While colorectal cancer rates are dropping overall, a worrying trend is emerging: cases are rising in adults between the ages of 20 and 50, who are not screened regularly. Given the necessity of early detection for current treatments, there is a growing need for effective treatments in advanced cases. Immunotherapy for colorectal cancer can be effective, especially in cases where tumors show high microsatellite instability. Join medical oncologist Dr. Van Morris of the University of Texas MD Anderson Cancer Center for a discussion of biomarkers, immunotherapies, and what patients with colorectal cancer need to know. Ask your questions about genetic and genomic testing, treatment options, and other topics in our live Q&A.
Tamron Hall: Welcome back! It’s my pleasure now to introduce you to Dr. Van Karlyle Morris from the University of Texas MD Anderson Cancer Center in Houston, Texas. Dr. Morris is here to fill us in on the latest advances in colorectal cancer immunotherapy. And you can leave your questions for Dr. Morris in the Q&A. Dr. Arthur Brodsky from the Cancer Research Institute will be passing them along to Dr. Morris. Dr. Morris, please tell us about the latest advances in using immunotherapy to treat colorectal cancer.
Dr. Van Morris: Thank you, Tamron, and thank you for the opportunity to speak today to all the patients and family members at the CRI patient summit. I’m here today to talk a little bit more about colorectal cancer and answer questions that that anybody may have.
A lot of what is exciting about colorectal cancer right now is, you know, is how can we incorporate immunotherapy into the to the management of colorectal cancer? I wanted to kind of start off by just giving a little bit of background about kind of the basic biology of colorectal cancer and why it may be that some patients respond very, very well with colon cancer who have colon cancer when treated with immunotherapy, a there are others that that may not. I’ll actually start at the bottom of this slide and kind of talk about patients whose colorectal cancer is characterized by something called microsatellite instability or what we say is an MSI high tumor. These tumors kind of inherently have higher rates of mutations in their DNA, which change the colorectal cancer cells and make them more recognizable by the immune system. So when we give immunotherapy these drugs, which kind of augment and increase and stimulate the immune system to identify, attack and hopefully kill that colorectal cancer, it’s more likely in these patients who have these MSI high tumors that they respond very, very well to immunotherapy. Unfortunately, even though colorectal cancer is the second leading cause of cancer related death in the United States, only fewer than five percent of all patients with stage four colorectal cancer will have an MSI high tumor where immunotherapy in and of itself may work very well. You know, what this means is that, you know, over ninety five percent of patients with colorectal cancer don’t have MSI high tumors. They have rather what’s called a microsatellite stable tumor here, which is something that you can see kind of described on the top part of this slide, and microsatellite stable tumors either are described by something called immune exclusion. So basically, there are immune cells. The body’s immune cells present kind of around the tumor, but the tumor kind of figures a way to kind of block them out and keep them from entering into the tumor and causing destruction. Maybe what’s more even relevant for colorectal cancer is this idea of what we call an immune desert. So basically, as the tumors are these tumors are kind of growing and evolving. They figure out a way to just remove all immune cells from their vicinity. So when you treat with these drugs, which are designed to kind of stimulate the immune cell because there aren’t any immune cells already in these tumors, the likelihood of the immune system working to fight this cancer is much lower, and because of that, when we treat, when we’ve treated patients with these MSS, microsatellite stable, colorectal cancers, we see that the responses of immunotherapy are very, very low, almost close to zero percent.
So some of these, some of the medicines we when I talk about immunotherapy that you may have heard about or seen on commercials on TV are drugs called is the scientific name nivolumab or pembrolizumab, apptivo and Keytruda, as you can see here. And just got FDA approval about a year ago for patients with MSI high colorectal cancer. I will show a graphic for kind of how this works, but the way that I kind of explain this to patients is this imagine that you go to a gas station and. You’re getting your drink at the gas station and you see somebody come in with a petty theft at the gas station. You may be the whistle blower that alerts the police to come, come rush onto the scene, you know, take care of the situation. And once everything is OK and under control again, then the police are able to go in and everything is back to how it was. And OK, again, that’s similar to how these drugs, these immune checkpoint drugs work. So just imagine when your body. The job of the immune system, you know, one of the jobs of the immune system is to recognize things which shouldn’t be in our bodies as foreign, attack those, you know, destroy them and get rid of them. So if your body has a cold, the common cold virus, for example, your immune system recognizes that virus shouldn’t be there. It like kind of whistle blowing the police it calls the immune system to that area has the immune system to go attack that virus, and then when everything is clear, once again, these immune checkpoint markers, PD one is when we hear about CTLA four, they signal to the immune system. Just like the cleared situation of the gas station. Everything’s OK again. The virus is gone. You can go away and go about on your business. So tumors are very smart. Tumors also shouldn’t be in our bodies. We’re not born with them. So in theory, the immune system should be going after them as well. But the tumors get very, very smart and basically say when that whistle is blown and the immune system recognizes, you know, that the tumor shouldn’t be there, the tumors put up these checkpoints, which say, “Hey, everything is OK, you can go about your business. No need to come and attack me,” and what these immunotherapy drugs do is they kind of block that signal and basically prevent the immune system from, you know, saying “everything’s OK” and allow the immune system to stay active income after that. So you can kind of see that kind of illustrated here. So the idea of immunotherapy is that it harnesses the immune system to still recognize and go after these tumors.
You know, we’ve done well in some patients with colorectal cancer, but we all recognize there is much room still for improvement. So much research is going to understand and bring better therapeutic treatments to our patients with colorectal cancer to hopefully offer them more benefit. You know, this involves learning how we can initiate an immune response to attack the colorectal cancers, to understand the role of the microbiome. So in other words, how the bacteria which are already in our bodies and in our colons interact with the immune system and may affect the response to immunotherapy and to identify markers, which can help us identify patients who may or may not benefit from certain immunotherapy treatment combinations. With the ultimate goal to extend the benefits of immunotherapy to all patients with colorectal cancer, and not just the patients who have these MSI high tumors.
Arthur Brodsky: So thank you, Dr. Morris, for that great overview of colorectal cancer. I thought it did a really great job of showing how what the state of the field is now, especially with respect to, you know, not every cancer is the same in really figuring out what’s going on in each patient’s tumor is so crucial to figuring out what treatment will work best for them, and you know, like you said, most of the some of the patients one with the MSI high cancer immunotherapy works well for, but we’re still looking for the right combinations and the right therapies for the rest of the patients with colorectal cancer. So right now, what are some promising clinical trials for colorectal cancer?
Dr. Van Morris: Yeah, I mean, I think that just in general to kind of step back, this is both a question using immunotherapy, but also kind of using something which we call targeted therapies. And these are some of the more exciting trials that that that are particularly excited me in the past year or so have been ways to target mutations and proteins, which turned the cancers on to kind of grow and divide. So, you know, each patient’s colorectal cancer may be different in terms of the various mutations which are present when these mutations are present, it’s kind of like an on switch that that makes the cancers grow, divide and spread, and what we’re learning are that there are new drugs coming out, which can potentially target individual mutations for patients with different subtypes of colorectal cancer and hopefully turn those off. One of the very exciting things we know that one of the most common mutations in patients with colorectal cancer is a gene called Korus, and, you know, the holy grail in GI cancers for four decades now has been, you know, finding a drug which can target crass, and we just have learned in the past two years there’s a certain type of crass mutation called a G 12 C mutation, and there are treatment combinations which can effectively treat that. So have you asked us five years ago, is there? How do we treat KRAS mutated colorectal cancer? The answer was with chemotherapy, but I think the paradigm is really changing. And the idea that we can hopefully target signaling of what we know is a major driver of colorectal cancers is changing.
We’re learning as well. There are other drivers which make colorectal cancers kind of grow and divide HER-2 new is one that we all that we know for years has been an issue in making breast cancers and stomach cancers grow and divide in recent trials are showing, you know, response rates in the 40, close to 50, percent range with new drugs. With that BRAF, that’s another a very BRAF mutations happen. You know, the prognosis for these patients, unfortunately, is very, very poor, and just in the past two years, we got the first FDA approval for drugs, which specifically target BRAF. So multiple trials are coming out, you know, that are giving patients non-chemotherapy alternatives that are effective in treating patients in the setting of kind of we alluded to earlier patients with MSI high tumors just last year. A trial came out that compared immunotherapy to chemotherapy directly, and similarly, there we saw that immunotherapy. Improve survival for patients with MSI, high colorectal cancers compared to chemotherapy. There are some promising trials, I think, looking at immunotherapy combinations. So taking those drugs I was talking about earlier that don’t work and another themselves in patients with microsatellite stable colorectal cancer and try to add new drug combinations kind of to that. And early on, we’re seeing kind of some exciting results, but it’s important to see these data mature to make sure that the initial signal we’re seeing really is extending benefit there.
Arthur Brodsky: So really quick before we move on. You mentioned BRAF as an important pathway. I was wondering if you could just explain a little bit more about that.
Dr. Van Morris: Yeah. So when patients so BRAF mutations, these also kind of like heroes that I talked about earlier. When you have a BRAF mutation that makes these cancers grow, divide and in the case of colorectal cancer, oftentimes spread to sites that were not typically used to seeing in our patients the bones, for example, the brain, you know, oftentimes. So we’re see these more aggressive cancers, you know, when the patients have colorectal cancer, that’s driven by a BRAF mutation. We know that chemo doesn’t work very well. And several years ago, a large international study showed that when you use a drug that blocks BRAF and kind of shuts it off called end crafted and you combine that with a drug called cetuximab. So there’s two drug combination patients did better than if they got a standard regimen for with chemotherapy for patients, four that’s commonly used in colorectal cancer. The problem is that even with that regimen, even though the survival improves, patients stayed on that study for only about four months. So while there was an approval like I mean, when you step back and look at the forest, the treatment only kind of held the disease down for an average of about four months, and you just look at that and say, even though that’s a baby step forward, that’s still not acceptable. So speaking of clinical trials, we’re interested here in at MD Anderson. We actually have a clinical trial that’s enrolling at MD Anderson that is using those two drugs, the IND crafted cetuximab and then adding immunotherapy to that in patients with BRAF mutated microsatellite stable colorectal cancer, and we’re still enrolling on that trial at MD Anderson. We’re very excited about what we’re seeing, and that trial will actually become a larger randomized study across the United States next summer that’s supported by the National Cancer Institute with the goal of using immunotherapy in a in a microsatellite stable colorectal cancer setting. Here, the BRAF mutated patients to hopefully improve survival outcomes. And so that’s just one example I think of many, which are promising for kind of novel new immunotherapy combinations for our patients with colorectal cancer, hopefully to do better.
Arthur Brodsky: It’s great to hear that there are so many promising potential strategies being explored for these patients, and then just again, before we go there, quick definition, which I think will be really important to clarify. You mentioned tumor mutational burden. What is the difference between that tumor mutational burden or TMB and tumor disease burden? And how are they how does each potentially serve as a biomarker that can guide someone’s doctor to determine if immunotherapy might be right for them?
Dr. Van Morris: Yeah, no. This is a really good question. So tumor mutation burden is, is this way that we characterize tumors by, you know, within a given patient’s tumor, how often are you seeing that the DNA is mutated? The idea there is that the more mutations that in theory, the idea is that the more mutations that you would see, the more opportunities the immune system has to recognize that, hey, something’s not right there, and I need to go after that. If a patient’s tumor doesn’t have a lot of mutations, there’s just fewer opportunities, potentially for the immune system to recognize that. So we know that in patients with MSI, high tumors that I talked about earlier, these patients have very, very high tumor mutation burden. And that may be one of several reasons why the immune system and immunotherapy response so well in this setting. Last year, the FDA decided to approve the use of pembrolizumab for patients with a tumor mutation burden greater than 10, and when we’ve actually looked at that in colorectal cancer, we’ve seen that. That actually, despite being FDA approved, doesn’t really show strong benefit specifically in patients with colorectal cancer and potentially if oncologists are using immunotherapy based on that FDA approval and colorectal cancer, when we know it doesn’t work in and of itself to use immunotherapy patients might miss the opportunity for more promising other clinical trials. So, you know, I think in our practice, or at least in my practice, I don’t routinely use tumor mutation burden. If a patient isn’t MSI high for immunotherapy, rather, I want to do everything I can to find a personalized combination clinical trial for them that scientifically and clinically may make more sense to hopefully help benefit them.
Arthur Brodsky: It’s great to hear, and so another patient just asked a question who unfortunately was just diagnosed with a tumor in their colon and is considering their options right now. How can someone go about seeing what their options might be and potentially enrolling in a clinical trial?
Dr. Van Morris: Yeah. So I think that question the first question, that conversation always needs to start with that patient’s oncologist. You know, we believe that in patients with stage four disease, all patients should have their tumors tested for these various mutations and other alterations in their tumor, which can help hopefully direct them to two personalized therapies. If that oncologist has access to a clinical trial, that makes it makes sense in their particular case, by all means, I think that that should be pursued, and then, if not, then I think it becomes a question of, you know, going to maybe perhaps a larger academic center which may have access to other clinical trials. I also want to highlight there are, you know, many patient advocacy groups which do a great job of working with patients and helping identify sites in trials that may benefit from them, fight CRC, colon cancer or among two of many, but also the. The National Cancer Institute runs a great website, www.clinicaltrials.gov and that lists all of the clinical trials that are ongoing in the United States that that patients can look into as well. So there are many resources and opportunities to find the right trial for them.
Arthur Brodsky: So, you know, we’ve mentioned mutations a bunch of times and clearly, they play a central role in cancer, not only the development and the progression of the disease, but also how it’s treated. So how are these mutations identified and are there any particular tests that are used?
Dr. Van Morris: Yeah. So there are many commercial tests which are available, and this can be done both on either a biopsy that was done when a patient was diagnosed. Sometimes this can be run on a patient may have had cancer years ago and had that removed from their bodies and later goes on to develop stage for disease. That tumor can be sequenced as well, but also like really interestingly, in the past five years or so, the ability to even from a blood sample to get information on tumor mutations, we can actually detect that from the blood as well, and that matches very well to tissue. So we can do it from tumor, but we can also do it as simply in even more quickly, oftentimes with a blood draw.
Arthur Brodsky: So Marina asks, “Can you combine an immunotherapy with another treatment for microsatellite stable or MBS’s colorectal cancer with a high TMB to improve treatment? Are there any combinations that are currently approved to do this? Or would this be something that a patient would need to enroll in a clinical trial for?”
Dr. Van Morris: Yeah, this is a really great question, and Memorial Sloan-Kettering, they looked at this question and published, you know, kind of a short series earlier this year in the New England Journal of Medicine, and they looked at patients specifically with microsatellite stable disease, and they compared their outcomes of patients with microsatellite stable colorectal cancer who received immunotherapy if their tumor mutation burden was high and if their tumor mutation burden was low, and what they found were that the outcomes were exactly the same for it, no matter what your TMB was, if you were microsatellite stable. There’s one small caveat there. There’s beyond the MSI high. There’s about one percent of patients who have who are who are not MSI high, but have something called a pull e or a pull de mutation. And this is something that’s tested for in the mutation test that I talked about, I was talking about earlier. But patients who have these poorly informed gene mutations have very, very, very high tumor mutation burden and respond very, very well to immunotherapy. So in the absence of a pull de mutation in the absence of microsatellite instability, I personally choose not to use immunotherapy off label, but rather to try to find a combination clinical trial for a patient, and I think that I mean, the unfortunate reality is that still colorectal cancer claims too many lives, and because of that high unmet need, pharmaceutical companies and scientists and clinical oncologists like myself are so, so interested in and pressing to find novel combinations. So there are many options seeking to help find what are those effective combinations for patients with MBS’s CRC. So there certainly are many, many options
Arthur Brodsky: Definitely agree with you that there are far too many people succumbing to this, this disease, ad so most of them, you know, are treated, obviously, and then the cancer recurs, which sometimes can make it harder to treat. But it’s these remissions that that prove potentially or very deadly in a lot of cases. And one attendee asks, “If my husband has a remission of colorectal cancer, does he need immunotherapy for prevention of a recurrence?”
Dr. Van Morris: There’s not any evidence that we have that it works at this point in time, but I think that this actually offers me the opportunity to kind of go back to this idea of circulating tumor DNA, which I which I talked about as a that we can detect from the blood. The presence of cancer, and that’s, you know, in the in patients with stage four disease, how we can define mutations, but we can also use circulating tumor DNA in patients who are who are in remission. To identify patients who may still have microscopic levels of tumor cells present that that that are releasing their contents into the bloodstream as detected by circulating tumor DNA, and, you know, even before you would be able to detect that on a CT scan, and there are trials which are now ongoing and being planned and forthcoming as well, which are looking to identify patients who are at high risk for their cancer coming back as defined by a positive circulating tumor DNA test and use immunotherapy or other kind of targeted personalized therapies for those patients, and we have those trials at MD Anderson, and those trials are also being conducted across the United States. We actually have a trial enrolling at MD Anderson right now in that setting. Looking at the BioNTech Emory vaccine that’s personalized for each, each person, each individual person, everybody gets their own mRNA vaccine if they’re ctDNA positive to try to understand better, you know, you know, kind of new techniques, new technologies and strategies for harnessing the immune system to fight cancer.
Arthur Brodsky: I’m sure there are many people waiting for those results, and hopefully with positive results, they could be expanded to help many, many others, and so, you know, we were talking, you’re talking about remission of a cancer that has already occurred, and one of especially high risk for it, and so with respect to that, you know, we’ve been talking about microsatellite instability, which is kind of a result of a tumor ending up genomically unstable, and related to that, I was hoping you could talk a little bit about Lynch syndrome, which can which is kind of, I guess in a way, a cause of that or can be a cause of that. So first, what is Lynch syndrome, and second is immunotherapy the recommended treatment for cancers caused by Lynch syndrome?
Dr. Van Morris: Yes, it’s an awesome question, and I appreciate the opportunity to talk about this, too. So Lynch syndrome is a hereditary condition where the genes, which so kind of going back sometimes when the when cells replicate the DNA can sometimes have develop a mutation if that replication isn’t perfect. Sometimes the DNA can add in more things into the DNA sequence that don’t need to be there and that can cause mutations as well, and normally, when those additions happen, we have this mechanism to kind of erase it and fix it and repair it, and the Lynch syndrome, that mechanism to kind of erase and repair and fix those insertions into that shouldn’t be there into the DNA goes away, and so, patients kind of lack that proofreading mechanism and that creates more mutations. So for patients who have the Lynch syndrome, Lynch syndrome accounts for about, you know, less than 50 percent of all MSI high tumors. But the answer to that question is yes. Patients with the Lynch syndrome, if they have stage four disease, should be treated with immunotherapy as opposed to chemotherapy based on that clinical trial that we saw earlier. Very interestingly, though. Dr. Kasia Ludford, a colleague of mine here at MD Anderson, just presented data at SVO the European Cancer Conference last month and showed that in patients who have newly diagnosed non-metastatic early stage colorectal cancer, that that is MSI high. Giving these patients immunotherapy may eradicate these tumors without the need for surgery and even a dose or two of immunotherapy in patients with Lynch syndrome when they took those patients to the surgery. The vast majority of patients had complete eradication of their tumor by when they went to surgery. So a major question now for us is can we use immunotherapy to offer a curative outcome in patients with the Lynch syndrome, or MSI high tumors that keeps them from ever having to go to surgery? I personally think the answer to that is going to be yes, and I’m really excited about this. But future trials are looking to prove in and validate that. So we should know more in the coming years.
Arthur Brodsky: That’s great to hear. You know, now I guess, turning to the holy grail, you know, it’s great that we have treatments and are developing more treatments that can potentially help people who have already been diagnosed with cancer, but again, the holy grail would be to be able to prevent it before it even arises, and so especially with people with Lynch syndrome who are at high risk of developing cancer, some of our some of our attendees are interested or have heard about and are interested in an ongoing clinical trial testing a new vaccine to prevent cancer in patients with Lynch syndrome, and they’re also interested in how they can learn more and potentially enroll in that trial.
Dr. Van Morris: Yeah, so I really don’t mean to keep plugging all of my colleagues, but I’m really glad you asked this question. So Dr. Jason Willis at MD Anderson is the national PI of a trial looking at using a vaccine which covers really the most, all the most common mutations that the immune system recognizes in patients with Lynch syndrome. Patients get to vaccine a vaccine at two different points in time and the goal here is number one to look to make sure, are we stimulating the immune system to potentially recognize that and then following these patients to make sure that the cancers don’t come back? I think scientifically, this is very exciting. I also like it because not only does it treat patients with the Lynch syndrome, who survivors who have already who have already survived one cancer from hopefully preventing another second cancer from developing, but it also allows providers patients who have the Lynch syndrome but have yet to be diagnosed with any cancer to participate, as well to hopefully prevent these providers from ever getting a cancer as well by this really scientifically interesting vaccine. If patients are interested, they’re welcome to reach out to Dr. Jason Willis. He’s on Twitter, or me, and we’re happy to help that patient find the opportunity to participate in that trial, which is actually enrolling across the United States.
Arthur Brodsky: Thank you very much for sharing that information, Dr. Morris, and for your overall informative conversation. And I’d also like to thank MD Anderson Cancer Center for supporting this program as an institutional host partner. You can find resources from MD Anderson and the resources section on this page, and thank you again to our audience who asked a lot of great questions that unfortunately we weren’t able to get to all of them, but I would like to remind you all that we will have a blog that we will be posting after the event, not directly after, but in the future, that hopefully we would be able to get to many of these questions. Thank you again, Dr. Morris.
Dr. Van Morris: Thank you.