Managing Toxicities of EGFR Inhibitors: Afatinib, Amivantamab-Lazertinib, Osimertinib

Speaker 1 Welcome back to the Oncology Brothers podcast where we focus on the latest updates and clinical pearls for practicing medical oncologist. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain in our ongoing series of Talk Shock. Today we're going to focus on common anti EGFR drugs that we are using in non small cell lung cancer with EGFR mutated disease. For this, we're excited to have Doctor Gilberto Lopez, division Chief and a thoracic medical oncologist from the Sylvester Cancer Center. Gilberto, welcome back as the last time we spoke was around World Lung 2024 conference where you had presented Skipper study focusing on how we can reduce infusion related reactions from Amivantamab. Given topic in hand, of course, we'll touch on that and a lot more. Thank you for joining us. Speaker 2 Hi Rahul and Rohit, always a pleasure to be here. Thank you for inviting me and let's get this started. Speaker 3 Gilberto welcome. So we recently covered metastatic non small cell lung cancer with actionable mutation in frontline space. EGFR space is changing way too fast. For the longest time we had a fat NIB and then ocmertinib give an incredible response and importantly really good tolerability. But for now, in 2025, we can do better than just ocmertinib, that is with amivantimab and lozertinib combination or ocmertinib with chemotherapy. But with any of these, we have to manage some of these side effects. Can we start off with afatinib first, which is now often reserved for uncommon ETFR mutations. But with this drug, we have to worry about diarrhea, rash, paronychia and mucositis. Can you touch on some of the clinical pearls and how to manage these in your practice? Speaker 2 Absolutely. The definition of getting old is when you remember things that used to be standard of care and that you don't really use anymore. Let me go back to jafitinib and erlatinib, which were the first two Canny's inhibitors that started using before we knew about the GEOPHARM mutations, specifically sensitizing mutations. And gefenib was a little easier to give than a lotnib, but they were both relatively easy drugs, especially when comparing with doublet chemotherapy containing platinum agents. What we worried about the most was skin toxicity. You have the acne form skin rash that we still are used to seeing today with Azimark name and maybe even more with a fat name. But that's when we started looking at this. In the beginning when we did not test for mutations, we liked sea rash because that was associated with better outcomes in clinical trials. That was one of the things we liked seeing because we thought it was a pharmacodynamic evaluation showing that the drug was doing what it's supposed to do. And indeed, what happens when you blockage of the thyrogen kinase inhibitors as well as monoclonal antibodies such as zytuximab and penetumumab that we use more in colon cancer than lung cancer, maybe a little bit in head and neck cancer for zytuximab as well. But what happens is that when you block your GFR, you do have effects in carotenocytes in the skin and you have cell damage that leads to secretion of cytokines by the immune system. You have IO 1, you have TNF being creased that creates an inflammatory milia and that ends up making it more possible for commensal bacteria to grow and cause infection. And with that, we have the spectrum of activities and measures that we can take to try to help. There's a few things with the skin toxicity that are class effects. We know, for instance, that exposure to sun, for us in Florida, that's a big deal. We have people that work as baseball coaches and are now on an event and actually it's it's funny that the most common reason I get second opinions for patients on Amivantam is because of skin toxicity. They want to know if there's anything else that we can do and we'll we'll get to that eventually. But these three things, you have the effect on retinocytes from the drug effect itself, you have inflammation and you have secondary bacterial infection. Usually for jafetnibin, nerlatnib, you did not need to start from the get go with oral antibiotics such as doxycycline or Minocycline. We treat it as and that's also true about the Mert nib. But with drugs such as a fat nib where we see more toxicity, we'd have to be more proactive. Fat nib has the same class effect in terms of toxicity in the skin and around the nails. For a fat nib, we tend to start antibiotics from the get go. We always tell patients to wear sunscreen and follow the cocoon regimen when they get a fat nib as well with their Latinib. With your fit nib, with Azimark nib, we don't quite need to be as aggressive, but with a fat nib we do see more skin toxicity. We do that as well, and I'll talk about that in more detail when we get to an event amount. But the thing that bothers me the most with the fat NIB, the thing that makes me extremely careful when I use a fat NIB, is diarrhea. Diarrhea happens for almost every single patient that gets the drugs, specially at the full dose of 40 milligrams. We also see grade 3 diarrhea, which is not something that we see with the other agents. Of course it can happen, but it's extremely rare and we do have patients complaining of some liquid stools or more often or soft stools, but it's really not as bad as the diarrhea with the effect. I have to say the only oral EGFR inhibitor that I've had patients coming into the ER because of toxicity was a fat in it patients developing diarrhea and actually needing IV fluid. So that's the one thing that we have to be very careful with a fat in it. Other things in the skin, Xeroderma, the dryness that we see, those are all things that been managed similarly for agents. Pneumonitis and interstitial lung disease, that is something that we need to cover because it can happen with any of these agents. And for instance, aerotnib, when it was initially used in Japan, patients were admitted because of the rate of ILD being more common in Japan. We don't quite understand exactly why, but that was such a common occurrence that many patients would be admitted for observation for the first few days. We don't see that as a problem as much as reduced with antibody drug conjugates, but it is something that can happen. It is something that you need to keep in mind. Of course, it's the pneumonitis that is different than the autoimmune mechanism that we see with immunotherapies. It is often just an infiltrate here or there. More often than not, they're asymptomatic. But if they do become symptomatic, that is something that we need to manage. Especially if patients develop shortness of breath, we often stop the drug use steroids. But you always have to have a degree of suspicion because the only way to detect will be with CT scan. That can happen not just with the fat name, but with any of our EGFR inhibitors. Speaker 1 A lot of this is class of fact. Gilberto, you touched on this, but the diarrhea that comes with afatinib is not trivial. We're using olzomertinib in adjuvant settings in consolidation settings. The reason we're not using afatinib in adjuvant settings in consolidation settings for these uncommon mutation is for that reason we always have to keep that benefit and side effect profile in mind. Keeping your patients on afatinib for three years or lifelong is not as hard. Speaker 3 Gilberto, a quick question about afatinib. Whenever you're tackling some of these side effects, the initial dose of afatinib is 40 milligrams. Do you do dose reduction or skip a dose or rather manage the side effect and still stick to the original? Speaker 2 Dose. So with afatinib within to be more aggressive with reductions in practice we'd start everybody at 40 milligrams, although for the occasional patient who's much lower weight, older and on multiple drugs and sometimes we might start at 30. Usually the recommendation is to start at 40 and go down as you see toxicity. So azimertinib was approved as kind of a home run drug. You have better efficacy and less toxicity and we usually don't see that. Usually we see better efficacy at higher at least different toxicity and ozimersenib was truly a home run. It is a drug that not only makes patients live longer with better control of disease, but also with fewer side effects. The difference is not that big when we compared to jafetnib, but it is bigger when we compared to erlotinib and afatinib. Skin toxicity is much less. It does occur, but it's much less than what we see with afatinib and certainly much less than what we see when we add on monoclonal antibody that targets EGFR as well. Many of the usual measures of sunscreen, trying to stay away from the sun. Interestingly, there's some gender association. Men tend to have worse toxicity with the class and then to stop the drug more often. Even though we thought that it might actually be the other way around, and even though it is not severe toxicity in the sense that we as physicians are used to see, this is something that bothers patients a lot. Having a skin rash all the time is not something that is comfortable. So we need to get better at managing it. Again, I'm going to focus more on what we do for that. When we talk about an event, a map, I'd like to talk about a couple of things that are not that common but important for people to know #1 the dangerous one, which is cardio toxicity. We don't do echoes for everybody, or we don't do the same type of follow up. But remember, her 2 is an AGFR class inhibitor, an AGFR class molecule, and we'd have the same potential for CAR toxicity with the GFR inhibitors as we have with her two inhibitors. But of course much less often we do EKG's to make sure to QT interval is not prolonged and stays within an acceptable range while on treatment. Although we don't do it forever, we tend to do it before treatment and for the first few months and eventually we almost always stop doing it. But for those patients that do have a history of cardiac issues or high risk or heart failure of those patients we are more careful. Some estimates have put that between 2 and 20%. The probable real number is somewhere around 5%. So one in 20 patients can develop cardiac. Somebody on Ozimark them starts having trouble breathing. You have no issues with the disease itself. The scans look control. Make sure you do get an echo to a certain name that the EF is still good. One more interesting, the thing that we see with azimertinib is elevations in creatinine. And while you can see actual acute kidney injury with azimertinib, more often than not what happens is that azimertinib blocks a pump in the kidneys. I think it is MAT 1, which is a multidrug and toxin flux pump. And what happens is that you stop injecting as much creatinine as you would usually do, and of course, the serum creatinine goes up. What we would do usually before sending anybody to see a nephrologist is to check site statin C, which is another way of measuring kidney function and glomerular filtration that does not depend creatinine. And most of the time that is absolutely normal and then you don't need to worry about it. Then it's also classic to see mild thrombocytopenia when we have patients on Ozimertin as well. Speaker 1 In my practice, I've done echo every three months for high risk patients on ozimertinib. That's a hard to class mutation. We're looking at monitoring them and picking this up early on can make a world of a difference. Again, because these patients are on these medications lifelong and when we're talking about these drugs, they're not benign, but ozimertinib has been one of the best tolerated drugs that we've seen. But again, the reason for us to keep bringing up Amylaz is because now we're doing better than osimertinib and that's where Miracles a study also comes in. We are seeing almost a year projected overall survival when compared to osimertinib. That's huge. But let's talk about Amy Labs Amivantamab Losartanib combination. Speaker 3 Let me jump on to that Gilberto OC Martineb. Do you do dose reduction or skip a dose 80 milligrams? Do you go down to 40 when you experience some of these side effects? Speaker 2 So absolutely, we have enough evidence to suggest that if you reduce the dose because of adverse events, you do not have a detriment in terms of efficacy. So we don't need to worry if you have to reduce the dose because of toxicity, you do not need to escalate it back. So if you have grade 3 toxicity and you have to reduce the dose to 40 from the standard 80 milligrams, which is not common but does happen, I have a number of patients that have had to reduce and use 40 milligrams as their standard. That is something that we absolutely have to keep in mind. Speaker 3 All right, perfect. Let's jump into the ambivantamab and lizard combination. Here are your thoughts on skip, IRR, cocoon and BT prophylaxis. Speaker 2 Very exciting times. I have to say that we were not as excited when we saw the PFS that initially almost two years ago we were OK, this is great, but it makes sense if we add chemotherapy or if we had a different agent that is going to block EGFR in a different way and with MAT and inhibition as well, we will have a better PFS. So does it really matter now? We really wanted to see overall survival and last year we saw the data predicting that we had more than 85 to 90% chance that the overall survival would become positive. And indeed we have seen that for Amy Lazer already that the European lung cancer meeting, it is clear that you can have much longer survival. You already mentioned infusion reactions. That's a major problem with amyvantamab when it's given IV. We have the split dose you get day one, you get day 2, you get weekly for the first five weeks and then bi weekly from week 7 on. And almost 70% of patients get infusion reactions that are not particularly dangerous but are extremely scary. And again we go back to cytuximab. This happened to a number of patients on cytuximab as well. Not that the same 60 to 70% level, but we had more than one patient when we started using cytuximab that ended up having hypotension in the ICS for 24 hours. Nobody ever died as far as I know from that. But it is very scary. It's something that if we can prevent, will make things a lot easier. Subcutaneous version not quite approved yet and that does make the infusion reactions a lot less than we see with IV. And as we presented with Skipper, by using higher dose dexamethasone as a prophylactic treatment before we do 8 milligrams BID starting two days giving one day prior and then 8 milligrams one hour prior to infusion as in the Skipper trial, we reduce that to about 25 to 30%. So it's something that we do as a routine now. The skin toxicity is truly what makes patients uncomfortable and that interferes through their quality of life. Not in terms of pain or any discomfort, shortness of breath, etcetera, but having a skin condition chronically, the patients can choose not to have that. They always would. Absolutely. Usually in terms of risk, we tell patients not to use very warm water when they wash their hands or when they wash their faces or take a shower. Hot water does make the skin more susceptible to the side effects. We also tell patients to avoid direct scent exposure to wear sunscreen. And then now we do have a formal regimen from the Cocoon study, which compared that standard treatment, which is you don't give anything besides just the usual recommendations in terms of lifestyle changes. And of course you could give patients topical or, or antibiotics once they develop symptoms versus a very proactive regimen that includes not just the oral antibiotics, doxycycline and or Minocycline, but as well as a ceramide based moisturizer. It's used once a day. The interesting thing about this one is most moisturizers we have to apply continuously and this specific types of moisturizers that include ceramide you can do at least once a day and that makes it easier, as well as a chloroxidine skin wash that helps us really attack all those mechanisms that cause the skin toxicity except for the EGFR part of it, but that without a doubt decrease the toxicity. And we saw the results that European lung cancer meeting as well, showing that you go from almost universal bothersome. I'm not going to use grade 1-2 and three, because I think that our NCICTAC is not ideal to manage toxicity because 2 can be pretty bad and two can be not a problem at all. If you have 5% doesn't bother you to 12% of the that's grade 2. But you can also have grade two that is not quite interfering with your activities of daily living, but it's covering your whole face. That's 18%. You can always remember the rules of nine from burns to estimate quickly what percentage of a patients skin is affected. Having gone through the toxicity, what do you do? Randomized trials show that by using doxycycline you can prevent that toxicity. And now with the chlorxidine wash and the ceramides based moisturizer, this should get better. But what we do when the skin rash is not controlled, So those reduction, of course those interruption, those reductions are extremely important. Topical retinoids is not something that we do because that does make the skin even drier and it can increase irritation. All the retinoids have been shown to improve skin toxicity. They have done these fascinating randomized trials and more with cephexamab than with amivantamab, of treating half of the face and leaving the other half untreated. Antibiotics topically have shown some effect in those trials, but topical retinoids actually not only did not help, they made things worse. They made the skin drier. That is not something to suggest, but oral retinoids you certainly can use when it's so severe and it bothers patients that much. This is something we can use. Always reminding colleagues that you should stop any tetracyclines or doxycycline before you start the retinoid so you can use retinoids if the toxicity is bad. It takes three to four weeks for things to improve, but you should not continue the doxycycline when you do that. You might be able to use other antibiotics. Sometimes if we don't see a response with doxycycline, we can use sulfatrimetropine. You can use other cephalosporins as well and you do see some responses, but it's always a good idea to start getting your dermatology colleagues involved when things are dead severe. But it is certainly the big question mark when we think about using Ambilizer. Of course, there's also the risk of blood clots. Both CDT and PE are an issue and we recommend that for the first four months you should be on adequate anti regulation. The medium time to a thrombotic event was 90 days, so at least four months of treatment is what we tell people to do. When you're using Ambien laser together with new agents such as Apixaban, we do not see a lot of bleeding, but you do need to evaluate patients cannot have any bleeding. Diabetes, you need to make sure that they don't have any contraindication and so on. So it does make the decision making process a little bit more complex. Speaker 1 Jill Berto, thank you so much for covering all that and again, a few things here. I said that the diarrhea from afatinib is not trivial. These side effects are not trivial when it comes to subcu formulation, which is not yet available. We're hoping we'll see less infusion related reactions. What you also brought up was keeping these cutaneous side effects and prophylactic anticoagulation. The good thing here is these side effects are predictive. So we have a road map ahead of us, but again, they're not trivial. We have to get better in managing these side effects. Gilberto, can you touch a little more about the infusion related side effects? If you do have infusion related reaction first time you're exposed to this drug, what next? Can we bring these patients back to reintroduce amivantamab? Speaker 2 So it's a fascinating side effect that it only happens the first time you use the drug for 95% or more of patients. It's a very unusual, we don't quite understand the mechanism. In a number of studies by the Inventimab we have looked at different markers of histamine release and a number of different things and we just can't find why. The interesting thing was that it happens for the first infusion but almost never happens again. It doesn't on occasion happen, but it's very rare. The recommendation probably will be to continue using the higher dose of decks that even when we do the subcutaneous conversion because you still have 20 to 30% when you have the subcutaneous. So you might reduce that even more, although of course that's extrapolation. We don't know that for a fact. Speaker 3 Thanks so much for covering all that, Gilberto. Managing toxicities is not just about comfort for our patients, but also about maximizing time on these effective therapies before we close. With regards to where Amy and last, they can sometimes have very common side effects. Do you go about decreasing dose for both of them or how do you go about dose reduction there so? Speaker 2 Actually, we try to reduce, you can't always tell what's causing what, but we tend to reduce the amivantamab first, OK. And then the laser depending on the toxicity with laser is supposed to be a little bit less than what you would see with monoclonal antibodies or even with other HFR inhibitors with the exception of azimertlin truly is something that you have to gauge in most trials. We kind of reduce both, but we don't really love the idea of reducing everything at the same time at the TKI still is the mainstay of treatment, so I usually prefer to reduce the meventamab first and then laser as needed. We will have more clarity moving forward as we start using more of these drugs. We will be able to test and fry different things. We'll see how that goes. Speaker 3 Well, the common theme is early intervention is the key here. One has to be super proactive. Jill Berto, thank you so much for taking the time to walk us through the common side effects and clinical pearls around anti EGFR drugs that we commonly use in our practice. For our listeners. Let us go for a quick recap. In today's discussion with Doctor Gilberto Lopez, a thoracic medical oncologist, we had a chance to discuss the key side effects for common anti EGFR drugs we use in our clinic for non small cell lung cancer with EGFR mutations. Thankfully, our patients are living longer due to these medications and managing side effects is the key to maximize time on these effective therapies. For a fat nib, managing that diarrhea with prophylactic antidiarrheal can be very helpful. When it comes to ausimertinib, though well tolerated, some low grade side effects can overtime be bothersome. Speaker 1 When it comes to amivantamab and lizertinib, there is a significant OS benefit here, but this is coming at a cost of unique side effects. Thankfully, most of these side effects are predictable and potentially preventable from being proactive to prevent infusion reactions to starting patients on prophylactic anticoagulation to prevent that VTE and then being aggressive and prophylactic cutaneous management is going to be the key here. We tend to see most of these adverse events with this combination early on, usually within first four months, but then they start to improve. Thanks for tuning in. Make sure to check out our other talk Check discussions, treatment algorithms, and conference highlights. We are the oncology brothers.