Toxicity Management of HER2+ Treatment Options in Upper GI Cancers – Drs. Geoffrey Ku & Shruti Patel

Managing Side Effects in Frontline HER2-Positive GEJ/Gastric Cancer Hello everyone, I'm Rahul Ghosain here with my brother and your Co host Rohit Ghosain on our podcast The Oncology Brothers. Speaker 2 Hello, everyone and thanks so much for tuning in. In our first episode of the series, we touched on current treatment landscape for advanced and metastatic HER 2 positive GE J and gastric adenocarcinoma where the treatment options are trastuzumab with chemotherapy and along with that is with or without immunotherapy. At the time of progression, we tend to rely on TDXD. Thereafter, relying on systemic chemo has been the usual plan. While we are eagerly awaiting to see the data from Zanadatamab and TDXD in frontline settings. But it's important to appreciate that all these treatment options in Stage 4 setting are with palliative intent. So managing side effects rather becomes extremely critical today. To touch on side effects and how the field continues to evolve by the minute, rather, we are excited to have Doctor Jeffrey Ku from Memorial Sloan Kettering and Doctor Shruti Patel from Stanford University. Jeff and Shruti, welcome. Thank you. Speaker 3 Thanks for having us. Speaker 4 Yeah, it's a pleasure to be with you. Speaker 1 Jeff and Shruti, thanks for joining us. Let's start with where most of our her 2 positive patients are today in frontline settings. Rohit touched on this, trastuzumab plus chemotherapy, usually full fox or K box and then adding pembrolizumab on top of this if we have PDL 1 positive disease. Shruti, can you start us off on this? Some of the common side effects we see here with this upfront treatment and some clinical pros around these. Speaker 3 Yes. So I would say like, you know, the frontline side effects for these drugs are actually similar to the frontline side effects that you would get whether you're using trastituzumab or not. So the typical side effects with K Fox or FOLFOX that we see, you know, of course, fatigue, nausea, diarrhea, but we also see hand foot, we see, of course, the neuropathy. You know, and, and I, I just important to mention specifically in, you know, GEJ cancers that I think about the most is these patients have a lot of nausea and dysphasia at presentation, right? And so something to really think about in these patients that maybe you're thinking about less in your patients with colon cancer is that they're coming with upfront quote UN quote, side effects, right? They're coming with upfront baseline symptoms that we have to think about. So those are kind of really the ones that I think about from that end. Of course when we're adding pembro, we're thinking about the immune related adverse events. I gotta say that I haven't seen the very much of like the interstitial lung disease, the scary kind of immune related side effects like the Ilds and the, you know, myocarditis, sorry. And then but you know, of course immunotherapy is not without side effects. You know, thyroid dysfunction I've seen pretty frequently, I've seen adrenal insufficiency more frequently than I would like. And then of course the Herceptin coming in, in those her 2 positive patients, you know, we, we obviously always think about cardiotoxicity in those patients. I will say that a lot of the cardiotoxicity kind of, I don't want to use the word lower, but it's, you know, just of course think of Herceptin. We think of cardiotoxicity comes from breast cancer where we're using another cardiotoxic medication with the Herceptin. And so while of course all these patients get their echo at baseline, we get echoes every three to six months. I think it is important to remember that you know, those rates are lower than we see when you have two kind of a two hit cardiotoxic regimen compared to you know K box or pembro is not as likely to cause those side effects kind of what I'll. Speaker 2 Say, well, thanks for summarizing that Shruti. And as you said that chemotherapy in addition to Herceptin or trastuzumab, we don't tend to see additive side effects there, which is a good thing because we have been using trastuzumab not just in gastric cancer but in breast cancer for some time now rather over 2 decades. But keeping in mind cardio toxicity, which is a class effect of anti her two regimens that is getting echo at baseline and then repeating it every three months. And then you add chemotherapy and immunotherapy for those additive side effects. And especially when immunotherapy, we tend to think that this is better tolerated, but it still does come with a side effect profile. We cannot just take that for granted. Jeff, anything to add here? Understanding Zanidatamab's Diarrhea and Infusion Reactions And also you have been involved with zanadatamab clinical trials. We are very excited to see what GI ASCO has this first door there. But this is already approved in biliary tract cancers. Any thoughts about where we stand with xanadatamab and also side effect profile? Speaker 4 Yeah, no. So I think maybe coming back to the first point, I completely agree with Trucy's the kind of assessment of, you know, pembro Tras, well Tras, you know, chemotherapy with or without pembrolizumab. The only additional comment I would add is that, you know, the cardiomyopathy is absolutely rare, but in the handful of patients I've who had cardiomyopathy, I think typically in consultation with a cardio oncologist it is possible to continue with the trazuzumab, you know, with, you know with close MOD monitoring and with medications like ACE inhibitors and Arbs focusing. You know, turning to your second question, yeah, I think all of us were very excited, you know, on behalf of our patients to see the press release that the phase three studies, Horizon Gea 01, which is a first line study of zetadatamab and chemotherapy with or without tizzumab APD 1 inhibitor, that it's positive overall and that these results are likely to be presented at GI ASCO in early January. So I think the one thing to keep in mind since we're focused on toxicity management is that, you know, in the phase two studies of zanadamab and chemotherapy, again with or without tislelizumab, kind of an unexpected synergistic toxicity was diarrhea. So zanadatamab monotherapy, which again is is now approved in biliary tract cancer really has very little grade 3-4 diarrhea. And even in studies when it's been combined with for example, pack a Taxol, now not a lot of diarrhea. But I think it does seem like there's a synergistic toxicity when it's combined with a fluoropymidine containing regimen. And you know, in the phase two study of zanadatamab with chemotherapy, the grade 3-4 diarrhea rate unfortunately almost approached 40%. And then subsequently the, the, the regimen was modified so that everyone got mandatory leperamide prophylaxis for the first week. And with regards to the modified full fault 6 regimen, it was further modified to omit the bolus 5 FU. So when all these maneuvers were taken, the grade 3 for diarrhea rate dropped to a slightly more manageable 20 to 25%. So I think as we await and as we see the phase three data, I think it's clear moving forward that, you know, toxicity management, in particular diarrhea management is going to be very key to tolerability for our patients, but also ensuring that they're able to continue the treatment and receive benefit. Speaker 1 Jeff, thanks for touching on that again. Just to recap, this is right now only approved in biliary tract cancer and we're eagerly waiting on the data frontline for G junction gastric cancer in biliary tract cancer, a small hint of infusion reactions as well with zanadatamab. Jeff, can you touch a little on this, what to expect here with that? Speaker 4 Yeah, I mean they, they were thankfully relatively run-of-the-mill infusion related reactions of this such a thing. I mean, so in other words, most of the time, you know, kind of, you know, could be, you know, you, you they give pre treatment with, you know, acetaminophen, Benadryl and then something like Famotidine. And and I think most of the time it was grade one and two. I think also I think as as we have you know more and more clinical experience, it may be that you know, we might have to develop other strategies for infusion related reaction management including prolonging the infusion including you know the addition of all the pre medications. But certainly I think in the limited number of patients that that that I saw in the phase two study, they were relatively mild in terms of the spectrum of allergic reactions that we can see and they and they seemed relatively straightforward to manage, which you know, certainly is good news. Speaker 1 Absolutely. And I'm going to piggyback on something that you touched on already. No 5 Fe bolus. In metastatic settings, we're rarely using 5 Fe bolus. And in my practice, if there's No 5 Fe bolus, I'm also not using Lucovorin. Navigating Enhertu's Myelotoxicity and Dosing Decisions So again, that would likely help with more diarrhea going down the list of her available options here. TDXD is approved in second line and beyond. And on our end, we've covered side effects for this particular drug as part of our toxic series as well. But Shruti, when you're using this today in your clinic practice trust is MEP Doris T can what is on your radar and some pros around managing side effects for this. Speaker 3 Yeah. So the one thing I'll say is that I, I maybe try to think about the more common side effects rather than the rare. Of course, you always want to think about the rare fatal ones, but I think that we have, we talk a lot about the ild right, with Tres, Tusmandroxa, Tecan and we absolutely should. But if you look at the kind of data from Destiny Gastrica 1 cytopenias were five times more common than ILD. And I think you know, grade 3 neutropenia alone occurred in more than half the patients. And so I would say I really think about the marotoxicity as like the dominant day-to-day management issue, especially since in the first line these patients did get chemotherapy. We know, you know, of course their marrow is affected and so well, I of course always check. Do they have cough, you know, have you know any exercise intolerance? All of that. Every time I see them, I think the things that I'm really making sure is like, what are the labs looking like? I look at their trends over time. Are they, where are they going, you know, in the next few cycles? Because I think that that's something that of course we want to talk about the bad, you know, the bad, bad actor side effects that can really do bad things quickly. But I think, and when I think about their day-to-day, you know, the, the chemotherapy piece of the, the ADC is not trivial. And, you know, and I think that that's really, that's kind of generally what I think about when I'm thinking about like seeing someone day-to-day. Speaker 2 Well, thanks for covering that Shruti, when we're talking about TDXDV, at least from community standpoint, we have utilized this in lung cancer world, solid tumors in general because of the bucket approval and also heavily in breast cancer world. Though I, I tend to rely and define this to my patients as this is the class of Adcs which is wrapped rather in a better delivery mechanism, but it still has chemotherapy related side effects. And Shruti, you summarized it very well that common things are still common. We tend to see nausea, vomiting, fatigue, alopecia, and cytopenias. Yes, ILD should be addressed because there is mortality associated with it, but other side effects cannot be ignored. Jeff, anything to add here when it comes to TDXD? Speaker 4 No, I actually think you hit the nail on the head. I think sometimes I think we all forget and we think of it as you know a pure monoclonal antibody, whereas I think the way to think about it is that actually at the end of the day it is cytotoxic chemotherapy. So, so the cytopenia is, but I think the nausea vomiting is also under appreciated. So you know our mandatory kind of antimatic regimen includes in a palinosotron and a prepotent and with that it's a little bit more manageable. I think the other relevant point to bring up, you know, since we're focused on GE junction and gastric is unlike all the other indications you mentioned, it's actually a higher dose. So the dose is in a 6.4kg per kilogram and not 5.4. And you know, I, I, I have to say it was not entirely a, an entirely rational decision because I think when they looked at the totality of the phase one, phase 1B data, I mean, it seemed like toxicities were similar and you know, efficacy was not different in, in that small cohort, but they went with a higher dose. And that really is the only disease setting. And I think, I think, you know, that there may be some soul searching around whether 5, 5.4 is appropriate. I mean, I think, you know, Destiny Gastric 03, which looked at a number of fluoropinidine plus, you know, immunotherapy combinations with TDXD. You know, they ultimately did lower the dose in one of the arms to 5.4kg per kilogram because they were seeing too much toxicities. And again, but this is in combination with a fluoropinidine and, and, and immunotherapy, you know, on its own we, we ultimately don't have comparative data as to whether 6.4 is, you know, superior or comparable to 5.4. So there is some clinical judgement actually as to, you know, what dose to use even for our, you know, GE junction gastric patients. Speaker 1 Actually, before we run away from this dosing topic, this was also touched with doctor Ritika Mehta in the first episode. Jeff, in your clinical practice, do you rely on 5.4 from a majority of your patients or do you rely on a higher dose? Speaker 4 Yeah. You know, I mean, like what Shruti said, I mean, I think part of the issue, one of the challenges I think with the subway gastric cancer is that a lot of the times, you know, the baseline cancer related symptoms are knowledge of vomiting, anorexia, you know, so, so you know, the, the toxicities of our treatments initially compound that. And sure, if, if the cancer responds, then those symptoms get better. So I, I, you know, I, I, I think it really depends on, on, on the day and even the time of day. But certainly I think if there's a patient who I think you know, is, is is fit and, and has minimal symptoms, I think the idea is to try and give them, you know, the, the maximum benefit. And, and do I, I will go with 6.4. But I think if someone is a little bit more frail, I'm extremely comfortable with with 5.4. Speaker 3 I was going to say. Speaker 1 Sorry I. Speaker 3 Was going to say that I dose reduce liberally like if if they start, you know, of course, if they look unwell upfront to the point where you know, then I'll start at a lower dose. But I am very happy to dose reduce at the first sign of like adversity so to speak. Speaker 1 And again, coming back to this idea, using this out in the community settings, we use 5.4 for almost every other disease sites. So even for GE junction gastric cancer, my practice ends up being starting at 5.4 unless it's a very young ECOG zero patient, then I'm starting up high and going back to where we started. Looking Ahead: Novel HER2+ Therapies and Key Takeaways Saying that her two spaces rapidly evolving. Jeff, coming back to you, any key studies that you're looking forward to at GI ASCO 2026? Speaker 4 Well, again, I mean, I, I think that, you know, the, I, I think it's likely that the Horizon GA 01 study will be presented. But otherwise, I think certainly I think you know, a little bit behind that. You know, there are, there are novel ADC's, there are other Tkis. There are also kind of bi specific slash biperatopic antibodies similar to Zanadata map that are being developed in China. And I think, you know, there are also even cellular therapies that have kind of initially been looked at. So again, I, I think it's, I think it's an exciting time and I think if, if the, you know, Horizon studies are indeed positive, I think we find they will, you know, have the, and have the opportunity to move the ball forward after nearly 2025 years of, you know, trastuzumab being, being the, you know, the, the preferred drug. Speaker 1 You know these are exciting times, truthy. What's on your radar that might be relevant to our listeners? Speaker 3 I mean, I would just say like obviously we're, we're all really excited for a new first line option, right. We've seen the early data and it looks exciting. I, I will say that I'm really looking forward to the side effect profile. I think that's going to be really important. We know that trezituzumab it it's just not the most toxic drug. You're adding it to a lot of other drugs. And so I think it's going to be really with their newer, you know, anti diarrheal kind of prophylaxis and all of that. I think I'm really excited to see kind of this, the comparison in that table. That's what I'm really looking forward to. Speaker 2 Well, exciting time. Press release does look impressive, but again, we'll see how the data plays out in action. We've seen close to about 40 to 50 new drug approvals and indications in the world of cancer just this year and has been the trend for past two to three years. And I predict 2026 not being any different. We eagerly look forward to the data at GI ASCO 2026. Shruti and Jeff, thank you so much for joining us and sharing your thoughts around one of the most important topics that is managing side effects for available treatment options. Those tuning in, let's go for a quick recap from today's discussion. In the second episode of our GEJ gastric adenocarcinoma, HER 2 positive series, we focused on toxicity profiles and real world management in the frontline setting. What we have is trastuzumab plus chemotherapy and pembrolizumab gets added if the disease is PDL 1 positive, which is our current standard of care. Here. We often have to keep an eye out for cardiac side effects and infusion reactions and additive toxicity from chemo and immunotherapy. On progression with trastuzumab diroxycan at hand, we worry about nausea, fatigue, alopecia and ILD. Rahul, your thoughts from discussion today? Speaker 1 Yeah, right. Educating our patients on what to expect can go a long way. And in this discussion we touched on other anti her two options such as zanadactamab as well, which is for now only approved in biliary tract cancer. And we're eagerly awaiting on the data from Horizon Gea 01 trial. But side effects that should be on our radar for this include diarrhea, fatigue, infusion reactions. GI ASCO 2026 is almost upon us. We look forward to seeing you all there in person. Thanks for tuning in. We are the oncology brothers.