CRC Updates from ESMO25: Dr. Hornstein (2025)

Manju George 0:00
Hello everyone. Welcome to Doc talks. I’m Dr Manju George, the scientific director at PALTOWN Devement Foundation, the nonprofit that supports COLONTOWN. We have with us Dr Nicholas Hornstein to tell us about the colorectal cancer highlights from ESMO 2025. Really sorry, we started a little bit late. We were having some technical difficulties, but glad to be here. And I know Dr Hornstein for a few years now, and he’s one of the emerging leaders in GI oncology, and I’m so excited to have him with us to talk to us about the latest in colorectal cancer. Welcome. Dr Hornstein,

Dr. Nicholas Hornstein 0:44
Thank you for the introduction. Manju, it’s great to be here. I hope that we’ll be able to go through some of the updates from ESMO 2025, if you’ve been following along, this was a conference held in Europe that showed a number of really practice changing things for patients with colon cancer. So we started a little bit late, so I guess I’ll just jump into it. But before that, my name is Nick Hornstein. I’m an MD PhD and Assistant Professor of Medical Oncology at Northwell Health, where I focus primarily on patients with colorectal cancer. I’m also on X @gimedonc. So that further ado, let’s get into the talk, which is titled The practice changers and the puzzles. So why are we here? Well, it’s really the power of partnership. So this isn’t just looking at data. This is looking at the progress we’ve made as a community over the last year, and at the end of the day, researchers and clinicians provide the data, but it’s really up to patients and patient advocates to turn that data into urgency and voice it into access and action. So that’s why I was really excited to talk here today, so I can share with you the things that I think are important for 2026 in terms of both being a patient and a patient advocate. So thanks for having me.

Dr. Nicholas Hornstein 2:09
Before getting into the data itself, I just want to give a kind of general disclaimer on Kaplan Meier plots. So Kaplan Meier plots are curves that basically look like steps going down, they help us to compare groups of patients over time, usually looking at a new treatment or a standard treatment, comparing the two. We look for gap between those curves that tells us basically how much better one treatment is or another, or the difference we see. The median is the average. It’s the middle of the two curves. So we might compare these two plots by looking at the medians. But the most important thing– these graphs are just showing averages for large groups of patients. They aren’t a crystal ball. They can’t predict what will happen to any one person. And every patient is an individual and not a statistic. So we use these graphs to help us choose the best treatment for the right patient, but each individual’s journey is absolutely their own, so I just want to make that really clear.

Dr. Nicholas Hornstein 3:16
So to start off, before we get into the new data, let’s talk about the history, and I’m going to bring us through three eras of colorectal cancer. The first era is really starting in the 50s with development of 5FU by a guy named Charles Heidelberger in 1957 and that was our main tool for a really long time. In the late 90s, we added on new chemotherapies, including Irinotecan and oxaliplatin, but this was really a one size fits all approach. Every patient with colon cancer got a similar treatment. And although these drugs did improve survival, they were a really blunt instrument. So if we fast forward to the targeted era, 2000 2010s, you can see we have improvement. Outcomes are improving. Mortality is going down. We learned that colon cancer is not just one disease. We discovered we could target cancer specific behaviors. We could starve its blood supply with drugs like Bevacizumab. We could block its growth signals with drugs like Cetuximab or Panitumumab. And the takeaway from this is that we’re starting to take steps into dividing this disease into groups, Ras, wild type, Ras mutant, and we can use that division to give smarter drugs that are tailored to individual patients. And by doing that, we’re improving outcomes somewhat significantly. And where are we today? I like to call the 2020s the precision era. We treat the individual’s tumor, not just colon cancer, and before we start treatment, there are a number of critical questions that we need to ask, is the tumor MSI high? Or deficient in MMR, this means it’s probably going to respond to immunotherapy and should not get chemotherapy. Does it have a BRAF mutation? That’s a specific genetic mutation that we now have really good treatments for, whereas previously, this was very aggressive and very hard to treat. And third, can we detect tumor DNA in the blood using something called ctDNA? This is prognostic, but not predictive, meaning we can tell how someone’s going to do, but we’re still waiting for trials to tell us exactly how to use this for treatment.

Dr. Nicholas Hornstein 5:32
The data from ESMO builds on this precision approach and helps us deliver the right care to the right patient at the right time, and in doing so, you can see we’re doing much better in treating this disease than we did even 10 years ago. So I think that’s certainly hopeful that in the future, it’s going to continue to improve. So section one, the Practice Changers. These are big wins. The data is so clear that it should change the standard of care today. So the first study I want to talk about is one called NICHE-2. This originally had a readout for ESMO 2025 but there is new data and a new comparison with standard of care chemotherapy. And I think the findings are so striking that we have to talk about it. So the patients are those with early stage operable colon cancer that is MSI high, meaning they have a mutation that leads to the ability for that tumor to respond to immunotherapy. This is about 15% of patients with colon cancer in this stage. And the question that these investigators are trying to ask, What if we give immunotherapy before surgery? And they basically got two treatments with immunotherapy. So in the first cycle, two drugs, nivolumab and ipilumumab, and then two weeks later, they got a second treatment with nivolumab, and then they went to surgery. All of this took six weeks from the time they started on this study to when they had surgery. And this was compared to the old way, which was surgery first, then either watch and wait or give chemotherapy.

Dr. Nicholas Hornstein 7:18
And in the new findings, they found that giving these two immunotherapy drugs, nivolumab & Ipilumumab, just once before surgery, caused tumors to basically melt away or disappear completely in nearly all patients. And what I’m showing you on the right hand side, in blue is this line, and this is comparing disease free survival. So does the cancer come back, and it’s over a few years to six years out. And what you can see this line is a straight line. Every single patient on this study that got immunotherapy did not have their cancer come back, which is amazing. And we compare that to chemotherapy, and you’ll see there’s two lines for t3 and t4 so different stages of the tumor. But clearly this is very different. You can’t tell the T3 and T4 curves apart here, because they’re both 100%. This is outstanding, right? This is frankly curing a disease in this setting. Every patient that has a dMMR tumor should know about it before surgery, and you should talk about, is immunotherapy an option? This is not the FDA approved standard yet, but many people are starting to use this in practice, because you can’t beat 100%. And some people are starting to ask, Do we even need to go to surgery if these are the outcomes? So we’re not there yet with that question, but there are a number of studies ongoing to investigate it, but very practice changing critical information for a patient to know before they’re going to surgery with colon cancer.

Dr. Nicholas Hornstein 9:06
The second study I want to talk about is BREAKWATER. This was a study in advanced colon cancer, so metastatic, and these patients that were included in the study had a specific mutation called BRAFV600E. This is normally a very aggressive subtype of colon cancer that we did not do very well in treating historically. The traditional way to treat this disease was to give chemotherapy, plus maybe another drug, like Bevacizumab. And the new way of treating this that was explored in the study was using two targeted treatments. One is a pill and one is an IV, encorafenib and cetuximab. And what you can see is comparing this control, which is standard of care, chemo, to this arm, which is chemo, plus this new treatment. The treatment, including this precision medicine approach doubled how long patients survived. We don’t often get to double things in cancer care with just one study. So this is a major step forward for patients with this specific subtype of colorectal cancer. This is the new definitive first line standard of care, chemotherapy, plus targeted therapy for patients with BRAF V6100E mutations. This was a study by Kopetz et al., and what they added on at ESMO was some new analysis looking into resistant mechanisms and how they can use Ct DNA dynamics to identify how patients are doing. And what they did is they compared patients who got this new targeted therapy plus chemotherapy to patients who only got the targeted therapy. And what they showed is over like a 14 week period if patients got chemotherapy, they didn’t see that there was any significant rise in resistance mutations, but if you didn’t give the chemotherapy, you got a very significant increase, so 7% versus 38% so this is arguing that, yes, combining chemotherapy with targeted therapy is the new approach, but also maybe we can use this information we’re getting from ctDNA to figure out what the next step is. So if we see resistance rising, we can intervene. Those studies are still being worked on now, but the takeaway for clinic today is for patients with a BRAF V600E tumor, their first treatment should include targeted therapy with chemotherapy.

Dr. Nicholas Hornstein 11:47
And the third practice changer, this is CHECKMATE 8HW, and this has been around for a little while. It was only FDA approved somewhat recently, but there was some new analysis that came out looking at progression free and overall survival. So this is meant for patients with metastatic colorectal cancer who have that same mutation I talked about earlier dMMR or MSI-high. In this setting, it’s about five to 10% of patients. So it’s a significant number. And the question is, we know that immunotherapy works for these MSI high patients. But is one immunotherapy drug enough, or should we combine them with a second, this ipilimumab drug I already mentioned. And in the trial, they compared one drug versus two drugs versus chemotherapy. And what they showed was, comparing these two drugs versus chemotherapy, there seems to be a pretty clear improvement in progression free survival. A lot of times in oncology and in science in general, we talk about p values. And here you can see p of 0.0413. Normally, people say p is less than 0.05. You might have heard this a lot. It’s kind of our standard. In this trial, there was a pre specified P value that was lower than this. So because of that, because this pharmaceutical company basically stacked the deck against them, they didn’t meet their end point. But does that really matter? I’m going to argue no, because if I look at these curves as an oncologist or as a patient, I can see that there’s a pretty significant increase in the number of patients who don’t have their disease come back. Comparing these two treatments, we have to weigh this against toxicity, and we know that there is more toxicity for Ipilumimab, but in general, the toxicity from these regimens, immunotherapy regimens, can be pretty well managed, as long as we have a suspicion for them, and as long as we’re giving the right treatments, such as steroids or antibodies to de escalate the toxicity, and at the end of the day, I can manage toxicity, but it is very hard to manage a cancer that has come back that is refractory to immunotherapy. So in my practice, I have 100% gone all in. I’m using this regimen for my patients with MSI high colon cancer. So I think this is a game changer as well. And most of the people that are treating colorectal cancer primarily are in the same bucket. So with that said, those are the practice changers.

Dr. Nicholas Hornstein 14:41
There’s some puzzles too. These studies are positive, but they don’t just give us a yes or no answer. The last three studies are Yeah, absolutely, you should do this. These are the patient populations. This is the new treatment. The puzzles raise new questions. Questions that are important to discuss. Many of these puzzles involve CT DNA and where its role is or isn’t in treating colorectal cancer. And to introduce that, ctDNA is also called a liquid biopsy. There’s a lot of words for it at the end of the day, it’s a blood test that looks for tiny fragments of cancer DNA in the bloodstream. Any day that goes on, normal and diseased cells live and die, and when they die, they release tiny snippets of their DNA into the bloodstream. We’ve learned as a research community that tumor cells release DNA that looks a little bit different than normal cells. So we can actually quantify it. We can pull it out, and we can look for things like mutations, methylation patterns, a variety of things. We can get a lot of information. So we use it in two main ways. It’s like a smoke detector for cancer. The first way is to tell us about disease burden. Can we find a spark, the residual disease, before it becomes a fire, radiographic disease, seeing it on a CT scan, and do something about it? And the second is, can we use it to make treatment decisions? Can it tell us if a tumor has changed and if a treatment will or won’t work? That’s going to be the context of how I’m going to talk about this technology in these next trials.

Dr. Nicholas Hornstein 16:32
So the first puzzle is called DYNAMIC III. This was a study in patients with stage three colon cancer, who, after their surgery, had their blood drawn and was sent for CT DNA analysis, they wanted to ask if we could change treatment. Can we give less chemotherapy like oxaliplatin, the chemotherapy that gives terrible neuropathy if too much is given? And what they found was it did not prove that giving less chemotherapy was exactly as good. The group that got less chemo had a slightly higher but pretty small risk of the cancer recurring. So 88 versus 85% the question, though, is, for patients with low risk stage three, is this an option? So the difference between giving ctDNA versus not was about 2.2% at three years. And it looks like this might be clinically impactful, and the reason for that is in high risk. There’s a big difference here. This is a 6% difference. It doesn’t make sense to decrease this chemotherapy based on ctDNA for this population, but when we’re talking about 2% let me show you what the alternative is. They were able to reduce the amount of oxaliplatin given to patients by a huge amount, 89% to 35% and by doing that, they significantly decrease hospitalizations from treatment and toxicity from treatment as well. So we really want to spare patients the side effects of oxaliplatin like neuropathy or hospitalization. This study says, Be careful, but talk to your oncologist about is it worth adding oxaliplatin in this setting if I am ctDNA(-). It’s a tough conversation. For me talking to older patients, it’s something that I bring up, and we’ll discuss, usually patients over the age of 70, I shy away from using oxaliplatin in this setting. And this gives me kind of more credence that that’s probably the right choice. For younger patients, I am still giving it, but it’s a conversation that needs to be had. So that’s why this is a puzzle and not really a practice changer, something we should think about and talk about. The other thing I’ll mention, the technology used for this test is a little bit different than the technology that we use in the United States. This is mostly a European study with a different blood test than we traditionally use here. I think as these blood tests get better, we’ll have this conversation keep recurring until we get to a point where the sensitivity of the test, the ability for it to detect tiny amounts of tumor DNA, improves enough that these lines will overlap. We’re not there yet, but hopefully we will be in the future,

Dr. Nicholas Hornstein 19:42
The next puzzle is a combination of two studies called CITRIC and PARERE. These are studies that enrolled patients with advanced or metastatic colorectal cancer who had been on many treatments before. And the question was, can we use targeted drugs like cetuximab or panitumumab until they start working. Usually we just stop after that, but maybe we can add them on again. Can we do a liquid biopsy to see if the resistance mechanism for these drugs has disappeared? And if it does, let’s see if it works. And what the study showed is that if the blood test is clear of these resistance mechanisms, these genes that we know stop the drugs from working, yeah, reusing the drugs works. So we see that over a period of somewhere between three and six months, the chance that you have this resistance gene in your blood goes down very, very quickly. So we know now that we basically have a new line of therapy that can work for four to six months, something like that. But it’s still better than not having it at all. So many patients will get chemotherapy in the first two settings, they’ll get a third line of maybe lonsurf and Bevacizumab, and then in this fourth line, we have a new option from these studies that we can use to re challenge. The reason that this is a puzzle is it’s increasing the complexity of giving cancer care to colorectal cancer patients. It’s not so much just following a straight line anymore of we’re going to take this treatment, followed by this one, followed by this one. Now we’re saying, Well, we’re going to do molecular testing. We’re going to look in your blood for resistance mechanisms. We’re going to circle back to an older line of therapy. And it’s really exciting in that it’s using this precision medicine approach to bring additional treatment options for patients, which is saving lives for longer. So it’s something to discuss, it’s something to think about for future studies, but it’s something that’s really exciting and interesting, especially the approach.

Dr. Nicholas Hornstein 22:04
The third puzzle, and I kind of waffled on whether this was a puzzle or a practice changer. I certainly am going to be using this in my clinic, but I’ll tell you why I kept it as a puzzle. Stellar 303 is a study for patients with advanced cancer who have been on standard treatments, so they’ve had their chemotherapies, and now are moving past that. And it compared the standard regorafenib to a new treatment, zinzilitinib and atezolizumab. And this is very interesting. Atezolizumab is an immunotherapy which we usually don’t use in patients with microsatellite stable colon cancer, which is these patients here. And it’s one of the first studies to show that there is a benefit of using immunotherapy in this patient population. It worked modestly. It worked enough that I will use this but if you look at the outcomes, it really only increased them by a month and a half. However, it’s a new treatment. It’s something new that we can sequence, and it’s something that we will absolutely be adding on to our armamentarium once it’s FDA approved, gives us a new treatment line. The challenge, though, is that in terms of safety, is pretty toxic, but 57% of patients had significant adverse events from being on this regimen. So for a month and a half, is 57% worth it, I think at the end of the day, for some patients, any new option is a lifeline. So absolutely. For others, the potential side effects may not be worth that benefit, but this is really the definition of a patient by patient decision, where a patient’s goals are the most important thing. But most important, I think that we need to have a little bit more information about sequencing. Can we use this followed by regorafenib and followed by lonsurf? Does this mean it’s another treatment in the line, or is it an alternative? I think it’s probably going to be another treatment in the line, because it has a very different mechanism of action. And the other thing, I think, is that the toxicity can be improved. We know from prior studies with regorafenib and lonsurf and Fruquintinib, all the third line agents in colorectal cancer, the toxicity we see in the trial is not reflective in reality, because in reality, we usually reduce the dose before we start, and we keep it at a lower dose. So I’m very excited for this regimen. I’m going to be using it in my clinic, but I think that there’s probably going to be some modifications, especially to the zinzilitinib dosing, which is the second drug in the regimen. I’m pretty sure that people are going to be dosing this a little bit lower. And that’s going to improve toxicity, but that’s kind of why this is a puzzle. There’s still more information that we need to help us decide how best to sequence this dosing and patient selection.

Dr. Nicholas Hornstein 25:12
So what are our takeaways for three key groups of patients, care got definitively better early stage dMMR, based on NICHE-2, these patients should absolutely be receiving immunotherapy before surgery, if surgery at all. 2. Advanced dMMR, CHECKMATE 8HW shows two drugs ipilumumab and nivolumab are significantly better, “significant” in loose terms, better than what was standard, either chemotherapy or single agent nivolumab and 3. In patients with metastatic BRAF positive tumors, adding on targeted therapy in the first line setting, as evidenced by breakwater, significantly improved survival. The liquid biopsy is the future, but it’s a little complicated. It’s creating new and smarter options like CITRIC and PARERE show us, and forcing new conversations about risk and benefit, like DYNAMIC III. We are advancing towards unlocking the immune system for micro satellite, stable disease. New drugs like in stellar 303, are still pushing the boundary forward for patients, but like always, we need to do better with toxicity, and we need to do better for selecting the right patients. And I want to leave with this, what is your role as an advocate or a patient? I would ask, Has my or my loved ones tumor been tested for dMMR, MSI before surgery, 2, RAS and 3, BRAF. These are key questions for precision medicine, and frankly, every single patient with colon cancer should be getting sequencing, because we also know from another study called ALASCCA, adding on aspirin for certain patients, has a significant benefit, and we only know that if we do sequencing of their tumor, 2, demand access to these new standard of cares. If you see one of these mutations or know of someone that has it, you should be asking, why aren’t we targeting this? Why aren’t we using this actionable information? And 3, participate. So I always encourage participation in clinical trials. Every puzzle study today is a practice changer tomorrow, and it’s only through our combined efforts that we’re going to be able to make these critical advances and help improve the standard of care going forward. So with that, thank you for tuning in and listening, I’m happy to answer any questions, and thank you for the invitation. Dr George,

Manju George 27:50
yeah. Dr Hornstein, thank you so much. Even with a little bit of delay, we were able to cover it quickly. So I think one question that I have is, when compared to, say, for example, CIRCULATE-US, how is DYNAMIC III different? And we have many patients who are interested in getting on CIRCULATE-US. So what advice can you give for them?

Dr. Nicholas Hornstein 28:18
So CIRCULATE-US is, is quite a bit different than DYNAMIC III. DY III uses a different blood testing technology, first off, and second off, the study was more designed as a de escalation study. CIRCULATE-US is designed with two thoughts in mind. One is escalation, can we add on more chemotherapy and power it in a way that we can actually get an answer? And two, can we de escalate as well? In DYNAMIC III, there were some patients who received escalation, but the analysis wasn’t really powered to address that question, so we’re still waiting for CIRCULATE and one other study to read out to give us a better understanding of how we can use this technology and potentially help patients by adding on more chemotherapy or help them by taking some away. I think it is a really important study to enroll to. Arvind Dasari is the global lead, and he is an amazing clinician and investigator, and I think he’s made every effort to make that study as patient centric as possible, and it’s one that I enroll to multiple times a month. So I think it is a very important study to participate in. Well, thank you for being a part of it.

Dr. Nicholas Hornstein 29:34
So any discussion regarding CHALLENGE? so CHALLENGE is a game changer. CHAL got a standing ovation at ASCO 2025 and it has single handedly caused me to change every one of my clinical notes, because now in every one of my notes, I cite CHALLENGE, and I tell my patients, you need to go and exercise at least 30 minutes a day, three times a week. I’ve even gotten to the point where I’ve tried writing prescriptions for a gym membership. I encourage every one of my patients to exercise based on the results. It was specifically for patients with resected colon cancer, but I think it can be really extrapolated from there. So it’s a really important study. It is a game changer.

Manju George 30:25
The other question is, about with the neoadjuvant, using the two immunotherapies, clearly there was 100% response in the NICHE-2 trials, right? That compared with, I mean, we have some patients in COLONTOWN who are on the ATOMIC regimen, right, combining chemo with immunotherapy. And I mean, for me personally, because I had stage three MSS rectal cancer, I got three months of chemo. And for me, it feels that like with someone with MSI High, having them get six months of chemotherapy seems like not okay, right? But there is also the issue that a lot of people know that their tumor is MSS or MSI high only after surgery, so then in the adjuvant setting, what advice do you have?

Dr. Nicholas Hornstein 31:19
So ATOMIC was a study that was designed in a different era. ATOMIC was written when there was not clinical equipoise for MSI high tumors, to only get immunotherapy, and it was thought that it had to include the standard, which was chemotherapy. We know now a lot more about MSI high tumors, and I don’t think anyone would propose in 2025 that we should be giving them chemo based on a few studies like Sargent at all. It’s a tough decision. I will say, in my practice, when I see patients with MSI, high, colon cancer after surgery, I ask two questions, one, why did I not see you before surgery? And two, is there a reason I don’t want to give chemotherapy. So patients over the age of 70, it’s a non starter. I’m only giving them immunotherapy for toxicity reasons, for patients under 70. We sit down and I show them a bunch of data, and we have a very, very long appointment where I walk them through– this is the standard of care. This is the responses we see to immunotherapy, and these are our options going forward. It’s a tough decision, though, and it’s one that, I don’t think there is a right or wrong answer to, and it’s very patient specific. If I can spare someone chemo, I absolutely will. So, does it help answer the question?

Manju George 32:56
Sort of. So, do you use ct DNA on those patients, and if it’s positive or negative, do you use that to guide the discussion?

Dr. Nicholas Hornstein 33:07
I do in my practice. It is challenging because that is not incorporated into NCCN guidelines, but what I discuss with patients is, if I’m ever doing something that’s coloring a little bit outside the lines. I explain why, the rationale and the clear fact that this is what the national recommendation would be based on our guidelines. But I do think it’s worth a discussion, and incorporating CtDNA and shared decision making can be very helpful.

Dr. Nicholas Hornstein 33:35
There’s a question about ABBV 400 I didn’t discuss it here because these were earlier phase one studies. So ABBV 400 is Temab-A which is a C-MET antibody drug conjugate being developed by AbbVie, it is looking to be very powerful and explored in colorectal cancer, as well as in some other solid tumors in the refractory setting, third line+ the response rate is light years ahead of the other agents we have in the space, comparing a 0% response rate for drugs like lonsurf or regerafenib to about an almost 30% response rate for Temab-A so the only reason it’s not a practice change here, it’s a phase one, but the moment phase three data comes out, I have a strong feeling that it will be practice changing, just not something we can bring into clinic today.

Manju George 34:36
So after the results from ESMO for patients considering to participate in clinical trials, like some of the early phase clinical trials, because that’s something that comes up for discussion a lot in COLONTOWN. Are there some broad areas that you would say, like go on a trial with an ADC, or go on targeted therapy? What are your recommendations?

Dr. Nicholas Hornstein 35:00
Yeah, so it’s a good question. There are a few broad swaths that I think about. For MSI High, they really should be looking at agents that are looking to overcome resistance mechanisms. There are a few good trials. There’s some work on Werner C helicse, that’s very interesting. It was also discussed at ESMO for MSS, though there’s a lot of things in development, a lot. I prefer targeted trials. So does your tumor have a specific mutation or protein expression that will increase efficacy, or trials that already has some readout. We just mentioned ABBV 400 for example. Barring that, there are a few guiding principles that I have. I try to avoid immunotherapy in patients with colorectal liver metastasis, unless there is an agent that is thought to overcome the resistance mechanism there. There’s a number of molecules in development, too many to list here, but at the end of the day, you should have a relationship with your oncologist where they can help guide you here. And maybe that’s the Phase One doctor you’re discussing with. Maybe that’s your local oncologist. Maybe that’s a third independent oncologist that can help you make these decisions. But for me, I’m doing this all day, every day. The only thing I really see is colorectal and appendiceal cancer, and with even that, it’s hard to keep up with it. So I can only imagine as a patient how challenging it is to parse this avalanche of information to determine which trial is best for them. So it’s important to be part of an advocacy group like COLONTOWN to discuss, it’s important to plug in with the right clinicians to also discuss,

Manju George 36:57
There’s a question about appendicial cancer,

Dr. Nicholas Hornstein 36:59
Yeah, so appendix cancer is tough. It’s a relatively rare disease, unless you’re a person that has it, in which case, it’s a very common disease because it’s your disease, and because of its national rarity or global rarity, there’s less trials specifically for appendiceal adenocarcinoma. Now we have data from phase one, two studies using things like immunotherapy that look very promising. We have ongoing studies. There’s one at MD Anderson looking at intraperitoneal paclitaxel, that is interesting, but there’s not a lot of studies specifically for appendiceal. We keep approaching groups try to put them on but given the rarity, it’s a little hard at the end of the day for appendiceal, I’d say, similar to what I just did, it’s important to see a clinician that knows the disease, that doesn’t just tell you, Oh, we’re going to treat this the same as colon cancer. Because there’s a lot of right answers, but that answer is the wrong answer. So just make sure you’re seeing someone that feels well equipped, that knows the appendicial literature. So you know at Anderson, JP Shen, at MSK, Dr, Foote, I’m around as well. But just seek out somebody that does this.

Manju George 38:20
Okay in the last couple of minutes, I know that we were planning to have a separate Doc Talk on some of the enrolling trials at your place. Are there some things just as a information, what are some trials at your place that have slots open, that people could reach out if that are interesting.

Dr. Nicholas Hornstein 38:40
So I brought in almost a dozen trials in colorectal cancer over the last year that are enrolling. So we hope to have something for every patient, whether that is somebody in the first line of treatment or third line. We also have some investigator initiated studies that I’m leading specifically for patients with newly diagnosed metastatic colon, pancreatic or endometrial cancer, as well as patients with later line colon cancer that are looking to receive a procedure called histotripsy to their tumors. And finally, although it hasn’t started yet, we’re looking to have another that will look to give patients with newly diagnosed resectable colon cancer a kind of new and exciting form of treatment. So those are some things that we have here. We also have a very significant portfolio in pancreatic cancer.

Manju George 39:40
Okay. And then to come to your Cancer Center, is it possible for people to have virtual consults, or do they have to be a patient to be referred to trials like, what? What is the procedure?

Dr. Nicholas Hornstein 39:53
Yeah, so we used to do that, but the FDA, in their infinite wisdom and Medicare had decided that we no longer should do virtual visits. So the approval has gone. However, if patients can pay out of pocket for that first virtual visit, it’s generally allowed. I’m happy to see patients in any way they want to be seen, and I try to be as flexible and accommodating as possible. I think it’s very hard to evaluate someone for a clinical trial without seeing them. It’s much easier in person, especially because we have to draw blood and make sure certain things are aligned. But at the end of the day, if patients would like to be seen, I will figure out a way to make that happen. My QR code was in the slides for my x handle, @GiMedOnc, and however patients want to reach out. You know, I’m here. I think there’s a lot. I think the thing that excites me the most is this trajectory we’re on to learn how to use immunotherapy for micro satellite stable tumors. There’s a lot of work going on now to try to figure that out. We’re not there yet, but I hope that in the future, with new agents, we’ll get there.

Manju George 41:02
Okay, and then what about like, something like CAR T or cell therapies like that? Are you thinking that we might be there sooner.

Dr. Nicholas Hornstein 41:22
I don’t know. I think that is tough. CAR T’s have a promise, right? And you read these reports of a patient having a complete response to a CAR T, we’re still learning. We don’t know enough about the immune system yet. In general, I don’t know what’s going to win out cellular therapies versus immune modulating therapies? It’s probably going to be a combination of the two at the end of the day. But I think the next era, after the precision era, is probably going to be the immune era.

Manju George 41:52
I think there’s a question about ADCs.

Dr. Nicholas Hornstein 41:58
There are many. I think there are some very good trials, like DESTINY, CRC 03, moving ADCs that are targeted, into the front line setting should be highly regarded. So taking a drug like T-DXd, trastuzumab, deruxtecan, if you have a HER2 positive patient right now, we’re giving it in the second line setting, which sucks. I know it’s gonna work, just no one’s done the trial yet. So those trials, I believe, are actively enrolling. But as I mentioned before, having a targeted ADC would probably be a pretty good bet if I was a patient,

Manju George 42:34
and then, there is also a trend towards, more standard of care, plus a novel agent, those kind of front line setting trials.

Dr. Nicholas Hornstein 42:43
Yeah, those are most of the trials. But in colon cancer, we can do that because FOLFOX isn’t too toxic if you dose it appropriately. Things like gastric cancer, where we’re giving drugs like FLOT, very, very hard to add on that next agent. So I think that is the paradigm. That’s what we’re seeing. There are some de escalation studies, but for the most part, it’s very hard to propose to a patient or to a company that we should do a trial where we are taking things away, because if it doesn’t work, you’re harming patients. And the first thing we say is, do no harm.

Manju George 43:20
And I think this would be last question, like with the new FDA, the recommendation about getting DPD testing before starting any 5FU containing therapies, is that something that you’re doing? Or what’s the general advice, I feel that we’re seeing a lot more patients asking about it and there are certain variants that are being tested and about dose reduction. And I think even when it’s dose reduced, people are worrying that, they’re getting less. Is it going to be as effective? So is there some advice that you want to give?

Dr. Nicholas Hornstein 43:59
Yeah, you know, the recommendation is a little challenging. It’s it’s kind of handicapped oncologists in a way where even if I feel like, Oh my God, I need to start right away, I’m going to get in big trouble if I start before that DPYD testing is back, and that can take one to two weeks. So the dose reduction is appropriate for the right patient. What I’ve been doing is I will send a DPYD the moment I meet someone, even if I’m not, even if I don’t know if I’m gonna give chemo, I just send DPYD, just in case and for patients where I need to start in the next five days, I do a ctDNA test, because as of like two weeks ago, New York State has approved DPYD determination from ctDNA, and they usually return somewhere between five and seven days.

Manju George 44:49
Okay, okay, oh, that’s good to know. There’s an option for doing those kind of testing. I think there’s one more question, which is for MSS stage IV RAS patient that’s chemo refractory and with no targetable mutations, where should they focus their energy?

Dr. Nicholas Hornstein 45:06
That’s tough. I would focus my energy on finding a good oncologist. I don’t think there’s any one size fits all trial, and it’s really important to understand a patient, their journey and see together what the best next step might be. So it’s hard to just say, like, Yeah, let’s do this study or that one, yeah.

Manju George 45:27
Okay. And then for patients with peritoneal metastasis, do you have any advice? Do you think that immunotherapy is giving some responses?

Dr. Nicholas Hornstein 45:38
Yeah, it’s funny. I’m giving a talk on Friday on peritoneal metastasis, specifically peritoneal metastases are very, very, very, very hard. They are the metastatic site that makes me the most concerned. I think there are some studies using PIPAC that are interesting. I’m enrolling some patients with them. But overall, we need to take a similar playbook to grossly distributed disease and really focus on our systemic therapies. So I don’t think there is a specific trial I would point to. I think it’s something where we have a lot of work. There was some more basic science work done about two years ago looking at the molecular driver of peritoneal metastases, something called mesothelin. But I haven’t seen any follow up for treatment, so we’re figuring that out.

Dr. Nicholas Hornstein 46:33
Is it liver Mets with an implantable device? Yeah, so that is not open quite yet. There’s a number of trials that, for whatever reason, aren’t on clinical trials.gov that are open at Northwell, but Anne the one you mentioned is for resectable liver Mets, where we’re putting a micro device that’s impregnated with a number of chemotherapy moieties, and it’s really designed to let us find more information about an individual patient’s tumor so that we can determine their biology. That’s the trial talk on Friday. I’m not sure if it will be recorded. I can look into it, and if it is, I’ll send it out on my Twitter account. It’s meant for a course for clinicians looking to better treat peritoneal disease.

Manju George 47:26
Okay, okay, thank you so much. I think I will keep in touch with you, because we will have, we are hoping to have the other talk at some time in the future, right, maybe after ASCO GI, something like that. Sounds good. Okay, thank you so much. I’m so sorry for starting late, but yeah, your time so much, and thank you so much for your time and for answering all our questions. Bye, thanks everyone for joining. Bye, bye.