better TORBT. But in these trials, it appears that CTDNA is good for bulky disease, good for MRD, but not good for local relapse. And Brian, there was a Mikhail presented, we were in the habit of not presenting our own work at this particular podcast. So, um, are you sure? I think so. Well, yeah, presenting, we're not in presented the CTDNA one. Mikhail's fellow presented his one and now you're going to present Mikhail's one. You're now presenting the CTDNA work and the UTDNA work from Neiagra. What did that show, Brian? Yes, I've been tasked with presenting an abstract where Mikhail was the first author and you were the last author. So this might be fun Mikhail. I did his own purpose, by the way. So this is, yeah, from Asco to you, 2026 from the Niagara study you mentioned. Did you like it, by the way, Brian? Did you like it? Did you like it? Did you like it? He thought it was good. 10 out of 10. Let me present it. Then the audience can decide. So EFS, the OS advantages. One thing you didn't mention in this about CTDNA from Niagara before I get into the UTDNA. And I thought this was very interesting as I looked at the slides again was that if you were the pre-radical systemic CTDNA negative population at a path CR 51%, that pre-radical CTDNA positive had a path CR 3%. So huge differences, which makes sense. The effect of drug systemically is measured by CTDNA is mirrored by the effect pathologically is measured by a path CR. So I just thought it was such a dramatic difference. And it really fits in with everything we're saying about the problem. Basically. If you're CTDNA positive, you've not had a path CR. If you're CTDNA negative, it's a 50/50 chance. It's 50/50. If you're CTDNA negative. So let's talk about urinary tumor DNA, UTDNA, which I think was the thrust of this presentation. So a couple things. At baseline, 85% of patients were UTDNA positive. That dropped down to 55% following the Oedgment treatment. This is in the combined arms. And that clearance was more likely in the Durveil-Mab containing arm. The percent with clearance was about 39 versus 27. So it was 11, 12% more likely to clear in the immunotherapy containing arm. And that clearance was in UTDNA was associated with outcome, just like it was for CTDNA. Again, across arms, if you look, it looks like there's about, I don't know, 30 or 40% difference in the probability of EFS based on UTDNA clearance. If you look at path CR again, these are time points before radical suspectomy. UTDNA negative path CR 72%, UTDNA positive path CR 18%. So what is that about? A fourfold increase in likelihood of path CR based on UTDNA status. And then lastly, there's sort of the combined analysis looking, if there's CTDNA and UTDNA, you can be double negative, double positive or have just one of those markers positive. And as you might imagine, if your patients who have double negative, you know, obviously have a higher chance of path CR well over 70%, compared to double positive where it looks like it's maybe about 5%. And then if your single positive, it looks like it's in the 20% range. So UTDNA giving status of the bladder, if you will, CTDNA, I think more reflecting systemic disease, but also can reflect what's going on the bladder as you just said with bulky T2 disease. And then lastly, I think the last slide was about the, what I just said, that there's additive value, right? So it's not one or the other that you can sort of further differentiate by incorporating UTDNA status, you know, into your CTDNA status. So I, it seems to me from the outside a little bit that it's the methodology for UTDNA is less developed, right? We obviously weren't talking about levels, etc. like you did for O11, so it's less developed. The other thing I thought was interesting from Tyler Stewart's discussion is, and I'd ask this to you before Mikhail is about, you know, how can you be UTDNA positive if you have a path CR? It sounds like there's, you know, clonal evolution of normal bladder cells, right? And that might be contributing to maybe some of those positivity in addition to non-muscle invasive relapse. And I don't know if we had a breakdown from this study, but I think it, it seems like this is going to be an important tool to complement CTDNA, to better understand what's going on in the bladder, and perhaps, you know, inform treatment decisions, including, you know, which patients should go to local therapy and which shouldn't. How was that? Yeah. Excellent summary. Yeah. Because, do you think, Mikhail, do you think he, I thought he put some bits of it, but I thought overall it was rescued at the end. Brian, can I ask you a couple of questions? Sure. When you sat through this, these presentations, I know you were texting me at one point, as you sat through these presentations, did you feel that this is something that's really revolutionary now? A year ago, you could say it's preliminary, and it was exciting. Do you feel now it's something that you just need to be using in your patient? [BLANK_AUDIO] CT DNA, not UT DNA. Is it something which is, you know, you've got a positive randomized phase three study, you've got trial after trial at meetings, showing almost the same thing. Is it something which is obviously now needs to be used and we should be monitoring patients in this space? Or do you feel actually there are some caveats to now? - I mean, I guess both. It's absolutely revolutionary. And I think it's gonna change the way we approach perioperative management of bladder cancer. I don't know if we know exactly how to use it in clinical practice, right? We haven't talked about perioperative EVDP and how we're gonna use it. And I mean, unless you're gonna say, if you've not cleared CT DNA prior to surgery, well then I'm not taking those patients to surgery, right? Which would perhaps be a very reasonable conclusion. I'm not quite there to say I know definitively what to do with everything, but I think compared to where we were a year ago, there's clearly more information. There's themes that are emerging. It's an important tool. It might just be a step away from saying, I know exactly how to use it in clinical practice. - So I think that's an important point to emphasis. So I think that God misjudged also at the meeting here and there that the idea that if you don't clear your, if your CT DNA positive or assesses it before cystectomy that you do so poorly, that you shouldn't be taken to surgery. So that's not true. So if you look at the curves, the EF curves based on pre-systeme CT DNA, then there are still patients who are being cured about 45% or such as remains without an event in follow-up and there's plenty of follow-up in these studies. So it basically means that we're gonna have to find out which of those patients have their CT DNA coming from mycometestetic disease and which patients have their CT DNA coming from local residual disease that can still be cured by surgery or maybe nodal disease. - And maybe that's where quantification comes in, right? 'Cause you'd expect systemic disease to have higher levels and you know, your disease levels. - In Niagara, there will be levels above which you probably have advanced disease. Because we kill, you're absolutely right. It goes 22% CT DNA positive pre-sodering Niagara, only down to 29%. So actually half the patients are being cured, are being having clearance. And obviously you wanna achieve that and surgery is probably the best way to doing that. So I completely agree with you on that regard. Because my question to you, or just before we get there by the way, this is the question always gets asked, so I'm gonna just repeat it and everyone knows it already. In Vigua 11 tells you when to start immune therapy in the adjuvant space and you give it for a year. It does not tell you when you can stop neo-adjuvant immune therapy for those people who have started a neo-adjuvant regime. And so if you started a neo-adjuvant regime and you've gone from CT A positive to negative, that might be because of the immune checkpoint inhibitor. And no one would wanna stop an immune checkpoint inhibitor or three months and no evidence for that. So I'm afraid. - Can I press you on that? I don't disagree with you that that's what the current data shows. Do you think we'll get you a day, however, that people are tailoring the adjuvant component based on CT DNA? - I think-- - I'm saying the data exists now, but not with the tezos. Some people cleared right away, some people cleared later, et cetera. - So it's complicated because we're always giving something, we're always giving a year of immune therapy. And so we, and cutting short immune therapy has not been tested. So it doesn't matter what, even if your outcome is 100% in the immune therapy arm, in Niagara, those patients went on to get more immune therapy. - But in the future. - Yeah, no, so I think it comes down to the, in the end still comes down to do you believe that you need more immunotherapy after surgery because in the CT DNA negative group, that's the group where you would maybe say like, "Oh, they got cleared, so I don't need to give any immunotherapy anymore," but reversely in the CT DNA positive group, I think I would strongly argue that that group is not responding to therapy if they're still CT DNA positive after surgery. So those patients also shouldn't get immunotherapies. So in the end, both if you believe in both arguments, you wouldn't give anybody an adjuvant immunotherapy. - And three months of immune therapy is not longer. And let's just rehearse this argument briefly if we can because I agree with what you've just said, Mikael. In the adjuvant setting, without prior immune therapy, if your CT DNA positive, you should start immune therapy early because those patients are in harm's way. And if your CT DNA negative, you've probably done for whatever reason, you've been lucky and you've done really well, and your risk of relapse is low and you can be spared immune therapy, which is associated with a 20% chance of life changing toxicity, and we know unselected trials are not associated with a survival advantage. If in the neoadjuvant setting, you've gone from positive to negative, you've had it, if you're positive, you've got a really lethal disease. Being CT A positive is bad in the neoadjuvant setting. Those patients go on and die of cancer. And so therefore, if you've managed to become negative, you should keep going when you're winning. And Mikael's absolutely right, if you go from positive at baseline where your hazard ratio is three, do a hazard ratio of six after neoadjuvant therapy, do a hazard ratio of 10 after surgery, what you're doing, you're not winning, whatever treatment strategy you're on, I'm afraid, isn't working and usually try something different. So the positive patients should start immune therapy for those in the adjuvant setting, but even if you've had neoadjuvant therapy and you're still positive, you should probably stop and try something different because it's hasn't worked. So it's kind of an adjuvant neoadjuvant paradox in that respect. - Well, if you're positive at baseline, if it's after a cystectomy or before, I mean, I think what I hear you saying is, you still need therapy, right? One group has an intervening cystectomy and one had it prior. I guess the question I'm getting at is, now we're not just talking about single-age immune therapy, now we're talking about chemo immune therapy, EVP, et cetera. So I understand we don't have data now, I'm just asking you to speculate that do you think we will be able to tailor, I would say treatment approaches in general, but I was focused more on the adjuvant space, adjuvant EVP, adjuvant whatever, adjuvant more toxic therapy. Let's put it that way based on. - What would you say if you're in the adjuvant space, if your MTM levels were high, you might under the C-T-N-A clearance with a tezlyzm, I have his only 26%, and it's 90% with EVP, I can see, and Jonathan Wright, thought he did a brilliant discussion, he phoned me up beforehand and said, "Tom, should we be giving EVP to those patients "with higher MTM levels after surgery?" And that's an interesting conversation because in the neo-adjuvant setting, obviously because there's a primary tumor there, your MTM levels are higher, but those levels are higher, not because of MRD, those levels are higher because of local disease. So there is a bit around, can we personalize therapy in that respect? - Michele, I'd like to also. - Yeah, I just think that we're focusing now a lot on that adjuvant setting, but we're entering a new era where we're giving everybody EVP in a new adjuvant setting. And I think with the foreseeable future, if you get EVP and you get surgery, and you still see TDNA positive, maybe haven't seen data yet from EVP, you're operative, but if you're still positive, that's gonna be a group that is going to be very hard to rescue. We don't have any really effective therapies for that group. So I think for the foreseeable future, that's just really bad news, mainly. What I think is now the excitement about, in this meeting, there was a lot more data about organ preservation, a lot more data about CTDNA and urinary tumor DNA. And I think what you said in the beginning was an important observation, Brian, urinary tumor DNA, we're not there yet. This is basically the first-- - They will give me a summary of where we are with UTDNA. You tell me where we are now. What do we do next with UTDNA and what does it tell us? - Yeah, so UTDNA is where we are now, is that we show that it for sure gives more of an impression, more of a measurement of the local tumor. So whether it's invasive or non-invasive, then CTDNA does, but it's still not perfect. So patients who were CTDNA negative and urinary tumor DNA negative, still in about 28% did not have a path to R. So we're still not completely able to predict this. However, these techniques were only at the beginning, and I would assume urinary tumor DNA assessment will be refined. And there was a lot more work to do on it, because I think work to do in the collection, work to do in perhaps in also levels of urinary tumor DNA that might be important. The other thing is that-- So I think it's not perfect yet. However, the big question is, is it good enough to work for bladder preservation? So I think that's where it's main purpose in a misonvasive bladder cancer is. If you have given your induction therapy, so let's say EVP and you want to think about organ preservation. but maybe not giving any consolidation at all. Is this 72% PATH-CR that you will have with a completely negative CT and urinary tumor DNA negative patient is that good enough? And I think I would argue that it may be, we have to of course do the trials for two reasons. EVP has a much higher PATH-CR rate than all the other drugs. So I think your margin gets better. And the second thing is that this is, I think what met in his trials showed is that even if you get a local recurrence, you still can be salvaged. - Then he's a gene too? - He's a gene too. - Right, different trial. - Right. - And retained too slightly different. - And he's a gene too. And they had local relapses. - Right. So I think about a third of patients who got a clinical complete response and got monitored, still had a local relapse, but none of them in the end had metastatic disease. This was, I think slightly different for retain, but he had a few patients with a local recurrence and then metastatic disease. It was a lot of data in there, so I'm not sure if I completely call it correctly, but I think that's what I saw. So I think if you're completely CT, DNA negative, urinary tumor DNA negative, clinically looking like a complete response, I think that group should definitely be tested for no consolidated therapy. It's not enough yet for inclinical practice, I think, but that would be a good thing to do in trials. What I think we have shown is that for all the other patients, so the patients who do seem to respond well, but don't fall into that bucket of a very strangely refined clinical complete response. I think our trial shows that these patients can get chemotherapy and still have very good outcomes. So I think we should get to a sort of a tiered approach where the really good responders, both in the biomarker and clinically, could perhaps not get any consolidation therapy. And the other patients, as long as they don't have clear progression, could get chemotherapy, which I think is a very good treatment that most patients are very happy with. Also, what you're saying is we're moving in, I think, is we're moving into a bladder sparing era. In that bladder sparing era, we're not going to have the luxury of pathological complete response. Pathological complete response is only so useful in the end and has a big downside because you have to remove the bladder in the process. UTDNA is marching towards being as accurate, but doesn't tell you exactly what's going on in the bladder. At the moment, we would have to continue to do cystoscopy to work out what's going on in the bladder. UTDNA is not accurate enough for that, but I think it's fair to say that from an MRD perspective, if your UTDNA negative, CTDNA is a really good marker of MRD and therefore CTDNA monitoring, probably is here already, UTDNA could be useful, but we need to do a bit more work. Is that fair? - Yeah, absolutely, absolutely. I think it was very interesting that there was a very small group and we didn't do much work on it because it was a small group, but this group that is CTDNA positive, but your urinary tumor DNA negative, that's the group that doesn't have any disease, probably any more in their bladder, but actually has nodal or macametostatic disease. And they do it, do the worst. [BLANK_AUDIO] [BLANK_AUDIO] [BLANK_AUDIO] [BLANK_AUDIO]