Redefining Immunotherapy (Ep. 3): Immunotherapy Toxicity: Prevention, Early Recognition and Management to Optimise Outcome

[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 Vodka series, Read Finding Immunotherapy Lessons from Melanoma. This is episode three where we'll focus on immunotherapy toxicity. How to prevent, recognize early and manage immune related adverse events to optimize patient outcomes. If you haven't listened already, I'd encourage you to go back and listen to our earlier episodes where we discuss how cancer hijacks and hides from the immune system, how immunotherapy works and the evolving approaches to making smarter treatment decisions in clinical practice. 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 Annesh De Silva, dialing in from Portugal. So we're now gathered to talk about immunotherapy toxicity. Don't fall through the floor everybody. It can be tiring, it really can. But prevention, early recognition and the management of toxicity to actually optimize outcome. Now I say that managing toxicity to optimize outcome, yes quality of life, but also survival we think. So let's open it up, who wants to start on this topic, very important topic and something that scares people from going for our doublet immunotherapy, which may cure, well it does cure more patients. Alex. So where do we start? Toxies is really important in any setting, whether it be neoagement, adjuvant, metastatic. It is a key thing that we want to minimise and as Dr. Ian said, we want to prevent it, where possible. Can we prevent toxicity? Let's talk about that, let's start with that. That's one of the first things the nuances of managing and between us, we'd have 50 years of experience of this at least we would. Yeah. 15 or sorry, you're too young. I don't know that you should be here out of math. So I guess a prevention of toxicity. Yeah. I'm going to flip that because I don't think we can prevent it in the current climate, but I think it's more about predicting who's at risk of it and selecting treatment to minimise that. So can I budge in there? I do think there's a way we can prevent it, but I'll talk about that after you've talked about what you're going to do. So when we give, obviously the single agent versus combination, the risk of toxicity is different. When we give immunotherapy on its own, which is what we do in melanoma, it's actually easier. When you give it in combination with chemo that can have additional mimicking different toxicities, it can be hard. You get neuropathy when you're on chemo and immuno or you get a lung infiltrate on a taxane and a PD1, it can be tricky. But I think so. The drugs you pick can determine the risk of toxicity, but the patient as well. So the classic thing that we deal with all the time in melanoma is underlying autoimmune disease. And we know people that have underlying autoimmune disease have a higher risk of flaring of their underlying toxicity. They probably have about a similar rate of a denover new toxicity, but that underlying flier is a challenge. And you published that. I think that was the first paper to publish that in the whole of the world in terms of immunotherapy and the analysis of oncology. What year was that? I can't remember now. It's 20 years. Long time ago. 10 years ago. Yeah, Alex, you were first author on that demonstrating and proving that, but you keep going. So autoimmune is something we flag. In fact, when a patient walks in, we have a box we tick, whether they have their own autoimmune disease, or whether they have a family history of autoimmune disease. So I think that's definitely that's a risk factor. It beyond that, it often can be difficult to try and predict who is at risk of getting a toxicity. These toxicies can occur in any organ at any time in young people, older people, good performance, poor performance status, do not seem to align with the underlying cancer, which is interesting in melanoma. We see a whole lot of people getting vitiligo when they get immunotherapy as a toxicity, but you don't get people with kidney cancers getting nephritis or lung cancer getting pneumonitis more often. And are any toxicities associated with good outcome? So in melanoma, we believe vitiligo is. The problem is by the time they develop it, you already know they've responded to treatment. And possibly tharatoxicosis may be associated with response to treatment in melanoma. They've been studies on other cancers looking at other things, but they're probably the more common ones that I don't mind seeing, shall we say. So Matt, I want to hear how you approach, let's say we've got a patient. Let's go to our most toxic regimen, which is an avolamab combined with epilumamab and PD1 CTA-4, because I want to talk about this. So I'm going to make you talk about it so I can talk about it too. But patient walks in, you've never met them before. They've got liver mets and bone mets, lung and maybe subcut. They're 42 and they're V600E. So you're going to reach for the combo. Easy choice. Easy to or clinical trial, but you know, you're going to go that way. Let's go epinevo this time. How do you talk to the patient about what to expect? And then how do you actually manage it? What do you do? So I think the first thing to say is that, you know, there's a lot of room for improvement in space. We've all had patients where we think we've sort of really drummed in the education about talks. And yet we'll see them in an emergency department. And when you question them in an emergency department, they'll say, "I've had diarrhea for five days." And you know what I said, "Call." This was one of the things to call about. So I think a couple of things, that's important. It's education. And you've really got to target your education to the patient. I think there are some patients who have different health literacies. In some patients, it's the partner or the child who's the main person that's going to be that, if you're like gatekeeper, they need to have access to you or your team. So, you know, for that, for services like mine, who are fortunate enough to have an MIA funded CNC, that contact is primarily that CNC. So a clinical nurse consultant? Yes. Who's at the front? It'll be different for everyone. The other thing that I think I'm really now putting into my education is this idea that talks and even stopping for talks is not bad. There is this phobia that we will stop their treatment. And if we stop their treatment, they die. And even if it's not stated, it hangs underneath them. So they put up with bad joints or they don't call you with the diarrhea or they don't tell their wife they've got the diarrhea. Because, and I think I now explicitly say that. And I often say, I have patients who got one dose of this stuff 10 plus years ago and are cured just to really get it out there. So I think this is a really important point and I'd love to weigh in here if I may. You may. Because thank you, thank you. Because we come from a tradition of chemotherapy. We come from a tradition of you've got to get the cell cycle. It's either going to be every two weeks. It's got to be every three weeks depending on the chemotherapy and it's half-life and what it's doing. And we treat two talks and we try to support the patient through the talks with your GMC SF for your anti-naudia prevention. This is different. This is not about treating to maximum talks. This is actually about stopping at any sign of talks because it's the immune system. It is not directly killing the cancer cells. So I'm with you. The way I do it now, because I've refined it now over 15 or between us 50 years, I always write things out because every patient's different and I have three things I say, I say, what do you have? What's this mean to the risk of your life and then what are we going to do about it and then go through things. But for ipinivo specifically, I write a timeline. I go zero weeks and then I go three, six, nine. And I say, this is today. I'm seeing you today. You'll get your injection maybe in a week or so and I put a big IV. But we're doing bloods today. I'm going to see you in three weeks, but big question mark. Most people don't get this second dose. I might delay it for two weeks or I might not give you any more and I might do an early scan. And that's because and I reinforce it once the light switches on, your immune system, it's on. You don't see me standing at the light switch, keeping it on. So I use a lot of analogies and really entrench this idea that you're probably not going to get your second dose and that's okay. So then when they come in and I said, we're not going to go, oh great, great. I'm not giving my second dose. My immune system's activated. I've got a bit of a CRP. They might even just a CK, a grade one hepatitis. I will not go with the second dose because we now know 70% of grade one twos. If you give them a second dose, we'll get a grade three. So that's how I do it now. Yeah, and I think that communication can't be understated because everyone has patients that didn't even talk about this every visit and yet there was four days of worry. The other challenge for patients conceptually, I think, and to be honest, how health systems are set up is typically chemo-tox, at least symptomatic tox, is after the dose. So right, you get full fox today. The nausea is early or late, but late means day four or five, right? The colitis is not day four or five, it's day whatever. And I think, so the whole way people's brains think is I, and how many patients ask you, "Oh, you know, it's slightly older patient," the daughter says, "Oh, if they got treatment on Monday, should I spend Monday night at their place?" Monday night is not the important night. No, it's actually Dave, for the first dose, you see it with the T-cells. It's about day nine to 14, where you might start to see the first C-R-P rise. And then when you give your second dose, it's basically any time after the second dose. But it's different. Yeah, with chemo, you say, "Look, actually, it may not be a bad idea to stay with mum or dad." Yeah, yeah. The first night, whatever. Alex. So I think, yeah, as you both said, it's all about education and immunotherapy education, not just general cancer education. Great. For the early years, we had people going to group chemo education to hear about their immunotherapy treatment. One-on-one education, ideally from, ideally, the nurse whom they will call if they have the toxicity is ideal and setting up those, the principles about one dose at a time and see how you go. We don't want to dose two toxicity. We want a dose to affect. Yes. And I think that that does. It does. Really, really important. And I think even. How do you read the immune system? Let's talk about that. So we're talking about how we dose not to toxicity. So they come in a week three. Let's go wrong the time. Like come in a week three. You've got the epinevo book, but you may not give it. What are you reading? What are you finding out from the patient and their bloods to make that decision? So, look at it. So, like always, I'm assessing response. You can actually detect response already. You can see their lymph node shrinking, their performance data says improve. If their pain is reducing, they're clearly getting better, ignoring all the rest of stuff so that their efficacy is obvious. We can sometimes see that. Or we're looking for any signs of toxicity. Now, just because you've got a little bit of toxicity doesn't mean you can't go ahead, but you've got to think about that. But what does that look like? Think about people out there who may not have treated as many patients with pure immunotherapy. Give us some fine. Like, you know, minor thyroid function changes. So they get a mild thyroid. Would you stop for that though? I would not stop for that. Why? Because it's irreversible once it's said in and it's not going to change how it is. Yeah, I wouldn't stop for that. Grade one hepatitis, so it's gone from normal 35 to about 55. If it was epinevo, it's a different discussion than if it was PD one month. We're talking a young guy with epinevo today. If it's epinevo, I might delay a week and repeat the LFTs and see what happens. And then you do another week and they're still grade one, but haven't gone up, but they're now 52. Would you go in? I would be. I wouldn't. I'd be tempted to give it a bit longer and maybe do an early scan and see if they're responding. That's it. Yeah, I would come with some. We know not only our clinical experience, we've published on what we call hyperacute toxicity, sort of bad tox after the first dose, but we also got trial data from after two dose epinevo. We're talking about one here, but even after two with a scan, often very early responses are seen, you can drop the epi. It's the epi that often drives a lot of that early tox. So if I'm in doubt at all, I just hang ten. I won't give it and I'll just do a scan, get them back. You've got time. Yeah, I also think there's some really subtle, not even enough to be called a tox signal, but. Give it some. So one that you see often when they push is this, they describe this kind of relatively mild fatigue, but definitely real fatigue. I think it's not. It's not like the PD1 afternoon two o'clock need a nap fatigue. It's more. It's obvious it's a change. It's after the first or second dose of epinevo. And it's often worse with the first dose or second dose. Sometimes a few fevers. That. The itch, I think, is actually a relatively okay. So often before the rash. That one's associated with responses. Yeah, and on bloods, the subtle bloods ones are. You know, you don't even get to the threshold of being called thyroid, but the TSH is to press the T-force normal, the air-synaphyl count that's gone from low normal to the top of normal. Oh, yeah, that's. All these little things that I think if you look hard enough, even patients on trial where we don't do this clinically, but you know, the lipase just flips up, you know, where you're not checking in the real world, but it's probably happening in lots of patients. Yeah. And I'm low to call them tox. Certainly I describe them to patients as minor, blood abnormalities that may sense that your immune system is being activated. Yeah, I say that exactly that. And I don't even call it minor. I'd say we've got evidence of immune activation. I don't want to hammer you too much. Let's just hang ten a bit and maybe do an early scan. Sometimes if I have a cluster of a lot of them, not just the fatigue, but a bit of fever is a bit of fatigue. The CRP's gone up to 30. A few things and there might be elderly or frail. I'll just hang ten. I really. The other one I think that happens quite often, particularly when I'm giving single agent in our older people, a sort of polymalger-like symptom, is really arthritis mild. They're all vagueness. They try and play it down because they don't want to stop and I'm still okay. And then you sort of look across and the wife's like, "No, he's not great." Because they all are worried. I think they're the sort of cues that we get that not all is well. Yes. Often the nurses know before us because they've had the chat that they've had to do actually before and they can sense things aren't right. I think they're the cues we get. And of course, we're talking about people that. If you've got highly ramp and aggressive disease and you're 40 and we've got to turn this around quickly, you can die. You may want to play it. You may want to. Yeah, you may, but remember if you're activating the T-cells and gets the cancer you're doing it, you're on your way. You can delay a week. You can delay two weeks. If we know we've all fallen into that trap in our having uses so much, you're better off waiting a week and just checking those LFTs one more time. But I'm going to move to another topic on this. Yeah, I was going to ask you something. Get anxious, but go for it. Yeah, probably. I'll probably. No, because one thing that I'm loving, I completely agree. I think the discussion about toxicity is very important and you touch on a lot of things. There's one thing that is important also is. So less is more sometimes and I think this is one of the cases because one thing that is I have to explain to patients I normally do is if we push too hard, then we are probably doing more harm because then we have a high toxicity, we have to give a lot of steroids, then we are doing the opposite that I keep explaining. So does that make sense to a stimulatory immune system to fight cancer? But then on the other hand, we are destroying your immune system with steroids. That's a good idea. So if we overdo it too much, we have to switch it all off and that might not be good for your cancer. Yeah. And it's much worse. So I use that also to explain to patients. Yeah, that's a good point. And I was just going to say on the back of what Anish was saying, we're talking about steroids and how no one likes steroids. I hate that. I think we in melanoma and increasing our oncology colleagues are really aware that we want to try and use as less, if you get tox to use as little steroids as possible and it's how do we get access to more targeted therapies? So this is beautiful. This is exactly what I wanted to get on to next. I was going to ask Anish, but let's go with you, Alex, and then go to Anish on this. So this is about specific tox we see a lot, especially with the bad tox. So we're talking hepatitis, collitis, the neuro tox, which can be very broad. There are three awful tox, any of the neurotoxy, and catalytides, the ascending neuropathies, the radiculopathies, the transverse myelitis, like it can come in any form, the aceptic meningitis. I mean, I've just mentioned 5 or 6 that can come. Plus diurea, which is the collitis, plus hepatitis, they're probably the worst, whatever one is going to be. And the myocarditis. And the muminitis. So the. Numinitis, we're getting. So that one, just get them to walk up and just take their oxygen and dry cough. But what would you like to say about managing those horrible ones? Yeah, so I think. So, you know, early recognition is key, and early intervention is key. I think what we are still dealing with in Australia, and I think around the world, is because often you need other specialties to either do a procedure to diagnose it, or to let you access therapy to treat it, it's getting people to understand that whilst these conditions mimic the idiopathic conditions they've learned about through their whole career and they see all the. So all sort of collitis, Crohn's disease, this ain't that. So you might be an IBD specialist, but when epinevo collitis comes in the door, it is not all sort of collitis, and it isn't something that's going to need a lifelong immunosuppression. You don't wait six months on steroids before you qualify for an infleximab. These things need being treated early. So rheumatology, this isn't something that you wait six months for a appointment. Yeah, methotrex say this, that just get on with the IL-6, knock it on the head, etc. Can you give us more on that collitis thing? Because I know with infleximab and VEDA loser-mab. Yeah, so look at. We know that if you've got a. bond or clear cut walking in the door patient that's two weeks after their first dose of it be an evil perfectly well and has torrential watery diarrhea that they don't have any other infective symptoms they've not traveled no one else to sick it's clearly they've got urgency nocturnal you know diarrhea it's a pinnevo colitis we get so frustrated waiting and waiting and waiting to well you've got to give them intravenous steroids and you've got to wait for them to go back to orals and then fail on the orals and then we'll scope them and then what would you like to do I'd like to give them infleximab in emergency yeah and they go home the next day and when we've been able to do that it's a very good outcome when you get it early and you get infleximab or sometimes if you get it really early and it's a bit milder villisma and stop the ebenevo for pizza any patient walks in with even three new loose don't give more ebenevo that is one time you have to hang ten probably never get another dose treat the watch the diarrhea send it for a car protector so I think so I think I think the most important test to be honest is excluding infection yeah that's full stop yeah you know and the two parts of that are history and the stool culture history is think I when was the last time you had a patient that you were surprised had effective now look I can remember honestly distinctly yeah out of you know arm and less nowadays because I'm on new ones with the management and usually the history is great you know the amount of them that get viral gastro of the optically grandchildren my parents is you know the grandchild who they babysit on Thursday brought it back but I think look this side so that's a point just to make that patient walks in do a stool culture and a cow protect and get the infleximab in their arm if you can but try not to wait too long for them to fail steroids if you have to go that down that path before trying to do it if the steroids don't turn it off in 24 hours yeah you should be thinking about it and you wouldn't necessarily wait for the viral stool culture to come back before you start steroids if someone's got great and a good story and a good story so I want to make that one last point before we go on to our next topic and that is and we learnt this as medical students and as physicians training 90% of anything the diagnosis is in the history 90% of the diagnosis in the history so so I just had a patient today came in on the weekend with back pain load down that then transferred to a headache then cramping pain down the back higher up then pins and needles and a few visual disturbances as far as I'm concerned that's a radiculopathy until proven otherwise needs to come in have a ck might be a triple M she feels weak but not quite and she needs an MRI lumbar puncture and an MRI brain right the history tells you everything she got a dose of steroids one dose IV and everything's fine and she's sitting up oh we want to stop the steroids no we need to investigate this the history is bad anyway so just to re-emphasize everything we just said on that so I guess but I guess one last thing to summarize that a lot I think with with good education and early recognition yeah even with our more toxic regimens they can be very safely delivered and the majority of our patients do not end up with life-changing permanent toxicity correct and they're alive with cured cancer so I think this should not be the barrier yep for a treatment that can be curative and we don't give all the immunotherapy we do not stick to that regimen if you get one dose of ib be nivo and they've got a great response you don't need to go to maintenance nivo either necessarily so all right that was a great discussion thank you 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 Myes Squib 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