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Early-stage BRAF V600E MSS colon cancer — What’s next after adjuvant treatment: Dr. Yaeger

Doc Talks

In this DocTalk, Dr. Rona Yaeger from Memorial Sloan Kettering discusses how to approach early-stage BRAFV600E MSS colon cancer following adjuvant treatment with PALTOWN Scientific Director Dr. Manju George. Recorded in June, 2024.

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. Today we have Dr. Rona Yaeger from Memorial Sloan Kettering Cancer Center to talk to us about what’s next after adjuvant treatment for early stage BRAF mutated MSS colon cancer. But before we start, I want to ask Dr. Yaeger how she got interested in GI oncology,  and in doing the kind of work that she does. Welcome.

Dr. Rona Yaeger  0:33 
Manju, thank you for having me, it’s a pleasure to be here. Like you mentioned, I’m very lucky that I get to focus on an area that interests me a lot. I work on colorectal cancer and targeted therapies. I find genetics very interesting. And when I was younger, and I saw the way you could see how colorectal cancer develops from polyps, I thought this is really an interesting area to work. And I like the relationships we have with patients, where I have many patients I’ve treated for many years, and have a very close relationship. So I felt like this was the right area for me. I see patients one day a week. And then I run clinical trials and also have a wet lab. So I have a nice combination of kind of all the components. But the actual work we do is very focused on colorectal cancer and targeted therapies. So thank you for having me and give me the chance to give an update on what’s next, potentially after adjuvant therapy for colon cancer with a BRAF V600E mutation that’s microsatellite stable.

Dr. Rona Yaeger  1:40 
So I wanted to just start off by talking about how we treat early stage colon cancer, and what we think of when we see these tumors. So this is a slide kind of showing the current paradigm of treatment. So initially, patients are diagnosed either they will have a screening colonoscopy, and something might be found in the colon, or they may have symptoms that lead to an evaluation with a colonoscopy that can show mass within the colon that is biopsied and comes back as cancer. The next step is to be sure there’s no evidence of spread. So patients have scans to look at the body, usually a CT scan to make sure there’s no evidence of spread. And if there isn’t, and the colon tumor is limited, the next stage is what we call a resection where we remove the cancer. So here you can see within the bowel, there is an abnormality that is removed, and then the bowel is reconnected. Following that, the tumor that is removed is studied under the microscope by pathologists who generate a report describing what they see. And that’s what’s used for risk assessment. So patients who have a tumor that’s limited to the colon has no evidence of distance spread are early stage. And if the tumor has higher risk features, such as having lymph nodes involved, involving the full thickness of the bowel wall, we often suggest additional treatment with chemotherapy with a goal to reduce the risk of recurrence. And if patients don’t have this features, they are then observed. And we watched patients for a total of five years, after which the chance of recurrence is so low that we say that’s it, you’re cured and you don’t need to be followed so closely. So this is our current paradigm. And we know that most patients are cured following this current paradigm, but there are some patients who still recur, even despite chemotherapy. So this brings up the question, is there anything more to do for those patients?

Dr. Rona Yaeger  3:40 
So my next slide is looking at colorectal cancer both in advanced disease and early stage disease, where we now see that it’s particularly when we think of advanced disease, the colorectal cancer isn’t a single cancer. We can define different subsets of patients and tailor treatment based on how the cancer is developed. So the first group that I want to point out is this MSI high. Patients who have tumors or MSI high either have a genetic predisposition, or they have a colon tumor that has evolved in such a way that it feeds into a similar pathway. And MSI, what does that mean? Basically, when cells divide, they need to make another copy of their DNA. And there are stretches within the DNA where you have the same letter are the same two letters of DNA that repeat. And in those structures when you make another copy, it’s easy for the enzyme that is filling in those nucleotides to slip because you see the same two letters repeating over and over. And so when that happens, there is afterwards a proofreading, where the copy that’s made is checked to be sure that it matches what was there in the kind of parent strand. And so people who have inherited problems with this proofreading function- there’s this cancer syndrome called Lynch, or people who have silenced the proofreading function in the development of the colon tumor or have what’s called microsatellite, unstable, MSI high colon cancer. And that name comes from the fact that these stretches are what’s called microsatellites and they’re unstable because they can be shorter or longer if you don’t have correct proofreading. So that’s a small group of patients with advanced disease. But it’s very important because first of all, those patients may have a genetic risk, and they need to be followed more closely and their family should be alerted. And also, there is now Immunotherapy. So they respond differently to treatment than other patients. But beyond that group, in patients with advanced disease, we have many subsets depending on how the cancer has developed. And one group is what you see in our title is this BRAF V 600E, where there’s a mutation in a gene called BRAF that can turn on signal to the cancer to grow. And that has target therapy associated with that. So we treat those patients differently. It’s also important because patients with advanced disease who have a BRAF mutation in their cancer have a more aggressive disease. And we know that the presence of BRAF V 600E mutation marks a group of patients who have a kind of a more aggressive, a tougher prognosis. And so those are patients we want to think about and figure out how we can give them matched therapy and what more we could do for them. There are other groups in advanced disease, we have other groups with matched treatment, patients who have amplification of a gene called HER2, or a specific mutation in KRAS you may see, I’m sure there’s a lot in Colontown about Biomarkers. So these are markers that we think about in patients with advanced disease. And we actually split the pie into what is driving the patient’s cancer, and how can we target that.

Dr. Rona Yaeger  7:01
When we look at early stage colon cancer, so again, this is colon cancer that’s limited to the bowel, has not spread beyond local lymph nodes, and is removed surgically. We really only think about this one biomarker, the MSI, and we know those patients do a lot better. And there’s a lot of studies now looking at giving Immunotherapy, potentially, after surgery, some trials even in lieu of surgery. So that’s an area of a lot of research. But the rest of the patients who have microsatellite stable colon cancer, are treated the same. And this is the large majority. And in the rising incidence of colon cancer in young people, most of those tumors developing microsatellite stable. So we know that in early stage colon cancer, there’s also a subset that had BRAF B 600E mutation. And there’s a subset that have this BRAF mutation that are not MSI high. It’s about 6% of patients. And we’re going to focus on them today for two reasons. The first is, like I said that in advanced disease, they have a worse prognosis. And we know that in early stage disease, they have a higher risk of recurrence. And the second is we have a matched treatment for them. We have a targeted therapy that goes after the BRAF, the altered BRAF. And so there’s a potential to do more.

Dr. Rona Yaeger  8:18
So what does it mean to say, oh, there’s this mutation and BRAF. What does that do for the cancer. So I have here a cartoon of a cell, and I’ll walk you through it. So basically, normally, a cell will only divide and grow if there is a stimulus to the cell, saying it’s a good time to grow. And so there are growth factors that lie outside the cell. This is the outside of the cell. Here, you can see below the membrane inside of the cell that bind to receptors on the surface, these receptors are meant to sense what’s going on outside. And when the growth factors bind, they basically are telling the cell this is a good time to grow, there’s a reason to grow. And when that happens, that signal is carried to the nucleus through a bunch of proteins that include the RAS protein, which is often mutated in colorectal cancer, and also RAF, which includes BRAF as one of the RAF proteins, and they signal down this group of proteins to get to the nucleus to say to the cells, it’s time to grow, we should divide we should survive. But at the same time, these signals are turned on normally there’s a counter signal, that puts a stop. So cells divide a little bit and then they stop. What happens in cancer is cells divide and they divide irrespective of having any growth factors, they just divide on their own, and they don’t have the normal brakes. So for example, this BRAF V600E is a mutation in BRAF, it turns on this RAF member and makes the RAF member turn on irrespective of what’s happening outside the cell. In fact, the BRAF V600E doesn’t need any activation from RAS, it’s on all the time. And if there is a feedback to turn off the signal, the BRAF is on on all the time, it’s insensitive to that. So that allows the cancer to keep growing. And all cancers have to figure out a way to keep growing. This is one way the BRAF mutation. Another way is the KRAS mutations that we often see. But today we’re focusing on BRAF, because as I’ve said, there’s matched treatment for it. So this matched treatment, there is an FDA  approved treatment for patients who have advanced disease where the tumor has spread beyond the bowel. So distant sites like liver or lung who have received prior treatment with chemotherapy. There’s an FDA approved a treatment based on an improvement in the time to progression for patients compared to standard therapy, patients live longer who get targeted therapy, and the quality of life is preserved. The targeted therapy consists of two components. It consists of a pill, BRAFTOVI is the trade name, encorafenib is the generic name. Patients take four tablets once a day. And it’s combined with an infusion called cetuximab that’s given intravenously, it can be given weekly or every other week, together with the pills taken daily. And what these drugs do the encorafenib+Braftovi binds to the activated BRAF and turns it off. And that’s the cetuximab binds to the receptor and turns off any other input into this growth pathway to hopefully turn off all the growth signal and to stop the cancer from growing. It doesn’t necessarily work for every patient. But most patients with advanced disease have some regression. And we think that this combination can stop the growth signal and most cancers that have a BRAF V600E. Most colorectal cancers, they have a BRAF V600E mutation.

Dr. Rona Yaeger  11:46
So how about early stage disease. So, like we said, most patients are cured. So these are curves that look at recurrence and survival after recurrence. So I’ll walk you through it. But basically, in black, you see the curve for patients who don’t have a mutation in the BRAF gene, or in the KRAS gene who have microsatellite stable and not the MSI high colon cancer. And you can see that all our curves are above 50%. Most patients are cured. But there is a big gap between the black and the blue or the blue is BRAF V600E mutated.  In the middle is a KRAS mutated so you see that the BRAF causes a higher risk of recurrence, but it’s a small effect. However, when patients recur, this is the survival after recurrence, we see having the BRAF leads to worse outcomes. So if we could prevent patients from getting to the point of recurring, it would make a big difference. So that’s what we are looking at with a new clinical trial that I am excited to talk about today. This is a trial that’s being done through the NCI so it’s open across the country. And it is open for patients who have early stage so stage three so that’s colon cancer that involves local lymph nodes, or stage two, T4, T4 means the tumor involves a full thickness of the bowel wall. So like if our bowel were like a hose, the tumor would reach the other side of the hose. You can see it through but it does not spread to distant site and might touch an adjacent organ but it is a contiguous involvement. So stage III, so nodal involvement from colon cancer or T4 full bowel wall thickness, patients who have received standard treatments, so these patients are considered higher risk, they would receive chemotherapy. In the study, if their tumor has a BRAF V600E mutation, they are randomized, half the patients will get usual care, which is observation after they finished chemo and half the patients are getting the targeted treatment of encorafanib and cetuximab for six months.

Dr. Rona Yaeger 13:46 
BRAF V600E testing is not currently standard, because like we said, we don’t really do anything with it. So patients who whose doctor has tested them for BRAF V600E, and know that their  tumor has a BRAF mutation, they can go on study based on that. But if their doctor did not test for it, if their site participates in this clinical trial, we set up retesting through the NCI where a few slides can be sent to a central lab. That’s a single lab working with the clinical trial, the single lab is in Dartmouth, a few sites can be sent and then your doctor will get a result BRAF V600 E mutation present or BRAF V600E mutation not detected. The patients start the study after they complete treatment. So there’s a lot of time after surgery, to think about the trial and patients only enroll after they complete treatment. So we account for the different treatments and also for the different extent of disease that patients had when they go on study. So this stratification is to make sure we have in both arms and equal group of patients who got FOLFOX or CAPOX–these are the two standard chemotherapies given for colon cancer. We stratified by the the length of time they got treatment, if they got three months or longer than three months, and also by the extent of the tumor that was removed, how far the tumor penetrate the bowel wall and were lymph nodes involved. And then we also stratify for something called circulating tumor DNA. What that is, is there are small fragments of DNA that are released by cells, they can be released by our normal cells, and they can be released by cancer cells. And they are available in the blood, in the circulation. So if the patient still has cancer cells present in their body, those cancer cells can release small fragments. And they can be detected. For example, they might have the BRAF V600E mutation. So there’s blood tests that are available to test for this, its not a standard test, but it’s being increasingly done with patients who have early stage disease. And if patients had this detectable DNA fragments from the tumor, we we want to have them on equal groups, because we know that that is associated with higher risk of recurrence. And the patients are then treated for the six months versus observation, you know what arm you get, there is no blinding, and then they’re watched, they’re followed as you would anyway, with scans and with blood tests to see what happens.

Dr. Rona Yaeger  16:13
So I just want to go over a little bit about the endpoints of the study and who is eligible. And then I’m happy to discuss and take any questions. So this trial is called a phase 2/phase 3 study, a phase 2 study is looking at the efficacy of an intervention saying how effective is this? And the phase 3 is saying how does this compare to what we do as a standard? So the phase 3 is saying do we affect the disease free survival? Do we have fewer patients recur when they get this treatment? But that’s a long endpoint, we have to follow patients for years. So we put in the study a phase 2, where we could look sooner and enroll fewer patients and be sure that there is something happening with this combination, before opening to the full phase 3. And so we’re looking at the circulating tumor DNA. In the patients who have circulating tumor DNA present, do they clear it more when they get this treatment compared to just observing them. And in the ones that don’t have detectable circulating tumor DNA, do they remain without detectable circulating tumor DNA, where they are in treatment, and if either group looks better for the treatment, we are good to continue and to proceed to the phase 3. The secondary endpoints, the other things we’re watching is we’re evaluating people for overall survival, we’re checking their toxicities from this treatment. And we’re looking at this alternative disease free survival from the time in which they had surgery to match with the published data on disease free survival. We’re looking at patients in the subset who have positive circulating tumor DNA, because we know they have a higher risk of recurrence. So maybe this is only helpful for those patients. And then we’re asking patients to fill out information-key symptoms associated with these drugs, which include rash, diarrhea, fatigue.

Dr. Rona Yaeger  17:58 
And so who is eligible? We went through a lot of this, but I want to reiterate –patients with colon cancer, that is stage III, that means colon cancer involving lymph nodes, or stage II, that is T4 involving the full thickness of the bowel wall, the patient’s tumor has a V600E mutation. If you don’t know if you have it, your doctor can send it to a central test, it requires only three slides and you get the result within a few days. Or if your doctor has already tested for that and they found that you have a BRAF mutation in your tumor, that is sufficient to get on study. The tumor has to be microsatellite stable, or mismatch repair proficient, so not that group that is MSI high that does better. All patients going on the study have to receive chemotherapy first. We require at least five cycles of FOLFOX or three cycles of CAPOX, they have to go on within eight weeks of completing treatment, no other cancer therapy besides the surgery and the chemotherapy, this is how well they have to be , you have to be more or less okay up in about for at least half the day. We know people just got chemo so we’re trying to be flexible, but we want them to be well enough to be on study. Similarly, we have some lab parameters, which we tried to make very flexible, because we know people just got chemo so their blood counts might be low.

Dr. Rona Yaeger 19:15 
So this is a national study. It is open in sites across the country. This is a map that  shows the number of sites currently, this is from clinical trials.gov. And you can see that in the northeast, we’re open in New York and Boston. We’re open in the Chicago area. It is open in Minnesota and Ohio. There are sites in Texas, and there are more sites coming online. I’m happy to connect people and to try to help figure out what site is closest. And also to turn to local hospitals and see if maybe they can open the study if there are patients who are interested. So this is my final slide I wanted to put up here. This is the clinical trials.gov ID for this trial. And this is the formal name of the study. It is a randomized study of the additional treatment with encorafenib and cetuximab versus observation for patients with Stage III or stage IIII BRAF V 600E in colon cancer. And I want to give a shout out to Qing Shi, she’s a statistician who helped me design the study. And the study’s open through the NCI, we have it open through multiple NCI groups to hopefully have national coverage. Thank you.

Manju George  20:31 
Okay, thank you so much, Dr. Yaeger. There are a couple of questions in chat. So one question is,  the patient, he’s concerned about once somebody enrolls in this trial, and then there is a recurrence and he’s on, encorafenib + cetux. What happens, he is using that one line of therapy already, right? So what are you thoughts on that?

Dr. Rona Yaeger  21:02
That’s a good question. So when the patients go on study, we do a CT scan, first, make sure they go on without any visible disease. But say a patient, like you’re saying in the scenario gets the six months of encorafenib+ cetuximab, and during that time, recurs. So that means that that tumor recurred through this treatment. So it is true, you wouldn’t give that treatment later, but it’s also true that for that tumor that treatment wasn’t doing enough, right? Because if the tumor was able to recur through it, even in the advanced setting, where are you starting treatment, when you see it, it was not giving you enough. There are trials for patients with advanced disease, but this is the only FDA approved treatment right now, that is matched for a BRAF V600E mutation. I think, while it is possible, this could happen and you wouldn’t want to give that treatment again, I think that it’s not highly likely, it’s quite unlikely to recur. First of all, the patient just had a scan, and they’re being followed within the first six months. And also we know that if you look at advanced disease, most people have some response, some shrinkage with this combination. But it’s true. It could happen. And if it does, this is just not the right treatment for your cancer.

Manju George  22:21 
Okay, continuation to that question is that they are wondering that prior exposure to E+C would make them ineligible for a trial like the SWOG 2107? Yeah, that would be the case.

Dr. Rona Yaeger  22:36 
Yeah, that would be the case. Because this trial, you mentioned is this combination of encorafenib and cetuximab  versus this combination plus Immunotherapy. And if this tumor was able to grow through it’s not a good treatment for that cancer. And so that trial, one half of it is giving you a treatment where the tumor would have already grown through that. So that is correct. Yeah. So we’re saying if you give it earlier, do you do better? And we don’t know. That’s, that’s what we’re asking.

Manju George  23:07 
Yeah. Okay. And then the question I have is that like, so the assumption is that, because these are people without any visible disease, getting them on encorafenib plus cetux early on, you’re trying even if there is microscopic disease growing that is not yet visible, because the tumor volume is so low this treatment is like, it’s almost like prophylactic treatment to prevent or delay the recurrence. Is that what the idea is?

Dr. Rona Yaeger  23:39
Exactly? That’s an idea. We don’t see anything. We know some people will recur,  so some people must have microscopic disease. And we’re trying to hopefully prevent the recurrence, or at least, to delay the recurrence and there is precedent in melanoma. The treatment with these BRAF drugs actually improves the cure rate, not these, but with BRAF drugs, improves the cure rate and we know in lung cancer, targeted therapy can also after surgery, improve the cure rate. So there’s precedent, but there’s no experience for this in colorectal cancer. So, so we don’t know we’re looking at patients with colon cancer here. Yeah.

Manju George  24:14 
Okay. And I think so this patient is saying that it’s a tough choice. Okay. So they’re asking why is the therapy not six months? Oh, I think they’re asking why the patient’s only need– I’m hoping that what this person is asking– is that you say that the patient should have at least three months of adjuvant chemo and then they’re eligible, right?

Dr. Rona Yaeger 24:14 
Yes, exactly. So they should get standard treatment at least three months, then they can go on to study and then we limited the time of the target therapy as six months. Because when we look at the effects of target therapy in the advanced setting, we see the greatest benefit within the six first six months.

Manju George  24:59
Okay. That makes sense. I hope your question is answered. And then I think that like from from our BRAF group, what we have generally seen is that, people after they have the treatment, they finish urgent treatment, they are very nervous about what to do next. So in that setting, I think having a trial like this, it’s something to do, because otherwise patients are just waiting. Many of them are really anxious that they might have a disease recurrence. So with this trial they have the feeling that they’re doing something more proactively to catch it, and then to do something about it. Right?

Dr. Rona Yaeger  25:37
Yeah, exactly. And so we’re thinking, this is a subgroup, but we have something we can do, and there is enough of a risk that we think it’s worth testing. Yeah.

Manju George  25:48 
Okay. And so the next question is, would stage IV have any chance of using this maybe after chemo can staging ever go down from 4 to 3.

Dr. Rona Yaeger  26:02 
So there are patients who have stage IV colon cancer, who can have all the tumor removed. And there are patients who have stage IV disease where the tumor is too extensive to remove. In the patients where it’s not all removed, these are FDA approved, they can get the BRAF therapy. In the ones where they might have a single or a few liver or lung lesions that can be removed, we don’t have data at that point for giving the additional BRAF treatment. And this study, we limited to patients who have stage II or III because we’re trying to select a group that is very similar. So it’s unknown. So at this point, if someone has stage IV, and they enter what we call NED, there’s no evidence of disease, they shift from visible disease where all disease is removed, they would be watched. Your doctor will guide you in terms of how long to do chemotherapy, but afterwards, just like the early stage patients, they’re watched and many of them can be cured. If this study, were positive, we may end up thinking about that stage IV setting but this study is limited to the stage II, stage III.

Manju George  27:14 
Okay, Thank you. And I think I asked this question before we started the call. But we also have patients who are MSI. High. Could you please explain why they are not included in this trial?

Dr. Rona Yaeger  27:27
Yeah, so the patients who are MSI high have a much lower rate of recurrence. So the stage II patients who are MSI high colon cancer, the rate of recurrence is actually very low. And most of those patients we just watch. And then the stage III setting there is some recurrence but the risk is a lot less than for the MSS, BRAF, V600E. And there are also studies in that group for Immunotherapy. So we think that there’s a very good tool available, and that rather than develop this treatment, in patients who are MSI high or the BRAF mutation, we’re giving a chance for the Immunotherapy data to develop where we think if more treatment is needed, there is a good tool there that could have a long, long effect. Patients here who are MSS can’t get Immunotherapy, the tumors don’t respond. And so we have to find another way to go after it. And that’s why we’re doing the targeted therapy here.

Manju George  27:51 
Okay, that that makes sense. So the this question is, so someone coming off adjuvant chemo with a ctDNA negative, do those people have a lower risk of recurrence?

Dr. Rona Yaeger  28:47 
Yes, they do. So we know that having detectable ctDNA after treatment raise raises the risk of recurrence, probably there’s some cells that are making this circulating tumor DNA. If ctDNA is negative, the risk is lower, but it’s not zero. So our study is enrolling irrespective of circulating tumor DNA. So there are studies out there that are for circulating tumor DNA positive only, this study enrolls either way, but we take the circulating tumor DNA into account to make sure that there’s an equal number of patients in both groups with that with that feature. But you’re right, that is a very important prognostic marker.

Manju George  29:31 
Okay, thank you. And the next question is, I think I’m probably missed it. What is the number of people or number of slots that are available for this trial?

Dr. Rona Yaeger  29:41 
The trial has about 200 slots for the phase II component and about another 200 for the phase III. So in total, it’s up to 400. So lots of slots because it’s a small subset of patients, so it’s no issue in terms of slots for the study.

Manju George  29:57 
Okay, so, for a patient who was stage III or you know, T4 stage II. So your recommendation would be that, if they know that they are BRAF V 600E, mutated, they contact, the trial sites to find out if they can get on the trial almost when they come to know of their BRAF status?. Yeah. And then for for the other people who don’t know their BRAF status, how would they go about getting the tests? What do you suggest.

Dr. Rona Yaeger  30:33 
So if you’re interested in the study, anytime after surgery, even during chemotherapy, I would discuss it with your doctor who can set up the BRAF testing. They can do it, if they are set up to do it with their own labs, they can just do it that way. If not, they can send it to that NCI central site, and then they’ll tell you whether the BRAF mutation is detected. And if it is, then you can talk about whether to consider the study. And then after you finish treatment, you’re already set up you know what to do, you know, oh, I’m planning to consider the study I want to register, or I’m not interested in the study. If the testing is done through the NCI, there is a consent form. That’s a pre screening. So you’re already set up to easily enroll on the study. But we know that most patients who have the the testing will not have the BRAF mutation, it’s about 6% of patients overall, who are microsatellite stable and have a BRAF V600E mutation.

Manju George  31:30 
Okay, so my next question is, is there like a specific group of colon cancer patients that you know, with a higher chances of being BRAF that you would recommend to ask their oncologist for this test? Like, what would that group be?

Dr. Rona Yaeger  31:48
That’s a great question. BRAF is, like we said, it has a slightly higher recurrence. So it’s associated with T4, and N2. So that means tumors that penetrate deeper and involve more lymph nodes, we tend to see that go along with BRAF. You can see BRAF in patients who are older, but sometimes those are MSI high and not the MSS. But you can definitely see as people get older, there is a higher incidence of the BRAF mutation. But often it’s a less aggressive MSI high subset. Otherwise, there’s no easy marker.

Manju George  32:27 
What about like ceacal tumors or proximal colon?

Dr. Rona Yaeger  32:33 
Yeah, it’s more on the right side. Yeah, that’s a great point. So we talk about the colon is like an upside down U. So the first part of the colon you have that arm that you that goes up, and so that’s called the right side. So the Cecum, the first part of the colon or the ascending colon, the BRAF V600E mutation is more common there. But it can be anywhere along the colon. Yeah, that is correct.

Manju George  32:59 
Yeah. Okay. So for us to talk about it in in Colontown, we could say that people with T4 tumors, and especially they have T for N2, then we would strongly recommend that they talk to their care team about this trial. And if they have not got a BRAF V600E testing, then this would be a way to get it tested. And then they can decide if they want to be part of the trial or not. Right, this will be an opportunity to find out if they have high risk disease that may have a high slightly higher chance of recurrence. So this other question, is they are asking if you must enroll within eight weeks of conclusion of adjuvant chemo?

Dr. Rona Yaeger  33:46 
Yeah, because we don’t want to have some people who go on and have had such a long gap. So we try to keep it similar. Yeah, so that’s where we are.

Manju George  33:57 
Okay, so maybe then another point to keep in mind is that it might be as as soon as they know their TNM status, maybe at that time is the best time for them to reach out and find out if they are BRAF positive, right?

Dr. Rona Yaeger  34:11 
I agree.

Manju George  34:11 
Okay, So let me see if there are other questions.I’m not seeing any so let me think if I have anything else.

Dr. Rona Yaeger  34:31 
I’m happy to talk to anyone. The trial’s up in clinical trials.gov My email is on clinical trials.gov. You can send me a quick email if you want and say, Oh, I have this scenario. And I can say it looks like this is appropriate or it looks like this is not the right study. I’m happy to quickly screen for anyone. I’m happy to speak about BRAF V600E. You know, you can connect with me if needed. But yeah, it’s as you said, so the T4 Stage III patients, patients who are at higher risk, it’s worth considering if you’re T4N2, if there’s something more you can do, it’s probably worth considering. So that’s a good group to look for that BRAF mutation to see.

Manju George  35:10 
Okay, okay, I think Julie is making a list of firstl ine trials that we were wanting to give more information to patients.  So we could talk about this trial in stage II, as well as stage III groups, and then say that, you know, if you don’t know your BRAF status, and you have a T4 N2 tumor, then this will be a great opportunity to find out if you have in the unlikely chance that you have the BRAF mutation, here’s something else that you can do.

Manju George  35:44
There is another question.

Manju George  35:54 
Oh, I think this person is asking, which is just a little more explaining of what we think is happening while the patient is on treatment? Is it removing any microscopic cancer or suppressing it?

Dr. Rona Yaeger  36:09 
So what we think is that the patients on the study had all the cancer that we can see removed, but we know that many of them, that’s all the cancer there is, and they’re here. But for some of them, there are cells that we didn’t see that are still there. And so the goal of chemotherapy is to kill those cells. But not not everyone gets chemotherapy  is cured. So that means that some of those cells, some people who have those cells, it’s only a portion of patients, but some people will have those cells, the cells are able to survive the chemotherapy. So the goal here with the BRAF treatment, is to try to kill any cells that have a BRAF mutation. And that’s what we need the tumor to have a BRAF mutation to go on the study. But if those cells have a BRAF mutation, these drugs will go in your body and all your circulation will hopefully get to those cells and hopefully destroy them. And so if that’s possible, that would improve the cure rate. But we don’t know. So that’s why the study is randomized, because any treatment has some risks. So we’re saying, you know, is it is it worth it? Do do we affect the chance that the cancer will come back to affect patient survival with this treatment? And also we ask patients, like what were your side effects, was it worth being on the study?. But that’s our goal. But if there are some cells out there that have the BRAF mutation, this treatment can get there and hopefully kill those cells.

Manju George  37:32 
Okay. And then maybe, I don’t want you to explain a little bit about the the idea of emergence of resistance. And you know, the selection of those things depend on what’s the initial volume of the cells, right, like, if there is very micro metastatic disease, and the number of cells is so small, then the chances of resistance emerging is much lower when compared to when there is established disease.

Dr. Rona Yaeger  37:58
Exactly. So that’s our hope here. So when patients have metastatic disease that we can see, there’s actually millions and billions of cells. And so when you give the target therapy, you don’t usually cure patients. The tumor shrinks, you can get a nice response, but you don’t usually get rid of all of it. So our hope here is that there’s very little right, we don’t even see it. And so that treatment here might be sufficient to kill all of that, just like Manju said that when there’s less there, you have fewer cells available to find a way to outsmart the drug. And so maybe if you’re killing off a portion here, you can kill off all of them, especially because they’re simpler. They haven’t figured out a way to spread yet. They’re just few cells probably that haven’t yet implanted and extended to be a visible metastasis. So that’s the idea. And that’s why we take hope that in melanoma and lung cancer, they actually seem to be curing more patients. So we see a paradigm where it is possible.

Manju George  39:01 
Okay, Thank you so much. This is about the Stand Up To Cancer, the Dr. Parikh’s trial. Has the arm with the targeted treatment shown any promising data?

Dr. Rona Yaeger 39:16 
So the Stand Up To Cancer trial has a BRAF V600E arm for patients who are ctDNA positive, and they have a BRAF V 600E mutation. They get the same encorafenib and cetuximab, but they also get a MEK inhibitor, Binimetinib. So they’re getting a triplet therapy. The FDA approved double a therapy but the triplet therapy is meant to have a similar effect to shut down this pathway. At this point, there are too few patients treated on that arm for us to know. But it’s really a similar idea, but that arm is exploratory in the patients who have ctDNA positive. So on some level the study is asking the question in a bigger way but it’s a similar idea. If given BRAF therapy after chemo improves the chances the patients will be cured.

Manju George  40:09 
Okay, I think that’s all the questions. Thank you so much. And I think that we will probably also share your email address with everyone. So you know if they have any questions then they can reach out to you. Okay. A recording of the talk will be available on Colopntown University.

Dr. Rona Yaeger  40:30 
Thank you. Thank you for the opportunity.

Manju George  40:34
Okay, take care. Bye. Thanks, everyone for attending.