SBRT for liver and lung mets
In this DocTalk, Dr. Eric Miller from The Ohio State University discusses SBRT for liver and lung metastases. Recorded in July, 2024.
Transcript
Manju George 0:00
Hello everyone. Welcome to Doc talks. I’m Dr Manju George the Scientific Director at PALTOWN Development Foundation, the nonprofit that supports COLONTOWN.Welcome to my first Doc Talk of 2026 and for those of you who are joining live, welcome. And I am so excited to have Dr Kopetz with us. And as many of you know, he’s no stranger to us in COLONTOWN. He’s an amazing oncologist, a very well known researcher , who designs these amazing colorectal cancer trials, and is a speaker at all the international and national conferences, and has received so many awards. And in between all of that, he finds time to engage with us, and for that, I’m so grateful. And he has many titles and honors, and I think to us, he’s a beloved oncologist who’s focusing on BRAF and KRAS mutated colorectal cancer. And so once again, I’m so thrilled to have Dr kopets with us to talk to us about the 2026 BREAKWATER updates. Welcome Dr Kopetz.
Dr. Kopetz 1:14
Yeah, thanks so much for such a delightful and kind introduction, and thanks for all that you do, and you really do such an amazing job of educating and advocating. And so we’re so grateful for community, for you as well. So delighted to be able to share some of the updates in BRAF.And I thought during this, I would take opportunity to kind of take a step back with a little bit of history, but then really talk about where we are. How are we thinking about this in 2026 so with that, I had to start with just the complexities that we’re dealing with. Don’t worry about interpreting all this. This is for the gurus in the field. There’s a Frank McCormick, he’s kind of considered one of the fathers of RAS and he’s kind of put together this pathway about all the complexities of how normal cells and then cancer cells signal. We kind of think about, and you may have heard in biomarker testing, kind of the key ways that colorectal cancer can acquire mutations. These can be through KRAS, NRAS mutations commonly, but also BRAF. And BRAF is a distinct entity. It’s probably the one that we were able to target first, but a lot of the lessons that we’re learning, and we’ll come back to this point that in BRAF are now being applied to KRAS G12C, and think in the future, G12D will be following right along in this path. So hopefully these wedges of targetable oncogenes will continue to grow.
Dr. Kopetz 3:05
Okay? I said BRAF was targetable. This now goes back for more than a decade where the kind of first inhibitors which some brilliant medicinal chemists figured out that you could actually target this specific mutation that’s present in BRAF. Now I’ll take a moment to say what we’re talking about is a BRAFV600 E, so it’s the most common mutation, but there are others. Now the others are a little more complex. Everything that we’ll be talking about in terms of targeting is really this most common V600E mutation. Others we’re not fully sure what to do with, because they’re so heterogeneous and complex. But the BRAF V600E, also common in melanoma, and some of the initial studies that kind of a classic one.
Dr. Kopetz 3:54
This is one of the first studies that we ran where we said, okay, let’s treat melanoma. Let’s treat colorectal the same and we got very different outcomes, and that kind of set us off down this path to try to figure out what is it that’s unique about colorectal? How do we better target that? So there’s really two main crux, right? We have to improve the shrinkage of the tumor. And then, importantly, really, really target the durability. And we’ll talk about that, about how can we keep the cancer, shrink it down, and keep it down for as long as possible? So a lot of the work has been trying to do both, and you’ll see progress has been made there. All right, so let me take a step back. If you were a medical student, maybe first or second month of medical school, you would get introduced this concept of homeostatic regulation and how it’s used in the body. But I think it’s a useful concept for us to understand, and it’s this idea that our bodies like to be in a certain condition and that they have feedback mechanisms to keep us in that that condition. And there’s the more critical the pathway is, the more critical that regulation is, the tighter the feedback is present. And it turns out that this growth factor pathway, we call it the MAP kinase pathway, it incorporates K RAS, NRAS, BRAF. Those are incredibly important for cell growth and healthy cell division, and so that the cells, especially the colon cells, have a lot of these mechanisms to keep that level of signaling just right. so this is homeostatic. And Walter Cannon really was the–and you can see how, just by virtue of the picture, how old this concept is, but we still see it.
Dr. Kopetz 5:58
So what does it mean? Well, when we are in normal physiology, you can think about your glucose levels, if you’re not a diabetic, about how tightly regulated that is, but even something simple, like your body temperature, right? So you go out and sit in the sun, your body temperature rises, your brain recognizes that. It then dilates your blood vessels and also induces sweating. And then the response is, your body’s temperature is restored, right? Very simple concept, but it’s this kind of regulation to say your body wants to keep its temperature in this really tight range, and it’s going to do everything it can to maintain that. So the same thing happens after targeting BRAF, right? So in a BRAF mutation growth signaling this tumor cell is has a level of signaling that it wants, and we can give an inhibitor of BRAF, but there are feedback mechanisms that this tumor uses to say, nope, nope. That’s too low. I want higher signaling in this growth pathway. And one of the things that does is it activates EGFR, and it turns out that that then reactivates the growth, and the signaling is restored from the concept of the cancer cell, right? So this is homeostasis from the perspective of a cancer cell.
Dr. Kopetz 7:29
Now, I know there’s a lot of aficionados out there, so if I were to do this and try to do this simplistic Frank McCormick figure, it would look like this, right? Where there’s this signaling cascade, where one protein, activates the next one, which activates the next one, and down at the bottom of that is growth, right? This is the signal that says cancer’s growing. So if we have the BRAF mutation now, green is kind of signaling, an activation that’s just pumping out signal– we inhibit BRAF, what happens? It gets shut down, right? So transiently, it does a good job, but what happens then is you get these feedback mechanisms that get de repressed. EGFR now gets turned on. It now signals around that inhibition. We’re still blocking BRAF, but there’s pathways to get around it, and the signaling is restored, right? So that’s why BRAF alone doesn’t work, because the tumor is adapting so quickly. Now, when you then now come in and block BRAF and EGFR together, that’s when you can shut down the system, right? It can no longer compensate. You block two key nodes and and that was the premise. So fast forward through a lot of clinical trials and work, the BEACON study was the first to really show this, that when you combine BRAF and EGFR, compared to a control arm, you can improve overall survival response rates in this setting, and this was in a later line population, where there’s improvements here from 5.9 to 9.3 months. So improvements, there’s a bit of a tail. This idea that a proportion of patients can really have a longer duration of that as well. And the overall the side effects that you can see here as well. So this was several years back, and resulted in approvals for the second and third line. But we want to do better, right? And so really trying to understand, well, how could we do that? What’s the path forward there?
Dr. Kopetz 9:47
So gonna take a step back to the lab, because I’m a physician scientist. So we tend to do something the lab, bring into the clinic, learn from the patients, bring it back into the lab, and kind of keep iterating. And so throughout all of this, we’re doing a lot of preclinical modeling of cancer. And so, how do we do this? Well, we use mice for this. And why mice? It’s kind of weird, right? Like, why do we use mice? Why don’t we use other areas or other model systems? So it turns out that we actually have a fair bit of similarity with mice, like 95% similarity to mice in our genetic code. A lot of the ways that the our systems work are very similar. And then there’s some practical advantages that we can house them in controlled environments. Can handle them, and they have kind of been used for decades, continue to be used for a lot of this testing, right? And so we’re really really, I think, thankful for the opportunity to learn as much as we can in these systems before we bring to patients, so we’re bringing better things forward.
Dr. Kopetz 11:04
So, you know, just want to advocate. This is kind of what what the mice look like. So we actually use these mice that don’t have any hair, so they’re called nude mice. So, and then a lot of times the tumors are kind of grown on the flanks of the mice, so we can put little calipers around it and kind of measure how things are are going and advancing. Now we take extraordinary care to provide a really good environment for the mice. We actually have veterinarians whose sole job is every day to check on the well being and health of the mice, and they get all sorts of like things to socialize together through all of this. And so just know that we’re trying to be really good stewards of this, and we don’t take this research lightly, but we know that it’s really important for our patients. Okay with that a bit of aside, because we like to show as researchers how can we do things right? And so one of the questions that we were asking is, how can we improve the targeted therapy, and we did an earlier study where we actually combined with the earlier generations BRAF and inhibitors with with irinotecan and we had patients that their disease responded. So we gave chemo, EGFR and BRAF inhibition, and not just BRAF and EGFR alone. And so the question was, okay, we had responders, and it was working, and we had some patients that were really generous, and they said we will be willing to do a biopsy so that you can take tissue out from my tumor and you can study it. And so we’re so thankful for the patient’s contribution to not only enrolling in research, but to support things like this. But what that allowed us to do is say, Okay, I’m going to take that piece of tumor, I’m going to take it back to the mice, just like you saw, and I’m going to grow that patient’s tumor on the flank of the mouse, and I’m going to propagate that tumor, so I can treat many different mice, and then I can treat that tumor with the targeted therapy alone, the chemotherapy alone, or the combination. And then ask the question like, if that model works, what was that the patient was responding to? They got three drugs. But did they need all three? Maybe you only needed two in this or our other one. And we were really intrigued. And I just showed three examples here, where you want to see things kind of going below the lines, the lower, the better, smaller the tumors here. And what we found was that the targeted therapy slowed growth. Chemo slowed growth, in two of the models, but you only really got regressions and things shrinking down when you did the combination. And so that was a really important finding for us. Now it turned out because I wanted to show all the data that one on the far right here. What that said is, you know what? The targeted therapy didn’t do anything. It was all chemotherapy doing the heavy lifting here, we would predict in this patient. And so we kind of expanded that out and looked at some really resistant tumors and showed that indeed, that when you combine this, we were using a full theory regimen, so irinotecan and 5FU, that you could really get these synergies and really suggesting that there is opportunities to improve outcomes and the durability through this. So that kind concept, as well as the idea to say, well, let’s try to get this into more patients sooner, really led to the idea of the BREAKWATER study.
Dr. Kopetz 15:06
And so what did we do? Well, designed this study, randomized 637, patients to a standard of care without targeted therapy at BRAF. Patients could still get BRAF and EGFR in second or third line because it was approved. But the idea is to start with standard chemotherapy in the control arm. Or EC, encorafenib, cetuximab and FOLFOX or EC alone as a kind of a third arm. And so we were trying to gather some data, like, do you need the chemotherapy there? And then we’re looking at progression free survival, response rate. Here’s the characteristics of the patients enrolled, and this really reflects a bit of what we see in kind of general practice here. So what do we see? So remember, we said we want to improve response rate and durability. So first thing we said is, let’s look at response rate. And indeed, if you look at the blue bar with the EC and FOLFOX now we had two thirds of patients approximately responding to the therapy, meaning the tumor shrank down by 50% or more, versus 37% with the standard of care therapy, a little more than a third. And that this was durable, and that was encouraging. So when we get a response and there was some increased durability, now one of the terms that we use to measure durability is progression free survival, as you’re likely aware. And so we looked at that progression free survival curve, what we saw was an improvement in progression free survival of seven to 12 months.
Dr. Kopetz 16:42
So what does that mean? I’m sure many of you are well versed in these curves, but I thought it was always worth to do a little bit of a primer about what this means. These are a measure of any time point along the way, the number of patients that are still receiving therapy and have not progressed. So we can look at this, and for example, we can see about it at six months time frame here, that 60% of patients were still on therapy and were free of progression. And over time, more patients progress, and you can see the curve coming down. And so by the time you get to 12 months here in the control arm, about only 30% of patients were no longer progressing. So we’ll say, Okay, that’s good. How do we describe the curves here? And so you’ll hear this term median, right? Well, what does that mean? Well, it means, really at that 50%, meaning half the patients progress before, half the patients progress after that time point. So the median here we use as our estimate. And you can see, you know, the median is a little over six months 7.1 exactly here in the control arm, but that median is closer to 12.8 months here in the in the experimental arm. Now we can use these numbers and now start to compare across different settings, BRAF has always been a tough or has not always felt to respond well to standard chemotherapy. FOLFOX, FOLFIRI alone, even with Bevacizumab, usually get like 6-7 months. Now, while the non BRAF colorectal cancer is usually around 10 months or, maybe 11 months. So this is really striking, because we’ve taken a tumor that had well worse than your average outcomes, and now with this regimen, now we have a median progression free survival that looks better than all the other tumor types, subtypes of colorectal cancer out there. So it’s a really big kind of chip. And I think, as we mentioned before, we also see this, this tail, and this gets a little noisy because we don’t have as long a follow up yet, but this idea of, this flattening here, and about a third of patients, even at two years, are kind of still ongoing, and that’s a much higher tail, as we say. So, the idea that there’s a subset of patients that we don’t fully understand why, but they get a really durable, prolonged outcome from this. So we need to know more. We need to make more people like that. So that’s one of our goals.
Dr. Kopetz 19:48
All right. Now we talked about, there’s a third arm, if you recall, right where encorafenib, cetuximab was used alone, no chemotherapy. And here’s the orange line for the encorafenib Cetuximab alone. So didn’t do better than the standard chemotherapy, but didn’t do worse either. So it is, it kind of is in that middle ground. The kind of interpretation of this is, you know what this is, typically the the EC alone is better tolerated than FOLFOX. If there’s a patient that is maybe not the best candidate for FOLFOX, can’t really tolerate it well, for whatever reason, there’s an option to at least do the EC alone, and that may be better than than other options for that unique case. But for most patients, we think that that is EC and FOLFOX should be there. Now, progression free survival is important, but remember I mentioned that well, the control arm could go on and they could get BRAF and EGFR right, and so is this just shifting when things are and if that’s the case, for what we really care about is, can patients live longer with this regimen?
Dr. Kopetz 21:08
And so that’s the overall survival– very similar. We use this median to say half of patients now, in this case, are living longer and half are living shorter than that estimate. But what we saw was that the standard of care about 15 months– what we expect on average, but that we’re able to double that number. So really, a doubling of overall survival is a really, a compelling number to see. And so now getting medium survivals that are much, much higher. What about that third arm? Kind of fell right in between. So, it’s not an unreasonable consideration to kind of start with that, but still not as good as the EC and FOLFOX alone.
Dr. Kopetz 21:59
Okay, thanks doc for showing all those complex slides. What does it really mean? So, here’s kind of that graphic summary, thanks to nano banana. I’ll say a little AI generated one. But what you can see here is that really, progression free survival, you’re reducing that risk of progression. And then that survival time is, in essence doubled, going from 15 to 30 months. Those are the kind of the key takeaways. Now, what about side effects here? Most frequent side effects are shown here, in this figure. And what we can see is that nausea, diarrhea, those kind of things that we normally think about with the chemotherapy, is about the same between these and that the real difference here is kind of in some of the BRAF specific toxicities. In this case, it’s looking at arthralgia and rash. So you can see that the combination of with encorafenib+ cetuximab can generate some rash. We use grading systems to grade one two, which means a more mild rash and arthralgia, and still impact quality of life. And so it’s something that we manage and work through with patients.
Dr. Kopetz 23:35
Now, one of the questions that’s come up is like, well, is this better than if we did really intense chemotherapy at the beginning. And so there are regimens where we put FOLFOX and combined with irinotecan and what we call the triplet regimen. And so this was just a bit of an aside to say that we looked at what patients could have gotten some of these more intense regimens, and then looked at some of the survival here. And the bottom line is that it didn’t matter in the control arm, if you use really intense chemotherapy that that really you got the best survival with the with the EC FOLFOX. Now we’ve been talking a lot about FOLFOX, and this is data from last year. So, but what about alternates? So we like our acronyms as we know and so FOLFOX, of course, is a 5FU oxaliplatin. Oxaliplatin is the neuropathy one. There’s the FOLFIRI, it is irinotecan and 5FU. And there are situations where patients, just may not be best served with FOLFOX. They may have had prior oxaliplatin exposure, may have had an early stage tumors, resected, got adjuvant FOLFOX, for example, and then the disease recurred later. Or maybe patients that have kind of diabetic neuropathy, for example, where they have other reasons for nerve damage. And then sometimes it’s just a lot of providers are looking at the side effect profile and just saying, you know, I just think FOLFIRI is a better choice in general to start with. And so all these things now to the credit of the sponsoring company for BREAKWATER they heard us when we said, we really want to have more options for our patients. And we want to generate data as well with with FOLFIRI. Right now, most companies, I would say don’t really do two studies to look at the same thing, but they heard us and and agreed to run this smaller study. So remember, before we’re looking at over 600, here we have like, 140 something patients.
Dr. Kopetz 26:02
And now this is just after the BREAKWATER finished enrolling. We then opened and enrolled this one. Endpoints, response, rate, side effects, very similar here. There was, interestingly less arthralgia and rash in this one, not sure I fully understand it, but it was that’s kind of what we saw there, but really low rates of grade three toxicities in general. So didn’t add much in terms of toxicity. Here again, we saw very similar, about two thirds of patients responding versus about 39% of the control arm there. So encouraging that there’s that much higher response rate, even with a FOLFIRI backbone. And overall survival, really early, we will have some updated data we’ll be sharing in Jun. But that this kind of really nice early separation of the curves that were similar in magnitude to what we saw before. So that’s great. It tells us FOLFOX and EC can be a backbone. FOLFIRI and EC can be a backbone.
Dr. Kopetz 27:15
So wanted to spend maybe the last few minutes and just talk a little philosophically, and that little more of the science here, right? So one of the questions is, wow, we’re doubling overall survival, not by bringing a new drug in, but by taking a drug that we would normally give in second and third line, and now combining it with our first line regimen. What gives? Yes, maybe it’s better, but why a doubling in overall survival? And, I shared some of that kind of concepts pre clinically, and I didn’t get into a lot of the deep science that led us to think that this could really work. But one way to really think about this is that when we give chemotherapy alone, and these are completely arbitrary numbers. We give chemotherapy alone, there may be 10 different ways that the tumor cells can develop resistance. When we give BRAF EGFR inhibition, again, maybe 10 different ways that resistance can develop, including acquisition of KRAS and NRAS secondary mutations, for example, which are really well described and and I didn’t present that data, but this idea that other mutations can develop that can reactivate the pathway. Now the concept, though, is that a new KRAS mutation is not going to make them resistant to FOLFIRI, right? And likewise, some of the resistance mechanisms to the chemotherapy may be blocked by BRAF and EGFR. And so it’s not that the cancer can’t find a way to develop resistance. Gosh, it almost always does, but we’re just making it much, much harder. So the idea is that the shared pathways of resistance are constrained, so that’s this lower level of number of mutation or resistance pathways that can occur. So by putting them together, you really make the tumor work hard to find some mechanism that will result in resistance to the chemo and resistance to the targeted therapy together.
Dr. Kopetz 29:25
Now it’s a great theory. Did we actually see any data about that? Like is what we have there? So I mentioned that, and we did a lot of work and published papers around different mechanisms of resistance to BRAF and EGFR when it’s given alone. These secondary mutations are kind of the key ones that we see. So what we did is presented some of the data on the CT DNA, so you can use circulating tumor DNA to explore the mechanisms of resistance there. And what we showed was that by month seven in the targeted therapy arms of the of the BREAKWATER study that EC alone, about 38% of patients already had these resistance mutations that were developed and evident. They developed KRAS variants, NRAS, MAP2K1, which is downstream, amplifications like MET or BRAF exon deletions, all these things that have been shown. But when we combine it with chemotherapy, now there’s no selective pressure, really, to generate that the chemo can keep the cancer from growing, even with those. And only 6% of patients at month 7 in the combination arm had that mechanism of resistance. And you can see, even at the end of study, after prolonged treatment, that we were seeing much lower rates of these secondary alterations. So we’re trying to and this is really where we are at the frontier of trying to understand this, is kind of the idea to say, how can we constrain the mechanisms of resistance. What are those two remaining shared mechanisms that are allowing the cancers to evade? We don’t think they’re genomic. They’re not acquiring second mutations, necessarily, that’s driving this, but there’s some tumor plasticity, state changes that are occurring. These are kind of the terms you’re hearing in oncology field now about what’s the plasticity of the tumor, like, how is it adapting to these different states? So stay tuned. But this is really where we’re working on it. We’re trying to nip these remaining things in the bud.
Dr. Kopetz 31:42
Okay, so adaptive resistance, you got your primer on homeostasis, right? There’ll be a test later on the homeostatic regulations, but this combination of BRAF and EGFR blunts that. It is a standard of care, but that the chemotherapy combinations have compelling biologic rationale, as well as the really now strong clinical data, doubling overall survival. And so that we do think that EC and FOLFOX, and I would say EC and FOLFIRI as well, are a new standard of care in the US and and I think this is even when you compare to the really intense chemotherapy there. The key for all of this is that in order to actually act early and take advantage of all this great biology, you got to know what your molecular subtype is, and so this is why one of the key things about this is molecular testing early. Don’t wait till second or third line of treatment to really start to act on the molecular subtype of your tumor. It’s really important for patients to understand their molecular subtype at diagnosis and act on it, if there’s ways to act on it, and so that’s really a challenge for us to make sure we’re communicating that to oncologists throughout the US and throughout the world. And I think increasingly we’re seeing that most, most providers now, are getting that molecular testing done and and making treatment decisions early. And just want to end by thanking the patients first and foremost. We are always trying to do better, and this is always bittersweet. When we see advances, because we see progress, but we also recognize how far we still have to go. And I just wanted to thank the the patients in the past who really participated wholeheartedly and in these, this clinical trials and the patients in the future that are still upcoming, and where we hope we’ll have better therapies to offer. So with that, thanks and happy to take some questions.
Manju George 33:57
Okay, thank you, Dr. Kopetz, that was an amazing presentation. As always, you take us through hard concepts, explaining them very simply. So thank you very much. So with questions, in COLONTOWN, people have posted some questions, and I had emailed you them, so maybe we can start with those, f you’re okay,
Dr. Kopetz 34:20
Sure, absolutely.
Manju George 34:22
Yeah. So the first question is, of all the patients on the different E plus C combinations, what’s the longest time in your experience someone has been on it? And the second part of it is, what do you think is the reason? Like, what have we learned?
Dr. Kopetz 34:39
Yeah, great question. I don’t know the answer yet about why. So we’ve had some patients that are now four years or so, on some of these combinations. The front line, chemo, plus a lot of times, what we’ll do is just continue the 5FU and encorafenib, cetuximab, and we’ve had patients on that two and a half years going on three so that really there is a subset of patients who can do really well with it. We don’t understand, we don’t know, if the tumor has some biology that’s called adaptive mutability, which is how the tumors change, in essence, they kind of turn themselves in and increase the rates of their secondary mutations, so that this is one of the ways the tumors can adapt. They start making more mutations. Each time they divide, they have more mutations. And the hope is they, imputing a lot of of intent to them, but the idea is that they, as they develop a lot more mutations they can find, stumble across other mechanisms of resistance. So there is some hint, maybe, that some of these really patients with really long duration don’t engage this adaptive mutability pathway, so their tumors don’t use this as a mechanism. But that’s I think, work that we still have to sort out.
Manju George 36:24
Okay, thank you. The next question is, what advice do you have for someone who was on FOLFOX plus E plus C and is now on maintenance 5FU plus E plus C. Is adding irinotecan to this at progression a good idea. If not, what else can they get?
Dr. Kopetz 36:44
Yeah, great question. So one point, not the question, is that when there’s this inclination, no one likes the pump, I get it, right? There is this inclination and maintenance to say, well, EC is working, what if we just stopped the pump as well as the oxaliplatin, right? And I really, I think that biology suggests that you need that 5FU, so I would say, try to maintain the 5FU now, the great question was, should we add more on to that? We just don’t know, to be frank, on this, I think, there is this sense that trying to put something into it before progression may not be the best approach, but we honestly just don’t have a good sense of this yet. I think we have tried it in some patients where you’ll start to see things kind of creep up. It’s not that full resistance is developed to 5FU and encorafenib Cetuximab, we either add the oxaliplatin in, or, if there’s neuropathy, add in the irinotecan, alternatively, so and that can work. The question is, is that better than than using irinitecan later, we just don’t know.
Manju George 38:07
For someone with a sustained response to E plus C and E plus C plus FOLFOX who is now progressing, what’s the best option next? Yeah, similar question.
Dr. Kopetz 38:19
Yeah. Great question. So there’s a few approaches there. There are studies to say, remember we talked about that these tumors are really dependent on this MAP kinase pathway. So there one approach is to say, well, let’s double down on this inhibition. And there is another protein downstream called ERK and so there’s a next generation ERK inhibitor. We tried ERK once, but that was really intermittent ERK inhibition, and that didn’t work. For the officianados, that had been tried once, but we think there maybe a better inhibitor. So there’s a study ongoing to double down on that pathway inhibition. The other is, we talked a little bit about the plasticity and the state changes. And so we have a study through the ETCTN or the NCI, federal government sponsored study, where we’re trying to use an epigenetic modifier. It’s called a BET inhibitor, but the idea is that it really inhibit some of these state changes. And so that’s a study that’s enrolling right now. And then there are studies to kind of ask questions about, well, what if you go and you do something else altogether, right? Like, if you haven’t gotten FOLFIRI, maybe you go and get FOLFIRI, you give it a break from EC. And what we see is that a lot of times, the tumors will rewire in order to evade the FOLFIRI. Sometimes they’ll shift back into a state that becomes EC sensitive. And so this idea to say, can you do what we call a re challenge, which is do something separate from MAP kinase targeting, and then come back and hit again with the MAP kinase. We see benefits with that with the EGFR inhibitors. This is a RAS RAF, wild type tumors that you can inhibit EGFR and then take a break and then come back and do EGFR alone. So that’s another strategy, but I think there still is a lot more that we can do.
Manju George 40:26
Okay, okay, thank you. So I think that brings us to the next question where people have asked, Can the BEACON and BREAKWATER regimens be reused? And then, if yes, like with EGFR inhibitor, we say, like, four to six months. Do you have any idea what’s the break that people would need?
Dr. Kopetz 40:48
Yeah, we don’t, to be frank, I think, we would typically check Ct DNA to make sure there’s no secondary mutations. All those are uncommon after BREAKWATER. But can be seen. So just make sure those have gone away. Because if you can still see a KRAS mutation present on CT DNA, then maybe it’s not long enough. You give it a little more time. But you’re right, we kind of think about, four month or so time away. It may be enough to have the tumor resensitize,
Manju George 41:25
okay, okay. And then the next question is, for people who miss the first line option of breakwater, what’s your advice on using this in second line or third line?
Dr. Kopetz 41:36
Yeah, great question. I think it does give us confidence that, bringing EC in combination with chemotherapy may be better than EC alone. So the the SWOG study that I showed the one with then looked at and second or third line looked at, in essence, BRAF, EGFR, with irinotecan, and that showed activity. And so I think if, for example, you got FOLFOX alone, I think there’s a rationale to say that you could do an EC, irinotecan, or EC FOLFIRI, in a second line setting. In that sense, all we have are these kind of cross trial comparisons to suggest, so in it, and we don’t have that, what we say level one, randomized data, but that tends to be my practice in those situations.
Manju George 42:35
Okay, thank you so much. The next question is, what’s the status of the E plus C Nivo trial. Do you have some updates?
Dr. Kopetz 42:44
Yes, so we’re going to be so that is a small kind of phase II study that is trying to build on the EC nivo single arm data there. The hope is there’s a subset of patients that may be deriving benefits from the nivo. So that one we should be able to present at ASCO this year. So we’ll have some of that that it was small the control arm was I think less than 30 patients there, but we’ll have that data.
Manju George 43:22
Okay, okay, thank you. So the next is, what is in line next, in terms of new regimens, now that breakwater is done, where’s the field heading? What’s cooking in your lab?
Dr. Kopetz 43:36
Yeah. So we’re really interested in the these epigenetic state, inhibition, I think the the idea to say that, that there’s a subset of cells that are kind of are adapting in some way to evade the those therapies. And if we can understand what those dynamic changes are, then we can potentially, kind of come in with inhibition and and look at different ways, the different vulnerabilities that may come up now. These can take the form of, potentially, thinking about ways to combine it initially, like, how do you extend duration when combination? Or can you understand these paths of resistance and then, kind of treat upon progression? So we’re trying to explore both ways.
Manju George 44:39
Okay, okay, thank you. So I’m done with those questions, and then here we have some Q and A questions. So those who are listening, if you have more questions, please add them in there. So the first question is, if there is a chemo for life patient, is there an argument to be made to do standard of care followed by E plus C or vice versa to prolong longevity rather than use the efficacy of both treatments together?
Dr. Kopetz 45:06
Yeah, no, that’s a, I mean, that is, that’s the angst, and I think that’s what surprises us about BREAKWATER. So the control arm, even if we limit to those patients who and the majority of patients, had access to BRAF, EGFR and second line in the control. So this was that study, in essence, the say standard of care chemo, followed by EC. How do patients live longer than when you put it all together? And the short answer is, it really matters, when you put them all together, that there’s a true synergy. It’s not kind of a one plus one equals two, but you’re getting much more. We think it’s because of and I know this looks like this question was like part way through my lecture, so hopefully I answered it with the kind of explanation of the how we’re trying to constrain the mechanisms of resistance. But I really think the data suggests that in this case, at least, it’s not about stringing it out, but really about bringing the best regimen together at the beginning.
Manju George 46:09
Okay, thank you. The next question is for can this drug regimen be used for patients without a BRAF mutation?
Dr. Kopetz 46:19
Yeah, great question that the short answer is, not, at the moment, there are, there been kind of different areas to explore in this space to kind of think through how you know what BRAF can do. One little bit of an aside is that there has been a recognition that the skin toxicity of the BRAF and EGFR combination is much less than you’d expect with EGFR alone. So the Cetuximab rash kind of acneform, kind of face trunk, but when we give the BRAF inhibitor, it’s actually less. They actually have much less, patients still have some skin rash, but it is substantially less so one of the areas has been like, Okay, well, could you use BRAF inhibitor to try to modulate some of that toxicity? But now, instead of taking it as encorafenib, as a pill trying to reduce that toxicity, there’s a company that’s actually made an essence of BRAF inhibitor skin cream. And so the idea is, could you just put a BRAF inhibitor skin cream on and treat the EGFR rash there? So that’s one kind of creative way where the BRAF inhibitors are being utilized there and I think in some extent, these drugs were engineered to be more potent against the mutated form of the protein. So that mutation is not there, it makes it a little harder to kind of utilize it, although I still think there’s some creative opportunities there, we just have not fully explored.
Manju George 48:07
okay, but in general, like to as a line of treatment for somebody without a BRAF mutation. You don’t generally recommend it?
Dr. Kopetz 48:16
yes, I should just be clear with that. No, we shouldn’t use it. There’s really no data about using encorafenib for anything but that BRAF V 600 E. Now the corollaries we also, I talked a little bit at the beginning about what about other BRAF mutations? And I think the data really has not.. we’ve tried for some of them. There’s different classes as we talk about them and characterize them, we tried these in different ones, and they have not provided benefits. So I know it’s tempting, because sometimes you say, Well, my report says a BRAF mutation, but they behave very differently than the V600E.
Manju George 48:51
Okay, thank you, for those who can only tolerate E plus C alone. Can it be continued once progression occurs, will it slow growth? Does it have to be stopped once progression occurs?
Dr. Kopetz 49:06
Yeah, so good question. We don’t fully understand all the dynamics of it. What we can say is that when we’re doing EC alone, that the mechanisms of resistance tend to be genomic, and kind of a get acquired pretty robustly. So we do think in those settings that kind of stopping the EC is beneficial, and that doesn’t necessarily result in any kind of progression or that continuing, it doesn’t result in more inhibition of the growth.
Manju George 49:46
Okay, so the next couple of questions, like in the BREAKWATER trial, do you have some data on whether people were able to get to surgery to resectability?
Dr. Kopetz 49:57
Right, yeah. So we do. There is some data suggesting, perhaps, that more patients may be able to get to surgery. We just, we need to kind of get that data little cleaner. It’s been a complex area, because there were several years because of the biology of BRAF and the outcomes, surgeons had just said, I’m not going to take a patient with a BRAF mutation to surgery. I just don’t think that it’s kind of beneficial in that regard. I think now the field has shifted a little bit, and people are more willing to do that, and we are seeing that, we are seeing anecdotally even, that some patients that go to the or for resection of their metastatic disease can have complete pathologic responses, which is just really extreme, great response to the treatment.
Manju George 50:53
Okay, okay. And then the next thing is do you have some breakdown of the people on BREAKWATER like, what kind of mets? I think you had the table, right? How many people had peritoneal Mets, and how did they respond?
Dr. Kopetz 51:09
Yeah, we don’t have breakdown by sites. It’s a great question. And so that we don’t have that data to say, you know that this group of patients perform better than the others. We do have in some of our waterfall plots, we can try to tease that out by eye, and then there are kind of we call forest plots, that have looked at that. The numbers are just small, but it looks like, in general, they’re performing better, but we don’t have, like, a breakout of response rate, for example, by peritoneal mets in particular.
Manju George 51:50
Okay, so next question is, what trial options are available for BRAF patients after BREAKWATER, you mentioned the BET inhibitor, right? Like, what else?
Dr. Kopetz 52:02
ERK and the rechallenge are the main ones that are out there right now being explored.
Manju George 52:08
Okay, the next question is, can you speak to any BRAF targeted therapies that are in the pipeline that are expected soon?
Dr. Kopetz 52:15
Yeah, so there’s work on on degraders. So degraders are one space. The idea is, instead of inhibiting it, can you grab the BRAF and just pull it and destroy it? So just kind of chew it up. Now, the cell remakes it, so you have to keep grabbing the BRAF and destroying it. So that’s kind of one of them. There’s been other areas to try to improve upon them. Kind of these next generation BRAF inhibitors that has some characteristics about how the different BRAF and CRAF and ARAF all kind of linked together. So these other family members, it’s B, because there’s an A, B and C, by the way, in case you want to know where the B came from. So there’s these other family members in the RAF family, how they interact. So there are some smart chemists out there trying to sort that out. We don’t necessarily know that they’re going to be better than what we have right now.
Manju George 53:19
Okay, okay. And then what about immunotherapy combinations? Is anything new being tested?
Dr. Kopetz 53:26
Yes, we have the PD-1. And that was done when we are looking back in the preclinical models. And again, always trying to learn everything we can and thinking about other strategies. The intriguing thing is that it really looks like that more than PD-1 is CTLA-4 that is the one that’s driving a lot of benefit, which is a kind of a common theme we’re seeing in in colorectal in general. That PD-1 is okay, but CTLA-4, really, is kind of what induces a bit of greater responses. So there is some intriguing data to say if we had the SWOG study that the encorafenib, cetux nivo study, would a CTLA-4 be better than that. So, these are things that we just have to try to prioritize the questions that we ask and try to understand if that’s going to be better. The other is vaccines. So there are some. There’s been a lot of push. Elicio, for example, the company that’s been generating K RAS vaccines for pancreatic cancer and then for colon and many others have been whispering in their ear to say, think about BRAF. Think about BRAF. So that’s on their radar. And so the hope is that maybe there could be some vaccine strategies to to kind of follow since we are talking about a single point mutation. So it’s kind of well aligned for that.
Manju George 55:06
OK. Next question is, are we close to a CAR-T, options for BRAF V600E?
Dr. Kopetz 55:15
Great question. We don’t see anything. I don’t know I say close, I mean, I think CAR- T’s have just been tough to try to find the cells that can get into the tumor there. So, so I would say we still have a little bit of way to go to even get CAR- T’s, in general, in solid tumors working. But we’re starting to see some, some progress. The difficulty is that you know when you have a single point mutation, that it’s getting expressed by a TCR, and these are really more like TCR TIL therapies where you’re trying to target the BRAF itself is that you’re looking for just a single mutation, and sometimes it’s hard for the immune system to tease out, like, really small differences in there. A lot of the CAR- T options are targeting completely separate proteins that are on the surface of the tumors. So the CAR-T’s are coming in and binding something on the surface that may not be related to V600E, so maybe that some of the CAR- T therapies being developed can be applied to BRAF population, but may not be BRAF specific.
Manju George 56:33
Okay, okay. And then in the BREAKWATER results, do you see a difference in patients who are younger with the BRAF mutation versus the older, right sided tumors. Is there a difference in outcomes?
Dr. Kopetz 56:47
Yeah, so that we have some data on early onset BRAF that says that they are deriving benefit from the therapy just as well as patients that are average age of onset. So I think the you know some subtle differences, but that there are some distinctions. Now, BRAF, in general, tends to be associated with MSI high in later onset BRAF, so I guess the caveat is that early onset less likely to have a BRAF associated with MSI high more likely to be MSS, but within the MSS BRAF, they tend to do the same as average age.
Manju George 57:36
Okay, okay. And then this is my other favorite question. So, with the pharmacogenomics testing, because we are combining E plus C with FOLFOX or FOLFIRI. Do you think that there can be more tailoring of the chemo part of the regimen so that people can stay on it longer? Are there any efforts to do that?
Dr. Kopetz 58:01
So, you know, we’re still, I would say, nascent in our understanding of pharmacogenomics. We know for irinotecan, UGT1A1, there’s some older data about the utility of that to kind of tailor things that really is more relevant for higher dose. irinotecan, kind of saturates a lot of the metabolism transporters, for the doses that we’re giving every two weeks, it’s kind of less relevant. So there has been some discussion like, Well, gosh, could you increase the dose of irinotecan in a patient that may have just the right pharmacogenomic subtype there, and I think that there hasn’t been a lot of work being done on kind of dose escalating the chemotherapy based on pharmacogenomics. But certainly a possibility. The problem is we don’t yet have pharmacogenomics for why the patients are responding to BRAF, for example, so we don’t have good answers there.
Manju George 59:03
Okay, okay, I think we are at time. And thank you so much. This was an incredibly informative talk, and I hope we can have you back when you have new trials and give a talk.
Dr. Kopetz 59:18
Yeah, always a delight.
Manju George 59:20
Okay, thank you. Thanks to everyone who was able to join. And as I said before, a recording of the video will be posted in COLONTOWN University in about two weeks. Thanks. Thank you, everyone. Thanks. Bye. Dr. Kopetz, bye.
In this DocTalk, Dr. Eric Miller from The Ohio State University discusses SBRT for liver and lung metastases. Recorded in July, 2024.
Recommended Resources
Research article
Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial
Scott Kopetz | Nature Medicine
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