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New Hope in GI Cancer Care: A Candid Conversation with Dr Yelena Janjigian
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Released: December 18, 2025

John Marshall
John Marshall, MD
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Since the recording of this interview, the US Food and Drug Administration approved durvalumab with FLOT chemotherapy as neoadjuvant and adjuvant treatment, followed by single agent durvalumab, for adults with resectable gastric or gastroesophageal junction adenocarcinoma.

 

New Hope in GI Cancer Care: A Candid Conversation with Dr Yelena Janjigian

 

John Marshall, MD: Hey, everybody out there in videoland or maybe you’re in podcast land walking your neighborhood. Maybe you have a pit mix dog you're walking because she hasn’t been out in a while, but wherever you are, this is for Oncology Unscripted, and I am a lucky guy because I am joined today by not only a great friend, but also someone who is really setting the standard of care for us in so many ways in GI cancers, and that's Dr. Yelena Janjigian. Yelena, how is New York City today? How is it up there?

 

Yelena Jangigian, MD: Thanks for having me, Donna. It's great. New York is the best place to be. It's beautiful and sunny, getting ready for holiday season. It's always good to catch up with you and talk research and talk gastric cancer and esophagus cancer outcomes.

 

John Marshall, MD: Do the stores already have, like, decorations ready to go up there?

 

Yelena Jangigian, MD: I have not been out, but I've noticed some things here and there in offices.

 

John Marshall, MD: What do you mean you haven't been out? You live in the hospital, in the clinic, don't you go out?

 

Yelena Jangigian, MD: Not out in shops, but I've noticed a few, like, you know, holidays, actually. Some of them are actually skipping Thanksgiving and going into holiday season decorations in random offices. So, but, you know, the spirit is, you know, cheerful in New York.

 

John Marshall, MD: It is a good time of year. I know you very well, and I know lots of our listeners know you very well. Give us a quick little bio on what you're doing right now.

 

Yelena Jangigian, MD: I'm a physician-scientist working at Memorial Sloan Kettering Cancer Center, focused on advancing care and helping patients with esophagus and stomach cancer live longer using both targeted and immunotherapies. Our lab is focused on trying to understand how we can overcome resistance to some of these medications using both tissue culture and other models. And, of course, I also lead a big group at Memorial Sloan Kettering Cancer Center. We have 45 oncologists all focused on one mission: to improve cancer care for worldwide options for gastric cancer, but also anywhere from esophagus down to the anal canal. So, it's a big group of very dedicated individuals.

 

John Marshall, MD: So now I know why you haven't been outside. Because you haven't slept, you haven't left.

 

Yelena Jangigian, MD: Annual review time. A lot of paperwork.

 

John Marshall, MD: Well, let's get into the weeds a little bit on how you are, in fact, helping to lead the improvement in outcomes for patients. But before we jump in, as an old guy in this space, I do have frustration that we in the GI cancer world haven't made more progress compared to our friends in some other cancers. And I know in upper GI and stomach and adenos, etc., precision medicine hasn't been consistent. Things that work in the metastatic setting haven't necessarily worked in the adjuvant setting. It's taken us a long time to get precision medicine targets that are viable for therapies, etc. What are your thoughts about that and why that might be so?

 

Yelena Jangigian, MD: So, yeah, I think it's important to start from basic knowledge that these diseases can be quite heterogeneous. And even in biomarkers such as HER2, cut-and-paste approaches from, for example, breast cancer into gastroesophageal cancer have not been the best way to do it. In fact, understanding the co-occurring alterations in our disease—the RAS pathway activation, the PD-L1 co-occurring with HER2—is what made the major milestone in the breakthrough in first-line setting beyond trastuzumab. So, I think understanding that this disease, in its nature, because of the nature of the GI epithelium, is more complex but also more heterogeneous than some of our other solid tumors is really critical. And also, because it's a rare disease in some countries, uniform and reflexive testing of biomarkers, where you get enough of a critical mass of data into the clinic so that you understand how each individual subset of a subset—for example, within HER2 tumors, p53-mutant tumors may do differently than p53 wild-type, RAS amplified vs RAS neutral—things like that. Until we do things in larger scale really going forward for all patients, we won't understand this nuance because in colon, breast, lung—the big three—there's more data, breadth and depth, these discoveries can be made.

 

John Marshall, MD: I was thinking about the idea of mostly colon cancer, and we've been seeing with IO therapy, where we're going to go in a minute, that even in MSS colon cancers, if it's primary disease, we are seeing responses when we would never see them in metastatic disease. So we're looking at microbiome interface or different biology of primaries versus mets. That's sort of what you're doing here with the Matterhorn study, is you're taking some leads from metastatic and applying them into the neoadjuvant-adjuvant setting. Does that feel right to you?

 

Yelena Jangigian, MD: Yeah, that's right. I think that whole paradigm of go to the late, late-stage setting, demonstrate benefit in heavily pretreated population, and only then move it to metastatic early line, and then only then move it to adjuvant or neoadjuvant space—that’s where the oncology field, I think, lacked an understanding of bigger leaps moved to perioperative settings or a minimal residual disease setting. Because you may not demonstrate a signal that you want in a fourth-line ECOG 2 patient with peritoneal carcinomatosis and ascites. By then, it may be too late. And that's what I think helped me bring, for example, agents like pembrolizumab-trastuzumab combination, Keynote 811. Because doing studies in later line, you understand that HER2 target becomes even more complicated. And again, targeting HER2 with just better HER2 inhibitors, as was working in breast, is not working in gastric. And so moving it to first line with dual immune checkpoint and anti-HER2 combination was the paradigm shift. And I think that's what we're trying to replicate in some other biologically important subset.

 

John Marshall, MD: I'll spare you having to do the weeds of the study. So, the Matterhorn study: neoadjuvant FLOT plus/minus durvalumab, regardless of PD-1 status, or as you measured tumor area positivity, or both, really, with pre-op/post-op kind of approach, placebo control, maintenance afterwards. Big study. Global. Josep Tabernero is always good to have as a first author. You're the senior author. How much of a pain in the neck is it to run a big clinical trial like that?

 

Yelena Jangigian, MD: It was fun to do, because we had to convince industry partners to do the study, because Merck had the Phase III registration perioperative pembrolizumab study. Going through to convince AstraZeneca leadership that their design was not as optimal as the modern FLOT approach—so high risk, high reward in some theory, right? But you're asking them to roll a bunch of dice—948 patients—and to be able to present that data. So, it was presented at ASCO in the plenary and then published in New England Journal of Medicine. It was definitely a high reward, and for the patient, and for the community. To be able to unify East versus West, put it all in the same trial—the trial actually recruited ahead of schedule at the time of the global pandemic—and it was always really rewarding to be able to tell patients that you had a great response, complete response, and to see the R0 resections. The dogma was that you need radiation for these patients, and we've moved away—even increasingly in the community setting. I hear from clinicians who came to me saying, “This is a perfect time for you to update us about this.” I'm taking this to the clinic, and it's part of the NCCN guidelines now.

 

John Marshall, MD: So, give us the high level. I mean, you got survival benefit, you got PFS, you got response rate delta, toxicity as expected—not zero, but as expected. High level, for our clinicians out there—what are the numbers they walk into?

 

Yelena Jangigian, MD: The timeline of this was at ASCO we presented the pathCR and EFS data, which was also published in Nature Medicine. And in Berlin, this past ESMO, we also presented—and this was a big splash—because it's been shown with immunotherapy before that pathCR may be improved, but will it translate to eventual survival. Check. And then, for the first time ever, we were able to demonstrate that you will also see OS benefit. And that was the splash at ESMO. We will be publishing that data in a manuscript format. To show that a pathCR can be an early surrogate of survival, and I think it's all important for us as researchers because, in my program, I have three separate first-in-kind ISDs in perioperative setting building on MATTERHORN. So, to know early which of the strategies will be successful to take forward in Phase III—waiting for pathCR would be much more practical.

 

One common public service announcement I want to make—people are still a little confused about the number of cycles in the Matterhorn. In fact, that’s probably one of the most common emails or direct messages I get on social media: Why did you only give two cycles of FLOT? We did not. A cycle was defined as two doses of FLOT. So, it's two cycles, but four doses of FLOT, and two cycles of durvalumab. Durvalumab is given once a month; FLOT is given every two weeks. So, this was, as you said, standard approach, and we did see improvement in event-free survival.

 

What’s important to look at is not only the hazard ratio, but the two-year survival benefit which was meaningfully improved. And the grade 3/4 toxicities—we need to be careful about. Most of the side effects are related to chemotherapy. So, as clinicians are getting more and more comfortable using FLOT in the clinic, the dose reductions, the hydration, the prophylaxis, potentially the Neupogen if needed—all of those will be implemented. So, NCCN already adopted these regimens, and we're planning, hopefully, for the FDA approval in the near future.

 

John Marshall, MD: Yeah. I think about the number I go in with—oxaliplatin in the adjuvant setting in colon, which is, you know, overall maybe 3%, 5%, depending on how optimistic I am on that day. Here, what's the number I walk into the room with a patient? Is it another 5% or so cured by the addition of the IO therapy to FLOT? Is that a fair number to walk in the room with?

 

Yelena Jangigian, MD: I would say, well, it depends. So, if we're looking at a final OS, the difference was closer to 7%.

 

John Marshall, MD: So, a little higher. More than 5%, I can say, right? And that tail does exist, and you've got a follow-up.

 

Yelena Jangigian, MD: Right, and that's every year. And then, I think if you think about it, this is looking at a large Phase III study. These are all patients who did not have all laparoscopy. They didn't necessarily have the staging that you and I could do in our practice with specialty care. So, I suspect that number—or at least in our cancer center—is better.

 

John Marshall, MD: Got to hold up, okay. Tell me about PD-1 testing. I mean, I realize everybody could be in on this study.

 

Yelena Jangigian, MD: It was an all-comer accural. We used tumor area positivity (TAP) as opposed to combined positivity score (CPS). It's reproducible, and there's data to show the TAP and CPS are equivalent. The benefit appeared to be irrespective of PD-L1.

 

John Marshall, MD: So, they could come in cold for PD-L1 and they're still eligible for the therapy based on the study?

 

Yelena Jangigian, MD: NCCN restricted it by TAP-1. Unclear for regulatory reasons—that may be amended, because this was a restriction before the OS data came in. So, we'll have to see. The EMA appears to be interested in approving it, again just from the discussion with colleagues in Europe, irrespective of PD-L1 because that's a huge patient population. Irrespective of that, most tumors are PD-L1–positive. So, if you're seeing a negative case, I would call your pathologist and make sure the cellularity of the case is sufficient.

 

John Marshall, MD: Take a look again. You know, I think immunotherapy is certainly one of those classes of drugs that we have the highest patient awareness for. I mean, they're always coming in and saying, “Shouldn't I have some of that immunotherapy stuff?” And in some cancers, it can be quite dramatic, the impact. What's your thought, and what are we doing about trying to further optimize the impact of the immune system on treating our cancers? Where are we at?

 

Yelena Jangigian, MD: Yeah, so our large biomarker analysis of CHECKMATE 649, which was the FOLFOX–nivolumab vs FOLFOX study in stage IV patients, showed that chromosomal instability tumors—so CIN tumors the hazard ratio in metastatic setting for addition of immunotherapy—is not as good. Hazard ratio 0.9 for survival. So, we know those tumors don't do as well.

 

How do we improve? Because they're relatively cold or immune-excluded tumors, but we're trying to boost that. We know that combining the checkpoint blockade with CTLA-4 inhibitors may offer some benefit, especially from the data we see, as you said, in early-stage colon cancer. But it's very tricky to combine it with FLOT chemotherapy. So, combination with TIGIT may be helpful because, again, it's an immune-boosting, dual immune checkpoint blockade. That's to be determined.

 

There’s also now Fc silent bispecifics with PD-1, CTLA-4—drugs like cadonilimab, which are approved in China and actually are coming to the United States as well in metastatic settings. So that's what I'm interested in. I think for a subset of patients, it'll be a combination of PD-1 plus tumor targeting, for example, for HER2-positive tumors. For another subset, we’ll be doing dual immune checkpoint blockade—either PD-1–TIGIT, if that data pans out, or PD-1–CTLA-4—with the backbone of chemotherapy, of course, for all. Because it's been difficult to move away from chemotherapy unless it's an MSI tumor.

 

John Marshall, MD: Tell us how we move forward. What's next out there for the treatment of upper GI cancers?

 

Yelena Jangigian, MD: Well, you know, today we had a press release. The zanidatamab data—it appears to be a positive HERIZON-GEA-01 study, whatever that will be. So, it's a positive space that will be interesting to see at ASCO GI. And then, of course, the biggest disappointment of the year is the FGFR2b data with bemarituzumab—with FORTITUDE-101 having a huge splash with a large positive interim analysis that subsequently dissipated, and the curves came together. You probably saw ESMO. I think it shows that we're not quite done with biomarker development in gastroesophageal cancer, and the best is yet to come.

 

John Marshall, MD: Just to let you know, for Washington, D.C., that wasn't the biggest disappointment of the year. There’s been other stuff that beat that, but we don't have to go into that. Dr Yelena Janjigian—the world’s expert and really thought leader in the space of upper GI cancers—raising the bar, curing patients right and left, not just in New York City. Go shopping. Get out of there and enjoy a little time. You've deserved it. John Marshall, on behalf of Oncology Unscripted, thank you, Yelena, very much.

 

Yelena Jangigian, MD: Thank you so much, John. Be well. Take care.

 

John Marshall, MD: Bye-bye.

 

This transcript has been lightly edited for clarity.