Ep 82: Best of ASCO: 2026

[Music] Melanoma Matsas is an educational resource and the opinions we express are our own, do not reflect medical advice. If you have questions specific to your own situation please contact your own clinician. This podcast may be available in both audio and visual so please check your platform. You go. Hi, welcome to Melanoma Matsas, I'm James Larkin. And I'm Stephanie Toul. Hi. So we're going to do best of ASCO, Kowloon 2026. And we thought we would start with the field data that Melanoma all of presented. But before that I think you thought you were going to ask me a icebreaker type question. Yeah, I have a quick fire for you. Which meeting is bigger as we're as well. Well that depends how you measure size to your number of people that go to. Registrarms maybe? I don't know, there's the answers to that. Are these figures easy to come by in the public domain? Yeah. Well they. Yeah. You must know the answer otherwise you wouldn't have asked me. Well I think it's something like 40,000 for ASCO and 36,000 for Esmo. Oh, so quite close. Let's back check that. And then. And then how many did you have a sentence this year? If how many any JM publications were concomitant with ASCO? No, but it was a few to say the least. You could be the name one at least, right? The pancreas one definitely. Say that drug name? Not very well, do you? Terax and Raster. That sounds pretty good. Well, do you be practicing any? Yeah, that's cheating. I think there were at least a couple of others. I must have it maybe something in lung cancer I think, but yeah, maybe one or two things in lung cancer. I honestly don't know. I think it's a good sense for any JM concomitant this year. Because you know, Esmo feels like it's boom, boom, boom, any JM, any JM. Niagara, you know, keynote 522. It's just that I didn't know. I don't know if I got a good sense of it from that. So definitely drugs and raster will definitely fact check. How many came out in common sense? It's probably right now sitting in the end of the day. But I didn't want you to cheat. So I didn't give you a heads up. Don't you dare. No. And then last question, do you know the mechanism of action of this directs on that? Yeah, it's called a K-RAS on inhibitor. That's all I know about it. So I learned this from going to that last thing on Monday night. The real benefit to that it was like disease groups gave their kind of top three to five to six presentations with the meeting. So it was really good for, you know, like a simplest like me who only practices basically one tumor type, one disease type, you kind of got to hear it from everybody. So what I heard from NGEI group is that most of the raster vendors that have been developed so far, targeted the mutant brass form, of course, but it's raster in its off form. And most of raster exists in its on form. And so this is kind of a molecular glue, the drug glues K-RAS in its on form, which is its most common IEA active form in the cancers, and then basically directly inhibits that. So now K-RAS and its on form cannot go on and do it. Normal oncologic signaling and finding because it's been glued up. So the risk of another fact check before we've even started, do you know if in principle that could work for other raster authorations apart from K-RAS and RAS being the one that would be of interest to us? Yeah, so that's the point is to date when we've been developing these, have they been all developed for the off state, but actually this, you know, gene/protein exists in the on state. And so if you are targeting raster, K-RAS in the off state is probably targeting 10% of K-RAS in these tumors. And so can you just make glues that will bind the sterically on-site of RAS, whether it's K-RAS, H-RAS, and RAS in these tumors? And then, you know, the other part of it is if you want to follow along how this drug and disease are doing, do you have a high shed rate from that RAS mutation, from that RAS tumor into the periphery to these all along? And my understanding in pancreas answers, you actually don't have a high shed rate. And so how valuable is looking for that CTDNA, despite knowing exactly what it's doing, it may not be as directly as surrogate. But anyway, yeah, so it's a possible strategy for other, I imagine, you know, that's what revolution medicine and all these other companies have had these good RAS. But it's a real milestone, isn't it? We should say. Yeah. I mean, RAS has now been drugable with soda raster. To get this in pancreas cancer, I mean, there's several videos now online of when, when Wolfen from Dana Harbor was presenting, and the Kafflin Meyer curve show up. Yeah, it's not as if they're the most dramatic Kafflin Meyer so you've never seen an oncology. But in this disease, where the last, you know, I don't know if it was in any J.M. or J.C.O. publication here, I just led to another fact, just in it, Torsiva, no, or Lotnib, Torsiva in pancreas cancer. It had an approval in the U.S. but not the UK, if I recall correctly. And it had an OS benefit of under two weeks. You know, but that was a major advancement is to improve survival. Plus two weeks in this disease. And now the OS was getting pushed out to, I don't know, a year or so. So big, big deal. But when Brian shows those curves, you know, this river rubs in the standing ovation. And it goes on for, you know, a minute, two minutes or so. He actually said that after. He said, I didn't the lot for that in my time. You know, he didn't know a lot for her. The disruption by standing ovation for his team. No big deal for them to be. I think we can allow, can't we going over a minute or two for a landmark development in a very difficult street cancer? Yeah, yeah. Yeah. And I think we're now as a consumer thing. I mean, that's metastatic right. But it's pretty interesting. Isn't it obvious questions about likely a balanced disease and kind of getting people into a situation where they might be up or worth they hadn't been in the past. So it really opens up all sorts of interesting possibilities, which I guess people are looking at over the next few years. And you bring up a good point. I mean, neoadjith and repair operative in pancreas cancer is a thing. I mean, they are using. They're now thinking about using it there. And then what would that maybe do for de-escalation big surgeries that we know often accompany, were susceptible pancreas cancer? Huge. So maybe that's a nice transition. I mean, another one of these kind of landmark events would be for you, the ol melanoma. But we've never had a targeted therapy that we've known could really affect meaningful efficacy. And we have these mutations that are kind of upstream of raster, G protein coupled receptor mutations of G and A Q G and 11. They're even more upstream of the raster, but they do signal down the raster. Raff, not kinase pathway in addition to protein kinase B signaling. So G protein coupled receptor mutation essentially will also activate protein kinase pathways. And so the first abstract we're going to discuss is this optimism of two. We said presented by Marlena Orlov global phase to be portion of a study that also has a phase three component. And this is first line treatment of metastatic uvial melanoma, HLA-AO201 negative. It's gerobicertib, protein kinase B and has been our plus prasautinib, which is multi kinase in this case for think we're explaining C metin condition. This was randomized against investigators choice, which in this study was essentially checkpoint inhibitor or chemotherapy. The phase two component that we heard about had a primary end point of primary and progression of reservible by the DICR, blind end dependents central review, and then a second degree of investigator initiated PFS. Ultimately, this data is what we think the company might be using to then go for accelerated approval, and then they will use the base three OS as the, you know, sort of confirmatory. So, Basery is enrolled, but basically the readout for that, the OS and point has not been uncovered for this analysis, so it remains blind and we will see that in a later date. What did you think about the data? Did you think anything about maybe dosing, demographics, anything jump out of you? Yeah, I mean just the background was interesting actually because this isn't the first protein kind of sea inhibitors to come along in this disease, we were just talking about that. And so we were involved quite a while ago with a trial of AEBO71, I think that was an over artist drug at the time in combination with a mech inhibitor, which actually in terms of combining these two drugs wasn't very easy. And actually there wasn't really any efficacy and that paper came out about three years ago. I think a quite an important point here was that biology was always strong here. And I guess what we're seeing here is actually a good drug to hit the target whilst that's a sort of important lesson, almost goes back to the early days with the whole business map. Seraf and Ib as a B-Rap inhibitor without going off on that tangent, you know. So that's maybe something important. Now I thought the data were great, I mean maybe just to talk about the dose because I guess I'm a bit obsessed about this. And whenever I see a trial like this I sort of think to myself, well, what dose has been given of the two drugs in combination and how does that relate to the single agent dose this goal? Because one of the things you brought up, I mean you asked a very reasonable question, how do I know what's doing what? What's the contribution of drug A and drug B and what was the single agent activity and what percentage of those drugs are we using here? And to be honest with you, I was a little data blind to it. I hadn't really remembered because you know it's been a while since we've seen this single agent for Chrysotin, for example, and the other agent Dr. Roussert had to get up. Yeah, so maybe just to talk about that now. Also for Chrysotin, which has now been around for a while and there's a few different labels and the normal dose is 250 milligrams, orally twice a day. And then in this study, basically the dose was 200 milligrams, orally twice a day. So that's 80% of the Chrysotin single agent dose without sort of getting into a conversation about what the MTD is or anything else, but it's about 80%. So I would say just from the first principles of combining targeted drugs, that's fairly respectable if I could use that formulation to say something's fairly respectable. And then Dr. Roussert said, again, if we look at the single agent dose, the phase one actually, I was just looking this up, it was in BJC, not too long ago. A lot of you different doses were tested and they landed up on 300 milligrams also twice daily. Again, you might have been able to give a little bit more. So in this trial, I'm just looking at the schema here. That's actually the dose I think that they're elected to go with if I'm not mistaken. So probably pretty close to what you're able to give as a single agent go on. Well, I mean, what I don't recall from that single agent paper is, you know, if the MTD was, did you say the MTD was 400 twice a day, the recommended, the RDE was 300 twice a day, was the RDE chosen because they knew they were going to combine it because efficacy wise, right, exactly. Efficacy wise is a single agent we thought already we had hesitations about developing as a single agent. So the RDE was, so in other words, exactly the 300 twice a day, but in truth is that under the MTD of single agent, which I think it is. Yeah, I mean, I'm just reading actually from the phase one paper, I'll say the citation in a minute, but there was one DLC of grade three hypertension treated at the highest BID or BD in British terminology dose, which was 400 milligrams twice a day to be really clear. So yeah, you know, it may well be that some more can be given. Let me just give you the citation of this. So this is BJC January 2023 and Sophie Pippenow, Pippenow, Neumann is the lead author of that. So it's worth having a little look at that. And it was called LXS196 at the time as well. So anyway, so it still gets back to the question though, doesn't it? So that's a bit of sort of spiel about the drug dosing in comparison with the single agent doses. Let's just say for the sake of example, they're both at least 80% again. Same coming from me. That's respectable. So do we know if you just given the derivative, what type of efficacy may have seen as a single agent at those doses? So again, and putting all the spot a bit on time, there's, and you're moving out of the center as well. Is that what that hand just demand? My hand gesture was wouldn't it be in that citation you just mentioned? Wouldn't the efficacy of monotherapy be in that citation? No, because it was a phase one and there were loads of different doses. So I mean, I was thinking about the neo-adjuvant and I know that's a completely different setting, obviously. But I guess it gives some sort of handle on single agent efficacy. And I mean, and the reason to debate this before you answer is of course that, you know, you know more about this than I do. The trial protocols obviously mandated that dose reductions be done in a certain way. And then assuming that this is approved, this combination which seems fairly likely, and hopefully we have access to it, we'll actually have to figure this out in clinic. How do we do our dose reduction? Which totally the right, the great segue. I mean, the truth is, so which drug is doing the efficacy, which drug is doing the toxic disease? Just like if you're using the Raph Mech inhibitors, you might hold both drugs, you might hold the drug that you think specifically is responsible and continue the other one going. In a way, you might say that the same thing happens with Ibimivo, you know, when a talk happens. And we don't know, we hold both in wait for talks to recover before we may be introduced one or both drugs. With targeted therapy, it's not that uncommon to keep a drug going while in talks is happening that you think is specific to the other. So what you're saying is absolutely right. In the real world separating out, the efficacy in the toxic disease will be important. Willed in the Oachina setting, I.E. Intact tumor in the eyeball help drill down where we're only using Daro monotherapy. Will that help drill down on the real efficacy of Daro mono? I'm not certain because does efficacy in a corroid restricted space equate to efficacy in a human touch and a sweet spread metastatic solution? I don't know. I don't know, I guess the answer. That being said, maybe we should talk about efficacy. Do you have the efficacy supplies? Yeah, we can. Yeah, I mean, you know, one interesting question obviously is whether regulators will take a view of what we've discussed or not, but maybe let's not blame on that too much now. Yeah, it's just cut straight to the chase. Primering point progression for a survival. Casiveration.4, 2 in Bicca. And then investigator assessed.36. That's quite high level of concurrence, I would say. So at the end of the day, we're trying to get my camera to it. You know, sometimes it's so finicky when it does it. I don't know how to get the fireworks to go off. That's tremendous for a disease like you feel. Can we just ask that it has a picture? Pass every share point for. Yeah, I mean, you know, and it's worth to say. And we mentioned the control on a bit of that. I think we call it the control on the Zepinevo. So that is a respectable control on as well. I think in this disease, you can't really argue with that. Go on. And did we even say numbers enrolled like what was the. Look at the demographic. Yeah, 210 for D+C if we're going to call it that. And 103 for the investigator's choice. We haven't really said too much about baseline characteristics. And you know, you're the expert of the disease. Yeah, they're fine. They're fine. But the Ibn-Evo being three quarters, you know, it humbles me. And we have to now say that this is an adequate and an appropriate randomized Ibn-Evo data set. Right? So as much as we might want to look at our single arm phase two non-randomized trials, if Ibn-Evo, the Spanish and the US trials, this is really the new benchmark for PFS, objective response rate. You know, it's going to be hard for us to convince everybody else the treatise. So you can get double digit response rates to Ibn-Evo when you couldn't get it in this trial. But the PFS is right there for us. The blind and independent central review of PFS is more than doubled. And it has a ratio of, you know, 0.42. So a control. PFAS of 3.1 and median and in the Dero-Criz arm it's 6.5. Great to see that kind of PFAS. We think that should undoubtedly translate to an OS benefit but of course let's be. The next thing we all think about is how much did it shrink tumors? What was the objective response rate? So there's some nice waterfall plots there, have blind independent and investigator initiated. Very reminiscent of an MRB rat mech days where the inflection frame is all the way to the left and the graph with the interventional experimental arm but an objective response rate here numerically within the web 30 what do we call it? 30.30. 30.30. So 37.00% in BIC 39% investigator assessed. Worth saying though that and I think we said this when we first saw the data. Investigators too is maybe slightly on the low side that 5.8 and 1.9 respectively and what I'm talking I'll just say something about duration of response 6.8 months actually depending on how you assessed it. So sort of you'd say behaving like a target if there are people perhaps in terms of duration of response and again I don't think either you or I could understand why there wasn't a duration of response quoted through investigators choice but that's a sort of minor thing I guess. Yeah also interesting to note that the investigators missed 5 complete responses that the blind independent central reviewers picked out so five patients on the experimental arm had a complete response unless I'm reading this table incorrectly that the investigators did not have probably those were some listed variants there you know we forget that when a list node gets down to kind of one centimeter short access were allowed to call it zero on a recent form maybe that's what it is I doubt it liver meant that investigators saw they were still measuring that the blind independence of no no those caught but anyway that's kind of interesting so all told you know the efficacy looks real here but now we got to get to toxicity because that's not a minor point here. Yeah and I've just got the toxicity summary slide up here so treatment related AES grade 3 or 4 about 40% the investigators choice 37% and there was one death in each arm and then they've got this complex bit at the bottom of the table leading to one of the drugs being withdrawn or reduced etc etc etc so you know you have to say that's not a minor level or I would say that's not a minor level of toxicity one comment second comment very difficult I think to compare side effects from target therapy with jet point inhibitors obviously because diary is the obvious one I mean that there's a really very different entities for example but again I think it's a sort of minor comment pick out don't you think yeah I think that's really a suit so I mean I don't want people to over interpret discontinuation here discontinuation on the investigators choice was higher sure but it's immunotherapy and so we do have to discontinuation rates what people run into those immuninated side effects let's recall that discontinuation due to targeted therapy in the 10% range is this surprisingly high number right and it's preferentially one drug over the other so that tells you the things and that's the side effects are driven or by one drug and the other compare this to the directs and rafts of data and pancreas cancer so one of the conversations that I that I had that thing I did on Monday evening so these patients so you know the there's this former congressman in the US and at month or two before asko he did and the York Times or interview as well as a podcast or so or maybe he has a podcast where he's on the drug and he showed the extent of the rash that people develop and it's not a rash it's like a toxic epidermal exfoliation that's happening and you know the I asked the pancreas guy I said talk about toxicity and he said oh you know what these patients get a little bit of rash and I said you call that a rash I sort of like taunted him from the audience you call that a rash I mean it looks like your shape is going to get fast right now that's this one patient who decided to be very public about his fight as that and so it's going to require a bit of management of that but what he said that I thought was really interesting is that pancreas cancer patient metastatic pancreas cancer patients are so symptomatic from their abdominal disease they might be obstructed in the pancreas or the bile duct they might be you know with tense abdomen or just like liver fully filling up with met whatever it is but generally it's the it's a billi area of destruction and things like that that causes symptoms as soon as they start taking this within day their symptoms feel better so they could give two shits about a rash right because they are feeling better I want to make the point that I think it's often said in our UV location so what he said is you actually have struggled to get these patients to hold their drug to let this rash heal because they are feeling so good on the drug there are abdominal symptoms or ameliorated they are going to keep taking it it's actually kind of the opposite of UV melanoma very few if any UV melanoma patients metastatic walk into the office symptomatic the liver actually doesn't have a lot of nerves in the middle it's around the edge right it's at the capsule so if a patient has one or two M1AV or even C2mers but they're sucked in the middle of the liver they're asymptomatic those aren't often at diagnosed this first line causing obstruction causing a lot of symptoms yet then they take these drugs and they start getting syncopy symptomatic peripheral swelling their rings don't fit their shoes don't fit their pants don't fit as well they start getting a lot of nausea and and the diarrhea so now they have a drug where they didn't feel their cancer before they feel the side effects of the drug and comparing contrast that with the drugs rusted with the pancreas icebergs they're paying so this discontinuation rate is mild on a clinical trial and I think that you know great I think in the real world we are really gonna struggle you are gonna struggle as the prescriber and I'm and the patient's gonna struggle to want to stay on a drug that is helping has a finite maybe course of helping but is so terribly symptomatic so this actually screams for really good supportive measures from the outset we need to make sure people have a real handle on this diarrhea the peripheral edema and the hypotension and Marlena kind of mentioned it in her presentation there's a run-in after a research at first you make sure people are off their anti-hypertensis you from the start you potentially prescribe them a low paramide or an antidireal measure to make sure they have for a real immunization or you get ready to start imaging that you get ready with kind of type of screening them for blood transfusions because it means a other thing that happens and you just kind of get prepared for that as the chrasatin and get padded you make sure you have close touch with the patient and on a clinical trial you do they come weekly in this for a little bit but in the real world we probably want to make sure we don't just give them a month's supply and let them out we want to make sure we have kind of weekly telephone calls with that supportive measures etc etc was that too much on fire? No I think it's an important point and actually just what you've been talking about we have quite a lot of this in kidney cancer as well with these combinations just when you start patients actually and I actually had this conversation in the next morning because I was talking about my madness and that problem was very similar we need to see each other quite a lot on it carefully first few weeks we need to get the dose right now that might be a good place to stop I think because and just to give you know props and congratulations to the investigators fantastic important moment in the disease I would say so fingers crossed for regulatory approval and access I say yeah I'll have to see that few in the chat great so we'll pick up another abstract soon let's ditch it together and you're gonna press top yeah okay now we're doing a hopefully a smooth transition in the video to talk about another astro abstract what do you want to talk about next the atom I was thinking I was thinking maybe we should do Kinects 942 first no we can it's a phase 2 five year update that's still out of them that's fine well I mean for sure obviously I think we can agree the main takeaway at askah this year was the youveel study this will be practice changing we hope looks like it has a positive signal hopefully supports a filing and then you know kind of the next big phase three that I would argue that we saw was in merkel cell phase three atom trial adjuvant novellumab versus I think it was placebo controlled correct yeah okay and so that you know it's 100 patients but it's phase three for this disease which is nice and maybe you want to just tell us the takeaway there the bottom line yeah I'm probably going to read up free survival and the hazard ratio for value map versus placebo was 0.61 with a wide confidence of about 0.3 up to about 1.11.2 so the p value for that was 0.013. They do quote another p value which is stratified age adjusted of 0.55 but actually it's sort of similarly broad confidence interval and the p values 0.075 and I guess you'd have to say and I think we said this at the time the shape of the curves that I mean there's a fair amount of censoring by the looks of it and actually they don't say on this slide the media duration to follow up but the curves sort of come apart quite nicely at the beginning but then it looks as you go further down the line as it were that they're coming back together again and again I think you and I said that when we saw it for the first time if I'm not mistaken. Yeah one of the things we should mention is this was a study specifically for Merkel's cell with lymph node involvement so they were trying it seems like to enrich for the population of patients who may benefit from that there have been two prior adjuvant trials admic O, Jurgen Becker and the European colleagues and then the stamp trial e-cog actin trial originally envisioned and run by Brian Gasman and then Jan Maynard presented the data the last year or so and both of those were essentially negative for RFS stamp trial had a signal for DMFS potentially but the question was there maybe the population they enrolled was too big and too much low risk disease so here they're doing the lymph node positive maybe that's the right population has the similar shape of the curve comes together sorry comes apart and then comes back together and in that case maybe the duration of treatments not long enough to you know that once the treatment is stopped you start seeing these recurrences or maybe further enrichment for the right population you know the population that really needs to be treated needs to come out I think he shellinger made the point when he presented this it was shellinger Batia at University of Washington Fred Hutch and eight other sites so it was a nine site essentially consortium trial really bootstrapped by the patient care consortium that they have for Merkel cell incredible you know a hundred patient trial and I think he made the point that there were deaths in patients without a Merkel relapse it's slide nine in this presentation and that brings up the difficulty with some of these endpoints like recurrence reservival or relapse reservival where survival is an event so death is an event even if it's from any cause rap so you know maybe another way to think about this might be time to progression or statistically you could analyze patients who die from other reasons but they don't count as your progression event you know so he had at least a few of those deaths without Merkel cell relapse on the avelamab arm that is bringing the curve closer together over time but quite a bit of censoring out at the end it is to be noted that at the placebo arm seems to have no recurrences after year two I don't know what explains that whether that's just not enough patients on that arm you know lost a follow up or what but the short answer is you know negative for RFS he did do some of this stratification and age adjusted I couldn't quite follow it but I believe you know it's a valid analysis where if you do it in an exploratory fashion and I like that he showed cumulative incidence curves rather than Kaplan Meyer for that you know maybe the cumulative incidence of Merkel cell recurrence in an exploratory fashion where they did it stratified an age adjusted maybe it is lower in the avelamab arm but overall I think the takeaway is this is essentially a negative study so kind of the third anti PD1 PDL1 this is the PDL1 of those three studies that's negative for adjuvant therapy in the all-comer population you know in this case with one family task business do you think there's a sort of statistical way to put these three small-ish quite unquote negative studies together or not because it slightly feels to me it's a rare disease obviously the efforts the investigators are fantastic laudable actually and I just wondering to myself you know had there been a kind of one big trial let's just say whether or not might have shown a signal but there's a I know there's a fair amount of hatches and I had to say the least gone yeah I mean in the in the drugs and in the populations from trial to trial but let's not forget the stamp trial was fairly sizable it was a few hundred patients you know yeah I think it would like 300 or so so yeah good efforts really good efforts and I think it tells there's something here we have to probably keep this which is the side if it's more treatment i.e. longer duration or just treating everybody at relapse you know is the is the reason the curse come back together is that you relapse on placebo and then you get salvaged by a vellumab in the metastatic setting and so maybe maybe it's a treat now versus treat later maybe we need to do a crossover I don't know I mean there's I don't think we're done investigating this I think we just need to think about what that trial design looks like and I know really smart people are thinking about that yeah I mean it feels to me like there's a signal in that right and actually most of the trials have so narrowly missed the primary end point which then I guess brings up some interesting discussions in clinic as well if you've got access which is actually the very final bullet point individualized decision-making regarding adjuvant therapy and clinical practice I think that's that's very fair actually yeah you agreed now let's get to your favorite study you've been itching to discuss this five year keynote nine four two update this is the phase two trial of entism ran on a gene plus per mer over general led virus receptive melanoma now published in JCO tell us about the authors and the trial design why is it my favorite study has you been mentioning it a few times okay yeah so we've heard this a few times now obviously this study Jeff Weber certainly presented the first day or I think and maybe even the the second the second read out from the study as well but anyway so Maccolino presented this at Asco on the Monday morning session manuscripts in JCO and just shout out obviously which I think is what you might have been drawing out obviously to Matt but also to Adnan Katak who was our fellow I don't know how long ago now probably quite a long time maybe about 10 years so it's great it's obviously you know makes me proud always to see Adnan as the lead author is there much to say about the study design or anything else that we don't know already probably not what do you think so I want to say a couple of things two to one randomization to vaccine plus pember over spember in the resected stage three setting the vaccine just due to manufacturing it's made either from the lymph node metastasis or the primary tumor or in some cases they look for both 34 new antigens per patient then turned into a vaccine with mRNA production and then the vaccine because of manufacturing comes in at cycle two day one of pember this is pember every six weeks so it's nine pemberalism ab infusions and nine vaccine infusions but the vaccine is given every three weeks starting at week six basically so cycle two day one so no you know the point was made when we first saw this survival curve recurrence re-survival curve is you know they may look pretty similar in the first six to 12 weeks and that's really because nothing is different between these two treatment arms in the first six weeks vaccine comes in at week six they're showing us the stuff in months so it's going to be hard that survival curves in months it's going to be hard to sort of really parse out where the six week mark is on that curve but you know previous publications you can probably go see it the other thing i want to mention is if you look at the demographics table so this was a study for resected stage three if you look at the demographics there are no stage three b patients in this study yeah and that's the other that's just the warning for me because in this phase two stage three and up no stage three b so this is a study of three c and three d and a limited number of stage fours but you and i both know that the phase three that has completed enrolling that we're waiting for the readout of essentially a similar schema vaccine plus pember versus pember alone is for stage two b and up clinical stage two b and up and so what happens when you start enrolling to be two c three a and maybe some three b's but maybe not if the study's a sort of a harbinger When the previous study was in the 3C's 3D's and limited stage 4's, are you going to be comparable data sets basically? Yeah, I mean, I wonder if that's actually almost the most important point here to look out for. I mean, just to know the numbers as well. So in percentages, pretty much 85% in both arms just under 3C. 3D, 2 to 4% to patients in each arm. And then stage 4 was sort of between 10 and 15% of the vast bulk here as 3C. So I think all of those points are pretty well taken. And the other point, I think obviously, is where the arrangement now fits into this. When we see the results of the phase 3, hopefully later in the year, it's going to be really interesting discussion to try and make sense of that in the clinic. Who might we be thinking about if we're assuming that the trans positive and there's approval and access in due course, what's the group of patients we're going to be thinking about this in? So I mean, I definitely want to watch for the future, isn't that? So anyway, I guess the takeaway at five years though, unlike the previous study we were discussing Adam from Erkelsel, these curves remain separated. Yeah. Not practice changing yet, not practice informing yet because we don't have access to this. But as you say, when we do have access, where to bring this in therapy may have slightly changed from when these studies were enrolling. So yeah, and maybe for the future, particularly in terms of neoagevent. And this is the question for trial design really isn't it? How assuming the phase 3 is in due course positive? How do we start thinking about incorporating this into neoagevent strategy? A lot of interesting stuff in that to think about I think. Yeah, I mean, no shortage of people have gone to Moderna Head and Merquist, the OES. I mean, certainly the swap group, we approach them in 2023. I know who's saying, Toby and Georgina and Christian and everybody is gone to Moderna and Merquist trial design. They've heard it. You know, path non responders, maybe it's for, you know, maybe this is for the neoagevent setting. Maybe it's just the adjuvant mop up of the non responders. Maybe it's adjuvant for everybody. It's really fun to discuss this if and when we see things mature. It may be on our horizon to see the phase 3 results soon. So stay tuned everybody. What else at Ask O? Did we hear? We heard a couple of cool pilot studies for neoagevent therapy. What sure kind of high level takeaway we heard. It be neorella and then we heard neo reny. Yeah. So I mean, in reverse order for me, I think neo reny. I mean, it's interesting really because they were presented right next to each other and Jeff Sorsman jumped straight up. On the mic to talk about non-randomized studies. And I think Georgina Law actually defended the position quite well for the neo reny study, which is to say, then this is thick primaries. You stage them so that it's actually stage 2. Follow them up with the moscopy. Take some of the thick primary out leave some in treat with neo rella. And then look for response for the residual melanoma that's left in situ and you're seeing high path response rates there in about 20 odd patients, I think, which are a mixture of 2a, 2b and 2c. And if I quite a lot of the patients, I think from memory around 10 or so were 2a actually. So for me, the clear thing that that demonstrates at least in the setting that Georgina and colleagues did this study is the feasibility. And I think that's a pretty promising area for us as a community to think about for the future. Go on. Cool. I agree. Cool. What about the if the neo rella triplet with the one that? Yeah. Yeah, that's right. So again, it's what 20 odd patients, I think, I'm a tahini presented it. If I'm not mistaken. We know a bit about ipinivo rella already. And we've talked about that before in terms of toxicity. And again, this was in stage 3. And we saw, you know, pretty high path response rates. And I think this is a little bit where Jeff Salsman was coming from actually, you know, but how do we really distinguish what we saw there? If you think about the confidence intervals for those response rates from what we know already. From s 1801 and the dean, so that's one comment in terms of efficacy. And then I think in terms of toxicity, and this is probably really there was one death from Mark Artaus. So what I think about this and you know, the expert and I'm not is that actually a common stop that. Some some some of these patients actually will do very well with synchlaxian anti PD one. If you just think about the toxicity. And then obviously with ipinivo per nadena, you're already seeing pretty high response rates and with some more toxicity. And I think thinking in a sort of, you know, let's say an otherwise uncharacterized population. And those we don't know that they've got features, bad features or anything like that. Giving everybody up front triple therapy. Actually, yeah, seem to be blunt seems like pretty heavy going to me. And of course, of course it's feasible in principle where of course it is. We sort of know that already, I think. Go on. And to comments, you know, is it feasible when there's one death or does that take away? Does that give us cause about the feasibility? Maybe that's more of a safety issue. But safety is marbled to me with feasibility. Yeah. You know, doing something and doing something safely are almost in the same breath. Of course that patient had, you know, it came out in the presentation. Maybe that patient had some pre existing auto immunities. The other thing to mention is it was one dose of triplet and then four weeks later it was a Nevorella dose. But even just with that, you know, like that, how much of that is over treatment to your point where maybe single agent or in the DNAS dial regimen could have been sufficient. And maybe it's also worth mentioning in Georgina's neorene trial. I think the non responders went on to get Nevorella in the adjuvant. So kind of a non standard adjuvant. But all very nice to see these kind of creative, innovative trials, not compromising a ton of patients to ask a question. But meant to get us perhaps to a randomized trial or get us thinking about hypothesis generation. And I think both do accomplish that. You know, Jeff was maybe overly critical about the number of patients that they put on these non randomized, but look in a 10 patient trial. You can always cherry pick your 10 favorite patients to make it look like they're also there's some psychology that happens when you know you have a 10 patient trial. It's not just the first 10 patients who are eligible to walk through the door. And a little more judicious about we only have 10 spots and you know, and it's just normal human behavior that will happen 20 patients, you know, a signal. Both for toxicity and possibly for efficacy may emerge a little. So I don't know any of the studies for these non randomized pilot. I actually like that they got drug company buy and to do it. They were able to design it smartly and here we are in 2016 results. It didn't take 10 years because that's the only new management platform is it doesn't take a long time to read these things out. So I think it's kudos to those investigators where we go next. I think is a podcast for another day. Yeah, I agree with that. So is that everything? What did you want to talk about your favorite subject? Yeah, I do think it's worth talking about another cool thing that came out of university Washington Fred Hutch from the medical oncology side. And this was in the rapid oral section. You're smiling. Tell me. No, because you actually haven't said what your favorite subject is yet. Carry on. I was a math person. So math is my guess is kind of gets to. I like to this presentation by Hemant. Kandalia and Hemant please reach out if we've if I've been asked her no wrong. I know I'm saying your first name right. I don't want anybody calling you he meant. But I don't know. I'm saying you're lasting perfectly right. Kandalia. Kandalia. I think that's right. And it looks like he might be a medical oncologist or maybe a medical oncology fellow because this is postdoctoral scholar. On response focused analysis of the impact of circadian rhythm on efficacy of first line immunotherapy in melanoma. That's a mouthful. But what this is and it looks like it's Shailander Vatia was the senior on this so probably very well thought out if Shailander is involved. It is you know, is there a time of day signal in terms of efficacy with first line, not a static melanoma. And I don't know. Did you click through these slides at all to sort of have a feeling on it. They did early before 1pm infusions late after 1pm 216 patients. 78 patients got their infusion and it's the first checkpoint inhibitor they looked at before 1pm 138 so almost almost 2 to 1 separation there. Got their first ICI infusion after 1pm. And I think it was any type of first line non-agiment so monotherapy combo. Um. I'm sure they know who got mono and combo, yeah, here it is in their demographics here. And ultimately they didn't find anything. And if you look at their kind of objective response rate by time, a day they do it by every hour and it's all over the place. So their conclusion, maybe you want to read off those conclusions? Yeah, early bird does not catch the worm. That's their conclusion. And very big letters at the top of the slide. No, I like the way they did it. They're using response rate. And of course it's a retrospective analysis and everything else. But I think they went about it in a pretty smart way I have to say. And so there's a few different data sets now and there'll be more in the future. I remain unconvinced as of now. And frankly I've always been unconvinced or skeptical as a better word. I haven't really seen anything to convince me that this is real at the moment. That's the bottom line for me. Selfishly I'm going to ask you to do a podcast on this paper that we have in press. It's been in press for over a month. And it's, you know, we looked at our phase three S1404 Ag event Pembro versus Ag event Ip-E study. Investigators choice mostly. And we looked at the Pembro only arm about 600 patients. And because it's phase three, registration and swab, we have the time of infusion. We don't have it on our phase two. So we don't have it for us 1801 for everybody that's been asking. But we have it for S1404. We not only have the time of infusion, we have which arm the IV was started on. You know, we have the time of every infusion and every laterality, everything like that. I mean, this is a joke, but like maybe we need to start looking at left arm versus right arm. Maybe the arm that's closer to the sun or closer to the equator. I mean, you know, this is kind of all that it's getting to. We looked and we couldn't find it. And so that's journal of oncology practice. It should be coming out. Meganoeth is the first author because she really has a great handle on this kind of data. And at the time we do that podcast, perhaps we can take a look at this lung cancer, nature medicine paper that since had a letter, a note from the editor on the website saying it's a week. We get to invite Megan. We can we definitely should. We definitely should invite her. I'd like to I'd like to do that. Yeah. Again, I said Megan, if you're listening, please come join us. I'd love that. Best of ask. What did we miss? I mean, there was obviously a great session until therapy. There was an abstract on Anzacel on OBS, one of my all incredible data. We're just not mentioning it here, you know, just because it's kind of still preliminary. Most places aren't going to access to this. Keep your eyes open for that or what's the thing that you say? Watch the space. Watch the space. Watch. Yeah. No, no, no, no. What did you say? Nothing else doing in British accent. No, I mean, I think we covered the main things. We touched on the main things. So there's some good stuff there. And I think I actually think it's only the therapy stuff looks really exciting, but as you say, relatively preliminary, but I'm sure we'll see more of that in the future. Yeah. Good. Watch this place. Okay. So we'll do a quick fact check on this one and then drop this one and turn around. Quick for you guys. All right. Thank you. Take care. Bye. You pressed stop, didn't you? Hi. This is fact check for the best of asthma, Asco, colon to any 26. I was getting confused. And there were a couple of things we wanted to do, one of which was number of attendees, I think, at Asco versus Asco. Which one's bigger? Which is bigger. And then there was a thing about simultaneous publications as well. So why don't you, as your American go first with Asco attendees and then I can compare with asthma. How about that? I mean, I'll tell you what my source is, which is maybe part of it on LinkedIn. There was a nice Asco, you know, posed from Asco. And it was just people walking around McCormick. I think it was a shot of one or two of the plenaries, probably Brian Wolpen's directs and rasset presentation. And you know, in there it says, we just had a great Asco blah, blah, blah. And it said 46,000 registrants, recognizing that that's a combination of probably in-person hybrid and then virtual only registrants, but 46,000. So that's the side. And that's kind of where I'd heard Asco was in the 40,000 range. Yeah. Fantastic. So that gives you a size. What about your breadth and a committal note? Like how many continents and everything? Yeah. Our accountants, probably there'll be people there from every continent, right, with the likely exception of Antarctica, right? But the reason I ask, obviously, is that so as Motu-25, I think 37,000 participants, this says, don't know yet for as Motu-2026, but from 174 countries and territories, we've had a lot of countries. Which is a lot, because I thought there was without wishing to do a fact check on a fact check. I thought there were only about 175 countries in the world. So the bigger question would be, which countries haven't sent someone to us, my last year, Carole? 181, maybe 184 countries in the world, something like that? Anyway, yes, we're not doing a fact check in the fact check. But because we've had this conversation when the Olympics come around. Do you say how many countries are there in the world? Yeah. So it sounds like at the time of writing, which is June 26, Asco's winning on size, right? But then we have to just check the comment about Brad Puthin. But we're not doing a fact check on that. We'll just leave that hanging there. And then we'll go on. And then any, yeah, will do you want to make any comment about, because they're the deadline for Esmo, regular and late breaking submission, at least the placeholder for late breaking says come through. Like, are you guys decreasing in your submissions increasing? Well, first of all, why are you such an insider? Why are you Esmo Illuminati? Illuminati, that word has a lot of baggage attached to it, actually. Anyway, yes. So as you know, I'm Santa Fe Coach, for Esmo 26 with Yelena. That's a massive, massively big deal, right? Congrats. I mean, thank you. Come on. As a career highlight, did Martin Never Chair Esmo, Santa Fe Coach, or Esmo? No, not that I can remember. When was the last time somebody from the Marston was a Coach, or Esmo? I think Johan DeBono, who is sort of ICR master, and Johan was around. I think it was 2013. Again, that's not a fact check of fact check. Actually, I was the. I can't remember which chat chair was that year. Either skin or GU. I really can't remember. But actually Charlie's one to my friend was one of the chat chairs that year as well. And I think Charlie was the last UK person to be Esmo. Oh, the scientific. Which was a couple of years ago. Harris 2022. I think we would both have that one, won't we, if I remember correctly. As 18-O-1 presentation for everybody else. OK. Finicky, Discussant, but. Yeah, triple. That was me, by the way, as well, just for the record. It was the start of our in-person friendship. We'd known each other on Zoom before that. But, you know, I liked your discussion, obviously. And then you were very kind and generous. You and Christian came to our 18-O-1 celebration dinner. Very kind of you guys to do that. Anyway, the point is, "Track chair, scientific co-chair of Esmo's, a tremendous honor." It really does mean that Esmo sees you as, you know, a really well-regarded voice here. And your institution hasn't had somebody do this for over a decade. So that's massively big. So I fully expect to see a Marsden purple banner in the Exhibitor Hall just with, like, you in a dunking booth. OK. So everybody can go. What's a dunking booth? I don't know what I mean. Were you sit on top of water? You sit on a platform on top of water. And then people throw a bean bag to try to hit a target. I like a kind of medieval sort of fare or something. Carnival game. Yeah. Oh, wow. OK. So what I'm going to say about the abstract is that I think we've just got the abstracts in and we have record number of abstracts this year. So that's great news. I'm not sure I can say officially what it is, but it's a record number. So that's very exciting and plenty of work to look forward to over the next few months, which leaves the final bit, which was about simultaneous NEJM publications, I think. Right? NEJM, and I also have JCO here because, you know, as the sort of companion journal for ASCO or as the premier journal for ASCO, maybe it's important there. You know, NEJM, and to be fair, during ASCO. during the week of Asco, I didn't log on to NEJM.org. So you know, sometimes during that week of a conference, they really promoted on their website. I didn't log on and I can't find any sort of fingerprint of that. In fact, the last really good NEJM Asco page that I can find is from 2019. It's actually NEJM.org/Asco2019, I think, is the page. I don't see that they've really dedicated much since then, which is a little strange, but this is what I see. I see six NEJM simultaneous publications. And actually, at one point, I had them all saved here because I thought it might be nice to tell you what they were. But apparently, I didn't say that. Let's see if this does it. Yeah, this isn't really going to do it. But it's obviously the Directs enrasse was a big one. There was a Myeloma publication, I believe. There was a lung cancer one, maybe even from a drug that's not even available, which is sort of the big controversy. And then for NEJ, I mean, for JCO, there were 10 simultaneous in JCO and six in JCO on college and practice. And so that's not too shabby. And obviously, JCO is proud to have those simultaneous publications. I think in Tizmaran, Audigene was one. So that might have been our only melanoma simultaneous. So yeah, that's the number of simultaneous publications. And what do you forecast? Why don't you make a prediction here? How many simultaneous NEJM at ESMO? And how many annals of oncology simultaneous publications? You're the-- Let's make a prediction. You have a position of insight here that would be cool there. Zero insight, actually, because-- No. You haven't looked at any of those pensions? No, of course I haven't. And even if I had, I'm sworn to secrecy. I'm going to say four NEJM, six annals of oncology. OK, we're going to do this like a game show. I think it's going to be 10 NEJM. [LAUGHS] How many did you say annals? Six. You think four and six. You think we're record-breaking abstract submissions. ESMO is going to have 10 simultaneous publications in these high-impact journals. Yeah. OK. I'm hoping to be wrong. I'm being conservative. Yeah. But you're being conservative. And what happens when you-- as a scientific coach, you're so low, lowly wrong with your estimate. I'm just not going to sign it. What do I get? No. Your term ends, basically, up to hand the thrown over. I think ESMO, simultaneous publications, annals, is going to be-- I'm going to say 15, 12 to 15. OK. So smaller meeting, but I think they're going to come out with more publishable material. Yeah. We can only have another day. We don't know at the moment. It's going to be a smaller meeting. I think we need to wait and see. Oh. Actually. OK. OK. Well, this is a fun fact check. I hope everybody is enjoyed our best of ask episode. Obviously, we couldn't talk about it all, but we hope we gave you something. So thanks, James. Bye. Bye. Bye. [MUSIC PLAYING]