Martha Raymond: Welcome to today's live broadcast and Educated Patient webinar: GI Cancer Therapies Part 3: Immunotherapy and Targeted Therapy in GI Cancers. I'm Martha Raymond, Executive Director of the GI Cancers Alliance. We are pleased to bring you this webinar presented by CURE in partnership with the GI Cancers Alliance and sponsored by Amgen Oncology and Elevation Oncology. We encourage you to ask questions during the event, which you can submit by typing them in the Q&A box you see on your screen. Now it's my pleasure to introduce our panelists for today's webinar. Dr. John Marshall, physician, Executive Director of MedStar, Washington, DC integrated hematology oncology division, director of the Reusch Center for the Cure of Gastrointestinal Cancers and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University. Dr. Tanios Saab, leader of the gastrointestinal cancer program at the Mayo Clinic Comprehensive Cancer Center, and vice chair and section chief for medical oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona. And Dr. Gregory Botta, associate professor of medicine at the University of California, San Diego School of Medicine, and medical oncologist specializing in treating solid tumor cancers of the gastrointestinal system at San Diego Health, San Diego, California. And now it's my pleasure to turn the microphone over to Dr. Marshall, our moderator.
John Marshall: Martha, thank you so much. And thanks for everybody who has joined us. For those who don't know, Martha runs something called the GI Cancers Alliance, which is the largest group and collection of GI advocacy, GI cancer advocacy groups really in the world. And we're so excited that she is joining us not only to introduce this at the beginning, but give us some level setting perspective at the end with helping with our Q&A. So we want our audience to interact and enter questions into the chat. And we will be happy to cover them at the end of the hour. So thanks to my co-presenters who have joined me from across the country, we were comparing weather, mine is still the worst compared to Phoenix and San Diego, but they're having sort of down days too, with temperatures in the 60s, but will will spot them that. This is the third of three in a series that we have done. And the first one was really all about what is molecular testing in general for cancer, how is it done? What is a liquid biopsy? What's a tissue biopsy? What's doing gene sequencing? How do you get a sample and just the mechanics of the testing, most of our patients understand the CAT scan and a blood test. They didn't really understand much about genetic testing. So we dived into that topic. And then the second was fairly specific examples of where precision medicine has translated into therapeutic changes how we're using this data into in clinic every day, day in and day out. Before we went live, we were discussing a case and talking about gene mutation that patient of mine had that we're trying to incorporate into a strategy. So we're constantly learning from each other as we grow in our knowledge about these molecular tests. But today's event, the third of the three is really more focused on the therapeutics and the new areas of both immune therapies and targeted therapies, which have emerged really, as a sidelight of this precision medicine effort. We've gotten a lot smarter to quit treating all patients with the same therapies. We it's no longer one size fits all. And we are increasingly aware that some patients benefit from certain treatments like immune therapies, and some patients don't. And so our biomarkers or molecular tests help us with that. But we thought it would be great to finish off this series with a really a deeper discussion on what we're talking about what is immune therapy, what is targeted therapy, and the like. So Greg Botta has joined us as you know, from the beautiful west coast, he's probably got a view of the ocean out his window there. I'm jealous of that. I've got the Washington National Flight Path, so you don't you can't have that one. But nonetheless, we're going to let you go and kick off things by giving us sort of your high level cocktail party elevator clinic level description of what the heck is immune therapy. Take it away.
Gregory Botta: Thanks so much, Dr. Marshall. Thanks for having me today. Yeah, so you know, I tell all the patients immunotherapy is a cancer treatment that gets your immune system, your own immune system, to help fight the cancer. And you know about your immune system, you know, it fights viruses and bacteria and parasites, foreign invaders in your system. The issue is, is that cancer from you is not necessarily foreign to a certain degree; it is you, it comes from you, your immune system is not necessarily meant to attack and kill itself, that's autoimmune disease. However, there are some times where the cancer can get to a point where it does look different, and your immune system can take care of it. And in that case, sometimes what our bodies need is just a little bit of help a little push, to try to get the immune system up and running and trying to attack and kill these cancers. Now, immune therapy is is a type of targeted therapy, we're going to talk about that. So I kind of put them under the same umbrella. But basically, what we're doing is we're getting our white blood cells, our lymph nodes, our organs and tissues that make up our entire immune system to try and turn its attention back on to the cancer, trying to control it, contain it and ultimately kill it. Now, cancer itself has figured out a lot of ways over the millions of years it's been around on how to hide from the immune system, how to prolong its life. And when it does that, basically, it creates genetic changes that makes it less visible to the immune system. It has proteins that turn off the immune cells on its surface. And it also changes its environment around itself to protect it from the immune system attack. And what we're trying to do now is tease out the intricacies of that defense system, and trying to get our immune system to actively attack and kill these cancer cells.
John Marshall: You know, I always use the "Star Wars" analogy: everybody's got one where it's the force field around the evil Death Star, the cancer and that force field we call PD-L1 and Luke Skywalker is the T cell out in his X Wing fighter trying to get in to kill the cancer and Han is on the planet to take out the forcefield. And then, and then Luke can can get. Do either of you have a cute way of describing ... it couldn't be as cool as mine, of course, but is it you have a cute way of describing immune therapy to people?
Gregory Botta: It's definitely not as cute as that. Yeah, I was talking about camouflageor a blanket over its ID we're trying to pull the blanket back. But yeah, I have almost a movie reference yet. I
Tanios Bekaii-Saab: The way, and it may not be as cute as well...But I mean, I think about it is if you think about that, the cancer cell and the immune cell linked, it's almost like a bear hug; they're stuck. And what these inhibitors do, essentially, they just unlink, they remove the cell a little bit away from the immune cell a little bit away from the cancer cell, and shut down the capacity for the cancer cell to neutralize, through this bear hug, the T cell. And this is when the T cell becomes you know, perhaps, you know, to your another analogy of "Star Wars," will get the mean cell out. It's really I mean, ultimately, it's just unlinking. And linking those two, that's what makes it invisible. And you know, the one thing and I that's actually discussion from this week with the patient ... one of my patients was pretty concerned about their own immune system, saying, "you know what, my immune system is perhaps weak. That's why I had cancer." I said, "Well, that's actually not how it happens. You know, of course, having a weaker immune system will predispose your will put you at higher risk for cancer, your immune system is pretty well preserved, it's the way it is able to see or view the cancer, it's not that it's weak." Because the concern was from that particular patient is, you know, "Can I go through chemotherapy? Can I go through other forms of therapy with my immune system being weak?" We're learning as we're essentially discussing those about what is the value of these immunotherapies? What do they do? And how does the immune system interact overall with the with the cancer and with the host, with the patient?
John Marshall: Greg, let's go back a little bit. We've been very basic through this series of sort of, you know, 101, how these drugs work and how the strategies go. So maybe walk us through conceptually what you classify as chemotherapy, and how they work versus say, well, we'll talk about targeted therapies in a minute but, but immunotherapy and sort of distinguishing how they in the end, help treat cancer.
Gregory Botta: Yeah, you know, I think broadly, you know, I think everyone knows what chemotherapy is until you actually say what makes up this group of drugs. And usually what I say is that these are the ones that basically attack the proliferating cells, the rapidly growing cells, basically cell cycle. And we know that based on its efficacy, it can work quick, because...
John Marshall: Go a bit more basic, I'm sorry to interrupt. So when we're talking cell cycle, the machinery of replicating the DNA so that you can become two cells, making copies, etc,
Gregory Botta: Right. We know that you know that every cell in our body needs to divide to continue living. And when it does, that single cell will duplicate itself and pull apart into two other cells. So that's the cell cycle. And that's proliferation or that cell growth. And then what ends up happening is cancer does that, does it very rapidly with reckless abandon, and without breaks. And when it does that, you get multiple daughter cells and son cells. And basically all these cells grow up in a huge family. They're all they're all dysfunctional. What ends up happening with chemotherapy, and I kind of think about it as a bicycle wheel, going fast down a hill, you're sticking a broomstick in that bicycle wheel, and you're trying to shut it down trying to stop that division, trying to stop those cells from growing. And chemotherapy does this through chemicals that, you know, were literally manufactured from world wars and textile industries. And we use them because they work — they stopped rapidly growing cells, but our patients understand this as well, right? The rapidly growing cells of our nails, our hair, our nerves, all of them are affected as well. So that's kind of chemotherapy broadly.
Gregory Botta: I think our audience ought to remember, too — sorry to interrupt, again — is that we cure cancers with traditional chemotherapy, right? There are many cancers where that's been successful, and it has we GI cancer doctors, yes, there are a couple of windows where chemotherapy is probably curative in the microscopic setting something like that. But it doesn't cure our diseases, which is really what we're trying to get to is something like that. Maybe Toni, maybe pick on you on that a little bit is, why doesn't it cure our cancers? Why? If you have the answer to this, you get the Nobel Prize, and you can stop working. But what's your theory on why chemotherapy in the end doesn't get the last cell?
Yeah, I mean, it is interesting that chemotherapy seems to have a dichotomous effect, whether it's used in the early stages, after you clear the more visible tumors, let's say in a patient with early-stage colon cancer, where we know that 5-FU, which is a drug that has a low response rate, and the more advanced setting increases the chances of a cure by an absolute 10 to 15%. That's a cure that's adding to a cure. So yes, we do know that chemotherapy does cure cancer, the problem becomes one actually, cancer multiplies and spreads in lots of different places, in hiding, or in plain sight. There's, as we understand, and more and more I know, you've talked in the in the last two presentations about the liquid biopsies, which is the summation of all these tumors shedding a lot of these DNA from various what we call clones, since we're gonna stick to the Star Wars theme, right? You know, cancer is multiple clones, not a single clone, it can start, you know, with just a single clone, and then as cancer multiplies, it becomes quite heterogeneous and very diverse. And it's its level of aggression, and its molecular diversity and genetic diversity makes it very tough to eradicate. But there are also other factors. So chemotherapy, which is a very nonspecific now, I would say that with a caveat, right, very nonspecific way of killing cancer cells, as Greg mentioned, it's mostly, you know, geared towards halting and disrupting the machinery at large, rather than a very specific target. But that's not completely true, right. We do know that chemotherapy has targets I mean, 5-FU or capecitabine are target therapies. I mean, they have specific targets within the cell. Unlike, you know, unlike immune therapy or target therapy, you know, their targets, can be affected quite significantly, you know, by that level of diversity and heterogeneity, which makes chemotherapy unlikely to achieve a kills and you know, saying, frankly, with immunotherapy and target therapy, as we talk also, we don't cure all patients. But it gets us closer to a cure, because we're hitting that Achilles heel more accurately than just you know, trying our luck.
John Marshall: So, Greg, I think so many people are hot on immune therapy, not only are you hearing the ad every night during Jeopardy, but you're you know, we're we hear stories of people, we see front-page, "New York Times" stories on rectal cancer patients where immune therapy makes it all go away in the right patient. So what's your thinking about how immune therapy is overcoming these clones, or maybe being able in the right patient have these much more dramatic positive results, compared to what Toni was describing for chemo?
Gregory Botta: Yeah, you know, and I think this kind of goes back to the selecting the right patient for the right treatment. And I think, you know, chemotherapy, we give kind of you have colorectal cancer, you get chemotherapy, and that's just everyone's in the same bucket. But what we're starting to realize is that there are patients in certain buckets where a different treatment will work better, or might get them that cure, and it's exactly what you talked about with these rectal cancer patients that were treated. So you know, about 3% of patients with rectal cancer, have DNA deficient mismatch repair: a biomarker that immunotherapy will work. And in fact, they said, "All right, instead of treating rectal cancer, traditionally, where we give chemotherapy and chemo, radiation and surgery put you through all the side effects, and a surgical operation at the end. Let's take this group that has this biomarker, give them that immunotherapy kind of see what happened." And of course, this was a small trial, and it's still kind of the data's coming out. But what they were able to say was that 12 of these patients had a complete response on a single immunotherapy. And as we can know, with immunotherapy, it's much more tolerable than chemotherapy, the side effect profile is different and you can't have side effects. So immunotherapy can have side effects. I tell patients, that's all the time, but it's different. And it's not as high a percentage, you know, we think about chemotherapy side effects, you know, 80% 90% of the time with immunotherapy, you'll get maybe 10% of the time 15% of the time. So if you select the patient for the right treatment, you can get a really good response. And I think that that's where a lot of oncology needs to get to is making sure we have characterized our patients as deeply as possible, so that we can give them the best responses.
John Marshall: So not for everybody. And I think that is a good point. And what we're all trying to do is learn who those right patients are, we're all doing studies combining, trying to optimize identify the right patients, because you know, you can backfire, you can give a medicine that's going to not help somebody. And as you say there, there are some serious side effects. I've been reflecting on our own hospital service here and immune therapies being used in all cancer GI cancers. And so at any one time in our hospital, there might be four or five patients who are having these serious side effects from immune therapy sort of autoimmune response themselves, that the immune therapies have woken up, that the body had shut down somewhere along the way in their lives. And it's kind of rekindled. And so I think that and so we do need to take that part seriously. Toni, you know a lot. How long does one need to be on an immune therapy to be sort of an optimum benefit?
Tanios Bekaii-Saab: That's a great question. So the short answer is: no one knows. The trials that at least with the MSI... So let's take a step back. So there are there are a number of trials that looked at immunotherapy in different GI cancers, if we take the nonspecific indication and more specific for colorectal cancer with MSI-high, so those are the hyper-mutated hyper-inflamed tumors, where the these immune therapies, let's say PD-1 inhibitors ... or PD-L1 inhibitors have shown just some, you know, incredible responses in about a third to 40% of their best patients. Those studies have limited exposure to let's say, pembrolizumab to two years. After two years, they stopped. But if you look at the curves closely, you can start seeing that the maximum benefit start shaping out at about six to 12 months. And the question is whether you really need to expose patients beyond that; that has not been answered. But it is clear that even after you stop at two years, the benefit doesn't stop for most patients — the benefit remains and we all have patients you know, who were exposed to six or nine months and had to stop because of toxicities. And their benefits remained for years and years and years, ie. remission. Now for other cancers where so the non-MSI high, let's say the PD-L1 positive gastro-esophagus cancers, where is another indication for immunotherapy (that's) not true for colon, say, or pancreas or others just for GE cancers, that hasn't been really eliminated in the more advanced setting, but when to stop with the understanding that for most patients, you know, unfortunately, the responses stop at some point anyways. (They're) not as durable as the MSI-high (cancers). So let's say two years is the cutoff point on clinical trials. But frankly, patients can benefit, even if it's if it's less than.
John Marshall: And, Greg, if you've had one before, and your cancer grows, are you done? Or is there a rationale for trying a different one or a different combination?
Great, great question, I think we're starting to realize that you can try and recapture immunotherapy responses by switching classes or combining with additional immune modulators or even chemotherapy. You know, this is very cutting-edge and early data that's coming out. But you're starting to see that by either combining two immunotherapies together and initiating a response or switching from PD-1 or PD-L1, or adding a chemotherapy backbone in, what you're doing is you're disrupting that immune environment, that defensive mechanism or variety of ways you're attacking at it from all different angles with different tools. And by doing that, you're able to initiate a new response. And I do definitely think that this is going to be some information is going to be coming on when to do that, how to do it, which patients to think about it doing it.
John Marshall: That's great. Let's shift gears. So Tony, I'm gonna pick on you to sort of lead off on this one, if you don't mind. And this is the concept of targeted therapy. And I know, it's something that's been around for decades in some form, as you say, chemo is in essence, a form of targeted therapy. But we do have this separate kind of classification as we think about new therapies for cancer. So maybe walk us through what this means what it's all about.
Tanios Bekaii-Saab: So, targeted therapies, it refers to molecular, or genetic basis for targeting cancer in a more specific manner, more precise manner. So if we think about this precision oncology, meaning that you have a target, you have it, think about it in a way, you know, when when if you have a driver, we call them driver mutations or driver alterations. So the responsible for driving that truck, that car, the whatever that driver is, is responsible, essentially, for getting the car from point A to point B, if you can target that specific driver, if that driver is the main driver for cancer bad, then you shut down the whole machinery of the cancer essentially kill cancer, reverse the course, that's the whole principle is, as we started learning more and more about what drives cancer, what drives these cancer cells specifically into acting badly into multiplying into spreading, and you can actually specifically shut down that one driver, if it's the main driver, then he essentially shut down the whole cancer that started in, you know, in the late 90s 2001, the story with, you know, Gleevec with Imatinib and leukemia, and then GIST...
John Marshall: Tamoxifen and breast cancer, I mean...
Tanios Bekaii-Saab: Yeah, these are targeted therapies, your driver, your main driver. Now, this gets a little complicated, of course, because it's not always true that the cancer cell has only one driver without a assists, without redundant mechanism that allows the cancer cell to overcome ultimately, the pressure on that one driver. But for many, we're finding out that this driver is essential. And if you can find it and shut it down, you get the cancers, the cancer is actually closer to remission. In some cases, even we see these durable remissions that are the equivalent of a cure in few patients. As we learn more and more about the assists and other drivers, then we you know, we start learning more and more about how to select better patients how to apply dual targeting, or salvage targeting. So meaning, you know, after one target being shut down, fails, you know, then you go to the next one in lung cancer, they've done that beautifully, right? I mean, they've gone after the target multiple times in different ways. We learned this a little bit more now in colon cancer, for example, you know, with dual targeting with targeting wrasse targeting BRAF. So understanding frankly, you know, the main drivers and the cell Which, you know, pathways are the assist is getting us closer to this more precise, a way of targeting cancer and and its aggression.
John Marshall: Greg, let me kind of come back to you this this era of targeted therapy, to me has really transformed the way we think about cancers in general. I mean, there's part of me, that feels, I don't know, I don't know if it's lucky or not. But a lot of these cancers fall into categories, when you start to do molecular testing that there are common mutations, common abnormalities, across 100 People with colon cancer across a bunch of people with gastric cancer, pancreas cancer, etc. And so and the impact that's having on everything, clinical trials, treatments for different kinds of patients, and then patient and physician confusion about what the right treatments are, for their kind of cancer. Could you maybe reflect a bit on either how you guys handle that information, how you test for it, how you categorize your patients, in that specific GI cancer, against this sort of one size fits all, strategy?
Gregory Botta: You're exactly right. That the one-size-fits-all strategy in today's day and age should only be used for those patients in which you can't get characterization for and you're just kind of left to we have to treat now, you know, some a patient in the hospital that needs treatment right away, because they're having difficulty breathing or, or liver dysfunction. Most patients today should be characterized, and whether that's with DNA evaluation of the tumor, blood screen stream, next-generation sequencing or germline sequencing, what we need to do is we need to start finding out what personally makes your cancer your cancer, we know everyone on this planet has different DNA, all different genetics, so all of our cancers are going to have different genetics, they may come from the same organ. But ultimately, each cancer is identified as an n of one for that patient walking through the door. Now, they might share that mutation, that common mutation with other people who come through your door as well. And you're right, we can start grouping these patients. And it's created problems and clinical trials, frankly, right, we have low number of patients to enroll. And we can actually open the trial because we don't see enough of those patients at center A or center B. And we're not really sure if we have you know, something really of potential worth. And I think that you know, that's that's the clinicians trouble and our to our dilemma, but it's our job to find out which ones work for our patients and get them to them. Because they do make real differences 20% 30% responses, and even in the patients who have MSI-high (cancers), although maybe in colorectal cancer, it's 15%, somatic and germline together, you know, you can avoid chemotherapy, radiation and surgery, and it's just unbelievable. If you select and find the right mutation, what were able to deliver, and I just see that becoming more and more prevalent in the practice of oncology.
John Marshall: And do you find that most of your patients know their, you know, tumor characteristics? Or? I mean, is it in their phone? Do they carry around their genetic report with them? How are how are we all keeping track of this information?
Gregory Botta: Great, great question. Yeah. So, you know, after they leave our clinic, they have their genetic information, or at least we're testing for it. You know, I, there's so many times where there's something just sitting there a gift for the patient, a low-hanging fruit for you, and no one has turned over that stone and look to see if it was there. And when you do that, you can say, wow, look, we have something to go on here. You know, the aggregation of that data is a big issue. And, you know, there's there's billion dollar companies out there aggregating this data and trying to deliver it to the clinician with some sort of explanation on how to use it. And truthfully, it's a it's a high hill to climb if you're not familiar with molecular biology and immunogenetics. But it's something that is unfortunately, or fortunately beginning something that's going to be part of our everyday practice. So yeah, I think that our EMRs or electronic medical records could do a much better job of integrating genetic data. We're working on that. But also at the same time, you know, our patients do need to have that that report and they do need to take it as they take their scan and their pathology report to their console or their second opinion, you need to have that genetic information.
John Marshall: So Toni, to that end, if my tumor has RAS mutation at the beginning, or or maybe I heard to abnormality that always going to be that way. Or you talked about clones earlier. Could it change over time or is what you have what you have?
Tanios Bekaii-Saab: So it is interesting. So the if you have a RAS mutation, it's likely to stick with you. Although now that we're learning about ways to target KRAs, the starting with G12. See, what we see some of the drivers is the appearance of other RAS mutations, or other alterations that perhaps drive resistance her to is very interesting EGFR, the same. HER2 amplification, predicts for benefit for her to target therapies, but also predicts for lack of response for EGFR target therapies. But most importantly, what we're finding is, for some patients, you get fantastic responses where her two is the major driver, and you don't develop a significant mechanisms of resistance. And then ultimately, you have lasting responses in this for the very few patients. For most patients, you know, some elements drive resistance. So some of them are actually interestingly, and we see that in some patients is, there's a mixture of her two clones, and those that either are low expresses, or non expresses refer to hiding somewhere. And when you actually eliminate the major, HER2 clones, then you see this rise of clones that are less driven by HER2 or less, you know, less sensitive to her do we see this, by the way, when we do the sequential liquid biopsies, we see these waves of criminality, the more difficult ones are when you start seeing actually co-occurrence of these alterations of with with RAS or MET or other alterations. So other genes that just, you know, hijack, essentially, the I say the bad pathway is to drive cancer cells in different direction, the despite the fact that you have expressed her to others. So that's, that's frankly, becoming one of the biggest challenges with these specific targeted therapies is, even when you identify the potential driver, you got a lot of mutations that that can arise a lot of cells with different commonalities that have these resistance mechanisms that ultimately take over, right? I mean, it makes sense once you if you have, you know, three different clones, just to simplify it. And the major clone is the one you actually have a targeted agent to, you're gonna hit hard, you eliminate that clone. And then the next clone that's going to actually find this open field for it is the one that's resistant to that therapy. We know that by the way, this brings us pretty close to the to the principles that have been applied in infectious disease with Clostridium difficile, right? Patients who would go on antibiotics, cleans up a lot of these major bacteria that are that are in the belly, and then the one that actually takes over is the one that these antibiotics don't target. I mean, the same principles apply here. So you can one major clone, other clones appear. And that's, that's how, you know, this ends up being dynamic. I call this dynamic targeting, rather than a static targeting is in the demo days of chemotherapy, you know, you go all in, but you don't have this, this granular view about what's taking over and why chemotherapy stops working. And frankly, you don't even have, you know, chemotherapy to salvage the resistance pathways with targeted therapies, it's a bit different. We know these targets, we're learning more about them. And as we understand them more and more, we're going to be able to as I said, you know, go with tool targeted with sequential targeting. And that's how ultimately, you know, we continue to advance the field of target therapy.
John Marshall: Dr. Botta, what, what kind of war are we fighting anyway? So, you know, I'm reading a spy book right now about World War II. So, you know, they're they just bombed an entire city, tragically as that was, but it was it took out the city, right? So are two of them. In fact, are we fighting drone wars where, you know, the, you know, we take out a single bridge, or a single safe house, and leave everything else around it to move on, versus just blowing it all up? So could you talk a little bit about the targeted therapies that are very specific versus ones that maybe are a little dirtier?
Gregory Botta: Yeah, no, you're absolutely right. You know, chemotherapy is kind of a burden the whole city down, you know, approach and what we're trying to do is trying to send, you know, elite targeting agents into the body and find what's going wrong and take care of it, leaving the healthy tissue behind. You know, I think that we're going to be closer and closer to being able to do that focus specifically on the cancer on what the cancer has broken and fixing it, and kind of moving on with as healthy of a body as we can. And we're starting to see that in patients who have either immunotherapy or targeted agents that are very specific for their tumor, and not anywhere else in the body, where you can give them a single agent immunotherapy with a metastatic patient, and they're up walking around living their normal life, and we've turned it into a chronic disease that they have, if they take their medicine, it's under control, but it's not progressing. And it's not taking over their quality of life, you know, in the future, and what we're what we're working with now we're going to get more defined and specific targeted agents. So you know, with EGFR inhibition, you know, we started with Cetuximab A chimeric EGFR receptor inhibitor, basically half mouse half human. And now that's Vectibix. And we're looking at, OK, a whole humanized monoclonal antibody. And eventually, that might be combined with another type of cancer or toxin that will deliver it specifically to the body. And maybe that will be combined now with a RAS inhibitor. And that will all be given at once. And what we're going to start seeing is, is that our ability to get the right drug to the right person and the right organ, with low toxicity, that switch, hopefully, you will start to flip. That's what I'm looking for. If cancer ends up not being cured, but a chronic disease with low toxicity, you know, we're in a better place.
John Marshall: I mean, I'm sort of similar but with, you know, Toni's point earlier about the different clones and the different pathways. And some of our drugs are very, very specific, as you said. But then we have others, I think about regorafenib, or some of the other what are called tyrosine kinase inhibitors, which I think of him as kind of dirty bombs. And the hope was that by hitting lots of pathways, whether your cancer had a particular mutation in that one or not, you'd not only hit the bridge, but you'd hit the other bypass roads to also get across the river, anything that gets you across. And it hasn't been as successful. There's been a tension in this era of targeted therapies about the broader you get with your, your attack your drone attack, if you will, that you do pick up side effects, but we aren't really seeing that realized benefit. And it's been more as you referred to hitting the bridge twice, right? If you have the EGFR drugs, in certain mutations, like BRAF, it does better to hit the same pathway in one way twice. And make sure the bridge is gone than it is to hit something separate. But let's take a few more minutes and talk about the, as you suggested chronic disease, low toxicity from your lips, to God's ears, right, because we're still managing side effects. There are some drugs that have very few side effects, but it's not trivial. The side effects are different from chemotherapy, I think about rash, I think about liver tests, lung tests, and blood tests and fatigue, sort of chemo as you know, you're down for a day or two every few weeks with these, you can be kind of down more chronically. So you'll want to comment a little bit about how you present these agents and their side effects. And are you doing any dose modifying in a way to try and improve that, Tony, maybe you start?
Tanios Bekaii-Saab: Yeah, again, it depends, you brought the issue of No, we got the two targeted therapies in broad categories, the multi-kinase inhibitors that hit a lot of different targets. Many of them actually, many of these agents end up being a little bit more toxic. And they may not have the same infectious because again, you're hitting you think about it, you're hitting a lot of targets at a low level versus a more specific targeted therapy that hits one or two or maybe three targets at a high potent level. So the toxicities differ a little bit fatigue, I would say is a common toxicity across all these agents. And it varies between you know, the different agents in terms of severity, but always remember, you know, we always need to remember that when you're talking about let's say a what we call a great to fatigue or even a great one to to fatigue, that's every day of your life. That's something that means you know, having the post flow of post COVID fatigue, that just doesn't go away. You don't feel like getting out of bed. It takes you know, the whole day to start off. So it's not insignificant and it, at some level those dependent, but so is the activity of the drug. So it's a fine balance. And that actually is one important aspect of this. And then, you know, it all depends on on the type of target therapy. So for her to, let's say, you know, there's certainly the risk of cardiotoxicity, mostly to the to the muscle. It's rare, but it's something we keep an eye on EGFR inhibitors. Because EGFR is commonly expressed in the in the epidermis and the skin in the colon, and the intestines. I mean, they share similarities. So the toxicities end up being mostly that rash, and that diarrhea, so these are more specific, etc. So it's, it's certainly is specific to the target. And as we, you know, start to look at those multichain is those inhibitors that hit a lot of different targets, then the toxicities actually ended up being a larger and a bigger tent. Now, it is interesting that for some of the agents, it seems that, you know, the toxicities may actually go down when you start combining them. One example is, you know, the BRAFV600E mutations in colon cancer and other cancers now, but in colon cancer, specifically, when when you combine the the BRAF inhibitor with the EGFR inhibitor, you actually end up with less toxicity. There's a protective effect that when you look at HER2 inhibitors, especially the tyrosine kinase inhibitors, in colon cancer, for example, we commonly combined them with their trastuzumab. Now it happens that when you look at the different, at least tyrosine kinase inhibitors ... two different ones, to tucatinib it is very clean in terms of its targeting for her to so you actually avoid a lot of the, you know, other obnoxious toxicities on the skin and, and a little bit less diarrhea, like bath and we'll have actually both. So, again, you have to know your agent, you have to know your targets. Some of these toxicities are common across all these agents. Others are more specific to the target itself and can vary again, depending on what the target is.
John Marshall: Greg, let me give you the last word on on targeted therapies, then we'll move on to our third subject anything to add to all of this.
Gregory Botta: The only thing I would add is, is that we're starting to find out that targeted therapies and immunotherapies combined are even better in some cases, you know, and we know that with the KEYNOTE-811 (trial) that came out, you know, saying that trastuzumab helps up regulate PD-1 PD-L1 and then coming in with an immune checkpoint. So there's anything oncologists are really good at are taking a bunch of tools and mixing them together. And I think that when these new agents keep coming out, we're gonna keep combining and finding out new ways of of using them to get better responses. So look for synergy as well.
John Marshall: Yeah, be careful with oncologists in the kitchen, because I know Dr. Saab cooks without a recipe. I don't cook with a recipe either. I don't know a doctor about it. But anyway, be Be careful because we mix stuff around and in the hopes of creating something miraculous. So we are continuing to work on that. We have lots of questions in the chat, and I do believe we'll be able to get to most of them. So I do want to leave the last at least 10 minutes for those questions. But we the three of us thought it would be good to kind of share with our audience about this concept of disparities specific and GI cancers but frankly, it's true in cancer care, and general and I might sort of take the lead to set this up. So for example here in Washington DC depending on what zip code you live in, in Washington DC your survival for colon cancer can be as great as one year difference. And we have already done the work to understand that this is not you know, genetic or racially based. But we do know it is economically base and if you drive 30 miles that way out into rural Virginia, from my office, you will be at a very good hospital but one that doesn't have all the bells and whistles that a hospital like the three of us enjoy working in, day in and day out with, you know, clear, incredible multidisciplinary team incredible tumor boards, access to clinical trials, high-end everything, if you will, for cancer care and, and a lot of our best results come when when these optimal teams. Then on the flip side, having patients and caregivers who are highly supportive of everything from showing up to clinic on the right days, to being able to manage side effects and maintain lifestyle as much as possible. And we recognize that both of those things are really highly privileged things in our in our global health care society, if you will, and our country, different from other countries, other countries, rich, other wealthy countries emphasize taking care of the middle, and not spending so much money on the high end, our country tends to spend a lot on the high end and forget some of the middle and really neglect the low end socio economically. So we're increasingly recognizing that there are many people out there, and many of you listening in, may understand this and feel this, that not everybody's getting the same cancer care, even within, you know, three or four miles of each other. And so we're beginning to look at, in Greg, maybe I'll start with you. I mean, we know for example, that it's really important to start your adjuvant therapy after your surgery within a certain window of time. You know, cancer is such a disruptive thing, we're seeing so many more people, young people who are parents getting GI cancers, maybe you could reflect a bit on, you know, patients that you've had, where they're, these added burdens of cancer have made it so that they can't really access what they need to access.
Gregory Botta: It's absolutely true. You know, you're absolutely right, the incidence of some of these cancers is actually increasing in these younger populations, and kind of in the prime of their working years, raising a family, and all of a sudden, they're stuck with a metastatic cancer and maybe even cured of cancer, but maybe they're the primary breadwinner in their family, and all of a sudden, there's a huge loss of family income, maybe then the car doesn't work, and you can't get it fixed, and you can't get transport. And, you know, we know that these socio economic barriers exist. You know, specifically in San Diego, we have a large Hispanic/Latino population, we have a very large Asian population, Pacific Islander population. And we know that these patients, genetics may or may not be different than those that are white Caucasians, but no one's looked, you know, and we don't know if there's really that big differences genetically in targeted agents for one or the other. We know the incidence of these cancers is higher in some of these populations, like gastric cancer, and the Asian population. But we also know that not only are we kind of having an obstacle of getting the genetic information and what it means most of our trials, again, our older white male, we don't know what happens in minority populations. We're also now stuck up against an obstacle where they can't get in for treatment, or there's not enough gas prices have spiked, at least in California to $7 a gallon, how am I going to drive in there? You know, there's no not as good public transportation as on the East Coast. There's all of these issues we are running into. And you know, all I have to say is being at a comprehensive center, thank goodness for our wealth of, of people to come and assist social workers, nutritionists, our palliative care group, they can do this on video visits, thank goodness now. And I think that that's really helped out our patients and stopping them from having to come to us we can get to them. But I'll be honest, I have a calendar meeting tomorrow for next-generation sequencing disparities meeting, because we just need to figure this information out.
John Marshall: Ya know, that's a big problem. Toni, I know, you've traveled the world. And I know, you've seen a lot of health care models around the world and the like, what's your, what's your just take on this subject? I mean, on one end, where that where the where the drill bit that's discovering and optimizing in our high end teams, are we leaving behind, you know, you know, information and knowledge that's accessible and useful to the global population? And how are we going to take care of each other?
Tanios Bekaii-Saab: Yeah, I mean, you know, we have to democratize our healthcare, essentially, I mean, it has to be accessible to all that is an expense to it. And the expenses, you know you have to give up some on the top to allow you know, the bottom to be able to get elevated through you know, oftentimes one of the arguments that always comes to mind when you know, in the US you have more, more access to drugs that otherwise wouldn't be accessible in Canada or other parts of the world. That's a short-sighted statement, because access means you can have, you can have a potential access to them. That doesn't mean you access them. So yes, they're available, but most people are not able to access them. For many reasons, mostly limited to financials. You know, in addition to, you know, the US still has a large rural population as well, that is also underserved and underrepresented as well. And that's becoming recognized by the NCI. Yes, is vast, and, you know, systems can tend to be present mostly around urban centers. But you know, one aspect of health care in the US that's very different from other parts of the world is the preponderance of essentially, you know, practices that are outside a large hospitals or large systems, which does two things, by the way, and not only that, you know, can certainly affect the way we deliver care, because it becomes more business than essentially healthcare. But also it diminishes significantly access to clinical trials and the capacity to accrue on clinical trials. And we see that that the only places where the US performs well, is an early-phase trials. And those are because run by mostly academic institutions, on large trials that address more important, you know, equally important, but I would say these societal questions, society, relevant questions, we actually underperform because those mostly run where the patients are being seen firsthand, and that's in community. So, you know, I think I think our disparities go beyond just access beyond just capacity to care for patients, but also availability and capacity to build clinical trials. As we all know, clinical trials are actually an essential aspect of how we care for patients and how we continue to develop sighs.
John Marshall: That's great. Let's go ahead and go to our questions, invite Martha to rejoin us on our call. There are a lot of questions in the box, we have about 9, 10 minutes to go. So one of them was an easy one. Is these being recorded? And can you go back and watch the others? The answer is yes. Those are, they are and I think they do go very nicely together. So there are different panelists with each of the presentation, so you get some different perspectives. And, Martha, I know you've got it probably identified a few questions on that you pick one, and then we'll go from there.
Martha Raymond: Sure. And again, a lot of great questions. One that I found very interesting from a patient: if you have an autoimmune disease, such as hypothyroidism, will immunotherapy still be an option? Or does that disqualify you? Dr. Botta, what do you think?
Gregory Botta: Great question. It used to be no one would no one would do it. No one would go through with immunotherapy with autoimmune disease, but I think you know, over time with more people using it. It's not an absolute disqualification for AIDS used in the clinic, maybe on trial, but maybe not in the clinic. We do have patients who have autoimmune diseases where there is a higher risk that a immune inflammatory environment induced by checkpoint inhibitor therapy will cause your autoimmune disease to worsen. That being said there are techniques being developed and ways in which we can monitor that and still give you immunotherapy effectively in to response. But yeah, you have to be at a center that either specializes in that or has expertise.
John Marshall: Okay, so one quick question is a T12C and TP53 together success for immunotherapy. Right now those two markers are not markers for immunotherapy. So but they are G12C has its own therapeutic target at this point. But people are beginning as we talked about, you leave oncologist and alone in the kitchen enough, they'll start to combine things. So we'll see if that ultimately comes out. Toni, hard question. What about TIL cells you hear about CAR-Ts you hear about cell therapy is that it's working very nicely in leukemias and lymphomas. Is that going to make its way a kind of targeted immunotherapy to solid tumors? You think?
Tanios Bekaii-Saab: Eventually, at some point, yes. There's a lot of work that's being done. So it's interesting to dig into take take a step back. For those for those cancers for those tumors where actually we found a pathway for immune therapy is where we're seeing a lot more activity with these T cell therapies. Makes sense? If if you know your immune system is is competent, and is able to is able to recognize and attack the cancer, then any manipulation around the immune system will allow that the bigger challenges and that's been our challenge overall, is the majority of the cancers in GI and gastric in the gastrointestinal system don't respond well or are all to immunotherapy. And so at this point of time, just just thinking about those cancers that the way we will we will get to the point. And this is where also solid tumors overall are more challenging than liquid tumors or lymph node lymphatic tumors, or lymphomas is, you know, the solid tumors are more complex, they tend to be more heterogeneous, more clonal polyclonal. And but also, you know, they typically, mostly, if you take a tumor, and you cut through it, it's actually there's very little cancer cells in there, most of it is a bunch of other stuff. fibrous tissue, supportive cells, you know, bad immune cells. And so you have to overcome a lot of other things, to be able to efficiently get those immune cells to the target. So it's more complex, I think, in solid tumors.
John Marshall: I think another one?
Martha Raymond: I do. And I would like to say to with all the questions if we don't get to them, if you contact us through GIcancersalliance.org, we will help you get the information. So and these might be our last ones just like a glossary of terms. What is germline and what is a biomarker?
Gregory Botta: Great. So germline is the DNA, you were born with the DNA that made you who you are, it's in your cells, and it's going to be in your kids' cells, it's going to be in their children's cells in your parents cells. It's the DNA that gets passed between family members. That's important because some groups of patients has genetics that make them high risk for developing cancers. But also it could be a marker of immunotherapy efficacy. So that's what germline is the other one Oh, biomarker. So what is biomarker? A biomarker is that flag in the ground that says, Use this drug? So basically, it's enables your oncologist to say, Hey, listen, we can't we found this marker or this flag on your cancer, this drug will work really well with it. And it enables you to kind of make a match between the drug and your tumor.
John Marshall: So I'll add one more question. And maybe get both of yours take any short answers to this and say yes or no. So the setup here, the question is the patient who's asked the question has a duodenal, stage three, mismatch repair? deficient duodenal cancer? And let's assume that surgery hasn't been done yet. Given the rectal data, some of the other data in MSI deficient mismatch repair colon cancer, is this a patient that you would start with immunotherapy? If you could get it Toni? Yes or no? Yes. Correct. Yes, pretty young. Get it? If any, probably could get it. Really, honestly, at this point, even stage three, Let me twist the question and say that you've already had the surgery. And the patients had the tumor resected. Would you give adjuvant immunotherapy, Tony? No,
Gregory Botta: No, maybe eventually.
John Marshall: Yeah, eventually. And I think it's really one of those things. It's interesting is that the role afterwards is less clearly defined than the world before.
Tanios Bekaii-Saab: Before just to be clear, they're all before is it comes with with also a discussion about potentially avoiding surgery immediately after?
John Marshall: Yeah. Okay. All right. I think that'll pretty much do it for our hour. So you guys are awesome. I want to thank Dr. Botta, Dr. Bekaii-Saab, and of course, Martha for hosting, and moderating, and I'll let her take it home from here.
Martha Raymond: Right. Thanks, Dr. Marshall. And again, thank you to our our amazing panelists, great, great webinar and a lot of wonderful information. So again, thank you to cure. This webinar, and the past two in the series will be available in the next couple of days on pure today.com And also on GI cancers Alliance website. So on behalf of the GI cancers Alliance cure our wonderful panelists. We'd like to thank our sponsors Amgen, oncology and elevation ontology for making tonight's webinar possible. So thank you, everybody, and have a good evening. Thank you.