ASCO 2025 - GI Cancer Highlights: DYNAMIC III, ATOMIC, BREAKWATER, MATTERHORN, DESTINY Gastric04

Intro Hello and welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Ghosain. As always, I'm here with my brother and Co host Rohit Ghosain as we just got back from Ascot days ago. So here we are diving into the most impactful updates from Ascot 2025 annual meeting with thousands of abstracts were presented. Today we're going to focus on GI malignancies and for this, we're thrilled to have Doctor Kathy Eng, a world renowned GI medical oncologist from the Vanderbilt Ingram Cancer Center here to guide us through five key abstracts. Kathy, thank you for joining us. GI Cancer literally took the center stage at ASCO 2025 with two out of five plenary discussions in this space. There's a lot happening. Speaker 2 Yeah, it was really exciting. I think it was a great year for GI, had a lot of pivotal information in regards to common practice patterns. And so it's very applicable, the information that we learned from this year's ASCO. Speaker 3 Indeed, it was quite a bit practice changing and practice informing. And as Rahul said, GI definitely took the center stage and one of your studies showed doubling of overall survival as well. So congratulations, we will be diving into that. We have 5 key abstracts, 3 abstracts from colorectal space, dynamic 3 study, atomic study and breakwater. Then we'll shift gears to upper GI malignancy, focusing on Matterhorn study and Destiny Gastric 04. Let's start off with the hot topic of CTDNA, which is utilized as a prognostic tool to deescalate treatment. Dynamic 3 Study What we are seeing here with Dynamic 3 study is rather the opposite of escalating the treatment in Stage 3 setting. Kathy, could you please walk us through Dynamic 3 study design and its findings? Speaker 2 I think people are probably very familiar with Dynamic, which was the original study that was presented and published regarding stage 2 patients where it was informative and making treatment decisions. Stage 3, you would think it would be more obvious to utilize. The purpose here is once again looking at the role of circulating tumor DNA. Patients were evaluated within less than six weeks from surgery and then randomized in a one to one fashion to either circulating tumor DNA informed management. If it was negative then potentially de escalating therapy. Meaning instead of giving FOLFOX, which we commonly do our K pox in the stage through setting, you would potentially reduce it down to five if you are nothing. For that matter, if you were circulating tumor DNA positive, the thought process was to escalate it. On the right you can see if you had not planned to originally give chemotherapy, you would at least give 5 if you are tape side of being or if you were going to get 5. If you keep side of being, you would give potentially full Fox or K pox for approximately 6 months. Same thing, three months maybe just escalate to six months or the consideration of full Fox Erie. The primary endpoint was relapse free survival. The results were very interesting. They were not what we were hoping we would get or thinking we would get based upon these findings. In red is the standard management arm, which is the standard of care and in blue is the circulating to redeem a informed escalation based upon if you were positive. It's important to keep in mind they screened over 1000 patients and ended up being about 100 plus or so patients that were circulating tumor DNA positive as you can see here in regards to recurrence free survival, they did not fare better in regards to dose escalation, which was a huge surprise for us. We're all in a bit of shock and keep in mind this is a phase two study, but they did screen over 1000 patients. And the fact that we don't have many treatment options in the stage 3 setting and we commonly prefer to reduce the use of oxaliplatin due to the risk of peripheral neuropathy. But in the setting of a positive circulating tumor DNA, which suggests that more than likely you have evidence of disease that's likely to return and may not necessarily be evident on diagnostic imaging. To utilize 6 months of FOLFOX or oxaliplatin based therapy did not provide any additional benefit in recurrence free survival. What is very clear post op circulating tumor DNA analysis, we know it's already prognostic and likely consistent with disease recurrence. They put it by their quartiles in regards to relapse free survival. What's really striking is that left KM curve of recurrence free survival and dose escalation. And if we were many of us were discussing this afterwards, is this an opportunity then do we not have the right drugs in the stage 3 setting like maybe oxaliplatin based therapy is not the best treatment and full FOX theory now you have to question is that dose escalation going to be of any significance? I do want to mention that there is an ongoing US trial called Circulating Circulate US, which is specifically for Stage 3 patients that is looking at the role of full Fock dose escalation. And that is a phase three clinical trial that is being monitored very closely. Whether or not this trial impacts that trial moving forward, I'm not on that steering committee for that trial. It's being run by doctors Dasari and Dr. Liu. But it'll be very intriguing what they decide to do based upon these findings. Speaker 1 Absolutely. Just to reiterate here, CT DNA being positive and when you escalated your treatment, this did not change outcomes. So based on Dynamic 3 study, we cannot rely on CT DNA positivity to attack the same cancer with more chemotherapy. Coming back to what Roy, you said, this is prognostic, Kathy, now that we have this data outside clinical trials today, how are you using CT DNA for that patient in front of you? How to use CT DNA in patients with stage 3 cancer It's a very common subject of discussion in my clinic. I don't necessarily order it on all patients unless it is part of a clinical trial. I do order in patients that I am maybe a stage 3 patient and I'm considering not doing any therapy. We do order in that setting. I have ordered it in our very high risk patient population. For me it's more about that surveillance period for stage 3 patient. We historically would only get a colonoscopy year one and then every three years thereafter and then an annual CT scan. But if I, I have a patient that has completed their adjuvant therapy and they still have persistent circulating tumor DNA or it was negative and then it became positive, I'm not going to wait a whole year before I get that annual CT scan. I'm going to move it up to a shorter interval. So for me, it impacts my surveillance period in regards to diagnostic imaging. I think right now it tells me that circulating tumor DNA dynamics for the stage 3 patient population, we just don't have great treatment options that are making that dramatic difference in current spree survival. Speaker 3 Kathy, how are you utilizing this for Stage 2 also? Speaker 2 Yeah. So for Stage 2, we do not have a clinical trial anymore. We had a trial and unfortunately that closed after interim analysis led by Van Morris because there was concerns about the technology which had just advanced so rapidly. Since that study was designed in my practice for Stage 2 patients, I will consider ordering if a patient is extremely anxious and they just want to utilize it as an additional tool, I'd like to kindly remind patients this is an additional tool like CEA, like CT scan, like your physical examination to help determine whether or not you're at risk of recurrence. In a patient with T4 disease, I may be more inclined because they are higher risk for recurrence or suboptimal lymph node dissection. Speaker 1 So for that high risk patient, OK, sticking with colorectal cancer, moving on to atomic power subject. Speaker 2 Matter, Yeah. Speaker 1 Which was a plenary study. The study evaluated here given at izalizumab with FOLFOX in stage 3 MSI high colon cancer. One big take away here is all our colorectal cancer patients should be tested for MSI status. Kathy, can you breakdown the study and its results? NICHE-2 We have phase two study by Doctor Miriam Schulabi in this space, Niche 2. When we're doing these cross follow comparisons clinically, what does this mean for us? Speaker 2 So this trial is actually created about 10 plus years ago and you may say why did it take so long, but for any stage 3 patient population with the primary endpoint is disease free survival, the follow up has to be long term, at least a median of three months plus and three years plus. This trial was designed when IO therapy was not the standard of care yet in the metastatic setting. So this is specifically once again for stage 3 patients deficient MMR instead of just giving COLFOX as a standard of care. If you are MSI high, this is the question, can you add IO therapy, in this case otezilizumab to your chemotherapy regimen to make it a better regimen for improving your disease free survival? And this was a 1 to 1 randomization. So patients got six months. Nowadays we don't give six months unless you're a high risk patient and you believe it is necessary and warranted to give them six months. But because the risk of peripheral neuropathy if you are considered a low risk patient, so those with T1 through three and N1 disease, then we would consider three months of oxaliplatin based therapy. So here we're doing 6 months as the control arm and then the investigation arm was 6, two months in combination with chemotherapy and continuing the Atezza for six months. Now I think it's important to keep in mind there was a third arm which was just IO therapy alone, but that was recommended to be removed from the original study design. The control arm for the six month duration, if I recall, was actually mandated by the FDA at the time. So there was a lot of different constraints because this this trial is ahead of its time. Let's be honest and I have to commend Frank Sinacro for his persistence and being able to enroll to this study. The primary endpoint is disease free survival and as you can tell your three-year disease superior for the IO combination, the hazard ratio is .5 and they want to achieve a hazard ratio of .6. This fulfilled the disease free survival primary endpoint in real life. What would you do? Well, I don't know if I would give six months of FOLFOX, but currently if you want to go by likely the FDA indication that will happen following this trial, it it's going to probably be, you know, approximately 6 months. So I'm sure they'll find some verbiage in combination with the otezilizumab. It doesn't answer the question about can you give Otezla by itself. Unfortunately we will not know that answer. The majority of patients, if I recall 60 plus percent were the low risk patient population to begin with. So they were the T1 through three and and one patient population. So I think that's important to keep in mind. Now you mentioned Miriam's study Niche 2. Niche 2 is different because it gave neoadjuvant IO therapy be before surgical resection. Then all the patients went on to surgical resection, looked at the role of pathologic CR. So it's very different primary endpoints. When this trial was designed, they were already nervous about giving IO therapies a single agent. So there's, it's just been a, you can tell that the science has evolved about the way we look at IO therapy in our deficient MMR patient population. I think this trial is still a very pivotal trial regardless of the fact that it took 10 years. But it provides us the answer that IO therapy has a role in the adjuvant setting for this patient population. Speaker 3 Thanks for covering that, Kathy. From clinical standpoint, if we have MSI high disease today, how are you maneuvering through that especially when on scans itself when we are relying stage 2 and stage 3 are rather hard to even investigate? IO therapy in stage 3 colon cancer Important to keep in mind, I forgot to mention Chilabi study involved nevo IPPY, not just a tetalizumab. So it's CTLA 4 but but also, so if you don't have a clinical trial, I'll tell you what I would do. But there is a ongoing study in the stage 3 setting for colon carcinoma for deficient MMR patients and that is the a 02 study. I believe that it's currently still enrolling looking at single agent tostarlimab in the neoadjuvant setting. I think it's going to be really interesting those results, but we'll stop to find out since it's still enrolling in the practical patient population. I think sometimes you have to also discuss you may have a patient that may not be the best candidate for surgery. You have your elderly hypermethylated MSI high patients and this would be more than appropriate to consider for them where you don't necessarily want to undergo surgical resection. Now for patients that undergo surgical resection, I think this tells you that you can provide IO therapy in combination with oxaliplatin based therapy. So I would not be opposed to three months and then doing a Tesla lizumab. I think the question is, do you do it for the duration of a year now because we know the neoadjuvant data is very interesting. Depends on which setting you're looking at. In the rectal cancer setting they say you still need six months and the neoadjuvant colon setting it looks like you only need one dose to Ctela 4 in two doses of IO therapy. I think there's so much to be learned in the setting, but I would say for practical purposes FOLFOX decide if it's a low risk or high risk patient population. That will determine your duration of oxaliplatin based therapy and then a TEZO no more than a year. Speaker 3 One has to stress how there were only two doses of nivolumab and one dose of epilumab I. Speaker 2 Think it demonstrates it's a different micro environment before. Speaker 3 Surgery. All right, Kathy, moving along to Breakwater. Breakwater It's Scott Kopez's. This was an international study. Speaker 3 International study which involved you. This is a high risk population with B RAFV 600 E mutation and historically this is a tough disease but here we are seeing doubling of overall survival. This is amazing and congratulations as our patients are living longer because of this. Kathy, could you please walk us through the study design and its findings? Speaker 2 Yeah. As you mentioned, breakwater is based upon the B RAFV 600 E mutation. These are proficient MMR patients. You know, historically these patients have a very aggressive tumor type, diffuse metastatic disease and encrafinib. And so tuximab was already approved in the previously treated setting. But can you move that combo forward to the front line setting in combination with chemotherapy? This was a very large international 3 arm trial originally with a run in phase just to make sure the dosing was correct and there were no significant toxicities. And we're really going to focus on the bottom 2 treatment cohorts, the Ankaraf and cetuximab in full Fox versus the standard of care. The Ankaraf and cetuximab in the original first arm was eventually removed because data from the anchor phase two trial did not show dramatic improvement even if you move to the frontline setting. So the primary endpoint here, we saw some data earlier with response that's presented at ASCO GI. Here we provide some interim overall survival data, but this is the official overall survival data for the combination with chemotherapy versus the standard of care chemotherapy, a significant improvement, progression free survival. But more importantly, I think the bottom right is just the best curve that could happen for this patient population. You know, our immediate survival for our stage 4 mesthetic colorectal cancer patients is between 32 and 35 months. And here with the combination with oxaliplatin based therapy and the doublet of ankarafimosituximab, they achieved A median survival of 30.3 months. It really gives a lot of hope to this patient population, which which always had such a poor prognosis with the best chemotherapy possible. Full Fox theory historically still had overall survival of 12 to 14 months. Here you see it's 15 months for whatever standard of care you choose. I should also mention there is an additional cohort that has completed enrollment. We don't have those results yet, which is Full Theory Plus and CRAFT and msotoximab. I'm looking forward to seeing those results too, but this is very, very helpful. Speaker 1 Yeah. Now this degree of overall survival in BRAF mutant disease is commendable, but we should keep side effects in mind. Cafe though as community oncologists we've used BRAF inhibitors and Melanoma lung cancer now here but can you touch on some common side effects with this combination and clinical pearls in managing some of the toxicities I. Speaker 2 Think it's very typical for any type of EGFR combination. You're going to have potential risk of rash, although it's not as significant as the standard irinotecan, seteximab or pennitchimab combination. You're still going to have a rash. You're still going to be at risk for diarrhea. You know, there's obviously going to be potential risk for mild suppression. It is a stronger combination, but overall I would say obviously fatigue but benefits far outweigh the risks that are associated with this regimen given these findings. Speaker 3 Thank you, Kathy. Now shifting gears to upper GI malignancies, the first one we have here is Matterhorn study, another plenary study evaluating periop dirvalumab with FLOT in resectable gastric and GEJ cancer. Upper GI Malignancies Your dirvalumab was tied in with the Azopec winner from last year. We have used this approach of perioperative therapy with immunotherapy in lung cancer, breast cancer as well. This is now being referred as D FLOT as Doctor Sam Klimner to use this term. Kathy, could you please touch on the study design and the findings here? Speaker 2 This is for locally advanced gastric adenocarcinoma. The criteria in regards to the T stage in the end stage, no evidence of distant metastatic disease. Good. PS This was an international study led by Doctor Jen Jiggian. This is looking at with, with with the placebo control arm with FLOT, with the one O 1 randomization versus drabalimab, the investigation arm with FLOT. And then following this new adjuvant therapy, patients went on to surgical resection and then they received adjuvant drabalimab FLOT followed by additional development. And the primary endpoint here was event free survival. Some earlier data had been presented in regards to response rate, but we've been waiting for the primary endpoint. As you can see here, the primary endpoint was clearly met in regards to the investigational arm and had not yet been reached. Answer reached was .71. The event free survival for the control arm was 32.8 months. You can see here at 18 months and 24 months there's a clear splay in the curves and then in regards to OS once again in 18 and 24 months also still explain the curves has a ratio .78. The median overall survival has still not yet been reached for the investigational arm. And so I think it's, you know, it's long term fall of now 34 months. You know, kudos to Doctor Jen Jiggian and her team for getting this trial completed. It's very large trial, little less than 1000 patients. And we were all waiting to see if these results were going to be positive and and they were, they were, they were very positive regards the primary endpoint. I think it's fantastic. Speaker 1 You brought this up. We've seen the similar approach in multiple different disease sites. One thing to keep in mind, this study was not designed to answer how much adjuvant immunotherapy the arm is really adding, but a few things that we can walk away with. The sandwich approach is not compromising surgical outcomes from other disease sites. If you have to extrapolate, we often see that the benefit is an all comers PDL, 1 positive PDL, one negative PCR, non PCR. So if this becomes available, this will be the new standard of care. OK, to close another practice reinforcing study in upper GI malignancy space Destiny Gastric O 4, you know breast cancer and upper GM malignancies have led the way in her two positive disease. TDXD as a bucket approval for all solid malignancies We now also have TDXD as a bucket approval for all solid malignancies for her two positive disease. Kathy, can you touch on this study design and its findings? Speaker 2 This was a really nice study designed this looked at DXD at the dose of 6.4kg per kilogram. This patient population would have received at least one prior line of therapy. Her 2 positive gastro adenocarfinoma, Her two status had to be confirmed locally or centrally. And the primary endpoint was overall survival as compared to the standard of care which is the currently in gramaceromat commonly utilized as the second line treatment option for this patient population. And the primary endpoint here as you know is the P value was overwhelmingly positive for TDXD, the hazard ratio was .7. It's a difference of 3.3 months in regards to primary endpoint. In regards to PFS, it was a difference of 6.7 months, but the hazard ratio .74. So I think these findings are going to change our approach to the second line setting for this patient population. If I recall correctly, looking at the SA ES, they didn't have any grade 5 Ilds. I was surprised they did not have any reported grade incidences versus prior trials in breast, gastric and colon cancer, which reported grade 5 ILD. I think this is really going to change our approach to this patient population. Speaker 1 And one thing to reiterate here is the dosing. This is 1 space where the higher dosing has been the standard of care. Whereas in breast cancer, lung cancer, we've been using 5.4. Speaker 2 Colon cancer, too. Speaker 1 So this dosing is something to keep in mind for upper GM malignancies. Speaker 3 And this again continues to reiterate that TDXD is a very activation. We've seen positive studies in breast cancer in later life and how convincing it was there we moved it to frontline and that's what we saw here at ASCO 2025 as well. When combined to TDXD with pertussumab when compared to Cleopatra regimen in breast cancer, it did show positive outcome there too. Well, we won't be surprised if we see similar thing in GI cancers and TDXD is move in frontline settings. But it is important to reiterate the side effects such as fatigue, nausea, alopecia and of course, not to ignore ILD, though we did not see any deaths, but it is an important consideration. Of course, it is associated with mortality. Kathy, thank you so much for breaking down these important studies from ASCO 2025. Before we close for our listeners, a quick recap. Summary In this episode with Doctor Kathy Ng, we explored 5 pivotal GI malignancy abstracts from ASCO 2025. First, dynamic 3 showed that CT DNA guided adjuvant chemotherapy in stage 3 colon cancer did not improve outcomes. CT DNA positive remains a poor prognostic marker rather than a predictive marker. Then we also touched on atomic trial, one of the plenary discussions that adding a tisalizumab to full FOX in MSI high stage 3 colon cancer improved disease free survival with a hazard ratio of 0.50, potentially redefining adjuvant therapy for this subset. Speaker 3 Then the breakwater trial established in clorafinib, cetuximab and FOLFOX as a new standard of care for B RAF V 600 E mutant metastatic colorectal cancer by doubling of overall survival from 15 months to 30.3 months in upper GI malignancies. We touched on yet another plenary discussion Matterhorn study that looked at the use of durvalumab in periop and post op with plot regimen for resectable gastric and GE junction adenocarcinoma, which showed improvement in eventually survival. Once available, this will likely be the new standard of care. Then to close, we had a chance to talk through Destiny Gastric 04 with improved overall survival and confirming TDXD as a preferred option in second line and beyond her 2 positive metastatic gastric cancer or GE junction adenocarcinoma. Thanks for joining us. Be sure to check out our other episodes on treatment algorithms, FDA approvals and conference highlights. We are the oncology brothers.