Standard of Care Treatment for Upper GI Cancer: A Discussion with Dr. Sam klempner

Intro Welcome back to another episode of The Oncology Brothers. I am Rahul Ghosn and I'm here with my co -host and brother, Rohit Ghosn. Our goal is simple, to support the community oncologist. In this ever -changing world of oncology with its influx of new drugs and therapies, it's easy to feel overwhelmed. That's why we're here to focus on treatment strategies and practice changing data in each episode, making the journey a little lighter for all our fellow oncologists. Speaker 2 With treatment strategies in mind today, we are focusing on upper GI malignancies and we are joined by Sam Klempner. Dr. Klempner is a medical oncologist at Mass General Hospital specializing in upper GI malignancies. Oh, by the way, he also serves on editorial part of JCO Precision Oncology. With his expertise, we'll dive into how to approach and treat upper GI malignancies focusing on adenocarcinoma. Sam, thank you so much for being with us today. Speaker 3 Oh, thanks for having me. I follow you guys on social media. Treatment paradigm for T2 disease and beyond Sam, thank you. Sam, looking at the algorithm, as a medical oncologist, we rarely see T1 disease. Let's take a few minutes to dive into reiterating the current standard of care. Can you start us off with your treatment paradigm for T2 disease and beyond in esophageal G -junction gastric cancer? Speaker 3 Yeah, the evolving paradigms. Thankfully, we have improving options for our patients. Speaker 3 I think setting the stage with staging is actually something that is underappreciated. These are tumors where particularly, you know, C -word 2 and 3, the lower G -e junctions and gastric cancers, we see a lot of peritoneal spread and you've all seen it in clinic. But it's surprising how often laparoscopic staging is missed as part of the workup. It's on our guidelines. It's there. It's just something that it takes time to coordinate, you know, find a surgeon, get someone to do it. But it is important because the last thing we want to do is put someone through a therapy and then go to the operating room and find a bunch of peritoneal disease. So, staging, of course, imaging, endoscopy, pathology, biomarkers are increasingly important to guide the therapy in non -metastatic patients. Speaker 4 So, Speaker 3 just recently in August, the NCCN added mismatch repair testing for all adenocarcinomas and squames, actually, because the MSI -HIGH or MMR -deficient patients do so much better and can be managed differently. But assuming we have someone who's been appropriately staged and has a T2 or higher or node, clinically node positive esophageal, GE junction, or gastric adenocarcinoma, the historical paradigms has been neo -adjuvant chemo -radiation followed by surgery and now adjuvant nebola -MAV consideration or perioperative chemotherapy. Increasingly, I would say, and in the future, I anticipate more and more of this may shift to perioperative chemotherapy, sort of an increasing minority for neo -adjuvant chemo -radiation. We're all very much awaiting for a big trial called SOPEC, which is comparing FLOT head -to -head against CROSS. Speaker 2 Thanks for walking us through that, Sam. We will dive into the MSI world shortly, but talking about our chemo -radiation approach in community, I feel like we tend to rely on chemo -radiation extensively and I'm hoping that approach will change, especially with these trials, which are awaiting results. Now, Immunotherapy in adjuvant setting talking about immunotherapy in adjuvant setting, if a patient who has received chemo -radiation and cannot undergo surgery, we see this quite a bit in elderly population, and have had radiological complete response, do you consider immunotherapy from consolidation standpoint? Speaker 3 Yeah, it's a great question. Comes up in our tumor board, comes up at the coffee machine, all kinds of times, this is a very common question. And I think, increasingly, we also see not only people who are unfit for surgery, but people who have a fantastic response to the neo -adjuvant component and then choose to forgo an operation. We see that in our own older population in particular. And so consolidation strategies are attractive. There are multiple phase three trials investigating this exact question. We don't have a randomized dataset yet to say yes. So the textbook answered here question is no. In reality, if we see someone who is opting not for surgery and had a very high PPL1 score, maybe greater than 10 or something, I have definitely done it outside of a protocol. But the standard would be not to offer immunotherapy in that scenario. Speaker 1 Tim, thank you for going over that. A few things to reiterate. When we're talking about cross versus flat cross, did well because it had higher PCR. Speaker 1 But I think it's important to acknowledge that this disease might not be a localized problem, but perhaps a systemic problem. That's why flat could be a better option. And I have to acknowledge that my practice over the years has changed in the community. I had relied on concurrent chemo radiation and then focused on other options. But What happens after surgery? now I'm relying on periop chemotherapy. Sam, moving forward from your paradigm, let's say flat, most of the studies, including checkmate 577, looked at adjuvant nevola map, but the patients actually received concurrent chemo radiation in that setting. Speaker 1 So a patient in your clinic gets flat, goes for surgery, there's residual disease. What does that look like? Are you going to get more chemotherapy, which is what we have done? How are you using nevola map in this particular setting? Speaker 4 Yeah, Speaker 3 another very common scenario. Someone gets flat, they see their pathology report and say, it doesn't look like this worked. And the vast majority of patients, more than 85%, will not have a path CR with four cycles of neoadjuvant flat. So it's expected that there will still be residual disease at the time of surgery. It sets up a scenario of what do we do after that? The trial included all those patients in adjuvant flat. And we're of course awaiting another perioperative flat plus PD1 in the Matterhorn study, but we have seen the negative 585 trial. Speaker 3 But we do, we know more about what not to do than what to do. For example, we know that it is wrong to give someone who had flat and then had residual disease, particularly residual node positive disease, to say that they should get a cross resistant adjuvant therapy. Speaker 3 So giving ipinivo after flocked is inferior to finishing out with flocked. That's a trial called the bestige. Speaker 3 And so that's an important message to get out there that even if there's some patient inertia to say, let's do immunotherapy after surgery as opposed to finishing out with flocked, that seems to be almost detrimental to patients. In addition, I think it was quite encouraging that as a whole, all of us are getting better at giving flat. In the original trial, only like low 40 % of people got adjuvant, completed the adjuvant component. And if you look at the recent trials presented, it's closer to the 60s percent. Speaker 3 So like on average, all of us are just getting better and familiar with flat. Speaker 3 So we're getting better at getting patients through it. So to answer your question, the answer is still flat in someone who has less than a path CR and even patients with a path CR as those patients were all included. We don't yet have evidence to say that we should routinely give immunotherapy in the neo adjuvant or the adjuvant setting for people treated on flat. I think there are scenarios that arise again, very high PDL one, someone who you didn't know was MSI at the time, and then you tested it on surgery where I would not give that person adjuvant flop, for example. So Early disease and MSI status there definitely are some scenarios that arise, but the standard would still be flat. Speaker 2 Sam, you mentioned MSI status in early disease. How prevalent it is in early disease and in such scenario, do you consider neo adjuvant PEMBRO or dual checkpoint inhibitors at all? Speaker 3 Yeah, as you guys have covered and as many people I think is getting out there in the world, MMR testing is really something we probably need to consider for essentially every adenocarcinoma. Indeed. It's rare, but it's a unique biology. And I think the totality of the data supports giving these patients checkpoint inhibitor at some point in their care, whether it's a neo adjuvant or adjuvant or both, it's of course open for debate. But the frequency of MMR deficiency in stage one through three varies from 10 to 20%. So it's not small. These are one out of every five, one out of every six or seven people will be MMR deficient. If you look at the patients over the 75 or 80, that rate creeps up to like 30 or 40%. So I guess so a little bit excited sometimes when I see someone who's like 85 with a new gastric cancer, because I think they have a high chance of being MMR deficient and that actually bears out sometimes. These patients do not seem to derive the same benefit from chemotherapy as MSS patients do. Speaker 3 So the current approaches I think are moving more and more towards neo adjuvant PD1 or PD1 CTA4 blockade, because there's very high response rates. It gives the patients perhaps a pathway towards nonoperative management in the setting of a great response. And we've had many people decline surgery and do quite well. There's multiple case series of this. But in fairness to your prior point, we don't have randomized data. And honestly, it will probably be hard to generate randomized data, because I think it's no longer really equitable to randomize a MSI high patient to a chemotherapy only regimen. Dual checkpoint inhibitors for MSI-high patients Absolutely. Sam, the same patient MSI high who you're considering neo adjuvant treatment, are you relying on single agent PD1 or you're going with dual checkpoint inhibitors? Speaker 3 The data we have, there's a phase two trial with IPI NEVO, neo adjuvant followed by surgery and adjuvant NEVO in a French trial, where the path CR rates were about 60%. There is data for single agent pembrolizumab in a large MD Anderson series. Speaker 3 And so I think the response rate does seem to be higher with dual checkpoint blockade. I think in healthy fit patients who don't have contraindications, I have been doing dual checkpoint blockade for many of those patients in anyone who I have any particular concerns because the toxicity is definitely greater with CTA floor. I feel very comfortable with single agent PD1, Pembrolizumab, etc. Speaker 1 Perfect. Speaker 1 Thank you. So before moving on to the metastatic space, I want to reiterate a few things for coming back to the adjuvant nevolumab. Again, the data did not pan out for gastric cancer. This is only for esophageal and G junction. As Sam, you've mentioned, this is more with the cross trial rather than periop flot and then considering any adjuvant component to IO. Sam, metastatic disease, your paradigm here. Speaker 3 Yes. I think, again, thankfully, we're starting to look a little bit more like lung oncologists. I started out actually doing lung cancer and really enjoy talking to thoracic oncologists because they're enbressed and everyone has to think very nuanced through these multiple targets. Metastatic Gastrointestinal Adenocarcinomas So finally, we're moving into this space with the metastatic gastrosophageal adenocarcinomas. Still, as you hinted at here, the main dichotomization is MSI status and HER2 status. Those are the ones that put you down different branches of management. PD1, we can certainly discuss, but in a HER2 positive patient, we now have phase three evidence to support trastuzumab plus chemotherapy plus Pembrolizumab in selected patients. And so again, getting back to that biomarker theme, what we've seen is PD1 expression remains important even in HER2 positive patients. Speaker 3 So now we're talking about it in double positive. So someone who's HER2 positive and PD1 positive, those are the patients that benefit from the triplet, full fox or Kpox plus Pembrol and trastuzumab. And the FDA actually revised the label for Pembrolizumab and HER2 positive to restrict it to PD1 positive patients because there was no clear benefit in the negative populations. In HER2 positive, most patients are PD1 positive, like 85%. So it's quite common to be dual positive. So what I do is we test HER2, MMR, PD1 for all of our new patients. We've moved to testing Clodin as well, even though the agent is not approved. For people who are PD1 positive, I find the triplet very active. Some of these really fantastic responses, we all see people two, three, five years out. And then in people who are HER2 negative, we, of course, MSI high remains the strongest predictor of immunotherapy benefit. But in the metastatic setting, that's only around 5 % of people. So then we start to move into these PD1 strata. And my take on the data is essentially, if the patient is CPS negative by an appropriate assay and a lab that you trust or pathologist you trust, then there's really no clear benefit to adding checkpoint to that patient. The other end of the spectrum is also quite clear. Patients who are CPS high, usually defined as five or higher, it's clear that those patients do derive a survival improvement. The one to five range, the ASCO line, party line is, you know, have this on a case by case individual discussion. And that's of course true for all of our therapies. Speaker 3 We have to have shared decision making for everything. But the data is not very strong for the addition of checkpoint inhibitors in the one to five group. I think you can make a case for it. Thanks Node-only patients respond well to immunotherapy and HER2-based therapies very much for going over that. And I like the part where we are getting into more of breast and lung space and seeing these biomarker and then deciding our approach based on that. Sam, let me just touch base on a very common scenario where we have a patient with distant metastatic lymph node disease, which is retroparitoneal and superclinicular, they receive systemic therapy. Speaker 2 And now those lymph nodes are not lighten up on scans. Do you chase surgery in these settings to really go after a curative approach at all? Speaker 3 Yeah, I think, you know, we're starting to get into this world of, you know, oligomets and can we salvage these patients to transform them into really, really long term responders, maybe even cures. I think, yes, we do think that way. Node only patients tend to respond very well to combinations, particularly immunotherapy and HER2 based. My general and our general approach has been that patient presented with clear M1 disease by nature of a non regional lymph node, say a superclinicular node and a gastric mass. Speaker 3 You know, their tumor has told you that it's figured out how to get there in the first place. So they are metastatic. So it's a systemic problem. However, if we can give that person, you know, three to six months of chemotherapy plus minus biologics and targeted and they can maintain that radiographic response, oftentimes what we will do is scope them to see what the primary tumor has done because oftentimes the primary tumor is not completely gone. And in those scenarios where there is residual primary tumor, but no evidence of any distant disease, we will entertain, you know, a very informed discussion with the patient about surgery. And we have operated on those people and some do very well. So I think that is a nuanced scenario. There are trials looking at more definitive oligometastatic disease, like someone with one liver met and a primary tumor. That I think pushes the bounds a little bit more for us. And Comprehensive NGS testing in upper GI malignancies we have not generally operated on all visible sites for those patients, but there are some large trials like a trial called renaissance that is studying that exact question. Speaker 1 Perfect, Sam. Actually, I'm going to dial the clock back a little at the time of initial diagnoses. We've talked about MSI briefly touched on cladin 18 .2 or via MSI testing. Speaker 1 A lot of this can be done with in -house IEC testing. Is there any specific role of comprehensive NGS testing in upper GI malignancies? And actually, when we're touching on cladin 18 .2, Zolbutaxabab is not yet approved. But if this was to get approved, this algorithm is going to change a little again. In that scenario, how are you going to prioritize Zolbutaxabab in high CPS score patients? Speaker 3 Yes, that's it's a very, you know, again, this biomarker overlap world is going to get very interesting and fun. Again, I think the prioritization of biomarkers probably comes down to the relative benefit and toxicity of a given therapy. Speaker 3 So someone who's MMR deficient, you're always going to pick immunotherapy, even if they're cladin positive or HER2 positive. Speaker 3 It trumps everything. And then probably HER2 is going to be next because we have long track record of therapies that are generally quite well tolerated. There will be HER2 positive, cladin positive patients, and that will certainly be a discussion. But, you know, we will see where the data shakes out. And then in the PDL1 strata, there's going to be cladin positive patients who are CPS negative, middle of Speaker 3 the road and high. I think in the CPS high patients where you, let's say, have two drugs that offer equivalent survival improvement. In the CPS high with the general side effect profile of immunotherapy versus Zolbutuximab, we may see an initial shift towards more immunotherapy in that patient population. It's also possible that cladin can be preserved for later line therapies as there are multiple other drugs in development. But you will have your option. You have a perfectly reasonable ability to give that patient Zolbutuximab if the agent is approved. Some patients will not have, they may have an autoimmune disease and that may be someone who would, Speaker 3 despite their high CPS, you may prefer to start with a Zolbutuximab based combination. And then of course, there's a lot of interest in generating sort of the analogy to TRAZ, PEMBRO, and FULLFOOX in the cladin positive, where you just have cladin directed therapy like a drug like Zolbutuximab, FULLFOOX plus a checkpoint inhibitor and say that way we'll solve this problem by covering all the bases. And The challenges of cladniomab-directed therapy in advanced disease that remains to be seen. Speaker 1 So, can I push a little more on this story? Because this is something we're going to be struggling with very soon. A patient who has progressed has a progressive disease on first line. They've never seen Zolbutuximab. They do have cladin 18 .2 in that scenario. In second line, are you going to give Zolbutuximab alone? Are you going to still give chemo back bone? What are you going to do? Because when it's approved, a good portion of patients have seen first line treatment already. Speaker 3 Yeah, this is a very tricky scenario. Speaker 3 I mean, we don't have data. We don't have Zolbutuximab second line versus Caxal RAM, for example. But it's hard when you know a patient has a biological target not to want to give them that therapy. I think my initial management is going to be trial, trial, trial, even if I have to send them outside my institution, I think trial. But not everybody's going to have access to trials. I would be a little bit cautious about giving a patient progressing on first line therapy Zolbutuximab with the hope that that's going to either salvage the response on top of the resistance to first line. And we just don't have data in combination with standard, you know, Caxal second line. So I think, unfortunately, those patients are going to be in a window where it's tempting, but it may not be the right thing. Speaker 2 Sticking to this theme of targeted therapy, in her to therapy, her to targeted approach, we have the data for trust use map with chemotherapy and now Pamperless map added. If Side effects of TDXD these patients are to progress, we were utilizing additional chemotherapy and taking off trust use map, which is different from what we do in breast cancer space. Now we have TDXD. Sam, could you touch on few side effects and how you manage those in your clinic when it comes to quad therapy or from TDXD here? Speaker 3 Yeah, so first of all, I think, you know, we've all learned from each other that sometimes the patterns of progression after some of these combinations are quite interesting. Speaker 3 So sometimes we'll see people who've been on, let's say, full Fox, Tres, Pembro, and then they transition to 5FU, Tres, Pembro, or maybe even just Tres, Pembro, and then they pop up like a liver met. But all their other disease looks great. Speaker 3 You know, those are patients where I'm sure you and us too, we're tempted to say, let's, you know, go after that, either surgically or some ablative therapy, because the rest of the disease is great control. And I think that's a very reasonable strategy for some of these true biologic like single lesion escape. So I would encourage people to think about that when they observe this clinical scenario. Of course, there are patients who have clear progression, you know, then you need to change therapy. My own approach in that scenario is try when we can to rebiopsy the people to understand the HER2 status. In the HER2 positive patients, I'm basically giving everybody TDXD unless there's a contraindication. In the HER2 negative, I think I will often consider TaxolRAM as a second line and preserve TDXD for a third line, since we have clinical trial data to support both a second and third line scenario. That's generally been my own approach. TDXD is a drug that for patients often feels a little bit like chemotherapy in terms of fatigue and some myelosuppression and periodically some GI effects. Certainly with any new drug, and this is well worked out in the breast literature, Speaker 3 you know, it's a learning curve to monitor and manage the toxicities. The one class with TDXD is really this interstitial lung disease. Often a radiographic finding without clinical symptoms. So try to look at the scans with radiologists. In patients who are symptomatic, you know, you basically treat and stop the drug permanently. And I've seen it and that is what should be done. Anywhere in between, you know, I err on the side of low threshold to stop the drug in the setting of, you know, clinical interstitial or pulmonary findings because we need to, you know, this is a long run, hopefully for our patients. So we want to preserve their performance and quality of life enough to get exposed to later line therapies. But I think it's quite a manageable side effect for the most part and often is not that common, you know, somewhere in the 6 to 8 % range of real ILD. Outro Thanks for covering that. And that is an important point. That is the quality of life of these patients, especially in metastatic disease when we are going after the palliative approach. Sam, we've covered a lot here and one can continue to go on and on because the field is changing by the minute. Thank you so much for taking the time to go over the current landscape for esophageal, GE junction in Gasberg, Edno -Carsinoma. For our listeners, let us go over a Speaker 2 quick recap. With a potential new target in upper GI Edno -Carsinoma to quad in 18 .2, this disease site is poised for another new change coming soon. With Dr. Sam Kleppner from Mass General Hospital, we had a chance to touch on this and current landscape of esophageal, GE junction and Gasberg Edno -Carsinoma. Speaker 1 In our discussion, we covered data around cross trial with concurrent chemo radiation versus systemic treatment for early disease. We then also touched on the role of NivolaMab in adjuvant settings. With all that is happening in metastatic space, we covered our current available treatment options. Make sure to check out our discussion on HCC and colon cancer to stay up to date in our GI series. Thank you for joining us. We are the oncology brothers.