Managing Toxicities of EGFR Inhibitors in Lung Cancer – Drs. Azam Farooqui & Joshua Sabari

Hello and welcome to another episode of the Oncology Brothers Podcast. I'm Rahul Gossane. I'm here with my brother, another community oncologist, and your co-host, Rojid Gossane. In today's episode of our TalkShek series, we're focusing on anti-EJFR therapies and non-small salon cancer. You know, it's great to see that these new approvals and combinations have resulted in improved overall survival, but let's focus on how we can keep our patients on these medications while also preserving their quality of life. To touch on this, we're excited to have Dr. Joshua Savari from NYU Langone Health and Dr. Ozom Rookie from Ironwood Cancer and Research Center. Josh and Ozom, thank you so much for joining us. Josh and Ozom, welcome from TalkShek Portion of it. It's an important topic at hand because what we are trying to see is how can we retain that quality of life for our patients so they can stay on these therapies safely for a longer period of time? So for today's discussion, we'll be talking about two single agents, Dr. Ossane Martinab and a fatneb and one combination that is Emmy Vantemab and Lizurtneb. Though given a strong data at hand, we are rarely utilizing single agents. We are using combination that is Emmy Lazz based off of Meriposa study or Aussie plus chemo based off of Flora II study. And how and when to pick one or the other, I'd encourage you to tune into our treatment algorithm podcast for this. All right, starting out with a fatneb. That is a second generation TKI. Josh, can you walk us through where does a fatneb fit in your treatment algorithm briefly? And what toxicities that stand out and clinical pearls around us? Yeah, so fatneb is a second generation EGFR inhibitor. And it's actually an EGFR and her panher inhibitor. So I don't commonly use it in the activating or common EGFR mutations anymore, such as X on 19 deletion or L858R. I believe the only time I'm using a fatneb in the recent era is in my patients with uncommon or atypical EGFR mutations, such as G719 or S768. And you know, fatneb has common EGFR and her two toxicities, most commonly cutaneous toxicity, such as rash, for example, arrathema, redness, we also see some's arraderma. We can also see significant GI toxicity. So diarrhea is quite common with this therapy. Rare, but we do see interstitial lung disease with this agent. And then some of the less common things that I've seen is, you know, ocular toxicities of conjunctivitis. 40 milligrams is the starting dose, but row it, most of my patients, I'm starting at 30 milligrams up front, actually, if I'm gonna use it. And I do dose reduce, we usually dose reduce by 10 milligrams. So if you start at 40 milligrams, we dose reduce to 30. And if you start at 30 milligrams, we dose reduce to 20. Actually looking historically at the efficacy and the 40 and 30 milligram dose do look to be equally efficacious in this population. One important thing to note though, is we don't see significant CNS penetration with this agent. - Josh, thanks for getting us started. You know, I can't remember the last time I used this. And it was likely for that uncommon egeopharmutation, like you mentioned. And that was also before we had these stronger options that are available now. And again, here, skin toxicity, diarrhea, that small risk of ILD, this will also come up with ulcer and muretinib. Those are the things to keep in mind. Awesome. - Before we go on, with regards to the fat nap, we have to keep what Josh stated was that diarrhea. That's rather the main reason we have to go about the ghost reduction. - Absolutely. This was very common in cumbersome. And a lot of the side effects where if your LFTs are going up or your white blood cell counts are going down, that's very different than diarrhea where patients are going in and out of that bathroom and are complaining and bringing that up. That plays a big role in quality of life. - Just a comment on this quality of life issue that we see toxicities and patient-seed toxicities. I think we do best for our patients when we see the toxicity from the view of the patient. - Absolutely. - Asom, let's bring you into the conversation. Anything to add here before we move on to awesome orthinib? - I think Josh covered it perfectly. I would also agree that I rarely use it. I think for like the S7 and S6AI and you know, a few other rare mutations which I don't have that many of. But definitely the ghost reductions either to start with or I think anybody I have on it has now been reduced. So I really don't have anybody on the full dose. Knowing that there are adjustments in place and that the efficacy is there, a really key. Because as we're probably gonna talk about what other treatments, I think any time I'm dose-reducing I think you can kind of see patients shiver a little bit of like it was just gonna harm me as far as my long-term control of disease. So I think this is a great example of a drug that definitely is gonna be reduced at some point. - That's a great point. When we dose reduce, we have to educate our patients that we're hoping to see equal efficacy. And there is data for dose reduction in these therapeutics. So important to tell that to patients when we do dose reduce. - And it's not only patients we're nervous to saying how much benefit are we going to lose. So I think these conversations are very important. Now on to osmurtenib, something that we've used heavily up until recently as a single agent in metastatic settings. This has also proved in adjuvant or consolidation settings for early disease. This is a third generation TKI. Asim, what are the toxicities you keep in mind with osmurtenib and any clinical pearls here? - I mean, such a tried and true drug. I think so many of us have great experience with this drug now. It's kind of in the king of the market for so long. But I would say, you know, the ones that we've listed here are probably the most common ones. The rash and some skin toxicity is something that we're seeing across the entire EGFR spectrum. But definitely something that we're counseling patients on in advance. I've had a few patients get caretidus, have to see an ophthalmologist. They generally get some kind of an eye drop. Most of the time they're fairly self-limited ocular toxicity and it's not something that we really need to make major changes for. They might experience so far. Cardiac toxicity, QTC needs to be monitored in every few months or so. I'll have an EKG for monitoring purposes and occasionally an echocardiogram as well to check for the potential for cardiomyopathy. ILD is definitely one that I've come across a handful of times where we have people who are getting pretty bad pneumonitis or interstitial lung disease from it. And so I think that's something that's always really key to key in on with lung cancer in general. And it becomes challenging when they've had radiation or they just have a lot of disease burning the lungs and teasing out, is it ILD from the osamiritinib versus could it be a radiation exposure effect or just the disease itself? And so that's one that I think I've struggled with as far as trying to diagnose it, treat according to steroids and then decide what to do with the drug after that. And then obviously some lab abnormalities with the electrolytes is another common one we've seen. Very rarely I think I had a case where I had some pretty severe anemia with the osamiritinib to the point where we had to do a bone marrow biopsy to look for aplastic anemia. Some of the hemolotic toxicities can be pronounced for some people. And then as we've kind of discussed with the fat nib, there are dose reductions that can be made. And so I definitely have a fair share of patients that we've dropped from 80 to 40. And to be honest, I would say that osamiritinib is very well-atalluated and majority of my patients have naples down the full dose. And then whenever we do have to drop to the lower one, I feel like they do fairly well with that also. So overall still a great option. Just obviously there are some better options with the combinations, but osamiritinib still think has a great place in the treatment paradigm. - And the big point here is osamiritinib is well-tolerated but not toxicity-free. The side effects one has to keep in mind our rash, diarrhea, dry skin, cardiac side effects like cardiomyopathy or QTC prolongation, electrolyte derangements as well, and that rare side effect of pneumonitis. Josh, anything to add here? - You know, I think that in general, my patients have underlying cardiac dysfunction. I watch them closely, right? I am getting echocardiograms on them, but in my patients who have normal cardiac function is very rare to see any cardiac issues, but what I do see though is fatigue. And fatigue is quite common. Upwards of half of my patients report some fatigue. So if a patient's reporting worsening fatigue, I do think about cardiac issues. You know, about 0.5 to 1.1% of patients have cardiac dysfunction. And I do tend to hold the osamiritinib until their EF improves. So if someone had an ejection fraction of let's say 60, 65%, they get an echo and it's 40%. I do hold the osamiritinib, resume, get another echo, and see if it recovers. If it does, we can dose reduced to 40, or I could continue on the 80 milligrams. But if they then have an EF reduction again, I do go to the 40 milligrams. It is interesting that if a patient has a persistently low EF, there are other third generation EGF RTKI that we can now utilize, including a lasertinib, which is very similar to osamiritinib and in clinical trials, it appears to have less cardio toxicity. Now, I want to be clear, the rate of cardio toxicity with osamiritinib is very low. But in a patient who experiences that, you can transition to lasertinib in this group. - Right, you brought up fatigue, Josh, with regards to fatigue now, when we are adding that with the combination of chemotherapy, we are seeing more of that. Now, moving along into our combination here, that is, amelast-based of meriposa study. With amelast, one has to keep a couple of things in mind, that is VTE, infusion-related reactions, skin toxicity, though with subcue formulation, which was recently approved, we have seen improvement in infusion-related reaction, which regards to skin toxicity, we have guidance around from cocoon study. Josh, can you touch on what to expect with amelast and supportive care around the cocoon study, what we are learning from that? - Yes, as we build on third generation EGF RTKI and look at adding novel therapies, so I'm eventhem having an EGF RTKI specific, we're clearly seeing better efficacy, better durability in this patient population, but I agree we're taking on more toxicity. So the most common toxicity, when I use amelast, which has EGF RTKI therapy and lasertin, EGF RTKI therapy, so dual EGF RTKI mission, you see more cutaneous side effects, things like, you know, rash, for example, on the chest, on the facial area, acne form, but we could also see more rash potentially on the scalp or the sideburns. We can also see things like infections in the nail beds and we can also see fissuring in the skin. So these skin side effects are quite common with this combination. So what we've done is we've looked at strategies to help mitigate or prevent this toxicity in the cocoon regimen. We know that using a topical emollient that contains seramide will dramatically reduce the rate of these cutaneous or skin side effects. We know that using chlorhexidine topical rinses to the nail beds and the toes will dramatically reduce the risk of infection in perinecia. We also know that taking oral doxycycline, 100 milligrams, twice a day, we can also use menacelycline for example. And there is topical clindemycin as well. These are antibiotics that help prevent infection. So we know with M.E.V.M.E.V.M.E.V.M. and Luzerdin M, there is a cycle of inflammation potentially if we don't intervene early, followed by infection. If we can break that cycle, we can allow patients to remain on therapy. It's important to note that we also can dose reduce or dose hold if we need to in this Asian population. But I think getting the skin or cutaneous toxicity is under control is critical to deriving that durable long-term benefit from this therapy. You know a few things to keep in mind here with that improved overall survival almost in years. Thankfully, some of these side effects are transient, particularly in first few months of the treatment and that discontinuation rate with this combination is low. Asim in your clinical settings, anything to add here is this contraindicated if someone is already on anti-cguagulation, be it for AFib or pre-existing PE or DVT? Josh had so many good points about the rash. I definitely want to just touch on that a little bit because I think it's such a striking side effect of this combo. And in the community setting, like I've had oncologists that I've talked to that are very hesitant to start this combination just for fear of the rash. So I think educating about the rash has just been so critical. And one thing that I found is that really it's the first three to six months that the rash really peaks. And then it's like suddenly a switch goes off and after a while the rash significantly improves. And so we try to get patients to really power through and stay on top of their prophylactic regimen during that time. And the other thing that I think a lot of patients will do is when their skin looks great, they kind of just slow down on all of the different prophylactic measures. And we have to kind of stay on top of them. So sometimes you really have to kind of almost scare or kind of get buy-in from the patient that you really have to do this kind of intensive combo. And a case of their confused if their skin and hair look great, but because they're not truly experiencing it. So I think that's been one challenge I've had in the community with the rash part of it. And overall the rash has become more manageable. As far as anti-coagulation, we definitely know that there were higher rates of VTE and some of the initial phase studies of this combination. As some of you already know, we are putting people on a prophylactic dose of a blood thinner. Per study for the first four months of the treatment, I will say that if patients are already on a blood thinner for some other reason, generally they're used on a full dose. And so I have not used that as a contra-nication to not use this treatment. If anything, they're on a higher dose than what was studied. And then for my personal experience and some of the experience of some of the community doctors here, I will say that we are extending the anti-coagulation beyond four months, although the trial did give that option. But I will say that some of us are continuing it beyond just because I think there's still some fear of potential risk there today. I'm hoping we can clarify further with more studies. And I agree. I think eloquent 2.5 milligrams twice a day is really my go-to in this patient population. The question of baseline brain meds comes up a lot. The question of lower platelets comes up a lot. I feel very confident if patients have sub-centimeter brain metastases that don't have any hemorrhagic component, I really have no issue with starting prophylactic anti-coagulation. I'm much more worried about the development of a VTE, the endosteromboembolism or opulmonary embolism on treatment. And the reason really for that first four months is because that's when we saw most of the VTE events on the trial. I agree with you as on that if patients are doing well, there's no issues with coverage for these anti-coagulants. I continue them because we know in general cancer patients and cancer patients with an EGFR mutation could benefit from being on anti-coagulation. Lastly, the platelet cutoff comes up a lot. Is it 100,000? Is it 75? For me, it's really 50,000. And less someone has active CNS meds that have hemorrhagic component. I feel comfortable using these agents in the 50 to even 75,000 range of platelets. Remember, third generation EGFR inhibitors are going to lower the platelets. And it's really not the number, but it's the trend. So someone is 250,000 platelets. And the next time you see them in clinic, they're 60,000. I'm much more worried about that than a patient who's 97, who then goes down to 50,000 or 70,000. So I think these are all really important clinical questions to think about. But we have a lot of experience now and a lot of data using these therapies and using this prophylactic or preventative anti-coagulation in this population. Oh, Josh, I am so glad that you brought that CNS story and use of anti-crackulation. This is sadly not an uncommon scenario where we have CNS involvement and we're questioning if we can safely proceed with anti-coagulation. And also with that platelet threshold, what we've seen, we are able to safely use anti-coagulation therapy. And also with regards to the dermatological toxicity, using retinoid supplements to help with the skin toxicity, one has to discontinue doxycycling and minorcycline. Josh, before we end this topic of anti-coagulation, if one is on prophylactic anti-coagulation for unprovoked VTE for any reason, are you increasing that dose to therapeutic level of anti-coagulation when starting MELAS? I'm not. If someone is on prophylactic dose of anti-coagulation, I would continue that prophylactic dose. And you brought up a great point as a thoracic medical oncologist. I'm somewhat chicken. If you're treating hematologic malignancies, 20,000, 12,000 platelets really doesn't bother a lot of the docs. Less than 10,000 spontaneous bleeding. But for me, 50,000 is really that cup point. In a patient with brain mats, I usually get my neurosurgeon involved just to get them to sign up. And so, I think the patients who are doing radiation up front, you have to remember that many patients live their full life with platelet numbers in this range. And again, it's more the trend, the trajectory than it is the actual absolute number. So, I don't think it's a contraindication to anti-coagulation. And again, if someone's on anti-coagulation already, either therapeutic dose or prophylactic dose, I don't add anything further that patient should be adequately anti-coagulated. All right. So, before we close, we touched on this in a fact, as well as all same-murtin. That is, if we are to dose reduce, we are not essentially affecting the efficacy or clinical outcomes. How about amy-las? If we are to dose reduce because of the toxicity, are we compromising any of the clinical outcomes here? So, we've seen robust data on dose hold and interruption. And interestingly, on the Mariposa trial, which is the original trial to define superiority for amy-vantumab and lizard, and it's over-awesome-murtinable-lone. In those patients where we held, and we looked at patients who were held versus not held, the progression-free survival was actually the same. Medium progression-free survival about 25 months in those who held, versus 25 months in those who did not hold. We've also more recently seen data on dose reduction, and you do seem to maintain the efficacy for PFS. We haven't publicly yet seen overall survival data in this patient. But just think about it in a common sense standpoint. If you want a patient to remain on a therapy, durably, the goal is to mitigate or manage side effects so that they continue to benefit from therapy. Interestingly, amy-vantumab has a very long half-life in the order of weeks, unlike some of the oral therapies we use that have half-life of days. So holding for one or two doses, you know, four weeks, for example, is totally fine in this patient population, particularly if you still have the lizard nib on board in the upfront setting. So, I'm going to do a problem with those hold, and also I have no problem with dose reduction in this patient population. Clearly, I'd like to mitigate the toxicity and see if I can improve it without a dose reduction. But if I can, I then do dose reduce. So, I'm going into those hold first, and then dose reduction thereafter. Dose reduction or dose hold to optimize that long-term outcome is clearly important. So far, a few things that we've touched on for a fat nib. We have to worry about rash and diarrhea with Aussie mertinib, that rare side effect of pneumonitis or other common side effects like electrolyte derangement should be on our radar with combination of amylase. We now have subcue formulation, which has less infusion reactions, and this can be given every four weeks, but we still need to be proactive at skin lotions and VTE prophylaxis. Asim, as we close, any final thoughts from your end in delivering this care and community settings? I think we've covered a great deal, and the only addition is obviously we have the subcutaneous version of amyventinib now, which cuts down infusion-related reactions significantly by, I think, about 80%. I think the VTE risk is also reduced for that too. And then one of the best things is you buy patients quite a bit of time back, because when they come in for that five minute injection, even if there is a monitoring period, you're getting them so much more time that they can be out in the real world, outside of the clinic with less side effects. So again, just looking for different things with cocoon and skipper, and then even with this sub-Q option to further the field as far as quality of life goes. It's great to be in this Egypthar space now, and so hopefully we have a few more studies coming out this year, so we'll just see what more we find out. Absolutely. Again, these interventions have resulted. and improved overall survival. Josh, your final thoughts here? - Yeah, I think great discussion, Osam. You made great points, especially with the M event that have subcutaneous. We really get rid of that infusion-related reaction. But we do see, still VTE, we do see cutaneous toxicity. So the point you made earlier about staying on top of the side effects, even if a patient is not having them as critical so the cocoon regimen, which we talked about is really important. And the VTE risk, we've sort of gotten rid of by using preventative, prophylactic anti-coagulation. So when you start M events, Mabin, and Luzerna, but it is a lift. It's a lot to think about and talk about with the patient. But if you want to achieve that durability with your patients, you do have to give the preventative medicines to allow patients to achieve that benefit on this regimen. So it's an exciting time for patients with EGFR, Mutant Lunk Cancer. I think monitoring toxicities, mitigating that toxicities, it's what's gonna allow our patients to have these durable responses. - Indeed, the theme is proactive as opposed to reactive. The big takeaway from toxic discussion is, how can we have these patients to live and stay on these therapies for a longer period of time safely while retaining the quality of life? Josh and Osam, thanks so much for taking the time to walk us through your approach and managing side effects with the EGFR inhibitors. On RN, let's go over a quick recap from today's discussion. - In today's talk check episode, we touched on EGFR inhibitors in non-small salon cancer, for Dr. Joshua Sabari and Dr. Asim Farouki. We started with a fatteneb, 40 milligrams daily, which is now mostly reserved for uncommon EGFR mutations. And even then, we're relying on other available options. For Osamurteneb, starting with 80 milligrams daily, this is still one of the most well-tolerated targeted therapies. But now with combination options in metastatic settings, this is not being used as a single agent frequently. That said, this is not benign, monitoring for electrolytes, skin rash, cardiac side effects, and that rare side effect of Nima Nitis is important. Roll head to your thoughts. - Rahul, to close, we touched on combination of amoevantimab and lizardnib. With amelaz, we have to keep infusion-related reactions, skin toxicity, and VTE on our radar. What we are seeing is with subcue formulation, we have decreased the infusion-related reaction, based off of what we've learned from cocoon study, we have decreased dermatological toxicity. From VTE standpoint, use of prophylactic anticoagulation for first four months is the key here. - But one last thing that came up, if we have to dose reduce or hold treatment for side effects to resolve, thankfully we're not compromising these outcomes. - Right, Rahul, I agree. Bottom line here is dose reduce, if need be, majority of these side effects we see for this combination are within the first four months, and being proactive is the way to go, rather. Thanks for tuning in. Make sure to check out our other discussions around treatment algorithms and conference highlights. We are the oncology brothers.