Episode 509: ASCO 2026 Review

[MUSIC] >> Welcome everybody to the Urami Go's host ASCO podcast. >> I mean, Tom and Eric, you're awesome. >> So, Kigelasin, Tom's interrupting my introduction four seconds in. >> [LAUGH] >> And we're going to recap some of the big ASCO data, some of which we talked about either in separate podcast or our preview podcast, but now with having seen the data, having a little bit of time to digest, also mentioning some other nuggets in there in ASCO that maybe we missed on our preview. So, Tom, I'm going to turn it over to you first. Welcome to the show, we're glad to have you introduce yourself to the audience. >> My name is Tom Pals, I'm a medical oncologist and I like interrupting you. >> And then, so let's talk about bladder cancer. >> Though, I scored bladder, I think, I don't remember, but I think I only scored it a five out of ten. >> I think it was a five, yeah, you went five and a half or something. >> Yeah, and I have to say, I actually really enjoyed it and I learned a lot. And I felt like invigorated a bit about direction. So, I'll tell you what I thought about it, a couple of things to start with. I'm going to try and pull it into themes, if I may. So, I'm going to start with an ADC theme. Me and Johan Lorio, Shulpa Gupta, we made a really nice video by the lake. After the mini oral session, but unfortunately the sound was rubbish, Brian, because I was in charge, and so it was just a disaster. But they said really important stuff. And so I'm going to try and repeat what they said. So essentially, this is what happened at the meeting. We had a series of ADC data, alone or in combination with PD1. We had a series of drugs, particularly, Topo-1 payload drugs, combined with Nectin-4 target. And famously, there were two lily drugs, LI-405 and LI-410. They both had about 100 patients, it was less, about 75. One had a 42% response rate, one had a 20% response rate. And they seemed somewhat identical. But you might remember from before, when we went to China, they were telling us that actually the detail of the metabolism of the payloads in poor. And here, we learned that was important, because in LI-405, the one with a higher response rate, which is metabolized by SIP2D6, if there was absence of that enzyme, SIP2D6, the patients were unable to metabolize the drug. There was loads of toxicity, and indeed there were some toxic deaths. So that's beginning to tell us that the metabolism is incredibly important in determining toxicity. And don't you think that's true for all payloads? Because I don't remember that story with a lot of the other EDCs, at least yet. I think it's particularly, because I think the Topo 1 payload metabolism is more complex than MMA. So I think it's true for that payload. So we've been talking a lot about linkomolecules and the importance of the linkomolecules. And you might remember previously we talked about the difference between SAC-TNT and SG and the linkomolecules being different, and that might be why they're different. And here, there is some truth there that the linkomolecules may have a role to play, but also metabolism of the payload is really important in determining outcome. So we learned, I think we learned a lot from there. And then we also had a drug called SHRA-A2102, which was the Chinese netting for topoisomerase drug. I'm impressed you're getting all the letters and numbers, right? Although I don't know if it's accurate, but. Well, there is a degree of autistic impression in this product, as always. But confidence is extremely important in life. But this was a third drug, and this was combined with a PD-1 inhibitor, and we sowed here path CR-8s of about 50% in 25 patients. Now that's not as high, it's 50%, it's not robust, and there are problems with it, of course. It's not a randomized trial. But we're beginning to see that these other class of drugs, this newer class, netting for topoisomerase, has really nice activity, and I think that was new. So I enjoyed that part, and then there were some more drugs, which I thought were controversial, and Johan Lorio, in this brilliant video that no one's ever going to see sadly, Johan then came forward, and he talked about two drugs, combination, very similar to EV Pembro, me too, like approaches, that's next in four MMA PD-1, in frontline metastatic disease. And our friend Jun-Go from China, he presented Boulot Thou Mervotin, which is a really difficult one to pronounce, and they showed 82% response rates in a relatively small cohort of patients. Now again, is it better or worse than EV Pembro? I don't know. But essentially it's saying the Me Too approach kind of is working. And then Johan Lorio showed Zeli Peeva-Doutin, a class Pembrolyzomab, and that you might remember is a different mechanism at action. It's the small peptide, but again, MMA with netting for, and they showed response rates of about 55% or two doses, one was 51%. But I'm giving them 55 benefit the doubt there. Both of these, I think the question that one could ask is, where do you take these forward now? Because you can you do a randomized trial against platinum chemotherapy? I think platinum chemotherapy, you can't do that study now. I think that Port Colis is closed, and the drawbridge is up, in my opinion. The UK, France, Germany, Italy, Spain, United States, Canada, Switzerland, Austria, Denmark, Japan, all have access. I don't think you can run a-- So what do you do then? Do you do it in a refractory setting? Well, again, it's not a new problem in oncology drug development, right? It's not a new problem, but you have great combinations. And there is a plan, so I asked a question. I never asked questions in meetings, because I'm soon embarrassed. But I did ask a question. And I asked June what was going to happen next, and Johan. And June said, look, we're doing a randomized phase three in China. We can do it against platinum chemotherapy. And the ins and outs of that in China, you know, that's-- I don't-- you know, I am on the impression that the DV Torrey-Pyman is the standard care, and they've shown that. So-- but they-- I'm told they're going to do that. But the Johan study was a phase two, phase three. And the initial-- you know, the optimist program, you try and get the right dose. And then once you've got the right dose, you've got to randomize phase three. The challenge with that, when drug development, and you're under huge pressure to get it done in the knowledge that you one might not be able to recruit, sometimes, you might have to leave that optimist program behind. Because it takes a year and a half to recruit the patients, get the study, look at the response rates, get all the maturity. And only then can you make a decision. And so Johan's answer was, we're waiting for more mature data. I don't think more mature data is going to help. Because, you know, what would you-- what would you do? You-- with more mature data, with a 55% response rate. Are you going to go against EV Pembro? I don't-- I don't think so. So I think this is a great example of, in my opinion, of the balance. If you're not first in an area, and you're not best, you need to go very quickly. Because I don't think non-inferiorality studies are going to work here. So I thought that whole new ADC discussion, I was-- it's right up my street, to be honest, Brian. But there was some other data which I did quite like. I quite liked the perioperative space and the quality of life data. And you and I, we did a podcast with Peter and Beth on that. And if you want to listen to that podcast, you could do essentially what we said, which I think is probably-- I think this is true. We keep doing studies showing no difference between active drugs with significant side effects and essentially no drug. The ambassador study, Pembro versus placebo, perhaps some small difference in long-term fatigue, but no real difference. Ram parts, again, investigate initiated, Duvalumab versus Pempers, but no control on, but no active therapy, no statistically significant difference. We saw the 303 data Peter talked about this. Nine cycle of EVPembro, no significant difference. I think the drugs are amazing. We're curing cancer and it's brilliant. But the drugs do have some long-term challenges and Beth described that quite nicely in her poster. We saw an update of EV302. And we haven't-- we talked a little bit about that in one of our podcast with Gopa, who really nicely presented that. L-Y-40, that Topo1, netting four data. But 302 update, I think we're beginning to-- I think the three and a half year follow-up. CR rates of 30%. Those patients, 85% alive, three years, were probably curing some bladder cancer patients with advanced disease. Quite a lot of bladder cancer patients with advanced disease. And I think that was-- and we showed maturation of response. And we showed the OS has a ratio still 0.53 at this three and a half year landmark. The curves are not coming together. And then there was some provocative data from the SAKK, which I'm still here because you can represent them. If I'm going to be slightly-- I'm going to be slightly closer. last half empty if I may, I thought mentioned by the way, not Brian, I've been pretty positive. I've been pretty positive today, I've been pretty positive today actually. I've taken the tablets. So, one of the time, Tom, you're quite positive. So yes, they're not a small twine. It was a small study. And we've done quite a, of course, I'm just going to describe it. So essentially, it's neo-aggiment gem sisterver plus BCG at the same time. And the hypothesis is that by giving local BCG, you may stimulate core increase and immune stimulant, increase your local and even your systemic response rate. And indeed, the data was really good with pathosirates. And I got this wrong. I thought it was 80 to start with. So you corrected me downwards to 68%. But still a pathosirate of 68%. That's higher than we've seen in EV3 or 3 and 3 or 4. Look, there are different ways of calculating pathosirate. And it depends on, you know, do you include all the patients with just those at surgery? Number one, number two is pathosirate is determined by how your patient population, if you have lots of early two disease and you do really good to your BTs, you're going to have better pathosirate. You know, we know in the control arm of 303, which was had sistectomy alone, the pathosirate was about 10%. So you can imagine that could go up if you recruit better risk patients. And when you look to the landmark analysis of this, these patients very few of them relapse. So I think this is a good phenotype patient. And I suspect the results are slightly better than you would expect, because it's a single arm trial. And there are studies like keynote 992 and Brian Yush, I think you and I chatted about this before, which is doing that's a radiotherapy trial of GMC trial, terrible chemoradiation versus that with Pembro. And, you know, I think that's an important study in this space, because we keep seeing these single arm trials with fantastic results. Do I think BCG is with immune checkpoint inhibition is synergistic? I don't, because otherwise we would have seen perhaps more dramatic results in album, which was exactly that. BCG plus the Tesla's Mab has ratio 1.0 in high-risk non-muscle and basic bladder cancer. And so if it's not doing anything in album in local disease, that study should have been wildly positive if Richard's hypothesis that the two are interested together in BCG, right? It wasn't it a different BCG than that. It was a recombinant. Yeah. It was a recombinant BCG, but I don't know how much difference that is. I don't know either, but it's not exactly the same. I guess that was my point. Okay, so I didn't mean to rush your novel there. You did burst it a little bit, bro, actually. You'll be pleased to know. I've not lost my train of thought. And Gary Steinberg came and he came to the microphone and said, you know, the urologist in the community came up and said, look, we've done these experiments. They've not worked before and they've done a single arm trial. It might be patient selection. We're not sure what's going on. Is it too good to be true? And I think, you know, Richard came back and said, actually, the hypothesis is pretty strong. Silky, what do you, other Swiss team in the World Cup, by the way? I bet they are, aren't they? Yeah, they are. Yeah, of course they are. Not of course. I mean, we are a very small country. It's a super nice surprise. Yeah, tell us. So, well, I think you did quite well in the last world, the last European championship, didn't you? Yeah, I think following the Swiss team with some interest. Oh, you have also a T-shirt. Yeah, you know the Swiss T-shirt. Yeah, I've got the T-shirt. So, what's your take on this and what's the word on the street in Switzerland? In Basel, word on the street in Basel. So, I mean, I have to say, of course, like, we are quite happy that a Swiss study made it into an oral. So, that's not something that happens a lot. I, you know, in the end, I like the concept. I think the study is interesting. And, you know, you never know what is really behind it. And the data is the data, but I agree with you that if you need a randomized trial to really say this concept is working, I can understand that someone is a bit critical. I, you know, I don't know, I can't remember, like, long time ago, there was this hypothesis that the BCG is working better in patients who are vaccinated, you know, like, long time ago. And in the States, very few people are vaccinated whereas in Europe, a lot of people are vaccinated. We're not having an anti-vaxxer discussion, are we? No, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no, no. I mean, I think about years, like, like, a lot of years ago, I don't know how it, how it is in the UK. But, I mean, in, we're not for vaccine. A lot of people are vaccinated against tuberculosis whereas I think Brian, if I understand correctly, that is not the case in the States. And there was the concept that may be BCG also in the localest setting, may work better in people who have been in the use vaccinated. But I don't, I mean, I'm not an expert in that. So, you have to, you have to tell me to or if that's true. So my take on, my take on this is, is for what it's worth is it is interesting that we're now in mustn't raise a disease, exploring local therapy. And the reason why I think this may be relevant is because if we are pursuing bladder sparing approaches in the future, which we are, it is possible that we need to address local relapse. If you give BCD induction and maintenance, and you have maintenance therapy after BCG initially, if you're giving Evie Pembro, and you're inducing a CR on the new stop therapy, should we be doing something to protect bladder? And I thought for me, that was one of the things which I thought, oh, okay, this is quite interesting. Whether it's white or not, I just kind of, it woke me up a little bit, you know? I think it points out that if, if we're not going to be cutting out everyone's bladder, that this, it's some sort of interversical therapy, whether it's this agent or something else, is probably going to be part of that bladder directed component. You know, and we can talk about chemo RT, but I think there's going to evolve an interversical treatment to, I don't want to say replace this tech to me. But in those patients who choose not to go or can't go, we're going to need to do something to the bladder. I don't think we can just leave it. Now, Brian, before we go, I've just got, I've got to say two things if I may. Number one, Potomac got FDA approved. That's your value map with BCG, got FDA approved. And just before the meeting, Maria DeSantis stood up, gave the presentation with the updated five year data. I don't think there's very much new in the data set in the data at the AUA. a decreased systemic rate, but actually, I think the conclusion from my perspective is in both arms, the systemic rate was actually pretty low, not many systemic rates in either arm. And you know, that balance, and I think that someone in the audience, and I thought the audience question, oh, I thought it was pretty, I thought someone came up and said, look who you're going to give it to? Maria said, look it's a shared decision making decision, which point I looked for you, looked for you, because you know, we're not fans of shared decision making. And so, you know, who all are you going to give the drug to? And I think that, you know, there may be, she said that someone who's not, who said, I'm definitely not having a cystectomy, I'm young, fitting well under any circumstances, I want everything I can to prevent having that cystectomy, and you need to give me the treatment that induces it. I think it's going to be interesting to see how much use it actually gets. Right? Yeah, I agree. And then especially when these patients come through urologists. Yeah, go ahead. Yeah, and also Tom, I asked you once, and you even you were not so very sure which patients you will treat that way. And then I guess when you say, even me, you're suggesting that I'm trying to give it or is it what I don't, you know, you're very sure about what you want to do. Yes. All right, so we're going to jump to prostate highlight of the meeting, plenary session. So, and we talked a little bit about this in the preview that talked to us about. I think Brian, if it's a prostate, Silky should say what the highlight of the meeting is. No, I was just going to agree with that Silky. Talk to us about the highlights. I'm fantastic. Silky, could I ask you a question? Yes, of course. Do you think for you, the telepro 3, which was the part data or the proteas data was more impactful, was a better more, which was for you. I know one was chosen as a plenary, because I think some people, including myself, when you get a plenary, you know, you think, oh, that must be the bad. But I, what did you think? What did you think? You know, I think the telepro 3 is kind of a me too, because amplitude is out. But it's better than altitude, isn't it? Did you think it was better data? Yeah, it's a bit better, but the whole population is not better. So it's not novel for you. I think we discussed it, and also it's not a very clean control arm, because a lot of these patients should have had, in my opinion, dorset axel, and they didn't get it. It's not a super clean study. It's not like amplitude. This amplitude was much cleaner, in my opinion. So I don't think telepro 3 should have made it to the plenary, if anything, but again, I'm super biased. I would have put reduce in the plenary. Okay, so before we get to reduce, why don't we go through the proteus in the telepro 3? You've talked a little bit about Talipro3, which is, I think it was for me, I was quite impressed with the data in the non-bracker HRRP. Yeah, I agree. I agree with that. Do you think that's just the vagaries of trial design or is it a different PARP inhibitor and therefore the ATM patients are benefiting, etc? Yes, so the ATM patients, or the patients with ATM alterations were not even allowed in our amplitude because they we hadn't shown a lot of effect in these patients in the MCRPC setting, if you remember. So, so I mean for me now it's quite unclear what to do with these patients with ATM that have in the subcube analysis seem to profit from the combination and so I think it's quite interesting. This would be the most robust data for those ATM patients, right? I mean if it's I guess because amplitude doesn't even include them, right? So there will be, I mean I hope that FDA is again doing like a summary of all these like where subgroups and then you know we will have maybe some combined data but and you know there was also the the small trial to trial CC first from Dr. Mokeo there are some patients or maybe you know we I don't know if they had ATM patients there because they were unselected but I hope we will have some more data that we can then combine and understand what's happening. So Silke you get a see you're seeing a patient in clinic previously untreated HRR non-brecker, high risk disease, high volume disease, what are you giving him? So non that site non-brocker, HRR, yeah, I voted, you say HRR all voted, yeah it depends which alteration, right? So this is this is the discussion we we had, right? So you wouldn't say you wouldn't go with the trial wouldn't you? Maybe not in all of the subgroups I would go for for sure for bad B2 because I think that that is one thing that has shown quite consistently that there is some effect then there is yet now again in talapro to the the CDK 12 alterated patients seem to have an effect the check two alterated patients if I recall remember well were like benefiting in both in amplitude and in talapro so for me it would make a bit of a difference which kind I'm not sure it's ATM now you would you would look at cross trials then you wouldn't just look in talapro three you'd say what's the totality of the data for mutation xy or z? Depending on what I want to give if I want to give the you know like it's just subgroup analysis and the groups are quite small and so it's probably the best for ever going to have right? yes exactly that's absolutely right I mean we can hopefully we can combine the data that we have but I will be much more prone to give that combination the answer talap combination to patients with non-broker age or alterations then the other neuropray abiratsion combination to be honest just because that there like the as you remember the the hazard ratio for our pfs was 0.8 in the non-broker mutate patients and it was much better for got exactly what it was but much better now in in this trial so so I think we have some hints to do it just the big surprise for me came with the ATM I don't know if these were all biallelic alterations I it's I think to me in the moment unclear should we should we move on to proteus yeah of course there was some criticism of the control arm of that and there was a lot of discussion around that and there was also some criticism around the switching to the endpoint to include pet rather than just radiology um there was what was your take on and of course there was also a discussion about the hazard ratio of 0.8 overall although it's statistically positive in this early setting not being that meaningful do you think that criticism is fair well yeah it's of course true right so ADT is is not a standard of care then you know but what Declan said okay but it probably doesn't harm um that that may be very true but but also you waiting for about six months for the the operation right so you could argue maybe that's not the best for all for all patients with high risk disease um yes and the other point is clearly the the MFS I mean we have shown the surrogacy with Chris Greenley um ice cap for conventional MFS with always not with that now mixed PSMA pet plus conventional I think that is is probably concern you know my bigger concern is that we probably over treat a lot a lot of patients with with giving them you know that much systemic therapy and I I didn't see until now that they were maybe looking who were the real the patients who really had the most benefit so we we probably now but I mean that's a problem with all our during the perioperative probably Benjamin right we treating a lot of patients for because you know they needed 2000 patients to show the difference we are now going in the you know in the setting of breast cancer trials that has never happened before in localized prostate cancer yeah so 2000 patients to show you a difference right so of course the smaller difference we can see a smaller difference maybe Enserrat would have been positive if we would have had 2000 patients we don't know but I still think we're gonna over treat a lot of these patients because a lot of these patients could have probably been treated with the surgery alone even and then what we sometimes forget is you know it's not not like in kidney cancer and blood cancer probably if you have if you have a relapse it's difficult to cure whereas in prostate cancer if because we have PSA and we can then give early salvage radio therapy you can still cure a lot of these patients so maybe you know it's a different setting and there you know I'm more kind of in you know have the impression that in the moment we would over treat a lot of patients when we give these treatments to all and you also I don't know if you heard it and there I couldn't really find that in the paper yet they said they started to do the cardio vascular exams so I guess you know they realized that maybe some patients would not profit so much from the ADT or heart would have a lot of side effects so I think that's quite interesting to look at as well what do you think what do you think the adoption will be is this something where surgeons will say great we want to operate on these people and now we have level and evidence to add systemic therapy you know is that a motivation motivation for surgeons to do more surgery or obviously radiation hormones is the other option for these patients yeah it was interesting right that in the chemotherapy discussion in the algorithm they made us have it didn't show up any longer and yeah I would say it's still you know you have two options and you should discuss them both yeah I don't know I think you know we have a very nice kind of tumor board where we can thus discuss all these things so I think it's an option more because sometimes I have seen patients who say I don't want regular therapy I want this cancer out I think it exists and then behalf for the the very high risk patients now an option to give a systemic intensified systemic therapy with it what I think is a good thing I have to say that a lot of urologists always kind of like argued that the good thing about the surgery is that you don't have to give this terrible ADT and now you know you giving the ADT so I'm I'm wondering what's going to happen to be honest yeah I think it's going to be interesting the only thing you know the only thing that I really I think we have to be aware that apelutamide and ADT have some side effect sure and some of it is really cardiovascular and I hope that everyone is then really going to do this cardiovascular exam that they obviously did so I'm literally on the edge of my seat around on this practice check. study that you talked about, the third one, the dark horse in this particular race, what was the study that you talked about that you said were for you as the most practice changing? Okay, so again, as I said, very biased is also Swiss study. This is outrageous. And then also it was sometimes about his studies all the time. I banged over 25 minutes about everything else. Yeah, that's true, but it was hard. I admit it. And then, you know, so, okay, yeah, and that's Swiss study. Tell me about this Swiss study. An old triad, let me, let me finish. So probably a lot of people didn't see it because it was in the oral abstract for best cancer, because it was a trial with more than 1400 patients and a bit more than half of them had metastatic breast cancer in the other were patients with MCO, PC and bone metastasis. And the idea was to test the know-zoomop every 12 weeks instead of the know-zoomop every four weeks in the indication for reduction of incidence of symptomatic cancer events. What's the benefit of know-zoomab and prostate cancer in this setting? Because it's a bit of a, give me a quick two minutes inopsis on the role of of this phosphonate here because there are different doses and some doses of treatment doses and some doses of prevention doses. And so what's the story here with the know-zoomab? Yeah, so this study is in the setting of MCO PC in the setting of MCO PC in all guidelines and we showed that again in P3, even if you don't give radium, you should give bone-targeted agents to reduce the incidence of symptomatic skeletal related events. We looked, for example, in P3, that in the fracture rate and even in the control arm, end-salutamide, first-line MCO PC, cumulative incidence of fractures at one year was 15.6%. So that's quite a lot. So of course it is also osteoporotic fractures, it's not only metastatic fractures, but it is something that is really not good for the quality of life and we also know that sometimes fractures can lead to hospitalizations, pneumonias, deaths, right? So it's really important to not forget in MCO PC if patients have bone-mess to give the bone-targeted agent in the dose for reducing incidence of skeletal related events. And this dose and schedule was monthly the know-zoomab. And we thought that, so that was the hypothesis that three monthly the know-zoomab is good enough, so that's 120 milligrams and that was the trial. So after induction dose giving every three months, the know-zoomab versus monthly the know-zoomab. And it was a non-inferiority trial and it was non-inferior and I guess that is now really something that has changed standard of care and we can give now three months later know-zoomab after the induction phase instead of monthly. You also have, of course, less side effects, less hypercarsinia, less ONJs and 2Z infections, so the two main side effects of these drugs. Is the one already downside to it to three months? I would be first question and can you go even even farther out or do you think three months is the the minimum? I guess if you got lots of friends in the hospital it's a downside because you won't see them so much. I mean this is one of the things that is nicer for the patients because they have to come less to the hospital and we made, we're going to make a health economic thing as well but if you look only at the drug costs you save 53% or something of drug costs we calculated for Switzerland so that would be like 15 million annual savings just for the drug costs in Switzerland. So I guess this is very different from country to country but in the end of course so it's something where you can give less without losing efficacy. Again it wasn't on inferiority trial. Could you give even less good question we don't know. Maybe the osteoporosis prophylaxis dose is enough. We don't know that that that wasn't the question. So Silky I was involved in organizing the meeting this year and I think you've made a pretty compelling argument perhaps the most important GU cancer dated presented wasn't in the GU cancer track. Fairly. Fairly down to you. endorsement of my organizational skills. I think they kept it away from you. Perhaps that's what happened I think this is really good. Let's keep it out of here. Do we do any cancer? I'm here it's time. Okay. Yeah finally. Okay let me know if my volume is okay. All right. So rampart was presented. This was the three-arm observation Dervomano therapy PDL 1 inhibitor or Dervatremi. Tremi C2A4 inhibitor in high risk by LivaVitch criteria intermediate or high risk resect at RCC. We saw data at Esmo about Dervatremi. We now saw data to ask about Dervomano. In the ITT the Dervomano hazard ratio is in the point seven range not significant. Dervatremi 0.65 I think was significant. But if you look at the curves they're almost entirely overlapping. And actually in the clear cell subset which was of course the majority of patients the hazard ratios were nearly identical. So I didn't see much difference between the arms even though I think with the vagaries of numbers one p value one one hazard ratio is just significant and one just wasn't. So I don't I don't know where this goes. I think it adds to the ledger of positive adjuvant immune therapy and kidney cancer and we've had data on both sides. I don't think you know for the toxicity of early C2A4 inhibition in this setting that there was demonstrated gains. James Larkin did show and we did a podcast with him about it about in the high risk group. So this is LivaVitch high risk. You do see more of us play at the curves. You see more of the evidence of potential benefit of C2A4 inhibition. I don't know that I see that moving forward clinically though again because I think there is a toxicity cost notwithstanding their quality of life data which didn't show anything which time you've already commented on. It doesn't really capture. We know C2A4 inhibition is toxic. I don't think there's a question about that but it just wasn't captured and there were some I think two toxic deaths on the combination arm. And Brian can you I mean so how are you talking now with your patients about the Pembro adjuvant because now we have another arm in a trial with the PD-1 PD-1 that that has not shown a benefit in I think quite similar population. So I mean how are you discussing this? I think it's the same you know I think you sort of and Tom I do do share decision-making unlike you. I think it's you know you talk about the potential benefit you know I talk about how you know there's an x percent chance that they won't ever occur without anything depending on their path features of course. I try and this will get to my next abstract to talk about the potential for life changing toxicity. You know that while most people may tolerate it well there's 10 or 20 percent but it's really going to impact them short term or even long term. And I you know it's I think it's a balanced discussion. I don't know that these data tremendously impact the discussion. You know I think each trial you start to look at you know on its own somewhat obviously you can look at the whole field but I think you look at on its own and you say 5-6-4 is convincingly positive for first DFS now OS etc. Absolutely. But I don't know how you explain it. I mean how is it I don't know if it's different okay. I mean it's easier to explain that. PDL one is less active in kidney cancer. The adjuvant it be NIVO's the hardest to explain. I put a slide in my discussion about the value of CTALE 4 inhibition broadly. I think that's a conversation we can have. My hands haven't had that conversation yet. Yes I got the most comments from my talk we're about my Bermuda triangle reference so I think that's how I'll be remembered one day. And we can so I don't know. I don't know it's cost without measuring mentioning 8 y 8. Right? Well apparently not. So I don't know so I don't think it changes it tremendously. You know I think it adds to the body of literature and it does say that there's an effect although not of monotherapy but again it's about the combination. So any subgroup of non-tier cell the non-clear cell was a bit all over the map you know it's about 5 or 10 percent. It wasn't central path reviewed yet and that will definitely change the classification I'm sure for at least a significant subset of patients. It's hard to know I put in my discussion that you know the point estimates are all over the place that confidence intervals are as wide as 10 to see maybe I should say it's a long state used to last. And I didn't I don't think there's a proven role for adjunct immune therapy and non-clear cell. I want there to be you know I want to help these patients but I have a really hard time with the benefit risk of that equation. I agree with that but I just think I feel that the dual valium ab and the derva tremium when you look at the shape of those kind of I know one's positive one's negative I know you've said this But this, I don't think this is a kind of a negative immune therapy adjuvant study. The study was, it stopped early, it was underpowered because the control arm changed to Pembro in the countries that were participating. There was a major interruption during COVID, you know, and both arm, the one was just positive, marginally positive, one was marginally negative. I think both overall essentially showed an effect, and I think that effect was mainly being driven by PD1, not by, I don't think CT4 edition made any difference, to be honest, I don't think. I do disagree. I'm going to get the, the high risk was pre-planned, pre-powered, but still a pretty small number of patients for the reasons you mentioned. So hard to, hard to think that suddenly there were a tremble becomes the standard in leap of a chyrus for a second. No, that's not. And there's no, there's no OS here, that's important to mention as far as you know, although as pointed out, you know, that the 564 OS wasn't positive till the 50ths, and though we had this right, the 57-month follow-up. Yeah, but the original has a ratio coming in the 0.5, 0.6, and the curves went apart. But so overall, I actually put this down as, I agree entirely with what you said. It's very hard to explain why I soak you, mark this moment. And it's very, very hard to explain. I find this background commentary going on very difficult for me to say what I think. So, I'm going to talk about another abstract home, by the way. At least, I actually, I'm going to talk about what Elizabeth Nally presented that you were involved with. Okay, I'm going to stop talking. I'm going to stop talking. There we go. Anyway, so this was, this was a different way to look at quality of life, and I think in some ways might have been some of the most important kidney cancer data at the meeting. And what she did in her group, they, with the help of, I think it was 100 patients who had gotten adjuvant Pembro, came up with definitions of four categories to define toxicity. So not CTC, a grading, not traditional quality of life tools, but four categories of non-significant, significant short-term toxicity, significant long-term, and then life changing. And there were sub-bullets, if you look at the presentation on how each of those were defined. And then looked at the adjuvant Atezo Study Emotional 1.0, and it was 46 percent of patients had fit into one of the significant or life changing toxicity. Now, some of that was significant short-term, but nonetheless significant. So it, it's a very different way of looking at the data. It'd be a very different way of counseling patients, instead of saying, hey, there's no quality of life difference, which is the conclusion of many presentations. It's saying, listen, you have about 15 percent chance of life changing toxicity, you know, and of 15 percent chance of significant long-term, et cetera. I don't remember the exact numbers in the sub-groups. But I think it, to me as a clinician, and I said this from the stage, I'm not a quality of life expert. But as a doc who treats a lot of patients, you know when you're harming people, right? We've all done it. We know when patients have bad side effects, you feel terrible about it, especially in the adjuvant setting. And I think it's a nice way to reframe the discussion, to think about patient counseling. And also the point, which I think Tom, you made earlier about the adjuvant Pembro study, a lot of these toxicities are emerging late. And if we're not following the patients or if they drop off, if they have a side effect, then we're paying attention to the wrong group of patients. So I think there's a lot more work to do, but I thought this was a really great first step. That's on, and Brian, you know, also what I really don't like is that expression, like in teleprosary, manageable side effects. I know. Yeah, it's more toxicity. But you know, like 40% of the patients need red blood to infuse, and you know, all the anemia symptoms. Yes. There was some baseline, but you know, if you have bad anemia, you feel fatigue and all of that. And I sometimes find this wording that we're using a lot is, you know, no new toxicity, manageable. I think it's kind of like kind of, I don't know, very, very centric for the doctor and not very centric. I was going to say it doesn't really capture the patient experience. It's a little bit like, you know, pay no attention to the man behind the curtain. There's nothing to see here. Everything's manageable. There's no, you know, when again, if you treat a lot of patients, you just know that's not true. Right. Not picking on any one therapy. That's true for pretty much every therapy we get. We give. So one of the things that she did, which I thought was interesting, was instead of measuring quality of life during therapy, which by definition, if patients are on therapy, they're probably doing okay, you know, because if things go wrong, people stop treatment. And then when they stop treatment, we stop measuring quality of life because the patient comes off therapy. And so we don't follow up. So, you know, if you, and then if you said that to my mum, she'd say, surely, she's the other way around. Surely she's one of the quality of life after the problem happens. Why are you measuring the quality of life and the patients before the problems occur? Your mum's quite smart, Tom. That's why I want to get her on the podcast, but that's how you keep saying this. I think she's saying terrible things about me. Of course. That's what I want around. That might be what you want to have her on the podcast. Yeah. So I think we've just got it backwards. And I think we have got it backwards. And we should start again, we should start again. We should start and how we measure quality of life. So I thought we know the podcast, the podcast, the podcast, right? The podcast. Why should we start again? I'm joking. I'm joking. I'm joking. I'm joking. I'm joking. I'm joking. What else in kidney cancer? Raine and McKay presented the, was it called radical? So is it one of the three of you? Yeah. One of the two, two, three, negative. Yeah. Yeah. It wasn't positive. I think the patients who ended up being, who went on ended up being a little lower risk maybe, then anticipated. So really great effort. We've not developed radio ligands in kidney cancer, but boy, patients with bone disease, especially multifocal bone-only disease, they don't do well. It's really, it's really a terrible situation for the patients. Lots of morbidity. They don't respond as well to our immune-based therapies or TKIs for that matter. So it's an important, effort, important subset of patients and, and hopefully not the last chapter and, you know, bone target at therapy in kidney cancer. And then there was a nice point made on there still here. And you might be able to add this. She did talk about P3 or, and she did talk a bit about how the mechanism of osteolytic and osteoblastic bone metastasis are very different in kidney and in prostate cancer. And just assuming that the drugs would work the same in both diseases, obviously, it's about the biology. It's not, it's not the case that all drugs work the same in all cancers. What do you think about that statement, Silky? Yeah. I guess that's true, right? Because it's, it's just a calcium mymetic, so it's going where you have an, like, kind of a, something going on in, in the bones and, and since kidney cancer mostly have patients have mostly lytic metastasis and prostate cancer patients mostly have plastic metastasis or mixed metastasis. Maybe there is a difference or, or maybe I, I don't know, maybe it's just not as important in kidney cancer. Maybe you should have, either, I can't remember exactly which, what, how many bone metastasis patients had to have. So maybe you need a, a sum of bone metastasis because in, in prostate cancer, of course, the bone metastasis are mostly predominant, right? They don't have also brain metastasis or liver metastasis or liver metastasis, they usually have. That's a good point. So that might be the driver, yeah, yeah, yeah. See that, see that. So the, the driver or the bone metastasis, right? Yeah, yeah. And then it's are usually the ones that respond much better to the home and the treatments and so on. And I guess that's a big, that may be the bigger difference between the two diseases. I'm going to do something clever now, I'm going to try and bring in the denosamab talk into the radium two to three talk in to kidney cancer. So to either of you give denosamab to as bone protect, as, for, for bone metastasis in kidney cancer, try and do that. If you're despairingly, I'll do it for patients with, you know, multifocal disease. If somebody has a single bone that that's been radiated, I'd tend that to. And, and, and would you, do you count them about osteonecrosis in the dual with vegetative surgery? Of course. You do the worst. And Silky, what about you, bisphospholates in kidney cancer? Yes. You do. If there are more than two bone meds, yeah. Yeah, I don't do it. I don't do it. I don't do it. Oh. Well, you're behind the times, Tom. Try to kept up. I will. Okay. Last thing. The last thing that I got to jump is the CT DNA data that Tony presented in Martin Boston, a really excellent discussion I thought of in an older generation exome natera assay. And only about, I think it was eight or nine percent of patients were CT DNA positive at baseline. So the sensitivity of that assay wasn't enough to capture patients. So positive patients had poorly, of course, but the negative patients were certainly littered with patients who were positive, but didn't have a sensitive enough assay to detect their positivity. So I think it's the beginning of the story that Terry has more sensitive assays, other vendors have assays. So I think we're going to see a whole lot more in this space moving forward. So it was nice to see some data, even though it does an impact, I don't think it impacts practice right now. Yeah, Brian. I mean, we've seen a lot of this kind of these exome, and of course, the message in bladder cancer and breast and these exome analyses. But we're now doing whole genome, we're planning to do whole genome analysis, which is going to be so much more, you know, I always liken it to drilling for oil. And just we can drill so much deeper and eventually we'll get there. And it's just for me in kidney cancer, CT DNA is just a matter of time, whereas I think Kim Won- if you like it. going to have problems with sensitivity, will always have problems with sensitivity and specificity, because you get these kind of unusual readings, which are hard to explain. And so I think that, I don't think this, I think this was the first step of a really exciting journey rather than we should close the book and move on. Totally agree. Totally agree. Brian, can I, can I cite an other study that probably didn't get through? Sure. But you can put it in, have you heard about the A-dream abstract? No. I've heard a number of MIMI. So this was enough so that I think it's quite interesting. You know that we try to do de-escalation, impatience, metastatic common-sensitive disease, ADT plus RP, with a very deep response. So that is now the first trial that has been reported. I think it's nice from Artich Chowry in, from Data Farber. It's a small trial, 75 patients. All patients had ADT and RP and the PSA, less than 0.2, after 18 to 24 months of ADT. And they interrupted both, the ADT and the RP. And the primary endpoint was treatment-free at 18 months. But with this covered testosterone, and that's the important thing, right? So that we covered testosterone, but treatment-free at 18 months. And it's, for me, very interesting because we, of course, we have the de-escalate trial and that's why we wanted to say that they had the statistic that said, I forgot, whatever is more than 35% is good. And they had 41% of the patients who were treatment-free for 18 months and testosterone recovered. So that, so they met their primary endpoint. And what is really nice, what they showed, is that the median time of treatment was more than 24 months or more than two years. Yeah, pretty impressive. Yeah. And I think it was one of many trials, correct me, from Ronk Silkie, that are looking at de-intensification. You mentioned another one. So this is, again, the beginning of this story. Actually, there's not that many. There is one from Johnson with search that is Libertos, but they stop only the ADT. They keep surprise the OP. And there is de-escalate. This is, that one, my trial, that's why I think it's really interesting, the EOTC trial that tries to randomize 1,600 patients, really, like, a non-interiorate trial, again. And unfortunately, the discussion just said we have to do first, the trials. They didn't, he didn't mention the trials that are ongoing, and that's why I take the opportunity and say that we escalate ongoing EOTC trial, and I think it's, you know, it's really an important question for patients. Oh, great. And this was really nice, because now we have the first hint that it really may work in patients, Brian, what's the highlight of the meeting for you? The highlight of the meeting for me, aside from our Uremigo's party. I would say bring it on. Bring it on. I think, you know, again, I think we gave away so many T-shirts, you wouldn't believe. Quality of life data that Mali presented, I think it could, exciting because it could lead to a whole new way of thinking about, you know, how we're affecting patients and counseling patients. I think that is implications beyond the edge of an RCC space, how about you? I quite liked the RAS inhibition data in pancreas cancer. I thought it was, I don't, you know, I don't, I think you, there was, I was, I was, I sticking clinic and said it could be a lot worse, it could be pancreas cancer. And, you know, and that sort of is ensuring for your patients time, that's really, well, it could be worse, like generally in life, and to have new treatments in pancreas cancer, I think, I think, I think if you, I just feel that there's going to open up combinations and cellular therapies and ADCs and all sorts in, in, of course, combination. So I'm really excited about the pancreas field. I think it was amazing. And also Tom, because it was a non-drogable target, right, for so long, I mean, we all just knew it, it's a target, but no targeted, yeah, so now we, we did it. So I think that's quite nice, no, this is very positive. It's okay. What was your highlight last thing? What was your highlight? Yes, I'm very sorry again, we used, I mean, we worked on that 14 years, so we started 14 years ago. So few years, so self-promoting. I mean, I know. It's worse than Tom. Yeah. I don't know if that's true, and I think I'm still worse. You can't see everything out, but I just said it, I just said it, it's not true. So Keith, thanks as always for joining, great session, we'll see you soon. Lovely to chat. Thanks, thanks, both of you, chat out, chat out.