Ep 62: Post PD-1 studies

[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. Hi everybody, welcome to Melanoma Matters, I'm Sutton Epitel. And I'm James Larkin, hi. Today we are going to record an episode on treatment beyond PD1 progression. That's probably the wrong way to say it because we have an episode called treatment beyond progression. It's the clinical trial data of what to do post PD1 exposure. So, PD1 progressing patience, there's a retrospective study from Australia, global really, but lead authorship is from Australia. There's a prospective single-arm study and then there's the perspective randomized phase, two trial, what to do post PD1 progression. So, let's do that. I guess a quick fire comes first and I had sort of teased you about this last week, but maybe we can just start. The mountains have just opened here. The skiers' orts are open. There's a little bit of powder at the base. Now, James, I know you're a skier. Have you ever had an on-mountain rescue or emergency? Not of myself. No, I can't remember that I've been rescued myself. Yeah, but nothing bad. I mean, I think just kind of orthopedic type stuff, if you see what I mean, I've been with people who've had various orthopedic issues, but nothing worse than that. So, should I ask you now about your most recent rescue or not? Yeah, sadly, I just had my first mountain rescue of myself last week, but it's a small. I just was snowboarding and a few trails were open and I ended up just on one of the flat parts, just boarding around a flat and you got to keep your momentum and I just got a little too close to the edge and slid over the edge and it was sadly, it was more of a, it was just basically a slope down, down, down, down into the trees. And I managed to stop myself before I got too far. So I went right over the edge, dug my board in and then had to hold onto a pole and then three men had to lift me out of the snowbank. So it was, yeah, it's gotten my heart rate going. So, that's it. Nothing worked. You did. Indeed. Yeah. Okay, so let's get into it, shall we? I guess, I mean, a couple of general comments, first I suppose, is that if we're talking about progression post-antipedie one, in principle, there's going to be a few issues about what was the timing of the antipedie one? Is it on treatment? Is there an interval? Was there adjuvants? And I guess the other thing to say is in this situation, I always, if I can, think is there someone where you could just do some, like, original treatment, depending on progression pattern, because sometimes that's relevant. So, actually, really therapy may be. And then the other thing, I think the other kind of border issue here is the b-waff mutation status as well, because it might be if you've got someone b-waff mutant that I know, and this progress post-antipedie one, you're going to want to go for targeted therapy. So we're just slightly parked that may be, because I think the crux of the discussion in this situation is going to be, would you want to go with it on its own, or would you want to use it be class antipedie one, usually it be me though. So it's pretty important questioning clinic. So in terms of evidence, I think the first relevant publication here was in this Paris de Silva last on ecology 2021, which in allows the seamer author of this. And this was a retrospective multi-institution cohort study, 15 centres Australia, Europe and the US, with about 350 patients basically. And then the crux of this really is that they were resistant to anti PD1 or PD1, there's some people that have a Tesla's map, so that's not in the abstract. And then in that situation they either got EP, or they got EP plus antipedie one, basically EP, if you need both. So the question here is, which is better, go on. Yeah, they just basically collected data. They sent around a spreadsheet, one of their kind of famous Australian spreadsheets and said, look, did you have these patients who took PD1 monotherapy? Important that it was essentially monotherapy they're looking at. In the adjuvant or metastatic setting, had progression, we'll have a separate episode on the definitions, the sort of SITC definitions of PD1 progression, primary, secondary, resistance, maybe as a matter of word. And so this was recurrence or progression after PD1 monotherapy. And if you had prior EP, they excluded them because this was really a study of IPE, switch to IPE, or add IPE to a PD1 backbone. And they just collected, what did you do with these patients in the real world? What did you do? And 15 centers across Australia, Europe and the US, they collected data on 355 patients, really, really impressive. It looks like majority of these patients have received Hembrow monotherapy as their prior, I'm looking at supplementary table S1, and then that's about two thirds of third of patients that received Hembrow monotherapy. And then, you know, it was kind of split almost 50/50 on the 355 patients going on to IPE mono versus IPE in combo. And maybe we just cut to the chase James, if you have it in front of you, the response rate to IPE mono versus IPE combo? Yeah, so I was just smiling then because you said that you looked at this up the entry. So basically, IPE, IPE 31% response rate, IPE mono, 1313% response rate. So I mean, comments there from me, I mean, that IPE mono response rate, I think that's in the bullpark that I've anticipated and probably predicted. And actually, honestly, I think even the combo response right there is possibly in the bullpark that, you know, one might have hoped for at least to expect it. Obviously, it's nowhere near what you'd seen a treatment naive population as expected. But for me, given all the caveats with the study, that looks like a real difference that I would say. Go. I agree. And I think that those, so this was the first study that put it in our heads. Can you get a response to IPE after PD1? You can, but it's in that low-ish teens rate. Can you get a response to combo after seeing PD1? Is the PD1 continuation adding anything in the answer? Yes. And in fact, it's giving us a response rate in that near 30% or around 30% rate. So I think that's all reasonable. If I wanted to address your question about the RAF status, I would refer people to the supplemental data of this Lancet paper. It's I think it's table s, oh, it's figure s1. It's OS by BRAF status. But, you know, it's small number. It's not that small number, as I should say, but it's only about 100 patients. Let's not get small to be clear. It's 100 patients who be RAF wild type and maybe 200 or so that were BRAF, sorry, 100 patients that are BRAF mutated, 200 that are BRAF wild type, hard to say that the curves are actually looking that much different here. They cross, you know, each of these groups cross, at least once, on the graph. So I don't know what to make about the RAF status. There is a P value associated with it in there, figure s1, but I'm curious because as I say, these curves cross. So I wouldn't say much there, but this study then really kind of opened the door in the US. There was the study by Olsen at all. Dan Olsen published in JCO in 2021 as well. And this was a prospective study. So this check patients who progressed on PD1 therapy as their immediate prior therapy, they could have gotten it in combinations. It didn't have to be monotherapy, but the the combination could not have been with CTA-4. And these patients got Pembro plus Lotus degree. So Pembro Lotus, it'd be single arm study, prospective, not randomized, but what did you think of the study, James? What are your takeaways? Yeah, so I think it's further support really for the idea that putting PD1 together with ANTI-CTA-4 in the refractory setting has got more efficacy, likely more efficacy at least, shall we say, than it'd be monotherapy. I guess that's my main take home. You know, there's always with if you're going to be some issues about those of the appeals you've talked about, elsewhere. The response rate just to get the numbers here was 29%. So of course, the interesting thing there is it's kind of almost exactly compordan with a completely different data source, i.e. the inner service to sell the data set. So, again, I think maybe setting the scene for randomized study. I mean, you know, God. Well, and just in the interest of time that study did end up happening. At the same time, we were developing a study through SWAG called S1616. I've told you about naming the naming convention in SWAG. So 2016, obviously, when this study got its first triage approval in SWAG, which means it was probably being developed and discussed the year prior. So around the same time as these studies, I was trying to look at the dates in the Wilson study, but I can't seem to find it. We could maybe fact check that for later, but the S1616 study was a randomized phase two trial. So now we go from retrospective data to prospective single arm to now a randomized phase two. It was randomized phase two of IB-NIVO versus IB post PD1 progression. Now these are patients who were primary refractory. So who had never gotten a response to PD1 in the prior setting. And it was looking at progression pre-survivol as a primary endpoint. And this study at the behest of CTAP really required randomization in a three to one fashion. I mean, Tony Rebus discussed the origin story for this trial a bit on that episode that we did with him, where he said, you know, the question was really just about adding CTLA4. But it was CTAP who said you'd have to randomize it. You'd have to do a CTLA4 alone arm. And so then we ended up with this three to one randomization. Maybe on another episode, we can talk about what these randomization imbalances actually do to the psychology of a trial. What does it mean when you're getting randomized to the arm that was only 25% chance of being randomized to? What does that mean as a patient or as a provider when you're designing a study like that? Are you building in some bias? Or are you saying we have plenty of data on CTLA4 mono. Therefore, we didn't eat more in this setting. But this study was, you know, I mean, that's not necessarily what we were saying here, but the study was only right around 100 patients, less than 100 patients, randomized three to one. And it was the standard dose of if I'm not mistaken, but we could also fact check that just in case at the end, maybe we needed to add some of that. Flip does iffy, but my recollection is that it was the standard dose it be. And I don't know James, you've looked at this PFAS table one figure one probably a few times. What do you think of these results? I don't know. I mean, I know the primary endpoint was PFAS, but I mean, I suppose I'm always in this situation a little bit more taken with response rate. I have to say, which slightly predispose is that your responses are going to be as durable as we expect. So that thing, that's quite important, what in terms of follow up. And I think it says we've discussed a lot. I think what's going to drive survival benefit is response durability, so just to sort of put that out there. I think this trial confirms the superiority of entity to let 4 plus anti PD1 in this setting. But I was going to just pick up a few really excellent things that you said then as well. I mean, I love that randomisation imbalance thing. I mean, is that even the thing? Is that like a known term? It will be really, really, really, no, no, no, no, but I haven't even thought about that. What are the consequences of randomisation imbalance in terms of bias and what it means for the patient? I think that's a great idea to talk about separately. Second thing that I was going to say, I'm impressed, really impressed by how many times you've already mentioned supplementary data in like 10 or 15 minutes. It's like must be at least four times, maybe five. So like massive kudos there. And then what was the third thing? Oh, yes, no. So the third thing I was just going to do is intra podcast fact check, which was about the recruitment of the Olsen study, I think, December 16 to November 19, 70 patients that I can just kind of knock that off there. So yeah, I mean, we could probably spend more time talking about the small study for, but for me, it kind of, I think, fairly definitively answered the question. What did you think? Yeah, I mean, just to detail the results, the response rate was 28% in the combination group and 9% in the Iphe alone group. But that was not the primary endpoint as you noted, the primary endpoint was PFS. So we don't, you know, the paper says how we don't have a p-value associated with that response, that basically just upholds those previous data sets that it's about a low double digit or single high single digit response rate to Iphe alone after p-1 progression and right close to 30% for combination. The PFS was statistically significantly different, but the hazard ratio 0.63, a p-value of 0.036. You know, I won't read off the median PFS numbers here because again, that's, as you say, that's maybe not what you're looking for in this patient population, but just to say on that curve, if you took combination, you had about a 37% improvement in your PFS than if you took it be alone. The thing this tells us there is value to keeping the PD1 going post PD1 regression, but it leaves us still open to many things, what do you do about acquired resistance, what do you do if this is coming off of the adjuvant setting versus resistance in the metastatic setting, which the study wasn't large enough to answer. And then I think maybe in the fact check, we can go back and look at the B-Rap status in all of these groups and just see how this combination did or even maybe Iphe alone in the B-Rap positive versus negative. Sounds good. All right. That's everything I think. Okay. Good. So PD1 regression, I think our takeaway is, combination. If you haven't seen the combination, it's reasonable to try it in the post PD1 setting, but the responses and durability mean certainly not be as good as they are in frontline setting. Yeah. All right. Thank you. Here, this is PD1 CTLA4. We don't necessarily have a robust data set on PD1-like 3 post PD1 regression with RelativityO20, but that was a small study. So. Yeah. All agreed. All right. Thank you. There's thanks. Hi. This is a fact check for episode 62, which Sapna is going to do, which is some stuff about Iphe dosing and infusion times Sapna. Yeah. When you had it in this episode of 16, 16, did the study, this is primary PD1 refractory patients randomized 3 to 1, Iphe or Iphe plus needle. And I just questioned whether it was full dose Iphe Nevo, exclusively or if they allowed for the inverted dose of Iphe Nevo. And in looking at this publication, this is the Vanderwald nature medicine publication. It's full dose Iphe Nevo. So it's 3 milligrams per kilogram of Iphe and 1 milligram per kilogram of Nevo. And then I just noted as I was reading this method section, something I was asking you about, which is about Iphe infusion times. So the original approval of Iphe was infusing over 90 minutes, whether as monotherapy or part of induction Iphe Nevo. And then at some point, and I don't know when, fact check with an effect check. The infusion, the label changed the infusion from 90 minutes to and so while this paper obviously talks about Iphe Nevo, it's that's just a historical artifact of when we design the study. But now it's infused over 30 minutes. And it makes the massive difference when you're requesting slots, at least in the US, because now you don't have to have 30 for Nevo 90 plus Iphe, maybe for Iphe, the flush period that we don't need a three hour slot, now you can just practically get back with the two hour slots. Anyway, just the same. Yeah, important stuff. Same for us. Okay, thank you. Yeah. [Music]