Episode 489: Live Podcast From EAU

Welcome to this live podcasting session, Tom and I were asked to do this a while ago. We're thrilled to be here. So as I think many of you know, we've been doing this podcast actually for over six years, we're almost to our 500th podcast. And we're really thankful to be here. And so on a normal podcast, we have one guest with us virtually and we're sort of going back forth as that guest, as you may know. This is a little bit different. So the idea of this, we have a couple topics in mind, but we really want to hear from all of you in terms of what you are. We're going to start with a bladder topic. We have also a kidney topic. Come up to the microphones. You may be in danger of being pulled on stage just fair warning. To introduce, my name is Brian Renium, a Geomatical Ancologist from Nashville. And I'm Tom Pohl's. I'm an oncologist too. Fabulous. So thanks for coming. So many of you. It's a big crowd. The room is full if you can't see. If you're just listening. If you're just listening, the room's absolutely full. Is it right? It's outside who can't get it up. But genuinely, if you do want to take part, we're super keen. Like really. And if you can say almost anything you like, we're quite open minded about the wording, aren't we? We don't mind grayish swear words. Yeah, no swear words, but that's really fine. Ideally, but okay. Where would you like to start? All right, let's start. So we're going to start with the bladder topic. So Tom, I'm going to give you a scenario. So I am a 56 year old medical oncologist. I have T2 bladder cancer. I was diagnosed. I have CT scan staging. Okay. So I have no distant disease. I don't think CT scaging is that helpful. Okay, hold on. Just wait. Okay. I have a tumor informed CT DNA that was negative. I have a urinary tumor DNA that was. But you don't know that because it takes six weeks to get a result. That's pretend I know it. But they're still almost. So you've done. That's quite hard. Because it takes six weeks to get that result. Not in my shop. It takes six hours. Okay. Very, very advanced. We all say we're going to have CTA analysis done. But we're going to have to make it turn around quickly if we're going to make decisions off the baseline level. Fair enough. I think what's going to happen is retrospectively we're going to find out that they were positive. And then you'll say, okay, what are we going to do? Okay, so let's say you don't know my status upfront for CT and UTDNA. Okay, please, we've organized that. Yeah, I'm glad we talked about this beforehand. So I have T2 bladder cancer. I go to you. You give me four cycles of EVP. I tolerated pretty well. I've maybe got a little around with you, but I generally get through it. I don't have any major toxicity concerns. Yes. Full cycles of EVP. You gave me four cycles. Yes. I come back to you. You're a urologist in this scenario. I come back to you and say, hey, Doc, talk me in or out of getting a suspect to me. Now I know my CT DNA. Let's say it was negative at baseline. It remains negative. And my urine tumor DNA is negative at this point after four cycles of EVP. Talk me in or out of getting a suspect to me. I mean, look, you've got a really kind of serious cancer. You've got a 50, like historically, there's a 50% chance of this coming back within two years, a historical data. And you've started a new journey with a neo-agent regime that's super active. The likelihood is in the future, you won't be needing to have this operation. Okay, but how about now? I got to make decision right now. And if you want that 80% event free survival at two years, this is what we did. We did the operation now. And then we gave you four or five more cycles afterwards. And then we gave you a year of Pembrolysmap. And I don't think we need to deviate from that. That's what I'd like to happen today. Now if you said to me, is there a trial where you could not have it? If you said to me, I'm not going to have it. No, I can have that discussion. But I'm not going to enter into this thing saying, we just spent 30 years trying to develop an effective regime. We've done it. We've done it completely off-piece and do something completely different. So I have to have a suspect to me. What if I. If you don't have a suspect to me and the cancer comes back and it all goes wrong. No, I understand. But I don't want to suspect to me. Let's say I don't want. Now I'm going to refuse. I don't want to suspect to me. What are my options? So I understand that. I absolutely refuse it. I was speaking to a urologist on the way here. I don't know if they're there in here in the audience who's done seven suspect to me on Neoage of an EVPembro patient. And six of the seven have had a pathosy on no cancer. And now he's saying, I'm not super comfortable just doing this for another 10 years of everyone not having cancer. So we're going to have to answer this question. Okay. We're going to have to answer this question. And in fact, there are trials answering this question. So we're going to do studies and there'll be quite a lot of them. They'll be investigated. They'll be company sponsored. They'll be EVPembro. Nine cycles with surgery in the middle. Tom, we have a real expert who's come to the might. Hail Vanderhaden. Yes. Hi, I'm Michiel von Heider. I'm a medical oncologist as well from Amsterdam. First, first of all, big fan of the show. It's great. And we didn't pay him to say that. So being is over. I got paid. Can I get some money for this? This is cool. We've got you a beer. So now I can just destroy the top. So, talk this. You know. And of course, you're going to say that you want to do trials and you know, you know, you feel obliged to say like, yes, you have to have the full regimen, full year and the surgery and everything. Everything, the whole shooting match. Look at Ryan's eye. I've been talking to this pretty smart guy. Looks pretty smart. He's a medical oncologist. He knows I'm going to have, you know, for the whole group already, a 60% chance of a PCR. Now, I have a T2 on a scan. Okay, you don't believe in scan. No, I don't believe in scan. I don't believe in scan. I have negative urinary tumor DNA. The chance that I have a PCR is really, really high. Can we do better than this? I mean, let's think a bit. So, Michele, what would you, the answer of the problem I've got with this is, and as she said it in the session earlier, is the immediate temptation is to go off-piece. That's the immediate temptation because we know best. And, you know, how many times are we done trials when we ask a question, which we think we definitely know the answer to, and we turn out, it doesn't work out that way. How many times have we done that? It happens to me all the time. And, I'm my concern around jumping into it, we just don't need to suspect to me anymore at this point, is that that's what we did. And, we don't do that. We don't know that, you know, we, I know you're, I suspect you're going to be right. And, I'm not just trying to tout that we should do the studies, but we should do studies, both single arm. I'd love to see if there's going to be a big single arm trial of 500 patients or somewhere around there, where you just get EV pen row. You don't have surgery. You maybe have surgery in the middle. And then you'll be, I don't know, because what's going to happen is this, I think these can happen. I think nobody's arguing against doing trials, right? Nobody's arguing that, oh, we shouldn't do the trial. So then, until we have that, let's do what we did on the test. So everybody has to undergo cystic disease. No, because you're right. Look at this surgeon, still I met earlier on, nice man. And you were both saying to me, Tom, the pressure is not to do that. There's almost a danger in us not being able to do the trials. Right. Because everyone's made their mind up and there's no way that people are going to opt to have anything about that. And the whole thing's going to become, we're not going to randomize, we're not going to have single arm data, we're going to make of that. And that just worries me a bit. We end up into Peter Albers in the room, Peter, you and I go back a long way. You will know in the past, we've done surgical trials where we thought we knew the answers to the questions beforehand. And therefore, we were never really able to do the studies. And it just ends up getting adopted. And then we go back in time and said, did we answer the questions robustly? I love how this topic worked. I'm not going to do it so much. That's my favorite part. Because you're so happy to go to the police. I'm all for the trials, I'm not arguing against it. But if I'm sitting in your office on Monday, right? And I'm refusing to stack to me, what are you doing with me? What are you doing? I'm giving you the full nine cycles of each day. Every day of the week. I've got you going, I mean, Mikhail, you would agree with that. So I mean, I was hoping to steer you already a bit of track earlier, but I just put it then a bit differently because the reality is in the trial, I mean, that they're a good job keeping everybody on track and getting surgery and actually getting half of the patient still at your own therapy. But in reality, a lot of patients are going to say, you know, you can talk to me whatever you want, I'm not going to have to suspect me. So what do you advise them in that situation? So I would have nine cycles of every week. I would not have radiation therapy. Why not? Well, what are you going to irradiate? This whole radiation thing I'm a bit confused by. Like, the bladder's there. There's no cancer, apparently. And you can't see it on the MRI scan. You're just going to, like, people say, we'll go for the bed that was there before, but this just feels like in the 21st century, the sort of the, the era of AI and all that, we're just going to give a random, we're just going to give radiation to the bladder generally and hope for the best. And there's no evidence of that. And of course, that worries me a bit, Brian, because that's worse. I can tell. But it doesn't, that's in the argument that I'm, but you agree with me. But you agree with me, right? You agree with the right therapy. But puzzle by, you're giving a cystectomy and not a nine months of therapy. And then, no, no, no, no, no, no, no, no, no. Nine cycles in all you've already had four. So that's five more cycles. It's a year of immune therapy. The majority of immune related side effects happen the first three or four cycles. The majority of the room, the adjuvant peer immune therapy is not associated with devastating toxicity. It's quite low incidence of that. We showed that in Niagara. And that five cycles, that further cycles of EV compared to having us a cystectomy, I think is a small price to pay. I think that's an attractive option. I am not happy around discussion saying, you know what, we've done all these experiments. We can just give three cycles and stop. That doesn't feel right to me. And we don't know enough about MRD. I accept, I accept the CTD data is really strong in this space. But we don't know how long you need to keep, how long EV Pembro you need to give. CTD dynamics are different according to different drugs. The CTD dynamics with EV Pembro, we've got no idea at the moment. So I'm not comfortable with that. I'm just saying we're going to be making clinical decisions in the absence of data for a while. Right? these other trials read out until we get data from 303 or 304, et cetera. We did a nice podcast with Macau on CT and UT DNA and remind me the data. I think patients who were double negative this from my agra, their past CRA was 75%. Yeah, and definitely that. In that range, only for urinary tumor DNA negative, the PCR was 72%. And then if you combine it to it, there's a few patients that have the CT DNA positive and urinary tumor DNA negative. So it's probably slightly higher in the double negative group. That's very technical. Pretty darn high. Yeah. So I'm just 100%. But Tom, I don't disagree with you actually that. For now, for patients who are going to take the advice and have the cysticomy, but in the argument is a bit peculiar that you say, I'm going to give a cysticomy and another whole set of therapy, but I think radiation is too much. It's not too much. I just don't think it's effective. I think once you go off piece like this, I just don't think there's any data to support radiation in this space. Once you've made the decision you're going off piece, then I think doing more of piece stuff doesn't really help. I don't think there's any evidence that radiation in a path to CRA after EV Pembro is helpful, particularly if you don't know what you're targeting. And so once you've gone off piece, it's like, okay, we won't do this, but we'll do something else bizarre. I don't think that solves the problem, you know. Do we have any radiation oncologists in our area? You too have super good to come up. Can I ask you a question? Shilpa Gupta from Cleveland Clinic, also a big fan of your show. So Tom, you said that if somebody has a clinical complete response, why do radiation? But you are pushing for radical cysticomy. Because it's a good response. They have a complete clinical response. But we have to use the data, like Brian said, we use extrapolate data. Now we don't envision doing an invigor oven one trial for every regimen out there. It will take five years and the field would have moved on. So why can't we extrapolate something that GEMSIS their value map or sorry, a TESOLISMAP showed or we've seen from GEMSIS their value map to EVPembro? So my concern around invigor 11 is that I think it has quite big implications for those cancers where we have inadequate biomarkers. I think in kidney cancer, by the time you have radiological disease, you've got a big problem on your hands. Advanced bladder cancer is a hard disease to treat. CTDNA allows us to treat the cancer earlier. A bit like PSA. By the time you've got measurable disease, soft tissue disease with prostate cancer, it's a real problem. Luckily, we've had PSA for a long time and we are happy incorporating that into our pathway. We will do the same with CTDNA. The problem with invigor 11 is it tells us when to start immunotherapy. The problem is, adjuvant immunotherapy is not the future. We're going perioperative immunotherapy. But why can't we apply the data from the Niagara CTDNA data to EVPembro? Because, well, two reasons. Dynamic changes with EVPembro are different from dynamic changes with platinum chemotherapy and immune checkpoint inhibition. We know the interaction between those two combinations are different. One appears additive, one appears antagonistic. So I'm not going into that number one. And number two is the CTDNA data from Niagara tells us two things. Number one is the most important thing is those patients that remain positive are in harm's way. And actually, if you're negative, you do super well. So why would you want to change a regime and you're doing super well on? Why would you want to stop the immunotherapy early if it's working? So my take on this is that's definitely give the year of immunotherapy, irrespective of the CZNRS. For those patients who were not clearing CTDNA, let's switch therapy around. Petros Grievous wants to do studies in that population. I think it's going to be hard to do because the numbers are relatively modest. But in the end, that's our focus with CTDNA. Being positive is bad. But Tom, what do you predict EVPembro would beat Gymsus in the metastatic setting it has? So even if the dynamics are different, what would we anticipate in terms of CTDNA? So the CTDNA analysis with EVPembro is going to show, so the first thing, and we have this, Jim. [LAUGHTER] A change. Jim. We have this discussion earlier on. You did your neoagement, the EPNivo prior to radiation and EPNivo prior to surgery trials. And I was saying to you that I thought CTDNA at baseline is by far the most useful indication of your risk group, not T stage. I think T stage at baseline and grade or baseline prognostications really poor. And in one of the trials in 905, the central radiology review showed 70% of patients had T3. And in the local review, it was only 30% had T3 disease. And so our T staging is rubbish. Pathology is not helping us very much. And actually, 65% of patients in Niagara with CTDNA positive. And it was 30% of patients in your radiation study. And your curves, I think, look really beautiful. But I just saying it's a lower risk population. I think it was 35% and 55% positive CTDNA at baseline. I'm just making some numbers. Yeah. So what was the point again? Your population is at lower risk. CTDNA baseline, positivity, even if known in retrospect, is really helpful because you know the risk when you start it. So when I was saying you don't know when you start, that doesn't mean no do it, because you do it in your positive and then you know, God, I've got a problem with my hand. If you're positive at baseline, definitely give the 9 cycles. I agree, by the way, if you're CTDNA negative at baseline, you're UTDNA negative at baseline, and you've got, they probably got low. Maybe you are a surgical patient under those circumstances. But you're still recommending surgery for those patients. I don't know the answer to that question. I'll look at what would you do in the scenario that I gave? So I think at this point, I wouldn't disagree that this is the full package. This is what we tested and this is what we should offer and advise. So the reality is that a lot of people, especially the people who read these studies and they look at their chances and they know that their chance of a path CR is super, super high. So we cannot ignore their wish to not have a system because I can fully understand their wish. And that's difficult because then we have to work outside of what we've tested in the trial. But I think we, if patients who are persistent and they wish we have to come up with something. And everything points in this case to a patient who has either a path CR, very, very high chance or limited local disease in such a patient who really refuses to see a second me, then I would say an ungradio-therapy would be a good option because we do see that patients who are on a wait and see, they do get local recurrences and they might sometimes get out of that. In the clinical CR patients, you're giving radiation therapy? Currently, when we cannot accurately predict a local. Are you giving the full-line cycles in the full year of EVP? Someone's confused. Well, that's then off label, so then you cannot give it any more, I think. So you would be stopping at that point? But that sounds awful. That sounds like a really bad outcome to me. You think so? Well, why didn't we do the randomized trials with four cycles in a row? Oh, after label would allow me to continue that? You would, though, if the label doesn't allow you. But advising your patient. If Brian came to me, if he was here right now, I would be upset if you went with him and said, "I'm still deciding who I want to do me." He's saying, "Have all cycles and radiation therapy. It's okay, it doesn't matter, mate." I'm saying, you definitely need the nine cycles and going off-piece and not getting the full treatment, that sounds like really bad. And by the way, you get one good go at bladder cancer. But can't only 50% patients go all nine cycles in the patient? So, Shubba, what would you do in this circumstance? How are you going to handle patients who get new adjuvant EVP, whatever CT urinary tumor DNA? I think we'll have a frank discussion with the informed patients. And if they refuse to stick to me? Yeah, we won't force them for cystic treatment because Tom, I think your philosophy is also that most people will be able to preserve their bladder in future, right? So, I think we have to use that data along with the tools like UTDNA, CTDNA, MRI imaging. And there's now endpoints published in JCO for how to accurately measure clinical complete response and monitor the patient closely. Would you give radiation to the bladder? After clinical complete response. Sure. So, I think right now radiation is still maybe radiation than doing nothing, yes, I would do because surveillance is not a problem. Would you bring some logic into this conversation, please? I feel obliged to have to defend the urology community. So, Brian, you've got a great case, he won't accept cystic treatment, but that's not the reality. Most people are shade to gray aren't they? And your reluctance to undergo a treatment depends upon what else you're offering them on that way. And I guess even in complete response, so in the population we understand pathological complete response, they still have a like a 10% recurrence and for metastatic rate down the line. And so, it's 90% survival, but it's not 100%. And in this case where you haven't done that treatment, albeit for the best intentions, when this comes back metastatic, what are you going to give that man and all that patient, how are you going to feel? Because you've got Tommy saying you have to have the trial treatment all the way through and then the natural temptations not been to do that, but just as ex our ex eventually will fail in some patients and then you'll be stuck with a very difficult situation. Yeah, agreed. I think patients will be trading off. Am I going to take my chances that I'm not going to have a bad outcome? What am I going to do then? How's it going to turn out? I don't know. But I think, I mean you tell me, don't have systemic discussions with patients. I think they're more worried about what's happening right now. Do I need this big operation right now? I don't think that patients are thinking, well, if I don't have it and I fail, and I'm not saying they shouldn't, but I don't think they think that way. So I think there's gonna be a lot of these conversations that are happening, like you said, the urologist you're in. I think there's gonna be a lot of these conversations happen. - I don't think the difficult conversations at that time, the difficult conversations in 18 months time when they come back to you when they have failed and you've missed a window and then it's difficult. We're gonna go that way. We need the evidence to prove it and you just need to know that extent and the difference in the changing management. But it's gonna be a difficult time for the next few years if we rush out stopping after EVP complete response. - Carla from Toronto. - Yeah, so I mean, fascinating show, fascinating discussion. - Carla, thanks for coming. - Thank you. So I think we do face this issue and we do a lot of bladder sparing at our center and I think I'm not currently comfortable with the data of doing nothing to the bladder. The retained data makes me very, very nervous. So in this situation, I would offer TMT and I would offer the additional cycles. I agree with your point completely that the systemic therapy that we've done, that you did on the trial has a benefit. And I think patients need to get that. I think we need to work to try to give them that agnostic that choice. And those are the trials we need, but right now if I have a patient who says I will not have a cystectomy, I'm not comfortable doing nothing to that bladder. - It's not the most well done bladder cancer. I agree with you. It's time for my question. - Yeah, I think we're gonna move to kidney cancer. - I have prepared a hand. - Right, Tom. - So Brian, I am a 53 wrong man. I have just had surgery for an intermediate risk cancer. - Okay. - You had an effect on me. - Yeah. - And I've got clear cell renal cancer. It's pure clear cell straight through. And the surgery's been successful, un-up and about. And I've come to you and I said, I just saw a presentation suggesting that Bell's Utefan with Pembrolysmab is my best option. I'm up for it. And let's assume that reimbursement will be a piece of cake. - Yeah. Tell me the pathology a little bit more. - It's grade three. - Or just tell me the risk of occurrence. - It's grade three. Okay, I'll go for it. It's a 40% risk of occurrence. - 40. Quite high risk. - On placebo, on no treatment. - On the placebo. - Yeah, by no more grams, it's 40% based on grade and whatever. Okay. And I'm the doc in this situation giving you advice. - Well, that's kind of what you do for living, isn't it? - Yeah. - Yeah. Listen, I mean, I think that the conversations I was having before ask a GU or like this, you know, I'd start out and talk about, here's how we estimate risk of occurrence. And I often go through with patients, you know, when they come from surgeons, they're often not really sure why they're in my office sometimes. They say, listen, you know, many surgeries are successful, but some aren't. And here are the features we use to estimate risk of occurrence. Grade and stage and whatnot, you know, I talk about like the Fox Chase Nomeogram, which we use. I also say that these tools to estimate risk are really poor. I think they're really poor tools. They're very crude. They're 20 to 25 years old. We do not have biologic tools either. - It's called a high grade chemo, that's because it is a high grade chemo. But it doesn't have to suck on the two features. - Yep. - Okay. 40% is sort of, you know, on the cutoff for me. I think if somebody's below that, I tend to lean away from adjuvant therapy. Right? And it's a benefit risk discussion, right? And so it's, you know, it's not right or wrong. - Okay. So, you're, I can see you breathing, Axel. (laughing) - Breathing in your neck. - So, in a 40% in a young man, is that pembrolismab currently? Let's just talk about pembrolismab. You're giving pembrolismab to those patients, surely. At 40% in be a discussion. I'm not necessarily pushing that patient. - Because those percentage benefits of OS for a 40 year old individual who's up for it, they are gonna be more, they're gonna be 7% more patients. - Yeah, listen if they're up for it, I'm gonna give it. - 7% more alive at five years. - Five percent? - Yep. - Well, in our slightly higher risk, population compared to the whole thing might be. - Now we're talking about subsets, okay? - No, I can't have a five. I'm gonna go five. I'll go five. But if 40% is higher than the control, okay? I'll go five. That's an overall survival benefit for a year of immune checkpoint inhibition. That's, is that not clear to you? - No, it's clear to me, I understand the data. I think really the philosophical discussion is because there's an OS benefit, does that mean you have to give it to every single patient who's eligible? - You don't have to, there'll be people who don't want it, but we, but, - No, no, but everybody who's eligible and wants it. - Jim's point, which is right, is in the end, as a doctor, you have a lot of influence. I'm not bought into the shared decision-making discussion. - Tom, Tom, why would you have a, - I thought a lot of thoughts. - If I sentence, I wanna come back to it, 'cause I know that'll go down really badly. - So if I understand you correctly, you would like to have it. - No one understands me correctly. - Pembro, Pembro, Pembro builds Zootifon based on the data that we presented. But why would you want to have an action therapy that currently has no OS benefit? - Well Pembro does. - Pembro does, but not Pembro builds Zootifon. - Okay. So the answer to that question is there. And we all need to do is go back in time. And we go back to Tony's original presentation, 564, Asco to you three or four years ago. And he showed very, very similar data. He showed a significant benefit in disease-free survival with Pembro, Lizamab, across poor subgroups of patients. He showed the curves, go apart, they stay apart. He showed us we did here, when we saw the curves that were going to show, and the tests, we survived an advantage, a PFS2 signal. And then we had immature OS, that original hazard ratio, and then guess what, that OS hazard ratio as it became more mature because it was statistically significant. - I would agree, but. - And there's a small minute we don't know. - But you don't get two goes at action therapy acts. You can't go back to that page, don't worry, what we'll do is come back in two years time and have the conversation. That's nice, fine, fine, fine. You come back two years later and say, you know what is now mature, so we're going to give you the action therapy now. - Because that's too late. - But you'd reasonably make a decision not to give it until there's mature OS. - Yeah, but you'd be wrong to say that there's not going to be OS at this point, and you'd be wrong to say that the indicators at the moment are the indicators at the moment are running parallel to what we did previously with 564. - Yeah, I'm not quite sure. - No, I don't think that's right. - The difference is like, the slide difference. - So first of all, I think the, at the moment, the curves go up at two years, that was the same as in key-node, I would agree. But I think the signal we saw there was a bit more pronounced and currently if you look at it, the bit more pronounced with 0.78, there's a numerical difference of 11 people who died. So 38, 49 could be anyway. - Accel, you're just adding-- - I know you were a scholar of history, we chat about history all the time. And you love the past, but yet you're not prepared here to look at the past and learn to the future. - But Tom, just because one trial followed a pattern. - Why is that, Tom? - Just because one trial followed a pattern, doesn't mean the next trial is going to follow the same pattern. That makes no sense. - Exactly. - Right. - But it could. - But it could. - But it could. - If the has a way, what? - It could, or it could not, right? We don't know. - But there was, what about PFS2 and these little bits and pieces? - Oh god, don't give me sorry, PFS2. So-- - I don't love PFS2 either. I've failed the PFS2. - But yet you still have been presented PFS2. - No, that's because that Brian, that is because PFS2 is a fair indicator of what might happen in the future. - You can sometimes work the pitch of his voice. - I didn't say PFS2 was important. I just said MFS and PFS2, give us the breast cancer doctors do this all the time. That gives you some, 'cause those OS curves at the moment at 96%, you can't, I agree. You can't tell that much from that. So we have to look at other indicators when we're making informed decisions and things like PFS2 and Potemma and MFS, the discussion is here. Eduardo, Eduardo, come up and give me a hand, please. - Give me a rest, yeah. (laughing) - Thanks, Tom, thanks for having me. - Eduardo, introduce yourself. I love your discussion. - Yeah, I'm Edward, I'm working in Belgium as a erologist, I'm not a medical oncologist. I discuss the light spark 22 trial, but I think I have to slide a little bit with you here, because I am a surgeon, not a medical oncologist, so I think we can heal people with surgery alone. But on the other hand, you know you have these patients that just ask 'cause like, I wanna do everything. Even though there might not be OS benefits, and this is something we have discussed, we all want the data. But if these indicators are here, there are a lot of patients that say, like, I wanna take the risk, I wanna do everything, I wanna have the added toxicity, I guess. If it's good to decrease the recurrences, so I would not be offered it to everybody, but still there will be some patient. That's absolutely what I wanna do everything. - And that's totally fine, right? If a patient comes in, says, I wanna do everything, I understand the risk, including the risk of death, right? In patients who may not have had recurrence, small but real. - Zero point. - If they wanna, that's okay. - Zero point. - Tom said he was up for it. - Zero point three percent. - That's not zero, right? - No, but your chance of dying a kidney can is four percent. - Right, but I'm saying those six patients who died in '02, too, could have never had recurrence, correct? - Absolutely. - Yeah, I'm not saying that. - All I'm saying is that if you were gonna have a form discussion with a patient, it's one of the problems. - You might die. - But the treatment related death is not, like it's, you know, the most dangerous thing about swimming in the sea in Sydney is not getting eaten by a shark, it's crossing the road to get there. But people are more worried about being eaten by a shark. So where you present these things, you said, oh yeah, there's a big chance of death and blah, blah, blah, blah, blah, and we had five patients die. So you ask me about a big chance of death. Those weren't the words I used. - Okay, fine, fine, fine. - And there were also three deaths in the Pembro Monotherapy arm. - For sure. - And there were zero deaths in the keynote, it's five, six, four trials. So obviously we don't want any people to die from treatment related toxicity, but it is extremely low. I think because it's a lot more patients in this trial. It's 1,800 patients. - I think it would. - I'd be very frail people, relatively. I don't know. I think, again, we're talking about benefit and risk here. The benefits are DFS now. Absolutely. May or may not be OS. You might think there is based on other indicators. I might be more reserved, but it doesn't really matter. I mean, it is what it is, but the data's the data now. And also, the risks are there now. They added toxicity of Belzu. And so you can have that discussion with the patient. Although, in your scenario, I have a 60% chance of already being cured by my surgeon. I'd like to also put it up here. I want to ask you as well. Is there any indication for single Asian pembrolismab, or does everyone get the combination of pembrolismab and Belzu turn? Those that wanted it-- if you've made the decision around risk and you've made the decision, the shared decision-- which I was a bit rude about a few minutes ago. Well, back a little bit. I apologize. That you're going to do something. Is it pembrol or is the combination? I think it could be pembrolmoneatherapy. I don't know. I've not had the discussion with the patient yet, but I think you could say, Doc, I want-- What? I want to do everything. Let me talk. But I want to do everything that extends my survival. OK. Well, then it's pembrolmone. Right? Edward Adwara says, Doc, I want to be as aggressive as possible. Give me everything I understand the risks. I'll light myself on fire, which some patients say. Then it could be the combo. But I don't think you can say it's all or nothing. I don't think that's right. You don't-- all or nothing. I think from our all. All-- Well, all or nothing. Well, I would just say, well, pembrol is the current standard of care, and the DFS is positive. But you don't have to be over-- Let me interrupt the overall-- The overall benefit. And therefore, I would say I would still advise patients to have pembrolism up for the time being. And we will have to discuss this in the guidelines. And I can't imagine, because we have precedent. So I can only speak on personal opinions, because we will have to discuss this in the guidelines. But you'll probably come up with a weak recommendation, because the OS signal isn't there yet. Or the signal is there, but it's not statistically significant. So that would mean for the community, if a patient wants it, you can give it. But I think the current standard with a strong recommendation is still pembrolmone. So that recommendations aren't that helpful for patients, because weak and strong, both the recommendations, you sit there as a patient. It's like, well, they're both recommended. What's the conversation that you have with a patient? So they come in this 53-year-old person, worry-round. Once they're up for therapy, they understand the risks associated with it, including their-- In action therapy, it has always been about overall survival as well. Since years, we are waiting for these signals. And that was also why keynote was such a bummer when it came in, because it had, for the first time, oval survival difference. Because otherwise, you are not looking at symptomatic progression. This is radiological progression. And just because people have a slight delay in progression or not, it makes a difference in the emotional status. But it may be just radiological window dressing. What's the conversation? You had a lot of toxicity to them as well. So let's just talk about the talks, if we like, because we haven't really focused on that. The toxicity of the immune checkpoint inhibition is relatively low, but potentially devastating. The adverse events with Bel Zootafan are potentially higher in its abroad. It's like the-- like, when you see the forest plot, it's more like chemotherapy drugs. It's fatigue. It's the things we measure. And we don't measure those tornado plots, don't measure immune to us. They don't remember the 1% cardiac toxin. So we've always got away with immune toxicity. And we're always brilliantly tolerated. Quality of life, no difference. We asked all the wrong questions. And the toxicity looks absolutely fine. But it doesn't talk about those 10% of patients that got life-changing to toxic. With this drug, it's awful. It's there for all to see. But that toxicity is probably easier to manage. It's fatigue. I don't know that it's easier to manage. It's fatigue. It's anemia. I'll agree with you. It's less devastating in that small subset, but I'm not sure it's easier to manage. You stop it. It goes away. And it's-- Yeah, but you can just stop it. Like you say to me, you're saying to me, look, I'm pushing you. Don't want to do that. I'm pushing you. Why are you starting in the first place? I'm pushing you. I'm pushing you. Look, bear with me. You're both-- both of you saying you're not sure you're giving it to everyone, although it has PFS. And so I'm saying to you, I'm a patient. Why don't we just start it and see what happens? What's the downside? You could do that. OK. Excellent. But you don't have to do it. I think that's the difference. I don't think it's mandatory. I think, again, if a patient said, doc, I understand the risks. I understand the benefits. Then sure, I mean, that's what's called shared decision making time. We'll talk about it after this. Yes, but we do need a lecture on that. Maybe, maybe silver, since then more-- Yeah, so I have a question. I was curious in the light spark trial, the M1 and EDS. Why was the time period 12 months? If they have such indolent, metastatic disease, and if it's resected, you're a-- It was 24 months in a week's year. So why? So why, in a patient who had 24 months ago, why would we give something a doublet? I mean, actually-- What is the rationale? You think it's too long. Yeah. So I have two different ways of looking at this. So if you look at-- So I think you also published on this, the Lurven-Udina score. So having a metastasis of recurrence in the first years, actually a prognostically unfavorable factor. And very often, before we had keynotes, I think in our surgical MDTs, if you do an effect to me and the lymph node pops up three months after surgery, our normal reaction would be to just observe it for another three months to see whether hell breaks loose. And if this doesn't happen, then you could probably go for local treatment. So I think when we did the same in emotion, O10, we were looking at metastasis longer than a year. Remember that. And that led to different results. But maybe it was also a different drug. So I think I don't know whether these early metastatic patients are actually the ones that should receive action therapy because they are probably already the rapid progressors. I think it drives the event range in the trial. I think it's a really complicated area. And I think the resected M1-NEDs are extremely heterogeneous group, right? And time to recurrence is one factor, but it's not the only factor, right? Site, you resectability, number of meds, organ. I mean, there's all these things. And so it's a widely heterogeneous group. So I think it's hard to make broad statements. I don't give Agiment Pembroder to resected M-E-D. M1-NED because it's-- I think it's under treatment. Right? It's such a high risk of recurrence at all my way. We mentioned A-W-A-A-A-T. We're going to have to-- They have such a high risk of recurrence. If it was me, I'd rather wait. And if I recur, give me double apply. I think the M1-NED population is a distraction from the main part of the trial, in my opinion. I agree. And it's, of course, 5% of the trial, 9% of the notes are two of my numbers. I don't think it's particularly helpful. And I'm keen it doesn't become-- I don't think it should be a major distraction when we discuss with patients. And I'm not pursuing that. And if people do want to do that, that's up to them. That's not the main part of what we're trying to do. Brian, by the way, if someone says talk about something else, please come to the line. I want more questions. Just a question. You're going to be intensifying the adjuvant treatment with bazoo defense. And what happens in the front line upcoming triplet trials will bazoo defense? Is the approach to do the kitchen sink in the adjuvant setting and then think later about what to do in the front line? I would love to hear where the field is headed. It's a good question. I mean, again, I'm not quite to the kitchen sink in the adjuvant setting yet. But I generally make treatment decisions with the patient in front of me. So I wouldn't necessarily not give the treatment because I'm worried about front line. I might not give it for other reasons, but I wouldn't for that reason. What Chilpo is referring to is 012, which is triple study with bazoo. And if that's positive, will there be re-treatment of patients who got adjuvant pembro, bazoo? I think yes. I think it's very different than immune therapy. I'm not a retreater with immune therapy, because there's not a bit of evidence that it's helpful. But I think targeted therapy is different. And we'll get into discussions about it. Is it six months or 12 months and all that? I think those are more rational discussions with the targeted therapy, with immune therapy. I don't think so. Brian, so this individual has agreed to start the combination. Handsome 53-year-old individual. And he's becoming anemic, and he's nine months in. Are you giving him a whistle of wheat in or are you stopping therapy? Or are you giving a blood transfusion? Him and Logan started at 12.5. Is now 9.8.6? I don't want to blood transfusion. I don't give-- I haven't given a blood transfusion for a hip inhibitor anemia in a really long time. And I've given a lot of them. I think if you use a lot of Ipo, ESA's or through it's stimulating agents early and often. So in this patient, I might have a little bit of a discussion and say, listen, we don't know that 12 months is magical. It happens to be one calendar year, which is why I was using the trial totally reasonable. But ESA is, to me, they're just so easy. They're not hard to do. I've not-- You worry it might make the cancer graph fast? No. No. Not a lot. Why you didn't know why? But chapter of my PhD was-- my MD was on that. Why? You obviously know red eggs. I mean, I don't think there's any evidence of it. I think that data is old, and that's when we were pushing patients to hemoglobin, so 14.15. I don't think there's any evidence of it in RCC. And I'm not pushing-- basically, if they're below 10, 9, I think it was 8.5. In your example, I'd start it once they get above 10, I'm holding it. And for this patient, they're going to-- to end up with two or three Epo shots, right? But if they also said, hey, Doc, yeah, I'm not really into these shots. I want to stop at nine months. I'd probably say fine. So I don't think I'd push them either way, but I'd be happy to use ESAs in that setting. Obviously, I haven't come across it. And what about how in the adjuvant studies, we are keener with being keener, and we can see this from the data, to not push therapy. So the proportion of patients who discontinue therapy is higher in the adjuvant setting than it is in the metastatic setting. What, how much toxicity are you prepared to go through with Belzutifan before you stop it? I mean, not a ton. I think I have a pretty low threshold to stop adjuvant therapy for talks, because obviously I don't know if that patient's going to recur. And I also don't know if that individual patient's benefiting, right? I only know if they didn't benefit if they progressed through it. So historically, with Pembro, Mono, I'm talking about, I get some creatinine bumps after two or three doses. And I'm like, I don't know if I'm the brightest. I get nervous and I stop. So I have a pretty low threshold. If you're asking about the Belzut component, I guess I'd be maybe more likely to push that, but honestly, I haven't thought through it. If we can switch gears just really briefly, and I know we haven't got much time, and please do if you have one burning question, we're up for it. But we did agree, or we didn't agree. But I thought we should talk about the light-spark data with the combination of an envatinib and Belzutifan, versus Cabo. That's a study which is in pre-treated patients that have had prior immune therapy. They're getting the standard of care, which is a Cabo's adenib, which we always felt has been super hard to beat. And then you've got L'Envatinib and Belzutifan. Of the two trials of the adjuvant trial and the metastatic study, which do you think are more impactful, and how would you score both trials out of 10? In terms of your-- I think, yes. I think 011 in the refractory is certainly more immediately impactful if you're talking about how many people I think will adopt it on day one, so to speak. Who are you going to give it to? Who am I going to give it to? Well, I give a lot of L'Envatinib and the front line. I wouldn't change that. So for me, personally, it wouldn't be many. But you just said it's going to be really impactful, but you're not giving it to anyone. Well, are you talking about it in my practice or broadly? Broadly, I think it'll be more impactful. For me, personally, it won't, because I give L'Envatinib. Me, too. Right. So there's not a lot of people who don't give L'Envatinib. But you wouldn't switch away from L'Envatinib. I'd give this. No. I wouldn't change my front line therapy. But you did Axi Pembro originally. Why not go back to what we started with? You remember that? Has it ratio 0.530S? Remember that day? I do remember. I do remember. Why not Axi Pembro first? Then, like-- I mean, you could. I'm not saying that's wrong, but I personally won't change my front line just so that I can give this second line. Where, again, we have PFS without OS yet. IPNivo post IPNivo. Would you treat-- Sure. Great regimen. But again, these are non-curative regimens, right? So now we're having a very different discussion than the adjuvant setting. So why is the regimen-- These are all non-curative? So you've just said it's more impactful than the adjuvant study, which I disagree with, by the way. And, but you're saying, number one, it's not curative. And number two, is you're not going to use it? I'm sorry. I'm very impactful to talk to them. My definition of impactful is that I think on day one, if both these regimens were approved tomorrow, I think more people use L'Envall in the refractory setting. A higher percentage of practitioners, forgetting about the number of eligible patients, there's probably more adjuvant patients, right? So that's all right. That's my definition of impactful. To my-- I'm my impact is slightly different. I see earlier disease. I think Belzutifan is probably a better drug giving a bit earlier. I agree. And under those circumstances-- and I think having positive trials in the adjuvant setting for DFS means more than in the metastatic setting, which we've have quite a few of before, including, for example, your access in the psoraphynip trial. I didn't want to bring that up, but I feel I needed to. So under those circumstances, I feel the adjuvant space is much more impactful than the second-line metastatic, which is palliative, and you can sequence the drugs there anyway. Yeah, I don't-- I don't just-- I think it's more potentially impactful. It depends how you define it. I was sort of using impactful more. And like, do I think people are going to use it on day one? OK. Like, is it going to impact practice? Now, I agree. The adjuvant's obviously a bigger space, more long-term outcome. So I don't disagree with you. Axel, could I ask you a last question? There's going to be a guidelines meeting for the EU guidelines. We're going to discuss these. Just discuss how you think the European-- you've got no idea. We've not met yet. We don't know what it's going to show. You chair. You don't think you even voted, I can't remember. So just tell me how you think the decision-making about these two pivotal trials-- the adjuvant trial and the immune refractory, the second-line or third-line trial. What conversation is going to happen? Neither have our West, both have DFS, both have positive signals, both have a toxicity signal. What are the two conversations in a take place? And what do you think-- where do you think this ends? You mean within the guideline. How do you feel that-- yeah, I mean, obviously, we have that in yet, so it's easy. But you can predict what you might have. So what we always did is when we look at the trials, we always look at the primary endpoints. We also look at-- we don't call it grade anymore. We look at the forest plot, the exploratory analysis and then look at the harm-spanifit ratio and then come up with a kind of recommendation. So without being too prophetic, I could imagine that we will very likely-- so we will discuss it in, I think, next week. And then if we reach consensus, then I could imagine that we take the precedent as we did with Keynote before we had overall survival. And we would say exactly what your argument was. Maybe in two years' time, it becomes positive, so we don't want to create an opportunity that patients don't get it. But for lights bar, 11, I think-- This is the second line, third line, medistatic study. Yeah, exactly. Because at the edge of the trial, you think it's going to go in the same direction, at five, six, six, six, seven. Why would we recommend-- And you'll still continue the strong recommendation for Pembro's-- personal opinion for those ones who listen. It's not guideline recommendation yet. But it's about what-- It might not be, because people might disagree with you. This is your take on it. Yeah. And just tell me what you think might-- what your take on the second line medistatic, third line medistatic, L'Empatinib, Bell's-- So obviously, I'm not a medical oncologist. I think L'Empatinib and Bell's would to fund, they have the toxicities and all that. But you know how they can-- You know how we discuss it. So yeah, obviously-- so I think Kabozzanternib is a powerful drug. The fact that it has been beaten in DFS, in DFS is important in those later lines. I can push you on that. So we're going to finish it. I'm sorry. But I'm going to push you on that. So I think it will be a big funded as well. Well, well, well. We have not been keen on DFS and advanced disease. We've always gone with OS recently, haven't we? With the exception was Bell's utafan heavily pre-treated. The original targeted therapy trials, the seditionative trials and the existing trials, the targeted-- But we never gave a volume up. But we never gave a good ol' five. It was also PFS, or another S. And that was compared to the weakest kid on the block, over the lineness, after a couple of lines. So here we have a trial that is a real classical sequencing trial. So I think 67% of the patients were being included after having received one line of treatment. So I think this is the classic situation. And then you demonstrate that you have a DFS benefit. And I think as someone put it, if you have a good drug in this situation, better go for DFS. And I'm confident that with time in the OS signal might occur. But it's also very difficult in these lines, because a lot of people get other drugs afterwards. So it might be diluted. Well, I think the DFS benefit is quite compelling. Axel, are we good? Can we come up? Yeah. Axel, thank you. Jim, Mikhail, Eduardo, Shilpa, Carla. Thank you very much indeed. Thanks for joining us. I hope you enjoy the rest of the meeting. Thank you.