GI ASCO 2026 Highlights MATTERHORN, HERIZON-GEA-01, BREAKWATER, COMMIT – Dr. Rachna Shroff

Kicking Off 2026 with Practice-Changing GI ASCO Data You know, here I am, I'm still catching up with all that happened in 2025 and we are just a few weeks into 2026 and we've already seen some exciting and potentially practice changing data from GI ASCO 2026. Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosain, as always I'm here with my brother and your Co host Rohit Ghosain. Speaker 2 Right, Rahul, we just got back from GI ASCO 2026 and now off to Gu ASCO 2026 in February. But focusing on GI ASCO, we saw 100 abstracts presented and we have hand picked four key practice changing and practice informing studies to walk us through all that at hand. We are excited to welcome back Doctor Rashna Shroff from University of Arizona Cancer Center. Rashna, thanks so much for joining us and hope you had a great GI ASCO 2026. Speaker 3 Well, thank you both for having me and yes, I did. Even though it was early in January, it was a great way to kick off the new year. Speaker 1 We have very little break after holidays and New Year, but lots of exciting data to cover Rush now welcome for studies that we want to touch on. Durvalumab with FLOT: New Standard for Resectable Gastric Cancer Starting off with an update from Matterhorn, which led to the approval of their valley map with flat back in November 2025 for resectable GE junction and gastric adenocarcinoma for second study. We're sticking with the same disease site, but in metastatic settings. We'll talk to one of the biggest stories at GI ASCO Zanadatamab in frontline settings for her two disease. The last two studies are looking at metastatic colorectal cancer breakwater for B RAFV 600 E and the role of immunotherapy with chemotherapy and commit study to start us off with Matterhorn, we're now durvalumab with FLOT in periop and post op setting is the new standard of care. Here at GI ASCO 2026, we saw a few updates around surgical outcomes and outcomes if FLOT as a treatment had to be modified. Rachna, can you touch on this study in the recent updates? Speaker 3 Sure. So Matterhorn as we all remember was a practice changing study that looked at perioperative addition of immunotherapy with drvalumab to FLOT in patients with potentially resectable or localized upper GM malignancies. And as you mentioned, this is now FDA approved. This is now our standard of care and seems to be really an all comers in the sense that PDL one status and such is not part of that label. This update was really important because in the real world, FLOT is a tough regimen. We have a number of patients that have to undergo dose modifications. There are questions around surgical outcomes and morbidity after perioperative therapy. This update looked at ensuring that our patients who are having any sort of changes in flat dosing, whether that be dose modifications or changes or disruptions and therapies, what are we seeing? Are we still seeing that benefit with durvalumab? And in fact, thankfully and in a very reassuring manner, it seems like immunotherapy is here to stay and it's here to stay regardless of biomarker status, but also in terms of changes or modifications in FLOT therapy. And you know, the other, the other big question is in terms of surgical outcomes, how many patients may get to surgery? What are the adverse events from surgery? While we knew that there was clear safety data with FLOT and durvalumab in terms of the neoadjuvant therapy component, what we also wanted to understand is, is there any increased risk around the time of surgery? And so this update really was reassuring both from a we can allow for dose for changes in modifications in flight and regardless of the addition of immunotherapy, the adverse events from surgery in terms of complication rates, SAE, surgical mortality, everything really does not change with the addition of dirvalumab. Speaker 2 Right. As you both stated, dirvalumab was approved in November 2025. But right after ASCO 2025, we started adapting this in our practice. It was dependent on the insurance approval. The approval in November 2025 was based on the primary endpoint, which was the EFS. We also saw the improvement in pathological complete response, which was rather 7.2% to 19.2% in durvalumab arm. Median world survival is not reached with durvalumab and Russia. What you shared, what we saw here at GI ASCO 2026 surgical outcomes were not compromised at when with the use of duralumab. Zanidatamab + Chemo + Tislelizumab for HER2+ Gastric Cancer All right, moving into our metastatic space from early stage. This study was the talk of the town Horizon Gea 01, which is anidatumab with chemotherapy plus dysalizumab being potentially our new standard of care once approved for her two positive gastric and GEJ adenocarcinoma. Rushna, could you please go over the study design? Speaker 3 Absolutely. So like you mentioned, I think this is probably the biggest splash that came out especially in the upper GI space. This is a study that looks at zanadata map which is a bi specific biperatropic it hit it binds to two separate sites on her two, her two targeting agent. This study looked at patients with her 2 positive, which they defined as IHC 3 plus or two plus with ISH positive by central testing in newly diagnosed locally advanced and unresectable or metastatic gastroesophageal adenocarcinomas. This was a three arm study. There was the control which I'll get to in a second, which was trustezumab, the her two targeting agent of choice and chemotherapy. And then there was zanadatamab with chemotherapy, zanadatamab with tislelizumab or a checkpoint inhibitor and chemotherapy. The dual primary endpoints of PFS and OS were looked at. This was the first interim look, initial data that we saw the control arm of trusteuzumab and chemotherapy. The big question and we'll talk about it in a second is the KEYNOTE 811 data, which was the pembrolizumab with trusteuzumab plus chemotherapy. That data was only recently FDA approved, which is why the control arm was trusteuzumab and chemotherapy. The PFS and OS data was exciting. So the PFS improvement with zanadatamab and tisolizumab with chemotherapy was a median PFS of 12, 12.4 months compared to just over 8 months in the chemotherapy arm, highly statistically significant. Similarly median OS 26.4 months with tislelizumab, zanadatamab and chemotherapy which you know is median OS is that we haven't really seen in her two positive upper GI malignancies and this was statistically significant as well. Now we still are waiting there's it's kind of too early in terms of median follow up for us to have seen what the zanadatamab with chemotherapy alone arm does and that component is trending towards significance for median OS. There's a numerical improvement, but it's not statistically significantly improved. But again this was just the first interim analysis. So I think after more events they'll be able to update us on that data. But what I took away from this is we have a new her two targeting agent, you know the tislelizumab component we can get to in a second with the recognition that this hasn't been compared to 811, but to Keynote 11. But zanadatamab is a good her two targeting agent. And I'll say that as somebody who treats biliary cancers and has been using this drug because for the first time ever, biliary cancers was first to the first to the to the out of the gate when it came to zanadatamab. And I think what we now know is we have a new standard of care for her two targeting in combination with chemotherapy. Speaker 1 Thank you so much for touching on that. Can I just briefly reiterate 2 things. One, the mechanism of action now out in the clinic as a generalist, we're also using bispecific antibodies for heme malignancies, small cell lung cancer. This is different. This is a biotropic antibody. So we're not seeing CRS. We'll touch on some side effects here, infusion related reactions, but this is different than the other class of bispecific antibodies. The other thing you brought up, that comparator arm, this ended up being a global study. So Keynote 811 got that Pembro approved back in 2021 and by that time this study was already enrolling. So at that time, I do think the two arms that we have in here are fair competitor arms. But now we're stuck with that cross trial comparison. Yes, we're seeing PFS improvement in both arms, but that OS looks stronger with that triple regimen of Xani chemo immunotherapy. So can you touch a little more on this immunotherapy story once approved, are you going to use triple regimen for all comers or chemo versus ZANI? Speaker 3 Yeah, I think that's a great question. Unless we see numbers like what we're seeing with the ZANI plus Tis, I mean 26.4 months, you really can't argue with that. And I agree with you that you can't do cross trial comparisons. But when we're talking about media and OSS that haven't been seen yet, I think it's hard to argue with the fact that more than likely once FDA approved Zana, doubt about tisalizumab and chemotherapy is going to be our go to. So importantly, PDL 1 status and such, at least in the forest plots that were shown do not show that there's any impact on PDL one status in terms of that tislelizumab component, which is consistent with what we see in some of the other data as well. So to me that triple approach unless we start to see something with longer term follow up play out with just the ZANA data map plus chemo alone. So this should be the new standard of care. Speaker 2 Question, could you please drive in a bit more into the side effect profile because we will be utilizing this agent more especially after biliary tract cancer and even here in gastric cancers. So a bit about diarrhea with regards to the medical management and also infusion related reactions that we tend to see in part of the study design. What we saw was that five FU bolus was omitted just because, again from the diarrhea aspect of it. Speaker 3 Absolutely. I think the other important thing about the study design is the fact that diarrhea prophylaxis was in this study. For those of us who use anadatamab, diarrhea is probably the biggest issue. Infusion related reactions was a study specific a of interest. Thankfully those are pretty. They were first of all very low grade and second of all very easily managed. The diarrhea I think is the one thing that does stand out and you know as the slide is demonstrating diarrhea was a problem, you know, even with the trastuzumab arm. Just to be clear, we know that diarrhea is an issue in upper GI cancers in the treatments that we're using. But I do think it is important to point out that with the zanadatamab, even with prophylaxis, we are seeing a fair amount of diarrhea. I mean, all grades is, you know, 7080% in, in both arms and grade 3 is lower. But I say all the time grade 2 diarrhea for a patient is impactful in terms of quality of life. So that I think is going to be the important thing to watch as we implement this in the clinic. Speaker 1 Butcher, can you touch a little more on the infusion related reactions as well, even though they were low grade? Should we decrease the speed of the infusion? Skip a dose? How likely is it that we'll run into this again at the second challenge, given your experience with biliary tract cancer here as well? Speaker 3 Yeah. So with infusion related reactions, I would say that in the Horizon BTC study for instance, you know there was there was clear protocol, protocol modifications around slowing of slowing of the rate at resumption. We usually did not see any recurrence of infusion related reactions actions. I don't know that they have reported on those specifics yet on horizon in terms of what happened after slowing of infusion rates. But with our experience with biliary cancers, that's exactly how I've seen it in the clinic. You know, I would imagine maybe you all have as well. And same thing with diarrhea, I think aggressive management of diarrhea prophylaxis and treatment for my patients, I skip a dose and that usually allows it to resolve or improve to at least grade one, if not go away. And then sometimes there's dose reduction, sometimes it's more just reintroduction with, like I said, a little bit more aggressive diarrhea management and we've been able to mitigate it, OK. Speaker 2 Perfect. Encorafenib + Cetuximab + Chemo for BRAF V600E Colorectal Cancer All right. Now let's switch gears to metastatic colorectal cancer. We initially saw data for breakwater, which resulted in doubling of overall survival for FOLFOX with nkorafinib and cetuximab for that B RAFI 600 E disease. Here at GI ASCO, we saw data with Folfury and EC Russian. I can be touching this study and its findings. Speaker 3 Yes, absolutely. This is a study in metastatic colorectal cancer with B RAFV 600 E mutated colorectal cancer. And this was the the comparison this what was presented here was the 3rd cohort, which was basically the comparison of the of the EC of the CRAFT and Texmab with a full theory backbone compared to the control arm, a full theory with or without bevacizumab. And the primary endpoint here was overall response rate, but obviously other key secondary endpoints like OS and PFS were looked at and this was 147 patients. So a sizable group of patients. Basically what we saw was, is EC for the wind. Essentially what I learned from this is the backbone does not matter, which is a good thing. For some reason the US biases towards full Fox first. But for those of us that want to give that full fury backbone, it's still, you know, in B Rev V600E that Ankaraf and ipsituximab component of it is, is critical. So you know, we saw patient, we saw overall response rates almost doubled with 6060 5% response and importantly duration of response not reached yet. So patients who are responding or responding durably, again similar to what we had seen in the full Fox backbone response rate, survival, PFS, all of the efficacy endpoints are checking the boxes. And so, you know, the take away to me is, is that full theory or full Fox can be combined importantly safely, but also with important improvements in response and survival. Speaker 2 Right. So Rush now with B RAFV 600 E, we have known that this is historically a poor prognostic type of cancer. But here what we are seeing with already approved full FOX plus EC and now with full 30 plus EC, as you stated, the backbone does not matter what we are seeing as oral survival with hazard ratio of 0.49, which is impressive and you're not matured yet, but we'll see how it all plays out. Rachna, if the disease was to progress on this combination of EC plus full Fox, would you continue the EC portion and then adding full theory? Speaker 3 It's funny, I asked Doctor Kopats, who presented this exactly that question, because I said that is gonna be the real question, right? We wanna use the full theory after the full fox, you know, B RAF. B RAF is a driver alteration. It doesn't change. He said that he does not think that we have any reason that we cannot yet. However, there's some really interesting emerging data around the B RAF resistance mechanisms that could be influencing our approach and understanding of this. That being said, I think to me after upfront EC moving on to bevisism AB, a VEGF or you know, something else would probably make I would probably feel more comfortable with it I guess. Speaker 1 And what the extent of that progression is also going to matter, right? If I'm seeing isolated change, I'll lean into radiation and consider maybe switching that full foxy fold for you. But if there's gross progression, then I will feel more comfortable saying I'm just gonna switch my chemotherapy and drop off that EC. Speaker 3 Absolutely. Chemo + Atezolizumab for MSI-H Metastatic Colorectal Cancer OK. Now on to our last study, COMMIT study for MSI disease, we've already seen single agent immunotherapy or dual checkpoint inhibition approved in 2025. With ipinivo, we saw PFS improvement with hazard ratio of 0.21. Here in COMMIT study, we're looking at single agent etisaluzumab or Etisal with chemotherapy. Vishna, can you touch on this study and importantly, who would be that right patient for this combination over dual checkpoint inhibition? Speaker 3 This was a study that you know, again the these studies are designed and take time, right. And so this study was designed with looking specifically at the MSI high or mismatched repair deficient metastatic colorectal patients who were newly diagnosed with like you mentioned kind of the standard chemotherapy FULLFOX Bev with the otezilizumab versus single agent checkpoint inhibitor with otezilizumab. And what we saw was that the overall response rate with FULLFOX Bev and OTEZZO was around a little over 86% single agent OTEZZO at 46% PFS. Median PFS with the OTEZZO alone was was not particularly impressive. But with full Fox Bev and a Tezo hazard ratio was just over point 4.44 or so with a median PFS of 24 plus months. And what's interesting is we don't see that overall survival benefit yet. You know, I don't know, there's, there's a couple reasons for why we might not have seen that yet. I mean, a could just be too soon. But also I think, you know, there's probably a fair amount of people that went on to get other checkpoint inhibitors and such that could be driving that OS outcome. Now in terms of how to decide at the end of the day, like you mentioned EPI Nevo, that hazard ratio is hard to argue. But I will also say that EPI nevo is tough, especially in terms of immune related adverse events and necessary introduction of steroids. The people that look like they could handle a dual checkpoint but also really need that kind of dramatic response cyto reduction. It goes back to the question of full Fox theory versus full Fox. Like who do you give that kind of more aggressive approach? It's usually those people that need response cyto reduction, that have disease that otherwise could impinge on hepatic function, things like that. The other question is, are you trying to convert people? I was having a conversation with Doctor Overman, the senior author on this, about, you know, the perioperative utility of some of these approaches and how we know in the neoadjuvant space with the stalamab, for instance, that we're seeing these phenomenal responses. I think those are the types of questions and factors that would go into treatment decision making. But at the end of the day, you want to see if there's no OS benefits. I think that's the other big obvious question here. Speaker 2 That's right, with no benefit. This definitely begs a question with regards to the MSI high story. In early stage MSI high disease, if one has not received IO combination or single agent, I'd be relying on chemotherapy after surgery along with immunotherapy based off of atomic trial. And here in metastatic space, if MSI high disease, then single agent. But also this impressive data that we have with dual checkpoint inhibitor and Russia as you stated side effect profile has to be definitely considered there. Question before we close, what we saw at GI ASCO 2026 was exciting data from GLP 1 agonist for risk reduction of colon cancer. Could you talk more about that and what is there to learn for us? Exploring GLP-1 Agonists for Colon Cancer Risk Reduction Yeah, you know it, This is, I mean, this is really interesting data and I think is is begging the question of what all of us are trying to understand, right? Because if these GLP agonists are just going to be part of treatment in a lot of our patients, is it decreasing the risk of cancer is a decreasing recurrence risk. This study by Colton Jones and colleagues really looked at the risk reduction between aspirin, which is not an easy drug in some ways in terms of things like gastric ulcers and GI issues versus these GLP ones. I think at least from a flawed way of looking at this, we have not been able to study this yet. I think it's really provocative and intriguing that these GLP ones are probably having a lot of effects beyond the metabolic syndrome, obesity changes that we're seeing. I was talking, we did the ASCO press briefing from the study and Julie Graylow was talking about how this is being looked at across cancers right now. You know, breast cancer, there's so much data around risk of recurrence after breast and colorectal and other cancers as it relates to obesity and exercise. And you know, that was some other interesting data that came out of GI ASCO in terms of just moderate walking, decreasing risk of early stage colorectal cancer recurrence. And so I think all of these things are going to play in together. What we really need to do is prospectively study this because I think it's going to be impactful. Speaker 2 Indeed, there's quite a bit to learn, but we do need prospective study and long term data to utilize in our clinical practice. Comprehensive Recap of Practice-Changing GI ASCO 2026 Studies Rashna, thank you so much for taking the time today to walk us through these key studies from GI ASCO 2026 for our audience. Please stick around for a quick recap from today's discussion today with doctor Rashna Ashraf. We covered quite a bit from GI ASCO 2026 particularly focusing on practice changing and informing studies. We started out with durvalumab from Matterhorn study in resectable gastric and GEJ adenocarcinoma. Big take home message from this was that durvalumab improved outcomes without compromising surgical metrics and durvalumab improved outcomes even when dose was rather individualized. And then onto Horizon GE 801 where we have Zanidatamab in frontline settings. Speaker 1 Rohit, this was one of the motivated studies at GI ASCO and we saw that zanadatamab improved PFS by more than four months in both arms with or without immunotherapy. But the overall survival data looks better with immunotherapy. Speaker 2 With zanadatamab we have to keep diarrhea and infusion related reactions in mind. Speaker 1 Yes, without a doubt. Then to close, we touched on breakwater where it reaffirmed that ancorrafinib with cetuximab and chemotherapy be a FOLFOX or FOLFIRI. This should be our preferred approach for BRAF V600E metastatic colon cancer. Speaker 2 Right at last we touched on COMET study. So chemo with immunotherapy outdid immunotherapy alone for metastatic MSI high colorectal cancer. In my practice if there is no contraindication, I'll still be resorting to dual checkpoint inhibitors. I also want to quickly take the opportunity to remind the recent Five FU and Cape Sided being FDA label updates for DPYD testing for anyone that will be exposed to these medications. Thanks for joining us. Be sure to check out our other episodes on treatment algorithms and prior conference highlights. We are the oncology brothers.