Episode 504: ASCO 2026 - ADC Drug Development in Urothelial Cancer

[MUSIC] >> Hey everyone, welcome to another Yuromego's ASCO 2026 podcast. This one is on Anombadi Drug Conjugates in your Ethelial Cancer who pleased to be joined by Gopai Air who presented some data about a novel ADC in bladder cancer. And we're going to use that data as an opportunity to broaden the scope and talk about the EV302 update that I'm going to ask Tom to do, talk about that data, and then talk generally about sequencing of ADCs and novel ADCs and some other data at ASCO. So Gopai, I'll turn it over you for a sec to introduce yourself and then we'll get going. >> So much Brian and Tom, this is Gopai Air. I'm a G-Metical Uncologist at Memorial Sloan Academy Cancer Center. I have a lot of interest in the Yuromego Cancer Translational Research and some of the new treatment modalities that are out there right now. So thanks for inviting me. >> Yeah, I appreciate you joining. All right, so Tom, we're going to start with you. EV302 presented an update. I think it was a three and a half year update. So why don't you take us through a little bit of that data and then we have some questions for you. >> So for those who have been or holiday for last three or four years or space travel, it works rather than in Pemberlism, I have a combination which has been really successful in your Ethelial Cancer. And in EV301 was single agent therapy, which showed actually pretty good response rates in heavily pre-treated patients. But there wasn't a huge amount of durability. But for some reason, we haven't got the bottom of it quite yet. When you put EV Pembro together in the frontline setting, you get much higher responses and you appear to get more durability than we expected. And so the original EV302 publication, unfortunately, the Doton, which is an Ectin IV ADC with NMA, Payload Pembrolysmab, obviously is PV1 inhibitor, in tool progression of disease. So many patients were on therapy for a long period of time. That was the study on the control arm, platinum chemotherapy, in frontline metastatic, your Ethelial Cancer, previously untreated, about 30% of patients in the chem-- In fact, at the end, about 60% of patients who progressed in the chemotherapy are ended up getting immune therapy. So quite high proportion to patients there. It was a big positive randomized trials, doubling in progression for each viral, doubling, Ival survival, 30% CR-8, 70% response rate. And here, we presented the three and a half year data updates. And essentially, that showed more of the same from an efficacy perspective. So the OS hazard ratio remained 0.53, which is really impressive. It seems to be plateauing at four years. It's probably going to end up being about 40% 5-year survival. The first trials that we did back in the day, we were looking at 5% or 10% 5-year survival. So it's a huge shift in that respect, which I think is fabulous. There's repeating. I mean, the plateau-- and I don't know if you're using these numbers to talk to patients about medians and their chance of being alive in five years, but the numbers seem wildly impressive to me. Yeah, I think-- and it's exactly what John Rosenberg showed in the phase 1b data, which was out of the US in the cis-part in Ineligible Population. 302 is always almost identically tracked that. And the consistency of the signal of EV30 of all of these trials, 301, 302, 303, 304. And some people say to me, oh, the OS signal in one of them, maybe some people say the Niagara signal was quite similar to 304. I don't think that's the case necessarily. 1 was 0.65, 1 was 0.75. The path CR8 in 304 was much, much higher. It was 55%, versus 37%, cross-dropping, and perhaps not quite complicated. But when you pull the whole package together, it's just consistently very, very impressive, which I think is why this sort of EV Pembroke first asked questions later, line, which some people like. I use quite a lot. Some people don't like, I'm sure. But there were some other bits in this data set, which I think were worthwhile mentioning. The first is we looked at platinum chemotherapy as second-line therapy. And in fact, we had 135 patients who were treated, which was 30% of the population, equal proportions, getting gem, cis and gem, carboh, and the response rate was 21%, and actually 20% for cisplatin and 22% for carbon platinum patients. So two observations there. Some of the previous data suggested response rate, second-line, or higher than that, for some retrospective data. I think 20% in my experience is probably about right. And there doesn't seem to be a massive bounce for cisplatin versus carbon platinum. Clearly, it's all just a caveat of data associated with it. But it's a benchmark for future trials. It's pretty disappointing, though, right? I mean, is that still the standard after EVP, right? With 20% response rates median survival less than 11 months? Well, I mean-- I mean, maybe it is, but I'm just asking-- I think the answer is-- Well, in our URMEGO score that we did, people didn't want to do that. In our URMEGO score, people wanted to do something else. So you get higher score for TDXD, although there's a best-of-hand for the patients there for the her two positive patients. And then, in fact, even FGFI and Abyssin at a fitting-eab scored higher than platinum chemotherapy, I'm not-- this is the most robust data we probably have now in this setting. And actually, I'll push back on you a little bit if I may, because the-- Pregnation-free survival median is 12 months, OS now, three years, median OS, about three years. And that's with this approach. And so you might say, why wouldn't you want to try and reproduce the results of 302 with your patients? And very few got TDXD. Lots got platinum chemotherapy, and that's how we ended up at three years. So I think it's reasonable to pursue this until proven. Otherwise, I don't get me wrong. You show me TDXD patients, 50 patients, her two, spectacular results. I'm all over it. I've got to tell you, I don't think the CITIM avidote will talk about this with Goper in a minute, but I don't think the CITIM avidote and the FWAT are in a necessarily in the sequence, particularly well. And then, Brian, I'm going to go real quick now if I may, because we're all excited to just talk about. There was some CR data. So the 30% of patients that got CR, the majority of those CR patients, didn't get CR on their foce scuffer scan. Indeed, there was evolution of CRs. And many patients didn't get CRs till six or even 12 months into therapy. And this describes, as you can imagine, an evolution of disease. It looks like the patients that get early CRs are more likely to have an lymph node disease. But it's also true that those patients with the longer CRs, they tend to have this form of tastercyts. And when you look at the patient population, CRs happen pretty much across the board, in one of the events, this will make non-variant astrology, et cetera. So, you know, and I also think there's some quite nice data in this data set showing that those CRs seem to be durable, very, very small percentage of those CR patients relapse. When we first made a podcast on this, you said, "Don't you think we're curing any patients "and me and me kill pride in both of them?" The nerd sat on our hands and looked like British politicians trying to answer questions. By the way, British politicians are not very good at answering questions, it might experience. And now I probably would come off that event and say, "I think we're curing some patients." So, bad accounts that I think we're doing it in advanced disease. And I don't think it's just the lymph node patients that I don't think it's just the muscle invading. - What percent do you think it is? - I'm going to go for 30, but I look, you've got 40% alive at five years. I'm going to go 30% if I may. - Okay. - That's where I'm going to go with it. There was some data, and of course, there's some data on duration of CRs and the CRs, as you can imagine, the sort of four-year landmark CR data. If you have a CR, your chance of being alive in four years is about 85% somewhere around there, which is pretty good. There was some duration of therapy data. We haven't really got to the bottom of this issue. We know that two years of Pembro, we know that about most patients who can continue on Pembro for that period of time, we know that the median duration of EV is seven months, but we know some of that will be because of progression of disease and because some patients progress in the first six months. We know that we show some data here, looking at patients who have had therapy for more than one or more than two years, and of course, if you've had therapy for more than one year, your duration of EV goes up, median duration goes up to 14 months and two years, obviously that means you're going to be on longer periods of therapy. My experience of this issue is extremely complicated. I think there are three parameters we've made podcasts on this before, but your baseline disease, patients with liver metathesis, with stable disease who are tolerating treatment quite well, they tend to go on for much longer periods of time. Those patients don't want to stop. Those patients that have had spectacular responses who thought they were going to die, those patients, particularly on these trials, wanted to keep going on because you've been told that you're going to be dying, I mean, you're in survival's only a year and suddenly you're two years in on your own this magic. So I think it's a very. complicated issue. I don't think EV302 is going to answer this question. I think the real world data programs like you, Knight and others are going to be better at answering this question in the future. So let me jump in with the question. In your practice then, if a patient achieved CR, are you using that as a time point to stop therapy, continue for two more cycles, or do you not really necessarily account for that, and you're just basically on toxicity? My conversation is evolving, and if you go back in our podcast, if you go to a prison sentence for 20 years and have nothing else to do, I can't think of it. Logged just to the space travel again. But if you did go back in time, I was stupid enough to go back in time and listen to our podcast on this issue. I think you'll see that the conversation is evolving with time. And I think particularly recently with the perioperative trials showing great results with nine cycles, and then we don't know the results to the vulgar trial, but it's positive with only three cycles. This duration of therapy conversation is evolving. When I started, I basically said, let's just keep going for as long as we can. This is a lethal disease, and this is brave. And I've had patients who have been on therapy for more than two years, and I've done that successfully in terms of outcome. I'm some of those patients who had a long-term neuropathy. I'm now more pragmatic about that, but I don't know the answers to these questions. I just want to bring open and ask you what you're doing in your practice in terms of duration of therapy and how toxicity aside, of course, you modify or stop for toxicity, but are you considering duration based on response or no? I am. I mean, a lot of the patients in the metastatic setting, especially the ones who have those liver mats who end up having a CR, I'm probably a little bit more reluctant about stopping treatment for those patients and then probably continuing, but the ones that have no-one metastatic disease, I feel like a little bit more comfortable there in terms of talking to them at least about discontinuing therapy. It's a complicated conversation because a lot of the patients are not willing to do that. And then I think the other thing that we can layer on top of this, and I know this has been talked about in the podcast as well as sort of, do we use circulating tumor DNA as well as another measure of disease control of microimmune disease? Are you using that in your clinical practice at this point? I know my colleagues have been doing that as well and so we'll usually do signetary testing and follow that and see if we're getting to zero. I think it does help conversation with patients in terms of- And then if they get to zero, you're not definitely stopping, but you're perhaps more comfortable in talking to the patient. Exactly. Are you ever stopping in somebody who doesn't achieve zero? I'm from toxicity, of course. Yes, I'm from toxicity. I have not to be honest. And I know that the patients probably would not want that either. I mean, we'd be kept going. Yeah. Tom, are you using CTDNA in the setting? I don't know, the availability there. So in the patients who achieve CR, I'm interested in CTDNA dynamics. And I have a group of patients who measure their CTDNA who clear it with EVPembro in advanced disease and in perioperative disease for tracking their CTDNA. And in some of those patients, they have- I think the Natera, the personalized tests are better than the bad panel based the test in my experience. I know other people might disagree with me. But the panel based test, that I left lacks- I think there's more still more false positivity. But we are, I'm sort of, you know, sometimes the numbers come back and I believe personally that there is data to support early relapse that predates radiological relapse and therefore becoming CTD- positivity a bad sign. And those patients who are choosing to stop EV who track their CTDNA and then restart if it was to bounce back is not something which is unheard of and in fact there are people who are doing that. I was way offstand at the count that- Yeah. Not that I'd recommend by any strength imagination. But the reality is that patients who are beginning to build up prefernorepathy after eight or nine cycles, in a CR, many of them are saying, you know, I want to come off now. Is there any way of tracking this more accurately than just waiting for the cancer to come back? And there are good trials that we could do out there. Are they being done or is this one of those things that's going to sort out in practice? I think we're really easy to do it. I mean, you could- because you just- Yeah. We could have to group almost as a community, we could agree, we're going to do this. We track patients respectively. We have CTDNA and RSS and all of the in the US. You can do it, we can do it in the UK. We can- I'm a prospective trial just a registry of sorts. Well, you know, I'm sort of a prospective registry. You can say- Yeah. But we're going to be following up with series of friends. I have the first of September, 2026. We're going to do this and this is how we're going to do it. I mean, you know, so I think it's doable. Whether or not you need all the funding, as soon as you say a trial, you have IMPs and all the bits and pieces. Suddenly it's 2035. Before you got the thing off the ground, you've got to get approval from a whole series of religious and emotional leaders across the world. We don't necessarily need that to do this. Yeah, no, I hear you. Okay. All right, where will we wait? Time three. Let's finish up three or two. We want to get to go. I thought I was just about finished. Okay, let me finish. What I would like. Yeah, okay. So finished. So I think number one, I think the transformative results have persisted. Often you see the Kaplan Markerves coming back together, particularly in your trials, Brian. But it's EV302, it's not. They're like train- the OS curve stayed low and really apart and it is a spectacular. I mean, it is. I mean, in huge global effort, it's been a spectacular result. And it's persisted. The CRs were probably curing some patients. We need to learn more about the management of toxicity and your optimal duration of therapy. And those trials, I think are ongoing. There's going to be a lot of work in this area. At the moment, there is a lack of clarity about how much is enough. I think it's great. We've got to where we are now. The story's not yet finished. Awesome. So given that given those results and the fact that EVP now is a frontline standard globally, we've started to ask questions before about, is sequencing of ADCs possible with the same target, different target, same payload, different payload. So go, but I think this is where your data comes in with this Nexus trial and this novel, Nectum Fort targeting ADC. So do you want to walk us through a little bit of those results? Yeah, that'd be happy to. So that's exactly right. I mean, it's basically a next generation. It's Nectum Fort targeting antibody drug conjugate. I think that was always the question as both you and Tom alluded to, you know, post Nectum 4 ADC therapy is Nectum 4 still a clinically relevant target. Is it still therapeutically tractable? And I think the short answer to this is yes. It definitely seems like it because the drug does have an objective response rate. It is active in the post EVP setting. So this is Nectum 4 targeting with a novel Topo 1 payload, Camp2TK 98. And it was specifically, you know, in this study, a physician is a Phase 1 trial looking at metastatic urethyl cancer and also some solid tumors that had Nectum 4 expression. And the key was the prior EV was permitted on this study. About 67% of the patients who were enrolled had received prior EVP or EVP before going on study. Pretty heavily pre-treated patient population the median number of lines of treatment was three. I think, you know, from the big question, and we can maybe talk about this separately, but, you know, from a safety standpoint, in patients who were carefully selected, and that was based upon the CIP-226 activity score. If they had sort of a normal activity score and were normal metabolizers of the Camp 98 payload, they actually had pretty, you know, it was a pretty well tolerated drug. I think Alopecia, Nazia, Discusia, and Fatigue were really the most common side effects that were seen, and they were mostly grade 1. It was a bit of a different story in the patients who had sort of lower CIP-226 activity, meaning that the payload was in the system for a lot longer. And there, you know, we did see much more significant toxicity, primarily neutrochemia and sepsis in patients, but very early on in the study, it was sort of mandated that CIP-226 genotyping be done for all patients moving forward. And so, really, you know, to try to mitigate that toxicity significantly in patients. Yeah, go. But just, was it, was it during the study that it was discovered, gee, there's this prolonged side of pinias that we need to test for the CIP-226, or was that from day one of the study, was that known to be a problem of the time to work? It wasn't from day one, but pretty early on. I think there were really only a handful of patients, like five or six patients that were enrolled who started to have these significant toxicities, primarily the prolonged neutrochemia and the fibromutropemia. And so, then the study was paused to enrollment to do a deeper diet, and what was going on with those patients and understand the safety signal. And then it was realized that really those were the patients who had sort of these very low to undetectable CIP-226 scores. And then the study was amended after that to do a prospect of typing for all patients. And then there was also a separate substudy specifically for the patients that had activity scores of zero. How common is a low score in a general population? It looks like less than 10 percent in this study, and that was, that's reflective of the general population as well. But there are certain geographical and ethical cohorts that seem to have higher numbers as well. So it needs to definitely be, you know, a part of, if I mean, depending on sort of where this drug goes in terms of development, it will always, you know, I think the fibres of 2D6 testing. Yeah. And then in terms of activity, you know, just kind of to take it to nuts and bolts there is 42% objective response rate in the patients, specifically who had the, you know, sort of normal activity scores of 0.5 or higher. And then it was about 33% in the cohort of patients who had had progression on EV and it was 67% in the EV/9 EV patient population. So it's an active drug. And hope that that prior EV started in our EVP. Was it immediately prior in anybody or was sort of variable, very, very prior if that makes sense? Yeah. Yeah. It was variable only a small proportion of patients, I think, you know, around 9% of patients had come off for toxicity. So most of the patients had come off for progression, but it could have been that they got intervening treatments between completion of EV. And so, do you know if there's anybody who went straight into this after EVP and responded? So not off the top of my head, but I can tell you anecdotally we did. We did enroll a couple of patients who went off EVP for progression and then started on this and did have objective responses. Yeah. And then my follow-up question is, is there anything known about necked and fore expression post-EVP? If patients had biopsies or anything, I guess with the activity you're seeing, it's obviously there, but I didn't know if there was any tissue-based data regarding that. Yeah. So actually, I'm glad you asked that. I'd like to, because I wanted to spotlight actually an abstract that's a poster at ASCO this year. And it's by me, Hal Stern, she's from David Agam at MSK, where they looked at actually a group of paired tumor samples just as you were saying, pre EVP and at the time of progression in patients. They're in their data and they looked for necked and fore IHC, they used an H score to compare pre-imposed. They didn't see any significant change in necked and fore expression in the post compared to the pre, so it suggests that necked and fore down regulation or necked and fore loss is not necessarily at least in this cohort a significant mechanism of resistance. But what they did also look at was they looked at a membranous versus cytoplasmic necked and fore expression. And interestingly, in the patients who progressed quickly, I mean, relatively quickly, meeting within about six months or so of EVP, it seemed like there was this shift to having a predominantly cytoplasmic necked and fore expression in the resistance specimen. And so that would indicate that maybe there is some down regulation where it's sort of transported from the surface into the cytoplasm, whereas in those patients who were on for greater than six months, there seemed to be such a pattern. So it might still be playing a role of this down regulation in necked and fore, but overall it does seem like in the overall cohort that necked and fore loss. So you folks have been working on this for a bit. And the Germans are involved and everyone's kind of. So where are we with amplification, membranous and cytoplasmic? My take on this at the moment is that the Germans came up with some nice retrospective work on amplification, which looked promising, but other groups didn't validate successfully. And then one or two groups have now looked at cytoplasmic versus membranous and pretty universally, people agree, seem to be agreeing that membranous seems to be more important than cytoplasmic expression in terms of looking at prime and deep response versus non-responders. If I got that basically right, we're all over the place. I think that's exactly right. Yeah, I think it's hard with fish as well. I mean, in terms of what you're going to call as amplification versus gain, what cutoffs to use, what assays you're using as well. And that might be one reason for why there's been a little bit of discrepancy in that in this poster, they don't go into, I think, the fish as much in detail, but we haven't seen the same correlation between fish amplification of night before and enhanced response to you. We were meeting highlight posters at ASCOGU on this topic, but Brian. I'm sun hero, Tom. I'm sun hero. I think you had to go to a separate meeting, Brian, so we missed it. I think that's what happened. So anyway, we did a quick shout out, whoever had that pretty in post at ASCOGU that we never did. And apologies for that, but we thought it was a nice piece of work. And I think this work is evolving a bit. But for me, one of the, do you want to go through the efficacy data? Do you have, actually, I think the response rate was in its four seasons, all right? Yeah, so 42% objective response rate, you know, in 31 or 33% in the post-ED population and 67% in EV90 patients. When we look specifically at the different dose levels that were tested, the four dose levels that were tested at the 3.6 milligram per kilogram dose level, which was what most patients went on to. The objective response rate was 47% in the post-EVP patient population. One thing though, also to keep in mind that they also looked separately at patients who had received prior to boy summaries and they heard therapy. And actually, there were no responses in that patient population, which is pretty striking. And it does seem to suggest that perhaps payload resistance is a significant issue that we need to be taking into account in urethelial cancer. I think we've seen similar patterns emerging in breast and other cancers, but this is really the first data that I'm aware of that's showing this in urethelial. I mean, that's striking, right? No responses versus the post-EVP response rate. I was just going to ask if there's other data in bladder to suggest that the payload is everything. Yeah, not that I'm aware of. I don't know if Tom, if you, if you're aware of others. I need to be talking about it for a little while with some of their retrospective analysis. They obviously have EV and DV, which they're using, but they haven't published that much on it. And they've also got a number of topoisomerase 1 inhibitors that they're developing with different payloads, dropped to SACT-T and T, as obviously one drug that's coming out in China. But there are also other drugs which are at the meeting. There's SHR-A2102, which is another drug, which is a net in four, topo-1 ADC, not dissimilar to what you're presenting here. And so there is some, they've got some of these retrospective datasets that which talk about the same thing. But I think this is the first time from a global perspective. It's been broad cast that it looks like the payload. And that also applies for MME, by the way, because there's no EV, DV data that's been broad cast. So this is quite, for me, this is the most important thing because drug development now, you're what you're saying is that we can keep going on net in four successfully. Anything, any response rate, I think above 33% is of interest. And of course, any. Where do you come up with that number? Well, you know. Totally made up. Oh no. That's a two-time-up-goverty, can with sort of 27, 28 EV when it first came out was 40. But those. Those are in ADC-Native patients, so. Yeah, but we need. We need. We need. We need. We need to be very careful of this population because this is not pure post-EV, Pembro. Yeah. And as soon as you've got a third and fourth line. You know, fourth line patients in bladder cancer do better than second line patients in bladder cancer. So, you know, as soon as you've got your EV and your platyne chemotherapy, you know, suddenly that population's doing well. So, assuming that the EV population response rate, post-EV Pembro, directly, if you progress on EV Pembro and you switch to these drugs, it's still in these 40% response rate. I'm not sure that's the case. So I think that these early phase trials, just because we're including EV patients, doesn't mean it's always going to work after EV Pembro. And let's have a look at our second line trials, post-EV Pembro. And as I said before, when you test platyne chemotherapy directly post-EV Pembro, you get 20% response rates, but when you do the retrospective analysis out of a moral-slown catchering when there are all sorts of other bits and pieces going on, the response rate is bound to 50%. So I think the cross-trial comparisons of phase two studies with different things extremely risky, and I stand by my 33%. Thank you very much. I just want people to know it's made up. It's fine if it's 33%. Obviously, it's made up. Obviously. I go for what else. Is there anything we haven't talked about? I think we went over most of the things I mean. No, I want to double down the safety. Where do you know is safe? Inzyme sounds important. We haven't seen this problem with other agents. There's a second lily drug that's being developed in the same session. I think it's one of the mini-orals actually, which is LY4104, which is similar. Actually, this drug comes from mass gen, as in go. And the response rate here is much lower, 18%. But they don't have the same issue with the enzyme. Why is it with this drug, and not Sassatuzum, I've got a T-can, and not SHRI. I want to know, are not LY41041174? I think that's a great question. One of the things I think has to do with just where these drugs are, how these drugs are and WB tabledized and how many different metabolic enzymes might be involved in that. It seems like with this drug, SIP2D6 really is the predominant one and not SIP3A4 and not some of the other ones, which is probably not the case with some of the other drugs that you mentioned. I would say that to me, this echo is a little bit with UGT1A1 testing. or DBYD testing, you know, in that we know that there is this population of patients that based upon their germline genotype for C2D6 or these other enzymes are going to be at high risk for toxicity. And I think that's what's driving this here. I do think that they did, you know, the appropriate thing in terms of sort of, you know, halting the study immediately, trying to figure out exactly what was going on with C2D6 within those patients who had those prolonged toxicities. You know, but it bears saying, and I think emphasizing there were three treatment-related deaths on the study, you know, two patients had sepsis, one patient had aspiration and monia, at least two out of those three patients did have C2D6 testing and they did have activity scores of the zero to zero point two five range. So clearly, I think that's an issue, but then you could also flip the script a little and say, you know, in the patients when they are selected appropriately with scores of point five or higher, it's remarkably well tolerated for, you know, but moving forward, would you just simply exclude those patients with low activity scores or do you think there's any place for, you know, giving them, you know, some dose, dose fraction, some tiny dose, is that safe? Exactly. Yeah. So, so there is a cohort of patients that they're exploring that in right now, specifically with the point two five activity score, where they are giving sort of lower doses to see, is it feasible? In the patients with an undetectable activity score, those patients are no longer being enrolled because it's just not thought to be safe for those. Yeah. But for what it's worth, like, C2D6 testing results are now actually starting to pop up in some of the commercial platforms like Tempest and others. And so, it seems like it's already being baked in a little bit into test, this type of perspective testing for patients as well that can get done. Yeah, fair enough. Super interesting. Tom, was there other ADC data we wanted to cover as well? Well, I think just before we get there, I think it is worth now just, we've got different drugs hit this meeting. We've got these two different drugs both by Lily, one with 40% response rate, one with 20% response rate, similar global type footprint, similar what appears to be a similar mechanism of action, one with an enzyme alteration which appears to affect metabolism, they've got different DAIRs, they've got different linker molecules. It's beginning to tell us that it's possible that this binary, you know, what's the tar payload, what's the target, and that will give you all of the answers that you need is actually not the reality, and that within the same class of drug you can have very, very different effects. And we're beginning to see, for example, Sassatuzumab govatecan, which I think is a great drug, but tropics for was not successful subvert for survival, SAC-TMT has launched a very similar trial, similar type design versus tax-synchemotherapy. Many people say, "All that feels crazy, you're doing the same thing, we're very similar." Obviously it's opposed to EVB and BRO population, so it's not exactly the same thing. But actually, I can see differences between these agents, and I think it is possible that we can have different activity with drugs, with a swathe clear from the back of the room to be similar in their interaction. So I think this is an important new chapter, and I also think this data tells us that keeping going with the same payloads and mistake, and then there was a little bit of Chinese data as well at this meeting, looking at the combination of PD1+ next in full, Topo 180C, only 37 patients, I know it's very small, all presentation in the same session, showing very high path CR rates and very high disease control rates. So the last piece of this jigsaw is that when you move these drugs into the perioperative setting, they appear to be also quite spectacular. So we know DVPembro is active, we know EVPembro is active, we know when you push EVPembro into perioperative space, you get spectacular results. We're now beginning to see activity for this new class of Topo 1 payload drugs, with either TROP2 or NXN4 as the payload. We're beginning to see with combinations either SACTIMT+Pembro or indeed SHR 102+ PD1. When you combine them, you're beginning to see similar results, not necessarily as good as EVPembro, but similar type results, certainly better than Platinum chemotherapy. So again, if you are on that spaceship or that prison sentence listening to our podcast, we were talking about EVPembro being sort of like swan event and it's unexpected and then we talked about Holmeneckin, minute DVTORI PENOMABLOTS amazing too. And now at this meeting, we're beginning to see a series of other combinations with different payloads and different targets coming through as well. So it looks like this is a much bigger field and new ethereal cancer than we originally thought. I have a final question about drug development then for novel ADCs. What do you think the path is going to be in what's realistic and by that I mean is it going to be kind of like a lot of drugs we tested in the refractory setting and here it would be post EVP. Then where does it go from there? Can you can you do a front line study against EVP? Can you go into the perioperative space given given those transformative results of 302 and 303 and 304? Like if you were developing this drug further as both of you or any any novel ADC for that matter, like what's the path? Go for dual, go for a first dual meeting. Sure, I can jump in. I do think that there's a couple of questions there. I mean, one is is there a path here to go up against EVP? And maybe that may not be so necessary in the sense that as you said, if most patients are going to be starting to get it in the perioperative space, that frontline metastatic space now is the post EVP space and most of these patients. And so that is a reasonable space to kind of stay in. I think in a lot of these studies that are trying to position themselves like post gem carboh or post gem cis may end up being that quote unquote first line metastatic line now. And then there's also the you know sort of ADCs, you guys mentioned all of the different issues with them, but it's also sort of variable targets as well, right? So I mean, there is like eyes a lot to my brain at T-cam, which is the EGFR HER3. And there may be others that are coming that are more sort of by specifics, right? Where they're going after more than one target at the same time, maybe trove 2 in active for FGFR 3. There's a few others that are going to phase one. And so I think it'll be interesting to see when you start to have a diverse array of targets that you're going after as well if you may see, you know, different activity there too. Yeah. I mean, my take on that is that urethelial cancer, the majority of patients get one or maybe two good go to it, but I've never seen second line therapy cure people. So I think we do have to have one really good go at it. And therefore I think there is a scientific need to go big early and develop triplets to see if it helps. It might be like kidney cancer where it doesn't work, but it may not. And I would like to see the trope 2, Topo 1, next in 4, MMA, double it, the dad trial that came along, but there are other trials exploring the same issue with response rates, which I think are not worthy. And so I would like to see I would like to see the triplets with dual ADCs with complementary targets and payloads with an immune checkpoint inhibitor. So that's number one. Number two is the forager two study, which is looking at the new EGFR inhibitor in FGFR. It's a lily study with EV Pembro Plus or Minus FGFR and FGFR ultra patients doing really novel blood tests, AV Pugratinib, which is a drug which I've really backled to pronounce, but I got right today, which I was extremely pleased with myself. We didn't even edit those people. We didn't normally go up with 5 or 6 edits with the these drug names, right? And so I think that's a cool study. I'd like to say the Vege FPD1 by specifics with EV PEP with EV. I'd like to see that piece come along. So I think building on EV is really important. I also do like the activity of Isobren, which is a her one, her 3 ADC, Topo 1 payload. We're going to see that activity in there's some Chinese randomized data. We don't know when it's coming out, but they're recruiting pretty fast. There's also a global study taking part with that too. I think that's an exciting drug also. And in the end, we'd like to see these drug maybe move earlier because it may be possible that you could say the EV Pembro for frontline metastatic disease and use other agents in the periopter space to cure patients. And then of course the last bit in all of this is can we improve our biomarker patient selection? Because the moment we're not working super hard on that. That's not because, you know, that's not because we're not always trying. I think people are, we talked a bit about that earlier, but we do need to work perhaps a little bit harder on that issue because we're now beginning to come to a place where patients are doing really well and who are those patients? Because then we can then focus on those that are not getting CRs to try and improve the outcomes of those individuals. Yeah, agreed. I mean, go, but you did report two CRs in your data set, including one post EV P. So I mean, Tommy said second line patients probably uncurable, but maybe that's not true. you know, with the novel ADC, I'm not saying it is or isn't, but I think you're generally right, right? We want to give our most active drugs up front and in double-edged triplets. We'll see how it plays out in bladder cancer, you know, as we've sort of seen in kidney cancer, but really, go for really interesting stuff. I think the field is exploding and the three-o-two data is interesting. Your data is interesting for a lot of reasons, so we appreciate you joining us. Thanks so much for having me. It's a great. (upbeat music)