GI Cancer ESMO 2025 Highlights: DYNAMIC-III, PEGASUS, STELLAR-303, MATTERHORN, FORTITUDE-101

Unpacking Key GI Malignancy Takeaways from ESMO 2025 Pre ESMO, there was a lot of hype around the data that was going to be presented at this conference. And you know what, It actually lived up to its hype. As a generalist, we saw exciting data across all disease sites. Some studies will change the way we practice, some will reinforce our current practice, and then we also saw a few negative studies. Today we're going to focus on key takeaways in GI malignancies after ESMO 2025. Hello everyone, welcome back to the Oncology Brothers podcast. I'm Rahul Gosain, a community medical oncologist here, as always with my brother and your Co host, Rohit Gosain. In our discussion today, we're going to touch on a few studies in colon cancer and upper GI malignancies from ESMO 2025. And to walk us through this data, we're excited to have Doctor Rachna Shraf, AGI Medical oncologist from the University of Arizona. Rachna, it's always great to have you. Thanks for joining us. Speaker 2 Thanks so much for having me, I love doing this with you both. Speaker 3 Rachna, welcome back. Let's start off with a bang here. CTDNAA, very hot topic in every disease site. And for us today from GI standpoint, we'll be covering Dynamic 3 and Pegasus study and then we'll dive into stellar 3O3 data on immunotherapy in MSI stable disease. And then and closing off with upper GI malignancies, 2 studies there we'll be covering as Matterhorn in resectable disease and Fortitude one O 1 in metastatic disease. DYNAMIC-III & PEGASUS: ctDNA's Role in Colon Cancer Rachna starting out with CTDNA story, CTDNA has rather been a prognostic tool as opposed to predictive tool. But at ESMO in bladder space, what we saw was in the core study where CTDNA is being utilized to guide our adjuvant treatment option. So a hint of rather predictive tool. But coming back to early stage colon cancer, we have two studies, Dynamic 3 and Pegasus in adjuvant colon cancer. Can you touch on these two studies and their findings? How are you utilizing CTDNA in your clinical practice outside of clinical trials? Speaker 2 I think the CTDNA story is rapidly evolving in the world of colorectal cancer in the GI malignancy space. That's where we have the most data and Dynamic 3 and Pegasus adds to our our understanding, but I don't necessarily think has has truly been proof of principle that we can use CTDNA to guide adjuvant therapy. Dynamic 3 was specifically in patients with resected stage 3 colon cancer, which we know there's a reasonable risk of recurrence in these patients. In this study, they used a minimal residual disease platform called Safer Seek and basically looked at CTDNA positive patients and determined about how to use that to escalate or de escalate therapy. Now this was a large study that randomized patients to standard of care or CTDNA guided management and upfront the physicians had to determine what type of adjuvant therapy was going to be given. And what they were really looking at is in the CTDNA positive cohort with the two year recurrence free survival was comparing escalation versus standard of care. It was over 1000 patients, but the CTDNA positive cohort was about 27% of patients with a little under four years of follow up. The two year recurrence free survival in the CTDNA guided escalation arm was 52% versus 61% in standard of care, a non significant difference. Importantly, we have proven that CTDNA positive patients after resection who have a higher risk of recurrence or do worse than those who are CTDNA negative in the post operative setting. But basically I think what this showed us is relative to the prognostic component, the predictive component or the ability to use CTDNA to guide determination around doublet chemotherapy or even full FOX theory. We still don't have proof of principle to show that escalation in CTDNA positive patients improves recurrence free survival. I think the Pegasus study is similarly adding to the story. It's a slightly different group of patients. It's stage 3 colon cancer and patients with high risk stage 2, which they defined as T4 disease. And this was a smaller study. This was about 135 patients. And again it was really looking at assignment based on CTDNA positive versus CTDNA negative. The CTDNA positive patients received three months of adjuvant K box, K cytidine, anoxaliplatin, CTDNA negative received single agent K citamine. And then basically at the time of adjuvant therapy there was a post adjuvant phase guided by whether or not they were CTDNA positive. If positive, they were switched to full theory for the K box treated patients and if they were negative, they were de escalated to Cape. Then for the single agent K patients, if positive, they were escalated to K box if they were CTDNA positive. And again this was a small number of patients, especially when you look at the CTDNA positive and the number of relapses seen. Out of the 135 patients, 35 were CTDNA positive and in those patients the relapse rate was 37% with a 2 year disease free survival of 61.8%. When you compare the CTDNA positive to CTDNA negative, the CTDNA positive had worse disease free survival. But when looking at the feasibility of being able to do the study, which was really kind of the real question was can you, can you get the time points necessary to do CTDNA, to get CTDNA results and then determine therapies as well as the primary endpoint in terms of just what what are we doing at that time point with disease free survival? It doesn't really change our practice the ability to test CTDNA. But in terms of how to interpret that and to use it to guide and determine escalation or post adjuvant phase therapy is still not there in my practice. I think it's very important to continue to understand how CTDNA can play a role in the setting of clinical trials. Understanding CTDNA positive or negative after curative resection will help determine stratification and risk of recurrence and overall outcomes. But I can't say that I'm using it right now to guide therapy in terms of adjuvant decisions, length of therapy, type of therapy, post adjuvant therapy, treatment planning. Speaker 1 You know, the idea of CTDNA guiding de escalation or escalation is huge. I mean, who would not want to use this to make sure that we're not under treating or over treating our patients? Right? At the surface, This is what this tool is trying to promise. But if you were to ask 5 medical oncologists, you get 10 different opposing ideas and recommendations around this. In my opinion, this is great, but CTDNA still remains mainly a prognostic tool. But Rachna, I agree with you that clear guidance on who is benefiting from this still remains unknown. Immunotherapy for Refractory MSI-Stable Colorectal Cancer OK. Moving along from early stage colon cancer to metastatic colorectal cancer here. Immunotherapy has made a world of a difference for our MSI high disease. However, for MSI stable disease, we've not seen immunotherapy make much of a difference. This is what was being studied in STELLAR 3O3 in refractory MSI stable colorectal cancer, where they're looking at the role of atizolizumab in combination with zenzelitinib versus regrafnib. Rashna, what did the study show and is this ready for prime time? Speaker 2 So this was a really important study because we know the role of immunotherapy in microsatellite instability, high colorectal cancer and there's a lot of interest with prior data in the MSS colorectal patient population. So Zanzalitimib. Zanzalitinib is a multi targeting tyrosine kinase inhibitor and it was studied in combination with the tesilizumab in refractory patients who had progressed on standard therapies and they were randomized 1 to 1 to the Zanzi Otezzo arm versus regrafinib with a dual primary endpoint of an intentional to treat analysis. OS look as well as those in patients without active liver metastases. And when you look at the final data, the median OS was numerically and statistically significantly improved from 9.4 months in the right graph and of arm to 10.9 months with a hazard ratio of .8. Median PFS was also improved from two months to 3.7 months. In the intention to treat population patients without liver Mets, the median OS was 15.9 months versus 12.7 months. This did not meet statistical significance, but this was a smaller subgroup of patients. I think it's important to recognize that this was a positive study. This is proof of principle that immunotherapy plus a multi targeting tyrosine kinase inhibitor may have a role in the treatment of refractory MSS colorectal cancer. So I would say, and I think the discussant did a great job of highlighting this, that the number of grade three treatment related adverse events was seen in about 60% of patients in the experimental arm versus 37% in the regorafinib arm. They were the things we would expect from multi targeting Tkis like hypertension and diarrhea as well as things that can come from immunotherapy such as hypothyroidism. Importantly, 5 patients died in the experimental arm. They were thought to be treatment related versus one in the regrafinib arm and that included things like intestinal perforation and such. I think it is important to recognize that this is the first positive phase three trial in metastatic colorectal cancer that shows an immunotherapy based combination may have a role. The hazard ratio with a risk reduction of 20% in a heavily pretreated population is important. I do think we need to understand some of the nuances #1 what role this could play in the non liver metastasis subgroup because we have seen that play out in a number of other studies. And then I really think we need to understand the risk benefit in terms of the absolute benefit that our patients derive from this combination versus the 60% who had grade three treatment related adverse events and especially the deaths in the experimental arm. So I do think it is potentially practice changing. I think, however, in terms of putting it into day-to-day practice, we need to really get our handle on that safety component first. Speaker 3 Thanks so much for summarizing that In refractory colorectal cancer if no actual mutations are present, we have limited options that is TAZ 1O2 with Bevisys and abrogorafinib or for quick based on the recent approval. What we are seeing here as you stated Rachna that oral survival is there that is it is a positive study, but this does come at a cost of significant toxicities especially when treatment here is palliative and intent. All right, switching gears to upper GI series, what we are seeing here is Matterhorn study. Durvalumab with FLOT for Upper GI Malignancies Since presentation at ASCO plenary session this year, we have seen this being practice changing right away where we saw rather durvalumab was flawed in peri offsetting improve EFS when compared to peri off lot a lot of his we adapted this in our clinical practice though we are still pending FDA approval. Here at ESMO 2025, we saw more mature data and overall survival across all subgroups. Rachna, what did the update show and post ESMO? Are you using this for all comers versus only for PDL 1 positive disease? Speaker 2 So therein is the question, right. I mean I think this was obviously the much anticipated OS data. And I think as much as we appreciate the event free survival impact, at the end of the day, the fact that this was a positive study in terms of final overall survival is a really important milestone. And I think it reiterates the fact that this was practice changing and that D Flot as everybody lovingly calls it should really be our new approach to perioperative management of upper GI malignancies. Importantly, with each additional readout that we've gotten dating back to the financial data and then the plenary session at ASCO and now this, no new safety signals, no new concerns in terms of long term toxicity. So all really important to reiterate and emphasize the role of immunotherapy in the perioperative space. Now the question of PDL one status, you know, when you look at what we see here in the breakdown between greater than or equal to PDL 1 positivity of 1% versus less than 1%, you know, I think it's hard to not notice the fact that the impact is greatest in the greater than or equal to 1% similar to what we see in other parts of upper GI treatment with immunotherapy. The higher the score in terms of PDL 1 positivity, the potentially greater impact. You know that being said, I think number one, I think how this gets approved and the label will drive this. But if we've learned anything from how the FDA has approached this in the upper GI space, they seem to have an all Comer approval approach because the intention to treat spinal OS is positive. In the world of genomic testing and such as turn around times improve, could we potentially really stratify this and feel even more strongly about immunotherapy and less strongly based on PDL one status? I think so, but in the curative intense space with minimal added toxicities from dirvalumab and a final OS intention to treat that is positive, I think I would not treat based on PDL one status. I don't want to wait. I want to get the ball rolling. This is the intention to cure and time is of the essence a little bit unless there is something that makes me weary of immunotherapy, you know, if there could be potential contraindications and or other reasons to to to worry about the dirvalumab component, in which case I would, you know, try to understand PDL one status better. But I think it's interesting that when you all did the poll, it was an even split in the real world day-to-day, just trying to get patients going on therapy. I think I will just get started with D Flat. Speaker 1 And you know, very likely we will see an approval here, but I am eager to see if FDA will take a stance around PDL one or not. Rashna, you touched on this. We did run a poll north of 200 votes on what would you do for PDL one negative gastric or GE junction adenocarcinoma. And there was a clear split of 5050. Some would use it for all comers and the other half was going to only use it for PDL 1 positive disease. But you know, this is where I would love to see CTDNA also playing a little more role. Can we forego immunotherapy part in someone who has complete pathological response if I'm using this perioptosop approach upfront? That's sad. Periop immunotherapy and additional post op immunotherapy has now become standard of care in almost all disease sites. We do this in lung cancer, we're doing this now in bladder cancer, We're doing this for breast cancer, triple negative disease and hair with Matterhorn. Targeting FGFR2b in Metastatic Gastric Adenocarcinoma OK, Now switching gears to our last study, Fortitude One O 1 in metastatic gastric G junction adenocarcinoma. Today in metastatic space, we need to know where to status PDL one score and Clodton 18.2 to come up with the right frontline treatment. Fortitude One O 1 is arguing that FGFR should be part of this selection criteria. Rachnaut, can you walk us through this study and its findings? Speaker 2 Yeah, this was an interesting and important study. Fortitude 101 was basically looking at, you know the the question of is FGFR to be over expressing upper GI malignancies? Is it, is it targetable with a with a monoclonal antibody? And this study had an interim primary analysis with a follow up of about a year and a later descriptive analysis closer to about 20 months, almost two years. And this was specifically in patients who were FGFR 2B positive, defined as greater than or equal to 10% of tumor cells and two plus or three plus intensity stating in the biomarker group. This was a 1 to 1 randomization of adding bemritizumab to full FOX versus placebo and full FOX at the time of the presentation from ESMO, this was looking at about 20 months of follow up. The median overall survival was 14.5 months in the experimental arm versus 13.2 months in the control arm with placebo and full FOX. So here the hazard ratio was .82. Previously, the hazard ratio was .61 with a statistically significant P value. The hazard ratio of .82 was now kind of crossing one in terms of the confidence intervals suggests that there is a diminished benefit over time in terms of using gemritizumab in the addition of full FOX. Now the caveats to this are #1 you know, post frontline therapy, what additional therapies were given and whether that can attenuate the overall survival impact over time. Additionally, we know we don't have immunotherapy as part of this. And you know what what to do with this information in terms of FTFR, to be targeting with chemotherapy in a setting of patients who are also technically standard of care is to give immunotherapy questions. You know, so this study, I think asks, in my opinion, more questions than it answers questions. You know, I think we know that we should be testing for FGFRTV #1 it is prognostic, but #2 we now have therapies that can target it. But I think the important questions are really remaining to be answered in terms of how this drug plays a role with the addition of immunotherapy and a chemotherapy backbone if it does, as well as really what the what the upfront benefit is. And in, you know, are there certain patients that need that upfront benefit? If the more prolonged follow up does not demonstrate the same OS impact, is it really just because of subsequent therapies versus, you know, targeting FGFR 2B not having that same level of impact? So more questions and answers. And I don't know that this is necessarily practice changing or paradigm shifting right now, but really just lends itself to some subsequent trials that I think need to be designed. Speaker 3 Thanks for summarizing that, Rachna. I will take a minute here to stress the importance of NGS. We've talked about this with Doctor Mark Lewis, who states that one would not treat breast cancer without knowing ER status, PR status and her two status and gastric and she junction adenocarcinoma should not be any different here. What we have is fortitude one O 1, though we have seen some benefit, but again, acknowledging that comparator arm did not include immunotherapy, which is the standard of care. Rush and I you've given us plenty to think about. Summarizing ESMO 2025 GI Cancer Highlights We really appreciate you taking the time to walk us through this important data. Before we wrap our listeners, let us go over a quick recap. Speaker 1 In today's episode with Doctor Rushner Shroff, AGI Medical oncologist, we touched on CTDNAS practical role in colorectal cancer with both DYNAMIC and Pegasus study. Let's not forget that we also had a positive study with CTDNA and bladder cancer at Asthma 2025. Then in metastatic colorectal cancer space, we touched on stellar 3O3 where we have seen improved overall survival benefit of roughly 1.5 months, but at a cost of significant toxicities. Speaker 3 On the upper GI front, mature Matterhorn data has solidified perioperative IO as a standard of care for resectable disease. Once approved, though, we'll still have to decide if this is something that can be utilized in PDL. One negative as well. To close, we touched on Fort to trial taking a look at FGFR alteration upfront, but this is less likely to change our treatment paradigm today meeting for sure. Thanks for tuning in. Check out our past episodes on conference highlights, recent approvals and treatment algorithms. We are the oncology brothers.