How to Treat Upper Gastrointestinal Cancers in 2025 - Treatment Algorithm

Intro Hello and welcome back to another episode of The Oncology Brothers. I'm Rahul Ghosane and I'm here with my brother and Co host, Rohit Ghosane. Our goal is to support you in the community settings where most of our cancer patients get care. Both Rohit and I are facing the same challenges being out in the community settings as a General Medical oncologist. There's a lot happening and things are moving fast. With all that in mind and our ongoing treatment algorithm series, today we're focusing on upper GI malignancies. Particularly, we'll focus on esophageal and GE junction adenocarcinoma and gastric cancer. For this, we're joined by our third brother, Doctor Timothy Brown, focusing on upper GI malignancies from UT Southwestern. Tim, welcome. Speaker 2 Thank you. I'm excited to be here and to talk with you all today. Speaker 3 Welcome Tim. We have quite a bit to cover in a very short time span. For early disease. We know if it is T1, upfront surgery followed by surveillance is in fact the standard of care with T2 or no positive. Medical oncologists definitely play a bigger role here. After ASCO 2024 and Azerpec data that was perioflot or conquering chemo radiation therapy. But given the survival benefit, we have been more relying on perioflot setting. Now can you start us off here with your treatment paradigm who gets perioflot versus who gets concurrent chemo radiation and tying in role of adjuvant nivolumab based off Checkmate 577 which was mainly for residual post chemo radiation stages. Treatment paradigm All yours, Tim. Speaker 2 Sure thing. So perioperative FLOT first came about in the FLOT 4 study, which looked at gastric and GEJ cancers. The question about perioperative FLOT has been long settled. From a gastric standpoint, these patients tend not to respond very well to chemo RT to begin with. For my T2 node positive patients with gastric cancer, FLOT has been the standard of care and will continue to be the standard of care. The main question that SOPEC was answering was perioperative FLOT versus as established by the CROSS trial in 2012, which was the carboplatin impact with Taxol with fourty 1.4 grades of radiation. And what the SOPEC study found was a benefit favoring the flat arm both in terms of overall survival, progression free survival and path CR rates, while also not finding any evidence to support a detriment from complication standpoint. So for patients who are candidates for either chemo, radiation or FLOT, FLOT seems to be the superior option. One other beneficial finding from the SO PEC study was in patients who did have a recurrence, there were fewer distant recurrences found in the patients who received FLOT, which supports the micro metastatic hypothesis of recurrences. Yeah, a few. Speaker 1 Things to unpack here, the reason why we continue to talk about FLOT versus concurrent chemo radiation out in the community. Concurrent chemo radiation is something that we're so used to less toxicity, we thought that better PCR. But again, Tim, as you mentioned, this is more of a systemic problem because of the micromats. Speaker 2 Absolutely. I I agree with that assessment there. There are some important caveats to the SOPEC study which I think may affect the interpretation slightly that oncologists should be aware of. The first main drawback was that the dose of radiation that was used in SOPEC was slightly lower than what was what is currently used and currently accepted as standard of care in the United States. The use of 41.4 a grade dose. The current accepted standard of care is around 52 grade. The other drawback to ESOPAC, which Rohit hinted on earlier, was that there was no adjuvant nivolumab used in the chemo radiation arm for those who had residual disease. The majority of patients who undermined resection did have residual disease and otherwise would have qualified for adjuvant nivolumab based off of Checkmate 577. Speaker 1 So now given that we have this data hand in hand for ESOPAC, we have Checkmate 577. Adjuvant nivolumab in patients with residual disease Let's take another second about this adjuvant nivolumab story. Tim, there are still some patients that will fall into this cross trial protocol either because they're frail elderly. Even if it's no negative disease in that particular patient, if they've gone through definitive concurrent chemo radiation and are not planned for surgery for any number of reasons, but they have residual disease. Do you consider nivolumab in those patients? Speaker 2 Yeah. For patients who have not undergone surgery but have completed chemo radiation, I don't know that I would necessarily move towards an adjuvant nivolumab paradigm. One of the Cal GB studies favored a switch maintenance approach using a PET adaptive strategy for a patient who I put through chemo radiation. They completed all planned treatment and still have residual disease. I might favor doing a couple of cycles of FOLFOX or other type of chemotherapy to see if I can further debulk them and perhaps convert them to being a surgical candidate. If they truly are not a surgical candidate after that I would favor managing them as you would an advanced or an unresectable patient, or rather a patient with advanced unresectable disease. Speaker 3 Right. This is one of those data free zones where you could go down the path of systemic therapy as you stated, Tim, whether that's with full folks or nivolumab. Again, we don't have any data here. Patient shared decision making is key. So before we shift gears, I just want to reiterate what Tim and Rahul you mentioned with regards to nivolumab. This is only approved for esophageal and gastroesophageal junction. This is a no go for gastric cancers at all. Although this is a small subset, checking MSI high is extremely important because we've seen some dramatic responses with immunotherapy. Tim at CHILI ASCO 2025, we saw remarkable results from IP Nevo combination and metastatic colorectal space based off of Checkmate 8HW study here, whether that being in early stage or metastatic MSI high disease. Do you lean towards single agent pembrolizumab or dual checkpoint inhibitors? Speaker 2 Yeah. I, I think that question really comes down to an assessment of the patient and whether or not you believe they can handle the potential adverse events associated with dual checkpoint inhibition, be it with durbatremi or ipineivo. But certainly we have great data across the multiple treatment settings, localized, locally advanced and metastatic that these patients with MSI high disease should be treated with immunotherapy if they are candidates. Speaker 1 All right, now switching gears to metastatic space. Metastatic space Things are exciting here. Tim. Walk us through your current treatment paradigm for metastatic esophageal G junction and gastric adenocarcinoma. We've seen some new approvals, including solbutuximab. Now, how's that changing your practice? The importance of biomarker testing. Speaker 2 Yeah, absolutely. And and this is a a complex topic that we can certainly spend hours debating. We do have to be comfortable somewhat with cross trial comparisons. What what I'm gonna say is based off of my opinion as well as what I've seen in practice in the advanced setting for esophageal and gastric adenocarcinoma, there are 4 biomarkers that every patient should have tested before you can design your treatment regimen. And those four are MSI or MMR clot in 18.2 by the ventana essay assay per two status IC with reflex to fish if needed and then PDL one. Now PDL 1 assays are also recently changing. Traditionally, we've used the composite proportion score, but as you see here with the PDL one greater than 1%, looking at tisalizumab, they use the tumor area proportion score. Those are not directly interchangeable, but there is a significant amount of concordance. Once you have all of those biomarkers, treating these patients becomes much more clear. The the easiest and probably most straightforward patient population to treat are those who have MSI high disease. For those patients, you can treat them with single agent hembrolizumab under the tumor agnostic approval, but we also have data in gastric cancer from Keynote 059. There wasn't a lot of patients who had MSI high disease, but those patients did have a good response to treatment. That publication was JAMA Oncology in 2021. There's also the often forgotten subgroup of Checkmate 649 that had IPPY Nevo. In that subgroup, the number of patients who had MSI high disease and those patients really did experience a profound benefit with IPPY Nevo compared to chemotherapy, having a median overall survival of almost 39 months with IPPY Nevo compared to 12.3 months with chemotherapy. These patients with MSI high disease respond much better to immunotherapy than chemotherapy and you can also consider using a chemo IO combination, FOLFOX and EVO. There are some data published on that which shows ongoing benefit as well. Speaker 1 Tim, of course, we've talked about the MSI high disease. What about the her 2 positive patients? Speaker 2 So I think the second most important biomarker if someone is not MSI high is going to be the her two biomarker. And the reason for that is these patients with her 2 positive disease are excluded from the chemo IO studies and were excluded from the chemos olbutuximab study. So they wouldn't have been candidates for those studies considering doing chemo IO or chemo zolbatuximab. It's going to be a data free space. So for these patients, we've known from Toga for many years now that there's a benefit from the addition of trastuzumab to target her too. We also know even more recently with the final analysis of KEYNOTE 811 being published last year, that there is an OS benefit to the addition of pembrolizumab for these patients who have APDL one CPS score of one or higher. We've known and I've seen in clinical practice, these patients tend to have a rapid and deep response to treatment that is reflected in the data with an objective response rate of above 60% for patients who receive this triplet approach. Speaker 1 These are exciting times as we talk about the second line and beyond. We'll dive into the recent press release of Destiny, Destiny, Gastric 04 as well. Timothy, your thoughts on zolbatuximab story? Destiny Gastric 04 Yeah. So this is an area that I've been interested in for a little while and I have to give a shout out to Uday Greywall, one of the fellows at University of Iowa with whom we have some work under consideration, hopefully will be out soon. My approach to the HER two negative and MSI stable patients is to look at both the CPSP DL1 score and the CLOD in score. For those who are have Acps, score 5 or greater is usually where I've set my cut off. I'm looking at doing chemotherapy with nivolumab for five or greater. It's based off of Checkmate 649. If they have Acps of 10 or higher, you could also consider doing chemotherapy with pembrolizumab for those who have a tumor area proportion score. We now have the approval of tisolizumab based off of rationale three O 5 and all of these studies are known to have a survival benefit, progression free survival benefit, objective response benefit compared to chemotherapy alone without significant increases in adverse events. I think it's a bit of a dealer's choice when you get to the CPS greater than 10, CPS greater than 5. I think Nivoli map has solid data and for two area proportion score of one or higher you can do tisalizumab and chemotherapy. For those who have Acps of less than one. I would look at the clod in score for those who have a clod in 18.2 positivity, which is IC 75% or more. There are solid data based off a spotlight and glow to support the use of zolbetuximab and chemotherapy. You have to be careful with zolbetuximab. There are high rates of nausea and vomiting. These patients need triple prophylaxis and you have to be prepared for managing that. However, there is a survival benefit over chemotherapy. The tricky part becomes what do you do for the patients who have Acps of one to five. For those patients, the data for chemo immunotherapy is less strong. I support an approach using chemotherapy with zolbetuximab with careful counseling of course, about the adverse events and then of course for the quadruple biomarker negative. So MSI is stable, her two negative PDL 1 less than one and clot in negative. These patients still benefit from chemotherapy or consideration for clinical trials. Next generation sequencing is also very important for these patients. Speaker 1 Can be touched on zolbatuximab and nausea. That is an on target effect. Usually some of that gets better as they get more and more exposure after first two cycles. But that triple anti hematic regimen is so important. Speaker 3 And also, Rahul, while we were talking about nausea, if you decrease the infusion rate, that nausea gets better. Speaker 2 That is true, yes, but it does make for a very long treatment day. Speaker 1 Yes, Sir. OK, before we jump on the second line and beyond, Tim, another not uncommon scenario ends up being patients with distant lymph nodes or oligo metastatic disease. Treatment of distant lymph nodes and oligometastatic disease You start them on systemic treatment and then three, 612 months later this shows up on your tumor board. These patients have dramatic response, not what we have some data from Renaissance trial, but can you share your practice for such patients? Speaker 2 Last year, as you alluded to, we did have some presentation of the of the Renaissance study, which looked at how to or look at the possibility of converting oligo metastatic patients into a curative state by debulking first chemotherapy plus minus Nevo or trastuzumab depending on candidacy resection and then further chemo. And the trial was unfortunately stopped early due to slow enrollment. But what they did notice is that they there was a increase in early mortality for these patients without any improvement long term for overall survival. And so I think for the majority of these patients who have oligo metastatic disease, unfortunately the data aren't there to support trying to convert to a curative intense strategy with the caveat that there may be a hint of some benefit that's going to need to be explored further in those who have retroperitoneal lymph node only disease. Certainly, patients who have peritoneal disease should not be considered for this strategy. Speaker 3 And all ties into the patient shared decision making and also the multidisciplinary approach. Now moving along into our second line space, with regards to her 2 positive disease, we have trastuzumab duroxtacan. Treatment of HER2 positive disease Just this morning we saw press release from Destiny Gastric 04 study stating oral survival benefit. We also have zanidatomab, a bispecific antibody that got approved for phalangiocarcinoma, which is being studied in this space as well and looks promising. We of course have taxol plus remicerumab, but options are rather limited. Tim, your treatment approach in Refractory is easier. Speaker 2 Yes, we do need novel agents in this space is a huge unmet need. Starting with the HER 2 positive disease, assuming that they were baseline HER 2 positive if they received the KEYNOTE 811 protocol or TOGA based protocol, I would favor repeat biopsy and repeat biomarker assessment. There is known loss of biomarker expression particularly after treating these patients. There's limited data, but it does support considering a repeat biopsy particularly if one would be readily accessible. If they retain her two positivity it would be reasonable to proceed with trastuzumab deroxtacan. We've had long term data from Destiny Gastric 01 showing a benefit in terms of objective response rates as well as an overall survival benefit months versus 8.4 months versus investigators choice chemotherapy. So with this Destiny Gastric 04 study, I think the the support behind second line TDXD is going to increase. Of course, prescribers need to be aware of the risk of pneumonitis for these patients. And even though it is a targeted drug, it can be quite hard on the bone marrow as well with a lot of cytopenias. So exciting data. However, we look forward to seeing the the actual data from Destiny Gastric. So for the her two negative population, for the MSI high population who received just immunotherapy upfront, you can consider re challenging with the dual checkpoint inhibitor if they had a good response or you can proceed with treating them as you otherwise would a first line management for these patients. For the remainder of the population, the data support either in ramy Ceriumab and Taclotaxel based off of Rainbow or even Folfury. You can consider the addition of Ramy Ceriumab for those patients too. Doctor Klintner had a nice paper published in 2019 that would support the use of Folfury ramy Ceriumab. I think the choice between the two really comes down to a discussion with the patient and and their comorbidities, particularly if they have any residual or lingering neuropathy from a FOLFOX based regimen in the first line. If so, it's going going to be challenging to treat them with remysterumab paclitaxel. However, the careful discussion with the patient should help you decide how to treat them. Speaker 1 And Tim, you brought up some side effects, be it neuropathy or pneumonitis with TDXD. The treatment here is palliative. So getting your palliative care team involved early on is also very important. Pneumonitis takes a lot of discussion time when it comes to TDXT, nausea, fatigue, alopecia or other common things that we have to worry about when it comes to trastizumab. Direct Tican. Tim, before we close, in your practice, do you use 5 FU bolus when you're using full fox or full fury? And do you check DPYD mutation for all your patients up front when they're using 5 FU or Cape cytopine? Speaker 2 Yeah, those are great questions. I completely agree with having palliative care on board for the advanced and metastatic patients. I think they improve quality of life and help patients live longer even while you're treating them aggressively. The five FU bolus, I generally try not to add it for my patients with advanced or metastatic disease. I might consider it in a young or otherwise very healthy person where there might be a benefit for additional debulking. However, you do intend to run into more cytopenias with these patients. As far as DPD testing, I'm not doing it routinely. If I run into profound issues with profound mucositis or cytopenias out of proportion of what would be expected, I would consider sending it. I don't think that the data quite support doing it as a routine practice, although that is an area of intense debate. Speaker 1 And I think the data continues to point things back and forth, and I'm hoping that we'll see a little more on that to either change our practice or reaffirm what we're doing. Tim, thank you so much for joining us today and going over your treatment paradigm for upper GI adenocarcinoma. Key Takeaways For our listeners, let's touch on some key takeaways from today's discussion. In this discussion with Doctor Timothy Brown from UT Southwestern, we've covered early stage disease and the nuances around Azopex study. Is systemic treatment with flat and then surgery followed by more systemic treatment better than concurrent chemo radiation and then surgery? Yes, but concurrent chemo radiation still remains an option for selected patients. Also, nivolumab for esophageal and G junction adenocarcinoma, post chemo, radiation and surgery for residual disease remains the standard of care. Rohit, your key takeaways in metastatic disease. Speaker 3 Right. Big thing here is the importance of biomarket testing. CPS can help us guide the use of immunotherapy. You have 3 available options. That is pembrolizumab, nivolumab or tisalizumab. Based on recent approval, we also now have solbutuximab for quadrin 18.2 mutation. And then her 2 testing upfront is extremely important. Thanks for joining us. Continue to follow along for more treatment algorithms, conference highlights and staying up to date with all new approvals. We are the oncology brothers.