FDA Approval of Durvalumab with FLOT in Resectable Gastric & GEJ: MATTERHORN by Dr. Yelena Janjigian

Unpacking the Matterhorn Study with Dr. Janjigian If you're feeling overwhelmed by the amount of data coming at us in the world of cancer, you're not alone. We've seen close to 10 new approvals and indications just within the last month and more than 40 new approvals in the year of 2025. And as a community General Medical oncologist, we need to keep up with all of us. We're hoping that these ongoing bite sized discussions will keep us updated so we provide the best care close to home for all our patients. Good afternoon everyone. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain on our podcast The Oncology Brothers. Speaker 2 Hello, everyone. Rahul, you're right, FDA has been busy, that's for sure, which is exciting for our patients to their families and of course us as physicians. Today's topic at hand is Matterhorn study, responsible for bringing durvalumab in earlier lines for resectable GEJ and gastrocadenocarcinoma. To walk us through this data, we have Doctor Yolina Jinjekian from medical oncologist from Memorial Sloan Kettering and the lead author of Matterhorn Study. Yolina, thanks so much for joining us and congratulations for this remarkable effort. And before you start, I need to ask you this question. Whose idea was that to come up with this clever name of D flaw, Doctor Sam Klempner or yours? Speaker 3 It was all Sam. In fact, I don't use D flat. I use the development Plus flat. I'm kind of a purist and D is a little too informal and I think the complete name is warranted for this study. But yes, you were there at ASCO. Indeed, it was a crowd pleaser, as Sam Lafin is. Speaker 1 Absolutely, Elena, welcome. But before we get into Matterhorn study to set the stage for our resectable esophageal G junction or gastric cancer options were concurrent chemo radiation based off cross trial or periop and post op FLOT based on chemotherapy. But then aspect study at ASCO 2024 helped answer that majority of these patients have better outcomes with periop and post op FLOT. This year at ASCO 2025, your study, Matterhorn was asking the question if we can do better by adding durvalumab to our standard of cure chemotherapy. Helena, can you start us here with the study design and the findings for Matterhorn study? Speaker 3 Absolutely. Matterhorn Study Design and Impressive Survival Data Mattacorn is the first global study to address this question in gastric and esophageal adenocarcinoma. The studies typically separate between East and West and the esophageal or GE junction tumors often include squamous cell cancer, which is of course a very outdated way to do the study. And as you mentioned, 90% of our patients succumb to the systemic disease recurrence. So to do it optimal systemic regimen was very important to me and our investigators as we were designing this question this study. So it was patients with previously untreated localized non metastatic gastroesophageal junction and gastric adenocarcinoma irrespective of PDL one status. And this is a global study enrolling patient in Asia, Europe, North America and South America. Patients were stratified by PDL 1 tumor area positivity, which is another test to do, which is similar and comparable to CPS, which is the what you probably used to hearing and metastatic disease and of course by clinical lymph node status, angiographic region, Asia versus non Asia. This was 1 to 1 randomization and 948 patients were enrolled. This is a large study. For the first time we were able to convince people from all over the world, including Asia, to give patients FLOT. The patients received standard FLOT before surgery. Here the cycle is defined based on dvolimab dosing. I get a lot of direct messages on Twitter and emails from all over the world are confused because it says 2 cycles, but two cycles include four doses of FLOT. It's FLOT every two weeks, a given for four doses with Durva given once every four weeks. That's why it's two doses of the Rolla MAP. We were able to demonstrate that this regimen is doable. More than 3/4 of patients close to all patients were able to complete these cycles. There was no compromise to likelihood of doing a complete surgery with addition of tabrolimab, which was again very reassuring to see during the immunotherapy while the tumor is still in place is so important because it can potentiate the anti tumor immune response that the body is trying to mount themselves and also to continue recovery and micro metastasis suppression while the patient is recovering from the operation. Typically the patients then received additional chemo immunotherapy and here are the survival curves that you know, put the smile on my face every time I see it never gets old. And we're preparing that subsequent publication for the overall survival. Of course, you know, we demonstrated pathologic complete response improvement. We demonstrated that translate to event free survival improvement with the two year landmark survival of 67% in a global study. But seeing overall survival data is so important and that's what will really convince people that this is the regimen to give with two year overall survival of 76%. That's kind of all there's to it, right? It's feasible and it improves all endpoints of clinical and the survival. Speaker 2 Data. Applying Matterhorn Data: PD-L1 and CT DNA Insights Congratulations on this effort, Yelena. It just does not put a smile on your face. All our faces when we were sitting through ASCO and now catching up with ESMO, Yelena, with regards to what we saw at ESMA was EFS and oral survival 2 common questions that continue to come up is can we extrapolate this data from GEJ and gastrocadenocarcinoma to esophageal adenocarcinoma? And also what we saw at ESMA 2025 was PDL 1 aspect. Can this be tailored to PDL one negative? Speaker 3 That's a very good question. In terms of esophageal cancer, it depends on the location of the tumor. Most G junction tumors involve distal esophagus and then it extends into G junction. In fact, I've never seen a pure esophageal adenocarcinoma. Of course, if there's adenosquamous cystology and if it's a mid thoracic tumor where an R0 resection is not feasible, this regimen wouldn't apply. Multidisciplinary discussion is so critical. We enrolled esophageal you know junction cancers at our site. We were that top enroller in the United States and we had 100% R 0 resection rate because we discussed these cases together, we carefully reviewed all the images. Patients with more advanced disease had laparoscopies. In terms of PDL one status, I think the data is clear that most of our tumors are PDL 1 positive. Even if you have any expression, there is a clear benefit and the hazard ratio is still below one for PDL 10 patients. The confidence interval is wide. So depends on how you see the NCCN approved this regiment right now based on PDL 1 overexpression for CPS one or greater. This was before OS data was available. There's talk with the EMA of approving it irrespective of PDL one. I can tell you it's unlikely that I for example, in my practice I don't by PDL one. It would be a shame not to be able to offer these patients the treatment because it is improved. Survival appears to be improved irrespective of PDL 1. Speaker 2 And as you said, the good thing is that majority of our patients are PDL 1 positive. Well, since the inception of this presentation at ASCO 2025, this treatment has been the new standard of care before we touch side effect profile and clinical pearls around that. Question is are we or we're treating some of our patients. This question comes about in breast cancer or lung cancer and throughout solid tumors especially when we have CT DNA at hand. Any role of that here based on Matterhorn? Do you utilize that where you are deciding should you complete durvalumab for one year time or halt it rather? Speaker 3 Sooner, yeah. So that's a great question. There's a lot of biomarker work that's currently ongoing, including Multiplex assessment, blood nucleoside assessment, looking at TCR expansion and so forth, but also of course, CT DNA. Would I change practice based on CT DNA? No, I think we don't have prospective data, but you probably saw it as MO in the presidential session. What we know is that CT DNA is a prognostic tool. Whether or not it's going to be predictive in colon cancer, it hasn't panned out in our disease. What I see in my clinic is approximately 20% of patients that are even CT DNA get negative will recur. And I think going by patients ability to tolerate adjuvant therapy or de escalation based on what the patient is doing is really the gold standard. How I approach this? I love to be fancy in my research, but in clinical practice, I stick to the data and I look at the patient that's going to be guiding star for this. Practical Strategies for Managing FLOT Regimen Side Effects Helena, this is actually a good segue because one big reason to worry about overtreatment is side effects. Here we saw that one got what we were expecting when you're combining chemotherapy and durvalumab. And thankfully, we did not see a whole lot of discontinuation with DURVA flat arm when compared to flat alone. Elena, can you touch on the side effects we should keep on our radar and any clinical roles around managing these when using DURVA flat? Speaker 3 Well, from the beginning, I can tell you in most of my patients who are your typical gastroesophageal cancer patient, maybe they're in their 60s or 70s who come in already a little malnourished, I don't use full doses. FLOT, it's OK. You're allowed to dose reduce from the beginning. These are not protocol patients. That's why I think even when we developed the Checkmate 649 regiment, right, more and more people are able to use FOLFOX, for example, because they don't start with full doses. FOLFOX, nobody does in practice really. And the same thing for a flat, I often admit, Luca Warren and if there's a question about adverse events and concern for nutritional dose reduce exile and dose attacks. So I think I would rather do that than drop the third combination. There is something important about 3 drug combination our disease because of its effect on the tumor and the microenvironment and augmenting the immune response that the derolimab then potentiates. I think seeing your patient sometimes in week 1 post treatment, if you're not comfortable with this regimen or having your nurse practitioner see the patient will give you a flavor of how they're tolerating therapy. The good news is however they tolerated cycle 1 is how they will be tolerating subsequent cycles. So what practically I do is give them all the anti medics to take home with including, you know, Reglan, Zofran, things like that. Sometimes some patients need olanzapine, but really, you know, most patients get away with just the minimal side effects if you monitor them carefully. Sometimes people need hydration at the disconnect and it just gets them through the bump. As you said, dorolumab does not add much of the talks. Most of the talks comes from the chemotherapy. You'll see data, I'm presenting it as well, Asia and Singapore next week that doctors in Japan, Taiwan and South Korea are able to give flood. You know, the the part of the world that never used to give flood. And what we also saw, you know, the dogma was like, oh, only Germans know how to give flood. That's not North Americans did very well with those intensity and delivery. I think the whole idea of giving the patients an opportunity to get immunotherapy an early phase of their disease is a game changer because we will be able to cure more patients. Speaker 1 You know, can I piggyback quickly on this as well, Elena, It was not just the West or the east. Even here in the US and community settings, we're struggling to give flat. And that's the reason why a lot of us in community settings, including myself, we're leaning into this cross study. But then again, post SOPAC and the idea that we're worried about micromats flat is now the standard of care. And I do think that we're getting better and better in managing this particular chemo regimen in outpatient settings. Speaker 3 I have not radiated a patient and probably goes to 6-7 years. I mean, you're doing your patients at the service. Speaker 1 Absolutely. Speaker 2 And with regards to when you mentioned that you dose reduce oxaliplatin and dositaxel, what dose reduction are we talking about 10 percent, 15% and then you up titrate if you see they're able to tolerate? Speaker 3 No, I typically don't titrate up because again, we're going for overall dose density, right? Ideally, we know that even an adjuvant setting, if you can deliver more treatment, that's better to avoid great 2 neuropathy. And no, I don't titrate if I make a decision based on, you know, percent of body weight that the patient lost, what are their abilities to eat? What is their base. And but I've given flood even in patients with pre-existing diabetic neuropathy and gotten away with it. The patients just want to survive this right? Even if they lose their hair. All of that is reversible is the main irreversible thing you worry about. I don't usually use, you know, delayed Ms. steroids because you remember, we want to preserve those gentle T cells, right? And we don't want to slag though. So if you know, I usually try to avoid steroids if needed. The oral steroids in some patients, very few of the younger women get a lot of nausea and so forth. So the dose reduction, your standard dose reduction maybe go down to 70 milligrams per meter square root of Oxali and DOSIA 40 or 35 depending on how so about 1520% and usually most patients require dose reduction. But if you hit them over the head with a full dose and they're running for the hills, you didn't anyone any service. Who Benefits Most and What's Next in Oncology Their managing side effect profile and starting right dose is the key. And again, majority of patients would go for DFLAT. The question is who would not Yelena with regards to someone that you would not consider this regimen, certainly someone who is contraindicated for immunotherapy or one who's not a surgical candidate, Who else would you rather refrain from this therapy? Speaker 3 So sometimes we see these octogenarians, there is a bimodal distribution of increase of GI cancers. We see the people like you and I, healthy individuals with no risk factors and those usually get G junction tumors. But also we have octogenarians who we've been living normal lives and then because they were on five and aspirin started bleeding or something like that. And if they have distal gastric cancer and you can get away with subtotal gastrectomy, let's not be too crazy. What are we actually trying to improve here? I would just take them to the OR and then these in the middle of people who are, you know, just borderline, maybe they're not all that resectable. Maybe, you know, eventually we could get a surgery done and they're, you know, not perfect candidates. I think it's justifiable to use full Fox Nevo in those patients. Sometimes we convert them to resection, sometimes not because for those people, you know, I think full Fox Nevo, you would be able to do for six months and then not rush to surgery, do surgery after six months. Speaker 1 Kelena, you've been part of many of these studies here in this space that continue to change the standard of care for this disease. And because of this, our patients are indeed living longer. Coming back to Matterhorn, thankfully, you brought this up as well. We're not compromising any surgical outcomes here. So this is now what we should be using in majority of our patients that meet this inclusion criteria. Elena, before we close, any final thoughts for our listeners treating this disease? Speaker 3 It's an amazing time to be in this field and like you said, even the surgeons are embracing this approach. I've been speaking at a lot of surgical meetings. It's devastating to have your patient recur. It's the worst day when something happens and I come home. To be able to get them through an operation successfully and to use these modern options, everyone's on board. I'm excited for this, and we can continue to build on that. We have now her 2 positive perioperative strategies, quad and positive and so forth. So stay tuned for more. Speaker 2 Exciting times and days, Yolina. Again, congratulations for advancing this field and thank you so much for touching on Matterhorn study and practical discussion around this where we now stand and we have development available with chemotherapy as a new standard of care for listeners. Let us go. We're a quick recap from today's discussion. Speaker 1 To summarize for the ones tuning in today, we've discussed the Matterhorn phase three trial evaluating dirvalumab added to Perioflot for resectible gastric and GE junction adenocarcinoma. At 2 year mark, the overall survival is close to 76% with dirvalumab and close to 70.4% in control arm. This is now the new standard of care treatment for this patient population. Speaker 2 Well, in my practice, I'm also extrapolating this data to esophageal adenocarcinoma, and that's exactly what Doctor Jinjaekin pointed out as well. Whereas for PDL, one negative, I have a low threshold to drop dirvalumab if I run into side effects. And yes, we did touch on side effects and clinical perils around this. Speaker 1 Well, at another thing to keep in mind is thankfully we did not see a significant drop off or discontinuation when dirvalumab was added to this treatment paradigm. Also, we're not compromising any surgical outcomes here. Thanks for listening. If he found this helpful, share the episode with colleagues and leave us a review so we can continue to reach out to more oncologists out there. We'll be back soon with more practice changing updates in oncology. We are the oncology brothers.