Redefining Immunotherapy (Ep. 4): Melanoma Treatment Strategy: Expert Perspectives

[Music] Welcome to Melanoma Insights for Professionals, brought to you by Melanoma Institute Australia. I'm Professor Georgina Long, medical oncologist and medical director at Melanoma Institute Australia. Welcome back to our special VODCAR series, "Redefining Immunotherapy Lessons from Melanoma." This is episode four, where we focus on melanoma treatment strategy. What we've learnt from monotherapy versus combination approaches, how we think about duration of treatment and key considerations around re-challenge after progression and retreatment following toxicity. If you haven't listened already, I'd encourage you to go back and listen to our earlier episodes where we discuss how immunotherapy works, optimizing treatment decisions in clinical practice and recognising immunotherapy toxicity early. Joining me in the studio today are my medical oncology colleagues from Melanoma Institute Australia, Professor Alex Menzies and Associate Professor Mateo Kalino. We also have Associate Professor Ernesto Silva, dialing in from Portugal. So, thanks again, all of you sitting here and having this lovely fireside chat without the fireside. We're now going to talk about our melanoma treatment strategy from our expertise over the combined 50 years. How do we treat and what do we treat with? I just want to let everyone know, go to episode two, where we talk about clinical markers and biomarkers because in that episode we discuss what goes into the decision between PD-1 monotherapy and doublet therapy. What we want to talk about now though is once we've selected our therapy, what's the duration of treatment? Can you re-challenge a patient if they progress? So, we need to talk about the nuances of that. And can you re-treat after toxicity? So, Ernesto, I'm going to open with you and talk about whatever you've liked of those topics I mentioned, whether it's re-challenge or duration or re-challenge after talks, or re-challenge after talks, re-challenge after progression. What are your thoughts on this sort of expert immunotherapy, management, and treatment? Thanks, Regina. Those are very important topics. I just want to refresh our memory on one thing. This is immunotherapy. This is not chemotherapy. So, meaning we are teaching the immune system. So, keeping that in mind, we don't have to be too aggressive. So, we have to see, do we really need to re-challenge? So, that's my main point. I'll just mention teaching the immune system. Please go to episode one on how these drugs work. So, back to you, Inesh. Yeah. So, for example, if we have a patient that has a toxicity, then my first question is, do we really need to go back to treatment? I think that's the first question, clinically, do we need it? And then, if we want to, if we decide, okay, clinically, we really have the patient had progression, and that's the best option, then of course, depends on the toxicity the patient has. And normally, I'm happy to re-challenge, but of course, there are some nuances. What kind of toxicity the patient has and the great, right? And one thing that's important is, we are considering different types of immun checkpoints, right? The toxicities that are linked or more common with epilimab, they are different than the one that happened with anti-PD1 monotherapy. So, for example, if a patient had a bad immunitis, I'll be quite resistant to re-challenge with anti-PD1, because we know it's more linked to that, right? But if the patient, for example, has hepatitis or colitis, and I really need to, I really, really need to re-challenge. Again, because I want to reinforce this, because it's very important to understand that needs, okay? So, for example, I'll be more comfortable to go back to anti-PD1 monotherapy, because we know that hepatitis and colitis, they are mainly driven by epilimab. Having said that, we know that, and we always have that cases, bad colitis and bad hepatitis, with anti-PD1 monotherapy. So, it's very important to understand the nuances of our patient, okay? I just want to give you a scenario to help you draw out what you're thinking. So, back to our patient that we discussed in episode three, the 42-year-old, V600E, liver, and what, you know, bone meds. He's got epinevo. You've given him one dose, and then he had a slight hepatitis grade one, so you're delayed, or we could did come down. It did come down. You gave him a second dose, he was fine, and then he started to develop diarrhea, and it got really bad that you actually had to give him a dose of infleximab. Then you do the scan, maybe you should have done it earlier, but then you do the scan. Exactly. And he's progressed. What are you doing in that situation? How long after starting? Six weeks. Let's say six weeks in. Six weeks after starting, he's progressing. Sorry. Okay, six weeks, well, let's do it. Now I'm going to change this scenario up, but just this first one. Okay. And the patient is off any immunosuppression. Is that right? He got the diarrhea six weeks after. You gave him immunosuppression. You did a scan at showed progression, and so now you're not knowing what to do with the patient. They got full dose of infleximab. And then now you're winning them. You're winning them off. You, I mean, yeah, so it was very responsive to steroids. Yeah. Okay, so what I would do, what I normally do in those cases is I tried to win off the steroids as soon as has rapidly, as possible, but again, always trying to be safe. When I say safe is before I win the steroids, I always check with patient. Are you okay? When he drops the dose, checking if he goes back, try to go back on the steroids, but what would you do? I said, we discussed all of that in our toxicity. So what do you, it's more the pre-sabre. Make the decisions. Make the decision. I would start with an evolve. I would restart with an evolve map for the beginning. I know that might be controversial. I would start with PV1 alone and see how the patient goes. And then I'll recheck in terms of response. Okay. I'm going to give, I'm going to argue sorry to cut your finish there. You got a young guy who said two dose of PV1 first scan shows progression. This is bad. Yep. This is bad. That's irreconous. I don't think more of us stand at the IOs. Okay. Now I'm going to change it up. Change it up. Now you've done an early scan and he responded beautifully. And you've given him inflexi, you're weaning off. Now what do you do? Now what do you do? Don't give any more. What would you two do? Look, so first of all, in the first situation, I think really what you're doing is this guy, a real progressor. And if he's Bearaf Mutton, if you don't think there's a window, you may have to switch now. Right. So bearaf Mutton. Yes. How much progression is he got brain men that are about to cause a problem, etc. Yep. But if you feel I've don't have a big window, he's either a pseudo progressive or is in trouble and he's much more likely to be in trouble. So you mean primary resistance? Yes. Correct. But you know, and if he's Bearaf wild type, you have less options up his sleeve. Yep. The responder. I look, I know there's this temptation to say you've responded to Pnevo, but when you in my mind, when you extrapolate from a few different sources of data, and there's lots of extrapolation, I think there is in benefit in people who've got an ipidriven talks to then give them single agent, Nevo. And so where's the data for that? So I think I'm going to give you three things. So O6-7 mandated stopping. Yep. Right. Stopping both. Both. Both. Yep. The first trial that didn't mandate stopping allowed you to drop the ipid was an ipid Pnevo study that we were involved with, which certainly has better landmarks. Except it was all Australian patients with high tumultation burden back to episode two, high tumultation burden, high tumultation, high tumultation. And I see. So not great evidence. Yes. And the third bit is there is a retrospective evidence. And the problem is this is never randomized, right? But I, I at least consider starting single agent. And there are certain toxes where if you've got a tox on ipidnevo, the risk of it in a tox with single agent, Nevo is pretty low. And I put colitis and hepatitis. The caveats being. Yes, it's meant to be. There's, you know, there's the hepatitis that was so bad their iron r got to four and you lost sleep. And there's the hepatitis, which was essentially transaminases in the thousands, but the billy rupture in an iron r state normal. They are not the same. Or in the hundreds. Yeah. So I think. I think there can't be a black and white plan, but I've certainly had colitis as I've never had given any single agent. Nevo too. And I've certainly had colitis as I've given things like. It's an interesting topic. What do you think of that? I like it. And then I'll weigh in. Because I have some opinions. I think it's hard. I think, you know, I do. And there's obviously some data. There's a bit of what the patient wants to do. And often they want to keep going, right? They, we just talked about that in episode three. I know. I know, but we've got to change their mindset. We do. For me, I think it's how bad the disease was at the beginning and what is their response. So I think this is where PET can be really helpful. So PET metabolic responses often faster than CT. And if you've had a PET-CMR, I'm really happy to stop at that point. - Really? - Almost at any time point. If you get to a PET-CMR, we stop. So for me, just on that second case, the first case where they progress straight through this is bad disease. And I'm sort of saying how Mary's, I'm just trying to find clinical trials before I go down the B-Raph Mech. Like it's horrible. The second, but he may have a benefit if you've given a lot of steroids, maybe you're not catching a response. And I was going to say, low dose, yeah, I wouldn't go nivo alone. Just spending on the severity, I might go low dose it be nivo, because he's B-Raph Mutant. If he's already having a crap time after two doses of full, I don't know the PD-1's going to turn the disease around necessarily. But I want to move to the second one, because I think that's the most important case. - But it's the most common thing. - And it's the most common. So the patients had a response where two doses in, they've just had the diarrhea, we're treating the diarrhea, everything's looking great. Let's say the PET-CMR, even if it's not, I would hang 10, wait, and do another one, and see where we're heading, if it's going to be a CMR. And also, if I pull the trigger on the maintenance nivo, I cannot give more epinevo. And we know that steroids and immunosuppression can mean you are likely to develop secondary resistance when you will want to re-challenge. So for me, this is my thinking is stop, scan, or wait, wait, wait, wait, wait, don't pull the trigger on maintenance nivo if they're in a great response. If they happen to recur down the track, which is not many, really, I've still got two more doses of epinevo, but I'll lower the epitome. - So there are some. - That's what I'd say. There are some local governmental restrictions around the use of drugs that do impact care. If there was more freedom there, that would. That might change things, but yeah, I think. - So I save up my more epinevo in case it's needed, because I've just given them immunosuppression. - Yeah. - Yeah. So what about the case? I'm going to give another case. So that was really about restriction. - Should we just jump to the duration questions? - Yeah, let's do that. - So I. I don't know how people describe it, but I use this spiel, which is essentially say, when we first got these drugs, we gave it forever. And that was on the assumption that it would stop working, because every other cancer drug we had stopped working. - Can you hear it? - So we gave it forever, or until it got toxic. We then started giving it for two years, and depending on how I say, "Well, two years is a lot of time." And then this friend of mine did this study that showed that if your PET scan looks excellent, not good, but excellent at one year, I'm very confident stopping you at one year. - What's the rate of progression after a CMR on the PET scan at one year? - Oh, it's like five percent. - Yeah. - Something like that's very low. And then I say, the other bit of information we have, - And who is the friend that published that paper? - You were, I also refer to you, but Alex was the. - I think Alex was the senior author. - I can remember. - Senior, and our 10 and Ben Kong were the first two authors of the thing. - Memories better than me. - Oh, and the third thing I'm bringing, just back to our talks discussion from early, from the last session, if I stop for a talk, that's okay. And I re-put that point in, stopping for talks means you can still be cured even with one dose, because I want to get it out of their head that you have to keep on getting the drug, because different people respond to it. And actually, I've got one. - So what do you do if they're doing brilliantly? - And they have one. - Like, they're doing great. They're just on PD-1 Monotherapy. There might be 75 lung meds, and they had a bit of a, you know, I don't know some autoimmune that you just wanted to. But they didn't flare. They're doing great. What would you do? A bit of psoriasis. - I do the pet. At a year and stop at a year. The one year is my default. - You don't go two years at all in anyone? - Would I discuss it? But no, they've got to have a CMR. - Okay, they've got to have a CMR. - And the other group, I'm a little bit nervous, and I go a little longer. And I'm interested in this often fits with the patient's personality, that their mindset. If I'd given someone single age in any PD-1, either adjuvantly or in the advanced editing. - Yeah. - And then I've had to treat them with epinevo. - Oh yeah. - Those patients are a little bit, they feel like they've. And the lotto is not the right word, but sort of got out of jail. - Yeah, yeah. - They are much more conservative, and therefore, their patients were saying to me, actually, when I put it to them, they're often going, well, look, this drug involves me coming every three or six weeks. - Yeah. - All right, I'm not getting talks at this point. It takes me less time to get this drug than it does to get a haircut. I'd rather go to two years thing. - But I tell you what, isn't that a weird scenario where you've got people that fail single age in PD-1, respond to the combo, but we think you've got to keep going with the PD-1 that are resistant to the works. - Oh, yeah, I'm not. - It's weird, it's weird. - It's weird. - I'm commenting about the psychology. - You know, not the biology area. - But there may be some biology to that. We don't know. - But if we had a better discussion. - Well, there was. -. the real thing in it. - Okay, I'm just going to say we have a good discussion at the beginning about how immunotherapy works. You don't have to do it, and that's where we've changed in the last few years. We're better at those conversations. But back to you, Inesh. - What's the data on epineval after PD-1? - Yes, so there are several studies, retrospective, larger perspective studies, and prospective studies showing that epineval, it's better than epileumab alone after failing PD-1. And that group is about a third. So 35, 33, 35%. So that's one point. And so there's a biology that we don't really have to say. - But then the maintenance. - The maintenance after that. - I'm with you. That's not make any sense, but probably there's some biology there. But I have a question in fact to us in three of you. So I agree with what you have been saying. I agree. I also stop early if we have the CMR. That all makes sense to me. But question, do you have any subgroup of patients where you treat for longer? And who are those patients? - Yes, it needs. - Partial metabolic responders. - And young patients who are tolerating for two years. - Yes. - My other one, in Esh said, the only ones I really do that win with are the responders that then get oligoprogression that then I treat with radiotherapy or surgery. - I reset the clock. - And I reset the clock in other two years for them. Which is to be honest what they're going to want to do. - Two other groups that I've got. One is the guy that I've known since I was a trainee. That's how long he dates back. - That means we'd know him. - No, no, great. You wouldn't know any. He would live in a matter of as an adjuvant treatment. - Oh yeah. - That's how long he dates back. - Oh. - Anyway, he has had multiple lines therapy. Most recently, Ippi Nivo responded. And then six months after stopping the two years of Nivo, progressed. And I've put him back on Nivo. And he and I have joked about treating until one of us retires. Right? - I've got a bunch that is not. - He's older than me. - No. - But you know. I've got a bunch exactly very similar. I can name them. There's about 10 or 11 of them. And they are what I call and I teach our fellows. They're my forever patients. They are on treatment forever. I have stopped them a few times along the way. And every single time they get progression, they need it forever. - And the other question for Anest is I have multiple, multiple medical patients who in that boat. And I know this is not a medical. - I'm pretty. - And it's a really challenge. You know, some of these patients are old. Well, a lot of the medical patients are old. And you feel pretty bad when you look and it says they're up to cycle a hundred of our. - Yeah, no, I've got that. - And so I think this is what we'll probably talk about in another episode. Is this idea of eradication versus pushing back into equilibrium? - Yes. - With checkpoints. - Yes. Can I just go back to the previous situation, or scenario where you continue treatment? So I just want to go back because I think if we think biologically and in terms of data, if we stop after one year with CMR, and for example, the case that Georgina and Matt just mentioned that you keep treating, you have stopped. And then the disease progresses. And then you treat and they respond again. So it kind of seems safe to stop anyway because if it comes back, we can treat. - Yeah, that's what I do. - This one on the other side. - Yeah, that's right. So my forever patients are forever because I've biologically tested it. - They've selected themselves. - They have, yeah. And they have to go back on our conversation. - And I'm happy we're not stopping exactly. - Yeah, stopping. And then there's nothing. Yeah, it's going to be better to stop. - Always. - I always stop it two years. Regardless, sometimes I'll stop earlier, depending on the patient's request. - And again, just I guess going back to, and this is all about how we set the patient up at the beginning. Expectations, do you flick the switch and it stays flick? - On. And as Matt said, it was forever. Then it was two years. I also draw on our neoagement data. One dose of drug, path-complete response, no recurrence. There's a lot of data from a lot of sources saying that, you know, it's probably individualized and you know, very few need prolonged therapy. - Well, let's touch on that one other treatment at this strategy. This is important actually because we've not talked about neoagement. I've mentioned the neoirini trial in some of the other episodes. Where are we treating patients now? Stages of melanoma, one, no evidence. Stage two, we've got evidence of phase three data for adjuvant PD-1. After a sected stage two, BLC. Stage three, we've got adjuvant and neoagevant and stage four. We've got everything that we've mentioned so far in all our episodes. Where are we treating with drug now without a doubt? Yeah, so I think it's interesting. So, and we'll come back stage two as a second. I've got a question for both, all three in a second. But really, we're reducing the adjuvant treatment and we're doing neo-adjuvant. And the term I use, you know, I hate our EMR, once you select the word palliative. But I use the term definitive immunotherapy use. So, to differentiate between neo-adjuvant really, and I have three settings, definitive, near-adjuvant, and the one that's reducing the most is the adjuvant setting. And I guess the question to everyone is, when's the last stage two patient you treated? Not the macroscopic neo-adjuvant stage two, that's neo-adjuvant. That's trial, but it's also a neo-adjuvant. Yeah, yeah. When is the last adjuvant stage two you've treated? Only on clinical trials these days. It's a rare patient. And even then, I think I've done one in the last six months, maybe. So even then in the clinical trial setting, if we look, we've had access to stage two treatment on a number of clinical trials, probably like four or five from memory, and the short period we had an access program. Over that time period, my use went down. Down, so. So my recruitment on the first stage two trial was much better than the last, you know. I think for stage two, the very people that would be motivated and wanting it, are the people that would follow up and have checkups and scans. And the fact that we still yet have no survival data for the higher restating of stage three, of treat now versus later. For me, I'm very disinterested in treating in the dark, exposing to toxicity, having no idea of drugs working or not. I think it's an old process. Paradigm. Yep. And I agree that idea of speaking to our patients and saying, oh, they go, how do we know if it works? And I say, we don't. We only know when it fails. That's adjuvant. You only know when it fails. And that's when it comes back. And that's a rock on their shoulders, really, that they have to carry. Whereas neoadjuvant is powerful. Not only is it better from phase three, nadena trial. It is better. And from the swag phase two, randomized trial. But it's information for the patient. It is such a patient-centered treatment. Whether you don't respond well to neoadjuvant, at least that's information and knowledge and knowledge is power for the patient. We can change up the adjuvant. The other big, really important adjuvant paradigm. And this is important for people to treat other cancers. So Alex treats breast cancer, our treat, colorectal cancer. Unfortunately, for colorectal cancer, our cancer patient gets adjuvant chemotherapy and then recurs. He or she invariably has incurable disease. Yes, the odd person will have one liver met and be resected. But essentially recurrence after adjuvant for the vast, vast majority of patients. Or sorry recurrence after early stage disease. To advanced stage. To advanced stage. Is typically means you've got incurable disease. But that's gen, so because of that, generally the adjuvant clinical trials have shown an overall survival benefit. But in melanoma, there is no overall survival benefit that we can see. I doubt there will be one. Correct. There will be in the neoadjuvant I predict. And I doubt there will be one in adjuvant because we can treat later and still cure. So the ability to salvage either in the neoadjuvant study or in the advanced setting. And the keys not. Salved to cure. Salved to. Yeah, not salvaged to palliation. Yep. So that's a big difference. That's an important point where not like, you know, ER, PR positive cancer. And the training may lose that if a training is in clinic with me, particularly, you know, my clinic, and Alex's clinic where I may see an adjuvant melanoma. And the next patient I see is an adjuvant colorectal, all in the same morning. They're different. And the difference is huge. Yes. Yeah. Okay. So take home. We'll just a speech. Take home points. If we put that together, we're increasingly limiting our treatment to neoadjuvant and advanced stage using a lot less adjuvant, particularly in stage two, but even in stage three, because we can capture them if they recur locally or in advanced and we still can cure. And that's the big take home in terms of the treatment timing. In terms of duration, it's getting less and less. There are a handful of patients that need it to two years. And there's another smaller handful that might need it forever, but you'd biologically test whether they recur every time you stop. And then in terms of retreatment after toxicity, we didn't touch on that. But you can retreat depending on the toxicity. It's actually quite doable. Sometimes I stretch out the intervals between doses or I will dose reduce the iffy if they had a colliders on full dose iffy. But they're the sort of principles. And everything is in oncology, I was just saying everything in the world, is risk benefit. But if you had a patient you gave tox to and you gave them three or four or five years of disease control as insivival. And that tox costs them two weeks in hospital. So they re-challenge. They would re-challenge. The two weeks was worth four to me. Yes. And I think that's it. I just want to touch on one thing about not treating the adjement setting, which is another melanoma. A specific thing. You have to follow these patients closely with imaging. The patient we can cure when they recur is the patient we see in clinic who has asymptomatic disease recurrence. The person you are less likely to cure, not you see her. And the person you get a call from in the middle of the night from the emergency department with interest or your role of demer. And so therefore you've got to surveil them with imaging. Doesn't necessarily have to be you that surveils them, but they need to be surveilled. And for a clinician who treats other cancers, whenever you stage someone, their brain gets staged in melanoma. And that doesn't apply to color, or cancer, as an example. Brain must be, must be imaged. Yep, agree. I'm not sure I agree with you that if you, I agree we should be doing scans regularly. But even if you don't, and it turns up, if it's an immunogenic melanoma, it'll generally respond. Yeah, just if it doesn't, it probably wouldn't have before. But yeah, it's written into the Bible too. But I think it can be harder, because if you do present with large burden, intercerbral hemorrhage, it's scary. It's scary. It's artificial. Yes, it's harder. And then you often your drug choice is different, etc. Okay. Well, thank you all for that. We could, we could sit here for another hour and talk about that topic. There's much more we could do, but thank you all for that great discussion. Thank you for joining us for redefining immunotherapy lessons from melanoma, brought to you by melanoma institute Australia, and made possible by an unrestricted educational grant from Bristol Myesquib. We acknowledge the cameraegal people as the traditional custodians of the land where we have been recording today. And pay our respects. This discussion was accurate at the time of recording April 2026, but may not reflect the rapidly evolving treatment landscape and approvals in Australia. For more practice changing education, sign up to our melanoma education portal at melanomaeducation.org.au. Thank you for listening.