hello and welcome back to another episode of the Oncology Brothers podcast i'm Rahul Gossain as always I'm here with my brother and co-host Rohit Gossin as we just got back from ASCO days ago so here we are diving into the most impactful updates from ASCO 2025 annual meeting where thousands of abstracts were presented today we're going to focus on GI malignancies and for this we're thrilled to have Dr kathy Ing a worldrenowned 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 the space there's a lot happening 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 indeed it was quite a bit practice changing and practice informing and as Raul 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 five key abstracts three abstracts from colar rectal space dynamic three study atomic study in breakwater then we'll shift gears to upper GI malignancy focusing on matter horn study and destiny gastric04 let's start off with the hot topic of CTDNA which is utilized as a prognostic tool to deescalate treatment what we are seeing here with dynamic three study is rather the opposite of escalating the treatment in stage three setting kathy could you please walk us through dynamic three-study design and its findings i I think people are probably very familiar with dynamic which was the original study that was presented and published regarding stage two patients where it was informative in making treatment decisions stage three 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 onetoone fashion to either circulating tumor DNA informed management if it was negative then potentially deescalating therapy meaning instead of giving folox which you would commonly do or kpo in the stage three setting you would potentially reduce it down to five or nothing for that matter if you were circling 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 fibop few or cape cytoine if you were going to give five of few capitabine you would give potentially full fox or capeox for approximately 6 months same thing 3 months maybe just escalate to 6 months or the consideration of full fox eerie 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 tumor DNA informed escalation based upon if you were positive it's important to keep in mind they screened over a thousand patients and ended up being about a 100 plus or so patients that were circulating tumor DNA positive as you can see here in regards to recurrencefree survival they did not fare better in regards to dose escalation which was a huge surprise for us we were all in a bit of shock and keep in mind this is a phase 2 study but they did screen over a thousand patients and the fact that we don't have many treatment options in the stage three setting and we commonly prefer to reduce the use of oxy platinum 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 full fox or oxali platinbased therapy did not provide any additional benefit in recurrence free survival what is very clear the posttop circulation 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 we were many of us were discussing this afterwards is this an opportunity then do we not have the right drugs in the stage three setting like maybe oxel platinbased therapy is not the best treatment and fuller 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 three patients that is looking at the role of full fox 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 Drs Dari and Dr blue but it'll be very intriguing what they decide to do based upon these findings absolutely just to reiterate here CTDNA being positive and when you escalated your treatment this did not change outcomes so based on dynamic three study we cannot rely on ctna positivity to attack the same cancer with more chemotherapy coming back to what Roy said this is prognostic Kathy now that we have this data outside clinical trials today how are you using CTDNA for that patient in front of you 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 three patient and I'm considering not doing any therapy we do order in that setting i have ordered it in our very high-risisk patient population for me it's more about that surveillance period for a stage three patient we historically would only get a colonoscopy at year one and then every three years thereafter and then an annual CT scan but if I have a patient that has completed their adin 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 three patient population we just don't have great treatment options that are making that dramatic difference in current spree survival kathy how are you utilizing this for stage two also yeah so for stage two we do not have a clinical trial anymore we had a trial and unfortunately that closed after intram 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 CA like CT scans 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 lymphnode dissection so for that high-risisk patient okay sticking with colurectal cancer moving on to atomic subject matter yeah which was a plenary study the study evaluated here given a tisalismab with fulfox in stage three MSI high colon cancer one big takeaway here is all our colurectal cancer patients should be tested for MSI status kathy can you break down the study and its results we have phase 2 study by Dr miriam Shalabi in this space niche 2 when we're doing these cross followup comparisons clinically what does this mean for us so this trial is actually created about 10 plus years ago and you may say why did it take so long for any stage three patient population where the primary endpoint is disease-free survival the the follow-up has to be longterm at least a median of 3 months plus and three years plus this trial was designed when IIO therapy was not the standard of care yet in the metastatic setting so this is specifically once again for stage three patients deficient MMR instead of just giving full fox as a standard of care if you are MSI high this is the question can you add io therapy in this case a tesalismab to your chemotherapy regimen to make it a better regimen for improving your disease-free survival and this was a onetoone randomization so patients got 6 months nowadays we don't give 6 months unless you're a high-risisk patient and you believe it is necessary and warranted to give them six months but because of the risk of peripheral neuropathy if you are considered a lowrisisk patient so those with T1 through three N1 disease then we would consider three months of oxyl platinbased therapy so here we're doing six months as the control arm and then the investigational arm was 6 months in combination with chemotherapy and continuing the atzo for 6 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 was uh ahead of its time let's be honest and I have to commend Frank Cynic for his persistence and being able to enroll to this study the primary endpoint is disease-free survival and as you can tell your threeear disease superior for the IO combination the hazard ratio is 0.5 and they want to achieve a hazard ratio of6 this fulfilled the disease-free survival primary endpoint in real life what would you do well I don't know if I would give 6 months of full fox 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 six months or I'm sure they'll find some verbiage in combination with the atesmmaab it doesn't answer the question about can you give a tzo by itself unfortunately we will not know that answer the majority of patients if I recall 60 plus% were the lowrisisk patient population to begin with so they were the T1 through 3 NN1 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 neoagant io therapy be before surgical resection then all the patients went on to surgical uh 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 I therapy has a role in the adipant setting for this patient population absolutely 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're relying stage two and stage three are rather hard to even investigate important to keep in mind I forgot to mention chilabi study involved nevoy not just a teslismab so CT4 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 three setting for colon carcinoma for deficient MMR patients and that is the A02 study I believe that it's currently still enrolling looking at single agent to staram in the neoagimment setting I think it's going to be really interesting those results we we'll still have to find out since it's still enrolling in the practical patient population I think sometimes you'd have to also discuss that you may have a patient that may not be the best candidate for surgery Right you have your elderly hyperthylated 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 oxylic platinbased therapy so I would not be opposed to 3 months and then doing a teslism app i think the question is do you do it for the duration of a year now because we know the neoagant data is very interesting depends on which setting you're looking at in the rectal cancer setting they say you still need six months in the neoagan colon setting it looks like you only need one dose of cta4 and two doses of IO therapy I think there's so much to be learned in this setting but I would say for practical purposes full fox decide if it's a lowrisisk or high-risisk patient population that will determine your duration of oxali platinbased therapy and then a tzo no more than a year one has to stress how there were only two doses of nolamab and one dose of epilamab I think it demonstrates it's a different micro environment before surgery all right Kathy moving along to break wall it's Scott coz's study and this was an international study international study which involved you this is a high-risisk population with BFF V600E 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 yeah as you mentioned breakwater is based upon the BRF B600E mutation these are proficient MMR patients you know historically these patients have a very aggressive tumor type diffused metastic disease and encorphanib and satuximab was already approved in the previously treated setting but can you move that combo forward to the frontline setting in combination with chemotherapy this was a very large international three arm trial originally with a runin 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 two treatment cohorts the ankorphin satuximab and fulfox versus the standard of care the ankorphin satuximab in the original first arm was eventually removed because data from the anchor phase 2 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 significant improvement regression 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 median survival for our stage 4 metastic colctal cancer patients is between 32 and 35 months and here with the combination with oxali platinbased therapy and the doublelet of encorathuximab they've achieved a median survival of 30.3 months it really gives a lot of hope to this patient population which always had such a poor prognosis with the best chemotherapy possible full fox Erie historically still had overall survival 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 the fury plus encarinuxmab i'm looking forward to seeing those results too but this is very very hopeful yeah now this degree of overall survival in BFF mutant disease is commendable but we should keep side effects in mind kathy though as community oncologists we've used BFF 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 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 arunotic situab or penitentim combination you're still going to have a rash you're still going to be at risk for some diarrhea you know there's obviously going to be potential risk for myo suppression it is a stronger combination but overall I would say and obviously fatigue but benefits far outweigh the risks that are associated with this regimen given these findings thank you Kathy now shifting gears to upper GI malignancies the first one we have here is Matterhorn study another plenary study evaluating perryobalomab with slot in rectable gastric and GEJ cancer here dervalab was tied in with the esopec winner from last year we have used this approach of peroperative therapy with imunotherapy in lung cancer breast cancer as well this is now being referred as defla as Dr sam Climpner used this term kathy could you please touch on the study design and findings here this is for locally advanced gastric adnocarcinoma the criteria regards the T- stage and the end stage no evidence of distant metastatic disease good PS this was an international study led by Dr jen Jigian this is looking at with with a placebo control arm with flot and with a 101 random randomization versus derbalamount the investigational arm with flot and then following this neoagant therapy patients went on to surgical resection and then they received adgant dervalab flot followed by additional dervalamab and the primary endpoint here was eventfree survival some earlier data have 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 it had not yet been reached hazard rates 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 display in the curves and then in regards to OS once again at 18 and 24 months also still displaying the curves hazard 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 follow-up now 34 months you know kudos to Dr dr jen Jigian and her team for getting this trial completed it's a very large trial a little less than a thousand 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 to primary point i think it's fantastic 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 adgivant amunotherapy 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 in all comers PDL1 positive PDL1 negative PCR non-PCR so if this becomes available this will be the new standard of care okay to close another practice reinforcing study in upper GI malignancy space destiny gastric04 you know breast cancer and upper GI malignancies have led the way in her two positive disease 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 this was a really nice study design looked at DXD at the dose of 6.4 four milligrams per kilogram this patient population would have received at least one prior line of therapy her two positive gastro adnocarcinoma her two status had to be confirmed locally or centrally and the primary endpoint was overall survival it was compared to the standard of care which is currently gremly 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 um 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 for the hazard ratio of 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 SAEs they didn't have any grade five i was surprised they did not have any recorded grade 5 incidences versus prior trials in breast gastric and colon cancer which reported grade 5 i think this is really going to change our approach to this patient population and one thing to reiterate here is the dosing this is one space where the higher dosing has been the standard of care whereas in breast cancer lung cancer we've been using 5.4 mill so this dosing is something to keep in mind for upper GM malignancies and this again continues to reiterate that TDXD is a very active agent 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 TDXD with partismab when compared to Cleopatra regimen in breast cancer it did show positive outcome there too well we wouldn't be surprised if we see similar thing in GI cancers and TDXDS move in frontline settings but it is important to reiterate the side effects such as fatigue nausea alopecia and of course not to ignore though we did not see any deaths but it is an important consideration because 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 in this episode with Dr kathy we explored five pivotal GI malignancy abstracts from ASCO 2025 first dynamic three showed that CTDNA guided advent chemotherapy in stage three colon cancer did not improve outcomes ctdna 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 tizzalismab to full fox in MSI high stage three colon cancer improved disease-free survival with a hazard ratio of 050 potentially redefining adgivant therapy for this subset then the breakwater trial established anoraphanib satuximab and fullfox as a new standard of care for brf v600e mutant metastatic colorectile cancer by doubling of overall survival from 15 months to 30.3 months in upper GI malignancies we touched on yet another plenary discussion matter horn study that looked at the use of dervalab in pererryop and posttop with flot regimen for rectable gastric and gj junction adnocarcinoma which showed improvement in event-free survival once available this will likely be the new standard of care then to close we had a chance to talk through Destiny Gastric04 with improved overall survival and confirming TDXD as a preferred option in second line and beyond her to positive metastatic gastric cancer or GE junction adnocarcinoma 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