Evolving Treatment Landscape of HER2+ Upper GI Cancer

Hello and welcome back to the oncology brothers podcast. I'm Robert Gossane and here with my co-host and brother, Rahul Gossane. With our platform, be it these podcast discussions or live conferences. Our goal is to keep our fellow community colleagues up to date on this current standard of care and recent advances. Today, we are going to be focusing on front line, her two positive G E J and gastric cancer treatment options. To set the stage here, it is important to acknowledge that when we're talking about her two, her two positivity here is defined as her two IHC 3 plus or her two IHC 2 plus fish amplified. And roughly about 15 to 20% of gastric cancer ends up being her two positive and 20 to 30% of G junction adenocarcinoma ends up being her two positive. We had a chance to talk through testing in our discussion with Dr. Tony Bekai-Sab and Dr. Rondal Graham. But today, let's walk through our treatment options for her two driven disease here. For this, we're excited to have Dr. Sunny Kim, a medical oncologist from University of Colorado and Dr. Sam Citron and medical oncologist from Memorial Sloan Academy. Sunny and Sam, welcome. - Thanks for having us. - All right, let's dive right in. Sunny, we recently saw some exciting data at GIOASCO 2026 from Horizon GE A01 study with Zanidaatmap in front line settings. But before going there, could you please touch on the current standard of care for her two positive GE junction and gastric adenocarcinoma in metastatic space while we are waiting after you, approval of Zanidaatmap here? - Sure. So I think it's important to know that the Toga study was the first one to really show that her two antibody trastuzumab plus chemotherapy showed a survival benefit over chemotherapy alone. And then more recently, keynote 8-1-1 was a pivotal trial that showed that chemo plus trastuzumab plus pembrolizumab was superior in terms of survival for PDL-1 positive, her two positive gastroesophageal adenocarcinoma. So for my patients, these days, for patients who are PDL-1 positive with her two positive advanced gastric and esophageal adenocarcinoma, I do offer them adeoblachema therapy with floor permitting and applied-num agent plus trastuzumab plus pembrolizumab. If a patient is PDL-1 negative, I don't offer them the pembrolizumab. So that's our current standard of care right now. - So many thanks for getting us started. Is your treatment all that different for esophageal adenocarcinoma in frontline settings? - Not too much because most of the esophageal cancer we see here in the US is distal esophageal cancer, which we categorize as gastroesophageal junction cancer. And if you look at the eligibility, most of the trials include gastric and GEJ adenocarcinoma. - Absolutely. So again, to retrate the current standard of care and it's up in chemo with trastuzumab plus minus pembrolizumab based on that PDL-1 score, SAM, Rohit hinted on this already, data from GI ASCO-20206 around Zanidatemab from Horizon GEA-01 looks promising. Zanidatemab's already approved here in BILIRI tract cancer. Can you touch into study design and define things for Horizon GEA-01? - Yeah, absolutely. So this was a three-arm study. It was a global study, although I think it's important to note that it was an XUS study. So the three arms, it was RMA, which was the control arm of trastuzumab and doublet chemotherapy. And that was one of the reasons that it wasn't included in the US because pembrolizumab was already approved in the US. And so it was included in other countries in North America, but everywhere else in the world. And then RMB was Zanidatemab plus doublet chemotherapy. And RMC was the triplet, but really four drugs. Of course, doublet chemotherapy was Zanidatemab and the PD-1 inhibitor, TISIL-izumab. And just to speak for a moment on this statistical design because it was powered to compare RMC to RMA and RMB to RMA, but RMC and RMB, which of course we're all interested in, was not powered for that direct comparison. Given that design, what did we see here? - Yeah, so, and I want to even take a moment to just kind of talk about the differences between Zanidatemab at a functional and mechanistic level because I think that will ultimately play out to some of the findings that we saw. So it's a Zanidatemab by paratopic antibody. So it's vice-specific to two epitopes on the HER2 domain, extracellular domain 2 and domain 4. So the binding of trastuzumab and protuzumab, which I'm sure a lot of folks outside of GI are familiar with and especially in the breast space. And so this binding is in trans, which really leads to a reconfiguration and the formation of these HER2 receptors. And so that has a number of downstream effects. So it certainly has comparable antibody-dependent cellular cytotoxicity and phagocytosis that's comparable to trastuzumab, but there's increased intracellular internalization and an increase in complement mediated cytotoxicity. That's some of the mechanistic rationale for why it's thought this drug might be work better than trastuzumab. And so what we did in fact see the results of the horizon study that we're presented at AskOGI is that both arms B and arm C led to a superior progression free survival compared to the control arm. And arm C, the immunotherapy containing arm and an improvement in overall survival compared to the control arm B is, you know, overall survival. This is the first interim analysis. So it's still not the final analysis. And at this point just missed the overall survival cutoff. - Well, thanks very much for summarizing that, Sam. Sonny, your take on this, Sam just mentioned where we are missing that fourth arm. That is the chemo plus trastuzumab, plus pembroluzumab. As a result, at this point in time we'll be left with cross trial comparison. We will get a chance to dive into the side effect profile as well, which is infusion related reactions and diarrhea and how to manage that. Particularly what we are seeing at least the current standard of care is based on pdl1 positive score when we add pembroluzumab to chemo and trastuzumab. What's any data map combination? We are seeing this regardless of pdl1. Now, if this was to become available, is this going to be your preferred treatment option? - Although we weren't part of the trial and I think there'll be a learning curve with understanding how to manage a diarrhea, which I'm sure we'll go into later. When we look at the overall survival of the quadruple, the zanny, Tisley, plus chemo versus chemo plus Tisley, I mean, this is a seven month overall survival benefit. And in a modern clinical trial, the first line setting, we haven't really hit over two years and here, we hit 26.4 months. So this was quite impressive in my mind. I will definitely be using it, especially for my younger, fitter patients who I think can manage the side effects. Also, it's really notable to see the median duration of response also in the quadruple. It reached 20 months here. So although we are left with cross trial comparisons, you do really wonder what that Tisley is doing if it's providing kind of that longer benefit, the longer survival benefit. Based on this, I thought this was an overwhelmingly positive trial and I'm eager to start using it for my patients. Sunny, are you going to be utilizing PDL1 score or are you going to be administering this regardless of that? - Yeah. When you look at the subgroup analysis, what's really intriguing here is that for the PDL1 negative tumors, we're actually seeing more of the benefits with the quadruple, which is, I think, really counter-tuitive to what we've seen in prior trials that included PD1 inhibitor. So I think for our patients, especially with PDL1 negative, her two positive gastrosophageal cancers, this becomes an extremely attractive combination. And I don't think we quite know yet why there's a improved response in the PDL1 negative tumors with the addition of Tisley. Certainly we'll be investigating that more, but it really opens up an opportunity for our PDL1 negative tumors here. - And another thing that we have to acknowledge that majority of the herd two positive patients are often PDL1 positive. So again, once we have default data, it's going to be important to parse out who was PDL1 negative and what that really looks like. - Some of you brought up something. - Well, it's interesting because there's a higher proportion of PDL1 negative tumors in this study, like upwards to like 20%, which is higher than what we would have seen in other herd two trials. - Yeah, and just to piggyback on that for a second, we are seeing this response and benefit across PDL1 positive or negative. So you also touched on the side effects. I think this is a good segue to talk through that. Sam, you brought up the mechanism of Xanida Tamaab. It's biotropic. Here, Daria was a big side effect and because of that, five or a few bolus was actually emitted from the get-go into trial. This is something we are often doing in metastatic settings anyhow. Another small risk was infusion related reactions. This is bi-specific, but this is different than bi-specific antibodies that we're using in community settings for small-solent cancer or hemolignancies. This is infusion related reactions that we're seeing with Xanida Tamaab instead of the CRS that we tend to see with bi-specifix. Sam, can you touch on some common side effects that we run into with Xanida Tamaab? And importantly, clinical pearls are on managing these. - Yeah, absolutely. And I think you highlight a really important thing. This is not a bi-specific with the goal of geography, right? Bringing the T-Set. the T-selling gauge with bringing immune cells closer. This is with the goal of enhancing specificity and receptor saturation. And so the main side effects, you know, there aren't fusion reactions, but they're very similarly managed to infusion reactions that you have with chest to the map. There were slightly more, you know, I think in the trial, it was about 4% up from 2%. So still, not something that would ultimately lead to discontinuation and something you'd manage similar to how you manage infusion related reaction from chest to the map. The main side effect was really, you know, diarrhea. As you and Sunny mentioned, and for all patients, it occurred about three out of four, 75 to 80% of patients. It's very similar in arms, B and C, compared to about 50% in the chest to the map arm. And as you mentioned, you know, dropping the bolus and that's something I similarly do for my patients with advanced disease, you know, just the infusional five of a few, and they date Institute, diarrhea, prophylaxis that included a pair of my for the first seven days. And what they saw really was that this was a symptom that was early in the treatment course, or usually the onset was within the first week. And then it also dissipated. So it was something that really, for the most part, improved within the first few weeks. So I think it's really important to, you know, as you mentioned, sharing with our patients the expectation to coach them through, this is time limited. We can get you through this period because there is a really profound benefit with this, with this drug. And so, you know, pro, proactive is better than being reactive, a modium adding in a modal on top of that is needed to try and get patients through that first month or so. - Right, diarrhea and infusion related reactions are the key here. Sunny, with regards to managing some of the side effects, especially infusion related reaction, if one experienced that during the first cycle, any precautions to keep that in mind for the second time around, and also dose reduction versus dose skipping, how any clinical opponents with regards to that. - Generally, with infusion related reactions, I have a need to do, to reduce what I'll do as I'll add pre-medications next time with anti-histamines, as well as steroids if needed. And then I'll slow the infusion down. That seems to be quite effective at producing the risk of a recurrent infusion related reaction. And usually when they tolerate that, the subsequent ones, we can start off slow, but have a low threshold to speed it back up to the normal rate again. - Thanks for covering that. And given the fact that the drug still targets the HER2 pathway, as a result, the class effect of dilated cardiomyopathy that we have to sort of battle through any pearls with regards to still doing an echocardiogram at baseline and then repeating every three months there. - Yeah, it definitely, this is a class effect with HER2 directed agents. When we look at the incidence of this, especially in the quadruplet, it's still less than 10% and I think overall minor, we have a lot of experience with adjusting, allowing for a break from the HER2 agent if needed. But I think this is not as much of an issue, say, with the diarrhea. So certainly needs to be monitored. Don't expect it to be a major dose limiting side effect though. - I know this is something we're already doing, but trust is in that, right? And even out in community settings, when we are using CrestismEb and PratismEb, we're not seeing a whole lot of higher CHF here. So this is what I would expect with ZanidaptimEb as well. - Again, the class effect indeed. Now, same based on this discussion so far, I'm very comfortable utilizing this agent for upper GI space. Now, if the disease was to progress, that is at least based on the current combination that we have while we await for the FDA approval is still chemo plus stress to use the MAP plus minus IO, if the disease was to progress. We have TDXD based off of Destiny Child. What's your practice here? Could you touch on that? - Yeah, it's a great question. I would say even before thinking about what the next line of therapy is, I think when patients, especially with her two positive disease, develop progression of their disease, as much as I'm able to and is safe and feasible to do so, I try and get a biopsy, specifically of a progressive lesion. So sometimes patients will have, you know, the endoscopy and the fact that most patients have their primary tumor in place makes that a relatively easy place to biopsy. But if they have regression of their primary tumor and they have a progressing liver lesion or lung lesion, then I do try and go for that if the patient is amenable. The other alternative that I've been incorporating into my practice is getting blood-based, you know, molecular profiling, which if it's positive and detectable and especially if something I have a baseline, and there is still an ERVB2 amplification, and that can instill some confidence that their cancer is progressing not based on a loss, because we do know that it, you know, obviously from data from Cheshires to the map and not so much from Xanadana map, but at about half of patients who develop progression do so because of loss of her two positivity. And so another her two targeting agent when the, you know, cancer is growing because it has not no longer addicted to that oncogenic driver is not gonna be as effective. But presuming that the tumors retained her two positivity, then Cheshires to the map, Dr. Rux T. Can would be in my second line choice, exactly as you mentioned, based on the destiny gastro-go-for trial, which was presented at the last ASCO. - And just to reiterate that TDXD is approved only for that her two positives, so that biopsy is mandated for us to use that, Sam quickly around the dosing here. This is different than what we tend to use in other diseases when it comes to TDXD, 6.4 milligrams per keg or 5.4, which is what we tend to use in breast or lung cancer. What is your practice around TDXD dosing? - You know, I mean, it's a targeted agent, but it is chemotherapy. And so I come to it with the mind of similarly, how would I dose chemotherapy in the patient that I'm treating, right? You know, it's a second line setting. So these patients have received chemotherapy before and their performance status is, you know, a wide range. We know either, I don't remember if it's nationally or globally, but more than half of patients don't even get to second line treatment in this disease. So we have a lot of work to do. And part of that is just because when it progresses, it can become so aggressive. So while 6.4 is the preferred dosing, you know, don't want to let perfect be the enemy of good, or however exactly the same goes. And if it's something that I'm worried, their blood counts or their fatigue or performance status or LFTs can't tolerate the full 6.4 dose, then, you know, I started a dose level minus one, but kind of keeping that in mind that even though it's targeted, it is still chemotherapy. - Absolutely. Sunny, do you tend to start at 6.4, makes per keg or 5.4, makes per keg and majority of your patients when it comes to TDXD? - I actually do start at the higher dose, but very low threshold to dose reduce, especially if this is a patient's second line therapy, I feel like they're a little bit more robust as opposed to, if I'm using TDXD in the third line, obviously with every line of therapy, these patients to get more fragile and I totally create a perfect as the enemy of good. And, you know, I think we have to understand that in these clinical trials, this is a different type of clinical trial patient versus what we see in the real world setting. - And then one has to keep the side effects in mind. Sam, as you stated, this is still chemotherapy, so we have to battle nausea, alopecia, fatigue and also importantly, ILD, because there are mortality associated with it. Sunny and Sam, before we close here, could you please tell us any key takeaways from the conversation today? I'll start off with you, Sunny, before. - Yeah, I think from an efficacy standpoint, this is a clear winner and I'll be offering list of my patients this therapy, but I think, you know, with the side effects, I have a colleague here who has told, you know, those running these trials that just own your side effects, you know, really be able to prepare the community, people have never used this drug, what they're in for, because it's fair to the patients to let them know what to expect, but like Sam mentioned, you know, we do expect the diarrhea to improve after that initial bout and hopefully, it'll stay tolerable for patients. - Indeed, exciting times we are seeing impressive results while we await for the FDA approval. Sam, are your final thoughts here with regards to what we've discussed today? - Yeah, Sunny mentioned, the majority of us have not used this. It's a proof-of-billionaire track cancer, but that's rare and, you know, the phase two study was very few, a small number of patients. So most of us don't have experience with this drug, but we didn't have experience with Zolva Tuxemab before that, you know, was a new drug that's now approved. So we will learn and we'll be proactive about the side effects, but the benefit I think is quite clear. - Indeed, at least from oncology standpoint, we see about 40 to 50 drug approvals each year. So we at least are very much adaptable to acquiring these changes. Well, Sunny and Sam, thank you so much for walking us through the current standard of care and recent data what we are seeing in her two positive space. For our listeners, let us go or a quick recap from today's discussion. For our listeners, just to quickly recap our discussion with Dr. Sunny Kim and Dr. Sam Citron, we touched on the current treatment options and new data that we are seeing in her two positive GE Junction and Gastro-Getanocorsanoma. Write this very minute. Our frontline treatment option for metastatic GEJ and Gastro-Getanocorsanoma is chemotherapy plus Trestusemab, where for PDL1 positive disease, we add Pembrolyzemab. Rahul, thoughts around the new data here. - I wrote that GI ASCO 2026. We saw data with Sunny, that the map with chemotherapy and immunotherapy, resulting in overall survival benefit here. If this is approved, this is very likely going to be our new standard of care. But with this, we have to keep diarrhea in mind and that small risk of infusion-related reactions. In the clinical trial, five FU bolus was omitted. This should be our practice in metastatic settings. In this study, we also had prophylactic antidiureals for first week. This is something that should be on our radar. We also touched on the data with TDXD in refractory settings. This is based off Destiny Gasfic 04 study. With this, though we have used TDXD now for multiple malignancies, nausea, fatigue, alopecia, and ILD is something to keep on mind. Thanks for joining us. Stay tuned for more discussions around treatment algorithms, FDA approvals, and conference highlights. We are the oncology brothers.