Thinking Outside-the-Box: Advances in Stage IV Colorectal Cancer Treatment: Dr. Foote (2025)

Betsy Post 0:00
I’m going to introduce Dr. Foote. We are so excited to have you here. Dr. Foote is a Gastrointestinal Oncologist at Memorial Sloan Kettering Cancer Center in New York. It’s such a privilege to be here with you this evening. And yes, this will be recorded. Someone just asked, will it be recorded and available, this is being recorded. It will be edited and it will be shared. So definitely being recorded. But Dr. Foote, we’re so, like I said, excited to have you here and to hear from you and all of your expertise. I know we’re all going to learn a lot tonight. And again, I really thank you for your time, especially being here on an evening. I’m sure there are many other things you could be doing. So with that, I’m going to turn it over to you, and we’re so excited to hear from you.

Dr. Foote 0:44
Thank you so much, Betsy. It’s wonderful to be with you here today and with all of you listening. Thank you for tuning in, skipping your favorite TV show to join us. So just like Betsy mentioned, I’m a medical oncologist. I treat patients that have colorectal cancer as well as appendiceal cancer, and I’m also a scientist, so I work in the lab and try to do translational research to discover new things about this disease, with the ultimate goal of starting clinical trials. I’m fortunate to work with a really awesome team for this and we’ve started several trials based on our discoveries. So today we’re going to talk about a lot of things, but I’m going to try and have some common threads through the entire conversation together. The main goal is to tell you a little bit about targeted treatments and specifically advances that have happened in the last year or two for Stage IV colorectal cancer. We won’t talk as much about early stage colorectal cancer, and I won’t talk as much about chemotherapy, so I’m going to really talk about some of the new therapies and new practice patterns that we’re doing and I’ll try and explain the reasons why.

Dr. Foote 1:46
I know there’s a huge variety in the audience of people, everyone from PhDs in science to maybe people that have just been diagnosed with this disease. So I’m going to try and use language that everyone can understand. I apologize if I sometimes go one way or the other, if I’ll talk a little bit too scientifically, or if I if I dumb it down too much, but hopefully everyone will be able to come away with something. And I’ll also try and speed up to get through the slides so that we can have a nice discussion later. These are my disclosures, nothing relevant to the talk. So first what we’ll do is we’ll discuss advances in protein targeting, so targeting cancer proteins, and then I’ll go broadly into how the immune system can recognize cancer. And then finally, we’ll talk about how this immuno recognition system is important for designing immunotherapy drugs. And I think throughout all of it, I’ll try and give you my honest opinion so you can make decisions for you and your family member. So there’ll be a degree of realism to all of this. I’ll tell you if I don’t think something works very well, or if it does work well, but through all of it, I’ll try to be optimistic. I’m a very optimistic oncologist. We’re all here because we have hope for a brighter future in this disease. So I will try to leave an optimistic pearl with every point.

Dr. Foote 3:03
Okay, let’s get started by talking about cancer protein therapies. So first I’d like to talk a little bit about what influences our treatment choices when we see a patient for the first time with this disease. So there’s a number of things that are obviously important when you’re trying to figure out how to treat someone. You think about what other medical problems they have, what treatments for cancer they’ve received before, how old they are, how active they are. You think about the amount of cancer that they have in their body, and whether it’s possible to try and remove all the cancer in their body or not, if they’re symptomatic from their disease. And then importantly, and I’ve circled it here. We also pay attention to where the tumor is located, and this is really important for protein therapy. We’ll talk about that. We like to think about the colon as a single entity, but in truth, it has distinct sections that grow as you develop from a fetus onto into a child. So these different sections during embryogenesis give rise to the colon as we know it, but the right side and the left side are pretty different actually. Theres different risk factors that can lead to tumors in both sides and the tumors that do arise have different properties to them. They can respond differently to treatment and has implications for our cancer therapy. The other thing that we think about is the molecular characteristics. So every patient that has stage IV disease should undergo genomic sequencing of their tumor. Standard of care across the whole country to understand the changes in these important genes that give rise to cancer proteins that can help power this tumor. Importantly, what we’re going to talk about now are inhibitors, drugs that can block these cancer proteins to try and slow down and kill the cancer. So these are four important targets that we think about that have relevance to the types of drugs that we give patients.

Dr. Foote 3:03
This is kind of a big picture slide for how we treat cancer now. This is like the whole presentation in one slide. I’m going to go through it with you. It’s a little bit of an intimidating slide but in 2025 based on some new trials that have been presented over the last couple of months, as up to date as that, these are the types of therapies that we give people. At the top of the slide, you can see general therapies that pretty much every patient with colorectal cancer is, you know, eligible for. Some of them involve chemotherapy. Some of them are chemo pills. And then down here, you can see, I’ve indicated these therapies as biomarker directed. And what that means is, there’s something special about the tumor that makes us think these therapies will work really well. Most of the special characteristics of the tumor involve some kind of mutated protein that we’ve detected with genetic sequencing. And so you can see the different types of proteins here I’ve outlined for you, as well as the respective therapy that might be beneficial in patients that have this mutation. And so we’ll go through these together. Word of caution, we kind of mentioned this in the beginning. People are not numbers, right? Statistics, big data, all of this helps guide decisions but we can’t reduce every person that we see in the clinic to a number on a curve. So when you’re looking at these research reports, when I’m throwing out statistics at you, just keep in mind, these are big picture statistics. They’re not meant to be individualized. Every person is different. Every cancer is different. Also, by the time a trial is presented, it’s already been going for several years, sometimes even half of a decade. So all of the data you see, in some ways, is a little bit old. The people that started this treatment are already have been on it for years. So it’s just important to keep in mind.

Dr. Foote 3:03
All right, so this is, this is one of the slides we’ll keep coming back to. This is a famous cancer signaling pathway called the MAP kinase pathway. And what this is, is it’s a series of proteins inside of a tumor cell that activate one another, and at the end of the whole signal, there’s a growth stimulus, something to make the cancer grow, to spread. These are very, very important proteins that the cancer likes. And so many of our drugs that we’re going to talk about today are inhibiting different steps of this growth signaling pathway. So EGFR can activate RAS, which activates RAF which activates MEK, which activates ERK and leads to growth. Colorectal Cancer really likes this pathway, so it tries very hard, even if we try to throw something to disrupt it, the colorectal cancer cell tries very hard to keep it going. So it has sneaky ways of getting around our drugs, and we’ll talk about that. But we do have these kinase inhibitors, these drugs that target different steps. So the first drug we’ll start with are drugs that inhibit a protein called EGFR, which is the very top of this signaling pathway. And these are drugs that might look very familiar to you, Cetuximab, Panitumumab, these are protein inhibitors that help block this protein from activating this growth signal. So one of the first and these drugs have been around for a while, so we’re going to try to learn a little bit about protein inhibitors by going through the example of how these drugs were applied to patients starting over 10 years ago. So one of the first lessons that we learned from these protein inhibitors is that not every person benefits similarly from those drugs. There are certain characteristics, maybe the location of the tumor, the genetics of the tumor that make these drugs work better, or make them not work very well at all.

Dr. Foote 8:25
And just to show you, this is a busy slide, but starting in the left, we have one of the oldest trials of this drug, Cetuximab, which is one of these protein inhibitors. And you can see in this trial, some of the patients were given Cetuximab with chemotherapy, and some of the patients were just given chemotherapy alone. And the scientists wanted to figure out if Cetuximab made the patients do better, made them live longer, and the first population of people which didn’t have any selection, these were all patients with colorectal cancer, the patients did pretty similarly, whether they got Cetuximab or not. So that wasn’t a very exciting result. That doesn’t, that makes us think that the drug doesn’t work very well. However, in the lab, we looked and we found that patients that have KRAS mutations, which we’re going to talk about later, don’t do very well with this drug. So we did a second study only with patients that have wild type, meaning they have normal KRAS and you start to see that this orange curve with the Cetuximab rises to the top, meaning those patients are living longer. They’re doing better. The further up towards the top the curve is that means the patients are doing better. And then as we go rightward, you can see, over time, we’ve gotten better, better at identifying the patients that benefit from this drug. So instead of just looking at 1 KRAS mutation, we looked at all of them, we made sure that there were no KRAS mutations at all. And you start to see this curve plump up towards the top even more. And you can see an increased survival benefit, going from 25 months to 28 months. And then finally, the last thing we paid attention to is not just the genomics, but where the tumor started in the patient. Remember, I told you there’s a difference, between the left side and the right side of the colon. So if we use this drug specifically in people that have no KRAS mutation and only have cancer that started on the left side, you see a really big benefit when you give this drug to people. Now all of these trials were done as patients, like third or even fourth treatment. These were done after patients had already had chemotherapy before. So one of the big questions that scientists tried to answer over the last year or two is whether we can use these drugs, these protein inhibitors, with the very first treatment that a patient gets alongside chemotherapy. So this was a very important question, because obviously the first question you ask your oncologist when you’re being treated is, what’s my first treatment going to be?

Dr. Foote 10:45
So the PARADIGM trial was a big study, was randomized, its a, big, big study, and it took patients with KRAS normal status, just like we showed you, before. If they had a mutation from KRAS, those patients did not go on this trial. All of these patients were getting this as their first therapy, and they had stage IV cancer. And what the scientists did is they compared addition of EGFR inhibitor called panitumumab or pani with your standard FOLFOX, which a lot of folks get with this disease. And they compared this treatment to the standard of time, which was getting FOLFOX with another drug called Avastin, or Bevacizumab, which is a another type of protein inhibitor that’s a little bit more general. Okay, so they wanted to see which strategy worked better. And specifically they wanted to see if patients lived longer if they got this drug, this EGFR inhibitor, first. And what they found is patients did live longer if they got the EGFR inhibitor first, compared to if they got it later, in the second arm, where they were given a different type of drug up front. So you can see, in the beginning, the curves are pretty close together, but towards the end, this blue curve starts to sneak upwards, and that’s where you see the benefit in overall survival. And so this was statistically significant, and this was this was a pretty exciting finding.

Dr. Foote 12:05
One of the lessons, though, that we have to learn is, and this is a pretty simple thing to understand, is when you give people strong drugs, it can work well against the cancer, but it can also cause a lot of side effects. And this was no exception. You can see in this curve here, we have different side effects the patients got from the trial. And you can see that patients that got the blue drug, the EGFR inhibitor, they had more of the side effects than patients that just got the standard therapy. You can see this blue bar is way to the left. You know, 70% or 80% of people got this really awful rash which I’m going to show you. You can see dry skin. A lot of these side effects were more in the blue curve. So the benefit that patients get better be worth it, because you can also get more toxicity from these drugs. This is what I’m talking about. And folks on the call who’ve gotten these drugs before may recognize this. It gives you an acne like rash, and it can be mild in some people, or it can be disfiguring, it can be really, really awful. And I’ve had patients tell me, this, this drug makes me feel and look like a cancer patient. When I go on the street, people notice and they think that something’s wrong with me, and it’s, it’s really awful to hear that. So when you’re discussing things with your oncologist, it’s just really important to talk about the side effects, and we want to make sure these drugs are benefiting people, so that it’s worth it. Now, importantly, with the rash, you can help prevent it from being severe. We do give people antibiotics, steroids, things like that, to help put on their face, to make the rash less severe. And in fact, it does. It does make a big difference.

Dr. Foote 13:36
One of the other interesting things about giving people these protein inhibitors as their first treatment is that you might be able to reuse these drugs later, even if the cancer grows on it. And let me explain to you why. So in the beginning, let’s say this is the tumor, and you can see the blue tumor spots are sensitive to EGFR inhibitors, like the one I’ve been talking about. They have normal RAS they don’t have a mutation in those cells, but maybe there’s one sneaky cell that has a mutation that’s just hiding out. It’s not a majority of the tumor. So you give the patient Cetuximab, an EGFR inhibitor, and you kill off a lot of these blue cells that are sensitive to it, so now the purple cells take over, and this is called drug resistance. And so let’s say you switch it up on the cancer, and instead of giving them this EGFR inhibitor for their next step, you give them a break from it and you give them another type of chemotherapy instead. And what happens is the blue cells start to take over again, and you might have a tumor that’s now sensitive to the drug again. So you can reuse it. Instead of throwing it in the trash can, you can reuse this drug to try and benefit the patient and string it along and doing this pattern of switching it up on the cancer to try and imbue this sensitivity again to the drug.

Dr. Foote 14:51
So what people did in this trial is they gave the patient a test. It’s called CT DNA. They looked in the blood to see whether there are any RAS mutations. So if there were not any RAS mutations, we said, Wow, this might work. We might be able to rechallenge people with this drug again. So they gave people the drug again, if there weren’t any RAS mutations. And what they found is about 30% of people who had progressed on this drug before, when you used it again after this sandwich method, they had a major response. You could reuse the drug again in the future, and over 70% of people actually had their disease control. So even if it didn’t shrink a ton, it was it was stable, it didn’t grow a lot. Now this is a small study, it needs to be validated, it was published in 2022 but it’s an important concept, and you can switch it up on the cancer to manipulate the clones, the little blue and purple and resistant cells, to try and switch it up and give people more benefit from their drugs, their chemo over time.

Dr. Foote 15:51
Okay, so we’ve added one plank to our our figure here, and we’re going to keep going because of the results we just discussed, most people will get EGFR inhibitors up front now with their chemotherapy, if they have no KRAS mutation and their tumor started on the left side of their colon. Now, the reason why I put an asterisk here is it’s still little controversial, even at MSK, because if you look at the data, and this is getting a little in the weeds here, remember I told you that half of the people got this other treatment, they were all eligible to get Panitumumab at some point in their cancer journey. And it was expected that maybe as their second, their third, their fourth treatment, they would get this drug, because we know, based on this data that it works for them. So this study was to say, Well, is it better to get it first or to get it in the future at some other point, and they believe that their data shows that it’s better to get it first. But if you look in the data in the supplemental section, only about half of the patients in the comparative arm ever got this drug, and so these patients were deprived of a therapy that really would work very well for them. So some scientists criticized the study by saying if everybody had gotten the drug later, then you might have actually seen those curves stay together. There might actually not be a huge benefit to giving the drugs up front compared to giving it later. So that’s an ongoing debate. But right now, the standard is, if you have metastatic colorectal cancer, you should get this drug up front with your chemotherapy, if you have RAS wild type, and you’re left sided. Okay, so that was a little bit of a long discussion. Let’s keep going. So here’s another signal in this pathway. This is another growth signal called HER2, and as you can see, it can activate the same proteins that we’ve been talking about.

Dr. Foote 17:36
So HER2 amplified colorectal cancer is rare. It’s only about anywhere from 1 to 6% of all colorectal cancers. Similarly to EGFR inhibitor benefit, it’s found on the left side of the colon, to pretty much, not exclusively, but about 85% of the tumors that have this, this trait, this HER2 amplification are found on the left side. And the way that we find is by doing a pretty simple test on the colon cells. It takes a couple days to come back. It’s available all over the country, and this is something that can be targeted with drugs. And there are drugs that can target it on the outside of the protein, as well as drugs that can target on the inside of the protein. And the spoilers, we often combine these two strategies for targeting this protein. The MOUNTAINEER trial, great name for a study, was a phase ll study. So everybody, pretty much got the same treatment. It’s a little bit confusing with this slide, but basically they got the same treatment. They got an antibody called trastuzumab, okay, or Herceptin, which you might have heard of in breast cancer. That’s the drug that attacks the outside of the protein, and then they also took a pill called tucatinib twice a day, and that’s the small little molecule that sneaks inside the cell and blocks the protein inside the cell. So we were hitting it from the outside, hitting it from the inside. And this trial recruited patients that had already progressed on multiple different lines of chemotherapy. All of the patients who went on the study had already had their tumor grow on 5FU, oxaliplatin, irinotecan so these were patients that maybe didn’t have as many options as the first study that I showed you. And the scientists in this trial were trying to figure out if these drugs could shrink the cancer, and it did. So about 38% of patients in this plot had a major response to the drugs.

Dr. Foote 19:24
Now, just to interpret this plot, you can see this is the change of the tumor from baseline. So when the patient started the drug, they were at zero. And then you can see that, you know, all of these people, each bar represents a person had their tumor shrink by this amount. So for example, this patient had a complete response, meaning their tumor completely disappeared, which is obviously amazing. This patient, for example, had their tumor shrink by about 30% this patient at the far left had their tumor grow by 40% so it didn’t work for everybody, but it worked for a lot of people, and about three quarters of the people, at least at the first scan, had their tumor stayed the same size or shrink a little bit. And these were very durable responses, meaning, when the tumor shrunk, they stayed shrunk for over a year on average, which is pretty exciting. This is really remarkable. So this opened up a new trial, which is going on right now across the country. This is for people as their first therapy. So we just talked about a trial before this one with EGFR inhibitors. The same principle applies to HER2. We’re trying to figure out if these drugs can work better if you give them upfront at the very beginning. So what people are doing with this trial is people that have HER2 amplifications, which is rare, but if you have it, you can be assigned randomly to either get standard of care, which is FOLFOX plus or minus one of these other drugs we’ve talked about, versus the new therapy, which of these two different drugs with FOLFOX as the first treatment, and then the people, we want to find out if this helps people live longer, to give it up front. So this is ongoing. There’s lots of sites around the country. There’s in North Carolina, in New York City, Boston, all over the country. Okay, so we’ve added HER2 therapy to our board here, and we’re very excited about these therapies.

Dr. Foote 21:04
All right, let’s talk about KRAS, which I know is a big topic nowadays. So KRAS is a part of this pathway that we just talked about. It’s a major growth signal in colorectal cancer. It has been the bane of our existence for a long time as something that was thought to be undruggable because it’s a very sneaky protein. However, we now find that it’s druggable, which is exciting and has given people a lot of hope. So KRAS is mutated in a lot of colorectal cancers. It’s mutated about a little bit less than half. About 45% of people with metastatic colorectal cancer have a KRAS mutation. But the really important thing here is that only about 3% of all patients have KRAS G12C. KRAS comes in a lot of flavors, and so most of the KRAS mutations are different than the one that we actually have a drug for. So this is really important, at least a drug that’s approved by the government there, as we’re going to talk about, there are drugs coming out for all the different flavors, but the main one that’s been approved only benefits, about 3% of people. So it’s important to keep that in mind. This is the drug that I was talking about there. There’s two different inhibitors right now that everyone talks about. One is Adagrasib and one is Sotorasib.

Dr. Foote 22:18
So what people did in the beginning for this study, is they saw whether patients that have this mutation benefited from getting the KRAS inhibitor by itself. And what you can see based on this plot, same plot I’ve shown you before, it’s called a waterfall plot, is that there were definitely patients that had their tumor shrink. About 19% of patients had the tumor shrink by a major amount, meaning more than 30% and there’s a good number of people that have the tumor shrink by less than 30% but still it shrunk. I told you, though these proteins are sneaky. They get around the therapy. So just like some of the other proteins we’ve talked about, when you inhibit KRAS there are these sneaky other proteins that try to bypass our inhibitors. So for example, you could see the normal RAS can go and activate the downstream proteins and cause the growth even if we’re blocking the G12C. That’s a little complicated, but it happens, this is how drugs become resistant. Excuse me, how cancer becomes resistant to our drugs. So one of the ideas that scientists at MSK helped develop, Dr. Rona Yaegar, who’s good colleague and friend of mine, is to try and use different drugs in combination with the KRAS inhibitors to make it better. So in this trial, Dr. Yaegar added a second drug called Cetuximab, which we just talked about in the very beginning of the talk alongside Adagrasib, to try and hit the same signaling pathway with two punches, one in KRAS and one in EGFR. And what she found is it made a huge difference, 46% of people had a major response. Look at this plot. It’s very dramatic, and 0% of patients progressed as of their first scan. So it made a big difference to have two drugs instead of one. And this is a big lesson for cancer in general. Having multiple therapies makes things better often. It helps prevent, prevent resistance. So you might ask yourself, What about the 96% of patients that don’t have this very, very specific flavor of KRAS? What about them? So this is a huge, busy slide. No one’s going to be able to memorize this, but these are all different clinical trials that are going on right now across the country, and you can see, I’ve circled some, I’m not endorsing any compound over another, but these are some of the ones that are a little bit more widespread and that they’re in more places.

Dr. Foote 24:31
Revolution medicine is a company that has been developing these KRAS inhibitors. They have trials all over the country, as well as Mirati, which has trials. And these are drugs that are in different phases of development, other types of KRAS other flavors. You can see these drugs inhibit KRAS G12D, as in dog, which a lot of people have. There’s ones that inhibit multiple types of RAS, KRAS. So these are very exciting drugs that are coming out right now. I will tell you a lot of people have this mutation. I talked about almost half of patients with colon cancer. So the trials are pretty competitive, they are hard to get on. They are. We have long wait lists, but talk to your oncologist, try to network between centers. This is a good option for people after they’ve gotten a lot of different chemos, when they have maybe a little bit fewer options, and we’re looking to be a little bit more creative. Again, a hugely intense, busy slide. The big point of this slide is really that we’re trying to hit not only the KRAS, but buddies that might help KRAS out to try and hit with two punches in the signaling pathway. And these are all different trials. Each number indicates a trial that is trying to block a partner that KRAS uses to evade our drugs. So you can see we’re not just hitting KRAS, we’re also trying to hit other pathway steps, and these are all clinical trials that are coming out. So I’m hoping this is giving people some hope that we’ll have new therapies, new protein inhibitors, to help people. So KRAS is on the board. They’re approved. It’s druggable. Big, big, big deal. And these trials just came out in the last year or two. Okay, another thing, sorry, my cat’s up here.

Dr. Foote 26:07
Another protein in the pathway that’s very important is called BRAF. And BRAF is a topic of conversation, I’m sure, in COLONTOWN and other colorectal cancer forums. BRAF is another important growth protein, and it’s downstream of KRAS. So BRAF inhibitors have been around for a little bit. You know, this trial was published in 2019 called the BEACON study, for patients that have a very specific type of BRAF mutation, we use BRAF inhibitors as well as EGFR inhibitors. So again, using two different punches on this signaling pathway, and what we find is, when we use these drugs later in the patient’s cancer journey, they can provoke a good response. About a fifth of patients have a major response when we have the two drugs together, and a bunch of people benefit, even if they don’t shrink over 30%, a bunch of people benefit, and it works better than chemotherapy. So you can see the blue curve here, which is the doublet BRAF inhibitors, patients live longer when they’re given that versus chemotherapy.

Dr. Foote 27:07
But we didn’t know if these drugs work well as the first treatment. Again, you’re seeing a theme here. We’re trying to figure out if using them first, not later, in a journey, but first makes a difference. And this trial came out like three, like two months ago. This is hot off the press. This is the BREAKWATER trial was presented by Dr. Scott Kopetz. It was published in Nature Medicine. And what Dr. Kopetz and his researchers did is they added BRAF drugs to FOLFOX as the very first treatment in a patient’s journey for patients that have BRAF V600E mutations. And what they found is when patients got these drugs up front, they lived longer or they had less progression than if patients just got chemotherapy alone. And you can see the response rate, meaning the number of patients that had a major shrinkage in their tumor was higher when you gave the BRAF drugs up front, 61% versus 40% of patients got chemotherapy. So this is a practice changing trial across the country now. If you’re diagnosed with colorectal cancer and you have a BRAF mutation, you will probably get the BRAF inhibitors up front alongside the chemotherapy. So protein inhibitors are moving up in the world. These are a bunch of just exciting trials to show you that we are making progress on figuring out not only what drugs to use, but when to use them.

Dr. Foote 28:24
Okay, let’s get into some really exciting stuff, immunotherapy. First, we’re going to start out by talking about how the immune system works. This might be a little basic for some but I think it’s helpful to kind of show you what immunotherapy is and how scientists think about it. So I study this in my lab. I work with Dr. Diaz, who helped discover a lot of this stuff. So it’s very dear to my heart. So let’s talk about how the body recognizes a sick cell, like a sick cell a cell infected by a virus. And this will tell you how a cell recognizes a cancer cell too, because it’s pretty much the same thing. So when a virus binds to a cell in your body, it deposits some of its DNA inside the cell. This DNA is weird, it’s not normal, right, to have a virus DNA inside of your cell, so it looks very different to the body than the normal DNA. The virus hijacks the cells machinery to turn this DNA into a protein called a neoantigen. And neoantigens are basically Neo means new antigen means protein signal. So you can think about it like a new, weird protein that’s not supposed to be there. The body has an amazing way of showing the immune system what’s going on inside of it. It’s like taking its own temperature. It randomly samples proteins inside of itself and then displays it to the immune system to say, hey, what does this look like to you? Does this look normal? It does that all day, and the immune system goes around and looks at these proteins and says, That doesn’t look normal, I’m going to kill you, or that looks okay, I’ll leave you alone. So it’s constantly doing this, and that’s how the body can recognize if the cell is sick, or if a cell is cancerous. This is the immune cell, a T cell, which looks at this presented peptide, this new, weird peptide, with this microscope, and then decides whether it’s going to kill the cell or not. Okay, depending on how weird or immunogenic the protein is, how weird it looks, the immune cell may determine the cells too sick and it’s too risky to let the cell stay alive, so it kills it. And by the way, there are other types of immune cells too that are buddies of the T cell that go around sucking up stuff just in the blood, all over the body, sucking up proteins and displaying it constantly to these T cells to tell people, hey, this to tell the immune system, this is what’s going on in my body right now, you need to go and find where this protein is and kill it, because this is not normal. This is not right. So that’s what our bodies have evolved. It’s pretty amazing. Cancer proteins are just like the virus proteins. They’re weird. They’re not supposed to be there. They help the cancer grow, but they don’t look normal. All the proteins we talked about that we inhibit with protein inhibitors, those are weird proteins. They’re not supposed to look that way. So the number of those weird proteins, as well as the type of the proteins, can make certain tumors more or less attractive to the immune system.

Dr. Foote 31:16
So if a tumor is cold, that means that it looks pretty normal to the immune system. The immune system doesn’t get very excited when it sees it, and in fact, it populates these immunosuppressive cells that quiet down with sleeping potion any type of immune cells that try to wander in and kill it. Meanwhile, on the other side, you can have these really hot tumors that have really weird, bizarre proteins, and the immune system gets very excited when it sees them, because it knows that is not normal. So the question is, I just talked about all these weird proteins, why doesn’t the immune system just take care of this? Why are we talking about chemo, protein inhibitors? Why doesn’t the immune system just destroy all this stuff itself? So cancer is sneaky. It has switches on the outside of the cell that turn off the way that, pardon me, the way that the immune system recognizes the cancer. So remember I showed you before that the cell presents these weird proteins to the immune system. So the cancer produces these switches to turn off, like a light switch the immune cell so it doesn’t recognize the cancer. It’s like an invisibility cloak that the cancer throws over itself to hide from the immune system. Immunotherapy helps to boost the immune system by eliminating these switches that the cancer uses to turn off the immune system. That’s one of the main ways that immunotherapy works. There’s other types of immunotherapy too. It’s a general term, but it helps boost the immune system to recognize cancer. This is a busy slide, but it’s a very, very famous and important one, done by Mark Yarchoan at Hopkins, my mentor, was involved with this as well. Different types of cancer respond differently to immunotherapy based on the number and the type of their weird proteins. Okay?

Dr. Foote 33:01
On the y axis here, you see how much the tumor shrink when you give an immunotherapy. So the higher, the better for us. This means that 50% of patients with this cancer will have shrinkage. At the bottom means that immunotherapy doesn’t work very well. On the x axis, you see the number of weird proteins inside of those cancer on average. So you can see there’s a direct relationship here, right? Tumors that are hotter, that have lots of weird proteins, also tend to do better. They have more shrinkage when given immunotherapy. Classic point is mismatch repair deficient or MSI, colorectal cancer, which is a very hot tumor, has lots of weird proteins, and immunotherapy works well for patients with this disease. On the other hand, patients that have the more standard, more common, mismatch repair proficient or MSS colorectal cancer, immunotherapy doesn’t work very well for them. They don’t have as many mutated, weird proteins.

Dr. Foote 33:54
So I just want to show you a little case study. This was a famous trial that we did that gained some attention, so I thought I would bring it up to show you as an example. So we looked at patients that have the really hot MSI mismatch repair deficient tumors, and this is in the early stage setting. So these are patients with stage two and stage three cancer, very important to know. So they’re the patients where they’re facing treatments like radiation, chemotherapy and surgery to try and cure their cancer. So this is a pretty rare it’s only about 5 to 10% of rectal cancer. And just like I mentioned before, the way that we typically treat folks with this disease is we give them chemotherapy. We can sometimes give them radiation, and sometimes we have to take them to the operating room. And as you can imagine, this is a lot of side effects for folks that have rectal cancer, the surgery can be pretty brutal. So we wanted to try and nice little animation there. We wanted to try and get rid of all that and just give people immunotherapy. Because, as I showed you before, we know that when patients have stage four cancer, immunotherapy works pretty well for them, if they have this mismatch repair deficiency, this MSI status. Okay. So we gave them a drug called DOSTARLIMAB, which is a inhibitor of the light switch checkpoint that I told you before, one of the switches that the cancer cell uses to turn off the immune system. We gave a drug that blocks that switch. So this is a patient who received, and this, of course, was given with permission. This is a patient who was on the trial. You can see a really ugly, nasty tumor in the rectum, okay? And on the scans we can see it too. It’s glowing very brightly. And this was before we started the drug. So after six weeks of getting the DOSTARLIMAB, you start to see something amazing happen. The tumor is starting to go away. And in fact, after three months, the tumor is basically completely gone, and you can see the signal in the scan is less, and you can also see that the PET scan is starting to look better, and it remained gone. It’s remained gone for over two years. So this patient was cured without needing chemotherapy, radiation or surgery. So one of the also interesting things just looking, under the microscope at these tumors. So this is what the tumor looks like before it got any treatment. And you can see this like green, weird looking cells here with blue. And then you see the soldiers come in. These are white cells. These are the CD8 cells that I was telling you before. And these are immune cells that are swarming into the cancer and digesting it and gobbling it up. And you start to see this reaction happening after about three months, you see that the tumor is red hot. Look at this. It’s melting away because the immune system is eating it from the inside. And in fact, by six months, the tumor is is basically gone, and you just see these white soldiers hanging out there patrolling the borders.

Dr. Foote 36:45
So this one patient had a fantastic response to therapy. What about the other patient on the trial? Well, they all did, 100% that was why it got so famous. Every single patient with rectal cancer that we we treated on this trial had a complete response to keep to immunotherapy, which is amazing. And so we got a lot of attention, It was on Instagram and we got a lot of phone calls, Dr. Cercek, Dr. Diaz, my colleagues and mentors, I work with them very closely on this study. They became very famous, and so it was very exciting. But what about patients that have stage four cancer? Right? We talked about how they can do well with immunotherapy. How do they do? Do they do just as well? They don’t do quite as well. I wish everybody was cured with this, but unfortunately, that’s not the case when the cancers become more advanced in a stage four setting. So we know from Dr. Diaz’s study, which I was with him at the time, that if you give people immunotherapy that have this rare MSI mismatch repair deficient type of colorectal cancer, we know that immunotherapy can work well. So patients that got immunotherapy Keytruda to or pembro, they did better than chemotherapy when they got this as their first treatment. So that’s why, if you have an MSI tumor, we typically give you immunotherapy first.

Dr. Foote 37:55
So one of the questions though is that was just one immunotherapy drug. What happens if you give people two immunotherapy drugs? How well do they do? And should we do that first?, This was a big question and it was just presented recently at ASCO GI, like two months ago. So they published this paper that showed no surprise, when you give people this rare type of mismatch repair, deficient cancer, MSI cancer, when you give people two different immunotherapy drugs, they do really well as their first treatment, this was their first treatment, they do really well,compared to giving them chemotherapy. So that’s all well and good. We kind of expected that. That’s sort of what I showed you on the previous slide too. How well do they do compared to people that just got one immunotherapy? So that was the update that just happened this year. When you get two immunotherapy drugs up front, you do better than if you just get one immunotherapy drug. And so this was a practice changing trial across the country. Now if you have an MSI colorectal cancer in the stage four setting, you will get two immunotherapy drugs up front, pretty much at every time point, you see a 15% or so benefit. So 76% of people are still on the drug without progression at 12 months, versus 63%. At two years 71% of people are still on the drug without progression versus 56%, so you can see there’s a big benefit here. Now we haven’t yet seen overall survival. This is only progression free survival, meaning the number of patients that had their tumor not grow at each time point. So it’s a little bit different. Overall survival is how long people live. Progression free your survival is how long people live without progressing. So this is practice changing.

Dr. Foote 39:26
I know I’m talking a little bit fast. I wanted to get to the questions, so I can answer some questions about this too. This can be a little complicated. So this was a paper that Dr. Rousseau and I published in New England journal that showed you that, unfortunately, for most of the patients with colorectal cancer who don’t have this special flavor, who don’t have this MSI, they don’t benefit from these drugs that much. Even if they have a high number of mutations, it just doesn’t work. In this graph, you see that the blue curve and the red curve are pretty much the same. Even though the blue curve, these tumors had more mutations than the red curve, it just doesn’t work that well, which is why most patients with metastatic colorectal cancer, if they’re not MSI, we don’t give them immunotherapy. So how do we make it work for them? How do we make it work for you? That’s the goal, right? To make it work for everybody.

Dr. Foote 40:28
And so we published this paper talking about this. You can read it if you want. So one idea is, well, let’s try to make our drugs better. Let’s give a new generation, a new wave, of immunotherapy drugs. And so these are some of the newer drugs coming out, Botensilimab and Balstilimab. We’ll talk about that in the next slide. And then there’s other types of switches that we’re looking to block, switches like light switches that the cancer cell turns off the immune system. We’re trying to destroy those switches. So we’re looking at new targets here, including LAG3, which is coming out in colorectal cancer, and there’s some more as well. So a lot of people have heard about Botensilimab. Botensilimab is a type of CTLA-4 inhibitor. So CTLA-4 a switch, like one of the ones I just told you about, people that have gotten Ipilimumab, that’s a CTLA-4 inhibitor too. But the special thing about bot is that it has a modification on its antibody that makes it much more potent, and we think that this can make it bind to the immune system better, and also maybe destroy some of the bad immune cells that aren’t helping us, that are dripping sleeping potion over the tumor, so that the good immune cells go to sleep. We don’t want the bad immune cells. And what we found in this trial of patients that had stage four MSS colorectal cancer. These aren’t the hot tumors that we talked about before. These are the cold colorectal cancer tumors. The vast majority of tumors that don’t respond well to immunotherapy, about one in five patients or so, one in four, one in five patients had a major response to these drugs. Pretty exciting. This had not been seen before with any type of immunotherapy in this before they got Botensilimab and they gotten a second drug as well called Balstilimab. Balstilimab is kind of your run of the mill, ANTI-PD-1 inhibitor. It’s very similar to Keytruda or Opdivo. Really, really important point, though, when we looked into the data, the people that did really well, did not have cancer inside of their liver, the patients that had cancer inside of their liver, this red curve, they didn’t do so well with these drugs. They progressed within a couple months. But patients that didn’t have liver metastases, that had maybe cancer only in their lungs, only in their abdomen, they did pretty well. These were the patients that benefited the most. So we think these drugs work well in patients without liver metastases. However, one important point, if you had liver metastases in the past, but they were treated with this light teal color, they did better. They did better than if the metastases were still there. So you can see this curve sneaks to the right, which means there’s benefit.

Dr. Foote 42:57
Okay, another way of stimulating the immune system is by peppering it with these weird proteins to try and get it really excited about seeing weird proteins so it goes out and kills the cancer. So you can do this with vaccines, which we’re not going to talk about today. That’s a whole talk in itself. We give people even sometimes viruses. We talked about how the immune system recognizes cancer, right, just like a virus. So we actually are manipulating this machinery to help fight cancer, and then some people use radiation. And this all is to stimulate the immune system to go and kill tumors. I’m going to wrap up in a little bit. So one of the kooky ways that we’ve thought about is to actually induce mutations inside of the cancer. Induce these weird proteins by giving mutagenic drugs. And that sounds really scary, because you said, well, mutations causes cancer, and now you’re going to mutate my tumor. Yes, yes, we are to try and make it hotter, and that’s what this trial did. It gave people a drug we’ll talk about in the next slide, a drug called temozolomide, which is a mutagenic drug to try and mutate the cancer, to make it hotter, to make the immune system recognize the cancer better.

Dr. Foote 44:01
So there’s two different trials that did this, the Maya trial and the Arethusa trial. And we gave people, I didn’t, I wasn’t part of the study, but the scientists gave people temozolomide. And these colorectal cancer tumors were a little bit unique. They had this thing called MGMT methylation, which I’m not going to get into, but it was a little bit of a unique characteristic that made us think that these drugs would work even better in these patients. And these patients got temozolomide to mutate their tumors, as well as immunotherapy together, okay? And about a third of patients responded again. This is something that we don’t typically see in these cold tumors, to the immunotherapy and the temozolomide, and this trial, and then the other trial, showed some benefit too. So this proves a principle that increasing the quality and the amount of mutations in a tumor may help stimulate the immune system.

Dr. Foote 44:54
Okay, let’s talk about T cell engagers. These are different drugs that are coming up for colorectal cancer, and we’ll talk about how they work. The basic idea is pretty simple. You have one end of this molecule that binds to the immune cell. You have the other end of the molecule that binds to a cancer cell, and it drags the two things together so they’re looking each other right in the eye. The immune system is looking right at a cancer cell, and then we pepper the body with immuno stimulating medicines to get the immune system really excited, and hopefully it recognizes the cancer as weird and kills it. Okay, that’s the whole idea behind these bi specific antibodies, okay? Or T cell engagers, that’s what these are called. So there’s many different drugs that are in clinical development right now. This is even a little outdated. You can see a lot of them are against proteins that you might recognize, such as CEA, which is a mucous protein that the cancer makes. And there’s a bispecific antibody, where one arm of the antibody binds to the CEA and the other arm binds to the immune system. And this drug is called Cibisatamab, and it was studied in a clinical trial with my colleague, Dr. Argiles is who I work in the lab with. And when they treated patients with this drug, it didn’t help everyone, but it did help some people. You can see people that have the blue line here, they had a response, meaning they had over 30% shrinkage of their tumor when they were given this drug. And this is the normal run of the mill colorectal cancer here that we’re talking about. We’re not talking about any special flavors. Importantly, you can see here on the scan some really interesting examples. So you can see this tumor in white that I circled, as well as this tumor after about four months, you can see the tumors have gone away completely, right? They’re not there anymore. Same down here. These are tumors in the lung, and you can see these tumors also went away. So this can be an effective drug, and we’re looking at ways to make it better so that it helps everybody, not just a few people.

Dr. Foote 46:48
Okay, lastly, let’s talk about CAR-T cells, and then we’re finished. So CAR-T cells are very exciting in principle. How they work is, we take blood from you, and we filter out your own immune cells. We then, in a laboratory, edit these immune cells by basically making them into super soldiers to recognize weird cancer proteins. That’s the theme of the whole talk, right? By giving them the spear that recognizes a weird cancer protein, the spear is called a CAR. Then we grow them in a dish in the lab, and we give them back to you, and in a bag, just like a you would get saline, we give them back to you. And the idea is that these CAR-T cells hopefully go and find cancer cells and kill them, because they’ve been trained like super soldiers. That’s the idea. So there have been at least two studies in colorectal cancer. They’ve been very small studies. This is a very expensive therapy. It costs, like, a million and a half dollars to make this because there’s so much engineering and work that goes into it. So this is something as a society we have to figure out how we’re going to manage because, with colorectal cancer, it’s a very common cancer, so, but in this these eight patients or so, you can see that for some people, it seems to have worked a little bit. The curves start to sneak to the right. About 40% of patients had some degree of response. Now, the other thing to keep in mind is, before everyone gets too excited, is these patients also got pretty heavy chemotherapy as a part of the trial. That’s for a biological reason that we can maybe talk about in the questions. So there are some people that look at the studies as well. They got pretty heavy chemotherapy. Maybe the chemo is actually what did the job and not these CAR-T cells. CAR-T cells are very exciting, but the problem is they swarm the tumor, and then they run into the sleeping potion that I was talking about earlier, the chemicals that the tumor and other bad immune cells make that put the CAR- T cells to sleep, so they charge in there with their spears, and then they get the sleeping potion, and they go to sleep. That’s the problem with CAR-T cells, so we’re trying to make them better. There’s lots of very smart people thinking about this. So this is our whole landscape of what we talked about. We didn’t talk about this stuff, but we talked about every single one of these, including the mismatch repair deficiency. And this is really the landscape of colorectal cancer management right now. We have BRAF inhibitors up front. We have HER2 inhibitors that are approved, EGFR inhibitors up front, KRAS inhibitor. So this is very exciting. These are a lot of advances that happened the last two years. Okay, I went a couple minutes over, but I just want to thank everyone. This is not science that we do in a vacuum. This is group science that we do with lots and lots of smart people, many of whom don’t get credit for their hard work. These are my colleagues, and I work on research trials with them, as well as my surgical colleagues. This is a figure that we did for Nature Medicine that we were excited about. And I just want to thank everybody who collaborated, as well as my patients. I know some of them are listening tonight, I saw some familiar faces, and happy to take your questions.

Betsy Post 49:48
Great. I have some questions here in the chat for you, and if I mispronounced something, you could just laugh at me. That’s okay. When you one patient had a question pretty early on, about nine minutes into the talk, and it is, when you block a pathway, could another pathway accelerate progression?

Dr. Foote 50:06
Wow, that is a very, very good question, and it’s something that’s scary, right? Because the last thing we want to do when we give someone a drug is make things worse in the end. So I will tell you there’s a very long, complicated answer to that. The short answer is, in the short term, it benefits patients to block pathways. The risk benefit calculus swings towards blocking a pathway. And you can see that with the survival data that I showed you right. Because if it ended up hurting the patient, their survival wouldn’t be elongated. There have been examples, though, to this person’s point, where that has accelerated things. And there’s some ideas, mostly around the sequence of when you give the drugs. Remember, I was telling you about sandwiching drugs with chemotherapy to try and prevent resistance. So I think that strategy is becoming a very exciting way to manage these diseases to avoid having resistance earlier.

Betsy Post 51:02
Thank you. The next question is, were patients with metastatic colorectal cancer, including liver Mets, excluded from PARADIGM?

Dr. Foote 51:10
Nope, they were in PARADIGM. PARADIGM was a great study. The only patients that were excluded were patients that had KRAS mutations.

Betsy Post 51:18
How does an oncologist decide between using pani versus Cetuximab is one better than the other?

Dr. Foote 51:25
So they’re pretty much the same thing. They’re pretty much the same thing. Cetuximab is a little older, but they they’re both effective. Cetuximab can sometimes give people an infusion reaction, like an allergic reaction. It’s pretty rare, but panitumab doesn’t really do that. So at MSK, we use pani, but if you use Cetuximab, it’s okay. Some people’s insurance only pay for Cetuximab, so it doesn’t change the outlook on the cancer and the infusion reactions are pretty rare.

Betsy Post 51:50
Are there any ongoing trials in MSS colorectal cancer using immunotherapy and radiation to test abscopal effect?

Dr. Foote 51:59
Yeah so this is a sophisticated question, so the ascopal effect is it goes back to the slide I showed you. I can get back there where the immune system has buddies that are constantly sucking up proteins in the micro environment of the tumor and presenting it to the immune system. So if you blow open a lot of cancer cells, they might release their weird proteins into the fluid around the tumor, and then the immune system can gobble those up and show them to each other to try and stimulate the cancer. The abscopal effect relies on this premise, because it says, If you radiate one tumor in the body, it might release its cancer proteins, and then the immune system will recognize it in that specific spot, and then go and find tumors in other places too. That’s what the abscopal effect is. The truth is, the abscopol effect is still fairly theoretical. It’s not thought to be as widespread as people sometimes think. There’s actually not a lot of proof that it exists. It’s very, very controversial. There have been some studies that show it, but I don’t think it happens as often as people think. There are trials out there for this. There have been studies that have been done that have been negative studies, frankly, but it’s still something we’re trying to get better at, including with new immunotherapy drugs. Maybe it’ll work better with these new generation of immunotherapies.

Betsy Post 53:23
Great. Why are metastatic colorectal cancer MMR proficient patients with liver Mets so much less responsive to immunotherapy?

Dr. Foote 53:31
Yeah it’s the million dollar question, right? Because most people, probably 95% of patients with metastatic colorectal cancer do not have those super hot tumors. And it goes back to the graph I’m trying to show it to you as I oops, I went too far. It goes back to this idea, man, did I keep skipping it? Sorry, everybody. I guess it was maybe earlier than this. It was here. It goes back to the idea that the number and the type of the proteins in the cancer determines how excited the immune system is to kill it. The normal MMR proficient colorectal cancer does not have anywhere near as many mutated proteins as the super hot one. This has 50, right, on average. This has like five on average. Okay, so that’s the difference here. These tumors have a lot of really spicy, exciting, weird looking proteins, and these ones don’t.

Betsy Post 54:29
Is there ever a reason to only use an EGFR drug without Folfox or Folfiri?

Dr. Foote 54:37
Good question. Yeah, we do do that, typically, not in the first line setting, because we know that chemotherapy can work so well for people in the first line setting, but we do use EGFR inhibitors later in a patient’s journey. And it goes back to that sandwich method that I was telling you about, right where patients can get the drug at one point in their journey. Up front, we do something else, and then we can rechallenge them with that drug later. So often, when we rechallenge people, I’m trying to find the slide. Whoops, here we go. When we rechallenge people, we use just the drug right here.

Betsy Post 55:11
Someone said, Thank you. Very informative. Does Bot/Bal work with BRAF?

Dr. Foote 55:15
Yeah thats a good question. You know, that’s a very good question. So that trial did not look specifically at BRAF mutations, so people with BRAF mutations were included in that study. If the patients did not have liver metastases, then I think there’s a good chance that it might work for them. But to be honest with you, the answer is somewhat unknown. We don’t know yet.

Betsy Post 55:35
Are TILs more promising than CAR-T for solid tumors like MSS colorectal cancer?

Dr. Foote 55:43
So we didn’t talk about TILs. So TILs are tumor infiltrating lymphocytes. So what that means is what scientists and doctors do, is they take the tumor, they harvest the immune cells that are living inside of the tumor, and they kind of spice those up. They train those guys to be super soldiers, and then they give them back to the patient. Another really cool idea, TILs have not panned out well in colorectal cancer. We’re trying to make them better, but they haven’t panned out well. We don’t necessarily give TILs the spear that CAR-T cells have. So the thought is that CAR-T cells is better, but these are all new things, and we’re trying to get better with them. So no one’s actually proven that.

Betsy Post 56:24
You mentioned that right sided tumors are very different than left side, do any of these trials or studies show effectiveness with right side tumors?

Dr. Foote 56:34
That’s a good question. Yeah. So the first trial with EGFR inhibitors, the Paradigm study, that study was in left sided tumors, that was the most the benefit that’s with EGFR inhibitors specifically okay. KRAS inhibitors are both left and right sided. BRAF inhibitors are both left and right sided. The Bot/Bal we talked about, are both left and right sided. So the only thing we care right now about left or right sided is really for the EGFR inhibitors. The other stuff is kind of controversial. To my knowledge, there has not been a drug that works better in right sided versus left sided disease. That being said, we could talk about that for a while,

Betsy Post 57:18
okay, a TCR neoantigen paper was published yesterday with 23% RR, but RR in synchronous metastatic colorectal cancer was only 9%. Is that true in RMC, 6236?

Dr. Foote 57:36
yeah. So this is a little bit of a I don’t know if I wouldn’t be able to answer that on the air. I don’t know if I’ve seen that paper yet. I’d have to look into it for you. I’m sorry, but that’s okay, but it’s exciting. Hopefully it’s real.

Betsy Post 57:51
How do immunotherapies work for patients with peritoneal Mets?

Dr. Foote 57:54
So good question, and I actually am starting a clinical trial for patients with appendix cancer with immunotherapies that only have peritoneal metastases. So I could talk about this for an hour. The short answer is that one of the reasons we think that liver metastases are bad for immunotherapy is that the liver is a very tolerogenic organ. The liver’s main job is to make proteins and break them down. So it’s used to making all kinds of weird stuff, and it doesn’t want the immune system to get really excited every time it makes something a little bit weird. So it has a lot of cells inside of the liver that drip sleeping potion everywhere, so that immune cells go to sleep and they don’t hyper activate and kill the liver. Because if your liver dies, it’s very, very serious. So that’s the evolution of how that happens, and it’s normally a good thing for us. Cancer takes advantage of that. Cancer sneaks into the liver, takes advantage of the sleeping potion, and hides out there. Okay, now, with immunotherapy, it’s hard for the cancer to be reawakened from its slumber, because there’s so many sleeping potion cells around it. So that’s why we think that when patients have liver metastases, they don’t do as well with the immunotherapy drugs. If patients don’t have liver metastases, then there’s less sleeping potion in the peritoneum and maybe in the lung. So we think these drugs can work better. That’s a very like lay person’s way of putting it, but hopefully it’s helpful.

Betsy Post 59:20
I’m currently on, I don’t know how to pronounce this, Adagrasib and Cetuximab, and my CEA has dropped to the normal range. There are conflicting theories about whether the cancer cells could be necrotic versus just less less active. Any opinion on whether Adagrasib can actually effectively kill the cancer cells versus keeping them stable?

Dr. Foote 59:45
Yeah. So it definitely can kill cancer cells. It definitely can. It’s a cytotoxic drug. It blocks the KRAS protein. Without that protein, the cancer cell dies, doesn’t have the growth signal, and the body digests it. So it is a cytotoxic drug. I’m trying to find it for you. Adagrasib is one of the KRAS -G12C inhibitors. That’s the main one that’s come out. And this patient, this person, is on both of them, which is the right therapy. So yes. Sometimes what happens is you kill off the most sensitive cells, and then you kind of slow down the ones that are resistant to it, or they don’t die completely, but they’re slowed down. So both effects that this person mentioned can happen. Typically, in the beginning you see the most dramatic shrinkage, and then you see more of a plateau effect.

Betsy Post 1:00:30
Great. Did you see the phase one trial with Bot/Bal plus chemo at ASCO GI 25? If you did see that, it seems there were responses in liver Mets. Do you think there will be a phase two trial?

Dr. Foote 1:00:44
No there wasn’t very many responses in the liver Mets. There were some, but there weren’t a lot. And some of the patients in that arm, I think that you’re referring to, had pre treatment of their liver mets. We could go into the details a little bit. There definitely is going to be another trial, for sure. I mean, these drugs are very exciting. We’re opening a trial in Appendix cancer at MSK for Bot/BAL. We have two other trials that are opening for Bot/Bal at MSK, one in rectal cancer and another one combined with some other drugs. So yes, it’s very exciting. The company is a small company, and they’re really excited as well, but they’re trying to find their footing. So yes, there are more trials going on and the hope is to not abandon people that have liver Mets. Of course, I hope to not give you that impression. That’s most patients with metastatic colorectal cancer have metastisis their liver. We’re trying to make these drugs better. Maybe there’s a combination medicine that can work with it, etc.

Betsy Post 1:01:36
Wanted to give you this compliment on the way of the questions, because it got a lot of likes, and I agree, very good presentation. Thank you for the effort you put into providing clear, concise information. So that’s getting a lot of love, and I agree. Let’s see another one. Could you explain compassionate use for Bot/Bal with named patient program, who qualifies? What it entails for the for the provider? Why? FDA only allows it for some drugs, any restraints on participants and travel required?

Dr. Foote 1:02:09
Yeah, it’s a good question, and one we don’t talk about very often. So without going into a 15 minute soliloquy, compassionate use is, is a way that companies can give people drugs that aren’t yet approved by the government for their indication. So Bot/Bal, right now, is not yet approved by the federal government. They have not demonstrated yet that they have safety and effectiveness to warrant giving everyone this drug. Okay, so while they’re in this period of talking to the government, your oncologist can write the company and make a convincing argument, saying, Please give my patient. Ms Jones Bot/Bal because she doesn’t have liver metastases. She only has spots in her lungs. She’s done really well. She’s very healthy. She doesn’t have any autoimmune conditions. Please give her this drug. And the companies, most of the companies, have a program for that. Now, drugs cost money, right? This is America, United States of America, right? This is not a perfect country for drug development. Drugs cost money, and there’s a lot of money in this. So even though you and your oncologist might want the drug, the company is not obligated to give it to you. Now, most of them can, but they have a certain limit on the amount of drug they can give out for free, right? And these drugs are insanely expensive, so paying for out of pocket could cost $15,000 every time you get the drug. So that’s the issue with our country. Most of the time, the drugs go into something called accelerated approval, which means the government Fast Tracks them. This is all being discussed with the current political situation. Please discuss with your representatives, with your vote, you know this is important, because drug development is being hindered by the current policies. Okay, I’m going to just tell you that right now. So these are all good questions. With Bot/Bal specifically, you can get compassionate use for it if you have a convincing argument. If you have liver metastases, the company is probably not going to give it to you. If you don’t have liver metastases, talk to your oncologist. You will have had to progress on multiple lines of chemotherapy so you can’t get it like as your first treatment, you’ll have had to say, I’ve tried everything. My cancer is still growing. Write the company, see what they say. I have been able to get it for one patient, it takes a long time. It probably takes about a month and a half. Too much information. Sorry.

Betsy Post 1:04:20
Thank you. No, I think that is very helpful, and I appreciate that a lot. We just have a couple questions. Thank you so much. Do you have any KRAS trials for appendiceal cancer patients?

Dr. Foote 1:04:33
Well, that’s a great question. I do a lot of work with the appendiceal cancer community as well. So right now the answer is, technically no. There are KRAS studies that are going on in MSK that are open to all patients that have a specific KRAS flavor, like we talked about right now. Most of the trials are for patients with pancreas cancer, but they might have arms opening up for other types of cancer. There are trials around the country that are enrolling people with appendix cancer. It’s hard to get a spot, but there are trials around the country that are doing that. It’s a good question.

Betsy Post 1:05:05
Okay, I think just two more. One is about immunotherapy. Will that work sometimes for brain Mets?

Dr. Foote 1:05:13
So brain matastases and colorectal cancer are pretty rare. They happen about 1 or 2% of the time. So it’s not a common situation, and it’s also not a situation that we’ve studied that well, right? Because we don’t have 10s of 1000s of people that we can look into our research and figure out if it works for them, anecdotally, patients that have lung cancer and other types of cancers that go to the brain more often, immunotherapy can work for brain metastases. So it could be something that we could approach. It would, you’d have to just be really careful about it causing an autoimmune reaction in the brain. Is pretty serious, so we’d have to think about it.

Betsy Post 1:05:47
Okay, what is your opinion? Let’s see. Sorry, are there any initiatives ongoing with reversion therapy, similar to that of what the KAIST Institute had discovered.

Dr. Foote 1:06:00
You know, I got to be honest with you, I’m not as familiar with the KAIST. I have heard of reversion therapy. I don’t know if I’m the best person to comment on it, though I’m not an expert in that but that is a good question.

Betsy Post 1:06:12
No problem, no problem. I wasn’t sure that’s okay. That’s okay. And this is our last question. Are you seeing potential in the antibody drug conjugate approaches ADCs.

Dr. Foote 1:06:24
Yeah, we didn’t talk about ADCs. It’s a good point. We talk more about immunotherapies and targeted therapies. So ADCs are basically antibody drug conjugates. What they are is they’re a homing missile that has an antibody on one end that’s like a receptor that homes in on a cancer protein, okay? And on the back of it, there’s a warhead, like a bomb. So it’s like a homing missile, and the bomb, what happens is the homing missile finds the cancer protein on the surface and then delivers the bomb to the cancer to blow it up. Now, it’s not actually a bomb, it’s a cytotoxic it’s a toxin. But that’s the idea. ADCs are very exciting. They’re very exciting. There are a lot of new ADCs coming. We didn’t talk about in this talk because I didn’t have enough time. I couldn’t tell you everything, but it is an exciting avenue. Maybe next time we can talk about ADCs. Right now, there aren’t a lot of ADCs approved. I will tell you, if you notice I didn’t talk about this drug, but for HER2 there is an ADC that’s approved called T-DXD. This is an ADC that targets the HER2 receptor, just like I mentioned, it has a receptor for HER2 and it delivers the bomb.

Betsy Post 1:07:32
Great. Well, Dr. Foote, I just want to thank you so much. I have been in this realm with colorectal cancer patient advocacy for years and years, and I learned so much the way that you took the time to explain this. It was very patient friendly and caregiver friendly. Some of these slides I’m definitely stealing, I think they would be great screenshots for a lot of our groups within COLONTOWN. So on behalf of our 13,000 patient, caregiver community in COLONTOWN, I just want to thank you so much, and I want to thank Dr. Diaz for recommending you and asking you to do this talk. We really, really appreciate it, and just can’t thank you enough, and I’ll definitely keep in touch with you and thanks. Thanks to all the patients and caregivers that came and asked wonderful questions.