Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome to “What I Tell My Patients,” Part 10, our final program in this week’s series of programs here at ONS. And tonight we’ll be focusing on gastroesophageal and colorectal cancers. We have a great faculty today, and as with all of our meetings, 2 nurse practitioners and 2 medical oncologists. We’re really thrilled to be here doing these 10 programs. We kind of view this as an integrated series of programs. We hope — we know many people go to all of them and others go to a bunch of them and then pick them up when we send out the video of these programs. So we kind of view it as an integrated approach, just to oncology in general. We will be talking about the nonapproved agents and therapies, so just check out the prescribing information.

For the clinicians here in the room, on your iPads you have all the slides we’re going to take a look at plus some other ones for you to check out, also a survey for you to take, and also if you have any questions or cases that you’d like to run by us, just put them in the iPad. For those of you who’re on Zoom, hey to everybody up there, and you have the same functions in the chat room including all the slides and this 1-minute premeeting and postmeeting survey. If you take that, you’ll get a lot more out of this program here tonight. We are video recording all of these programs, we’ll let you know in a couple weeks for your colleagues who weren’t able to come here, they’ll be able to check it out on replay.

These 10 programs together — this year we had a little bit of a different approach. And to enhance the programs, we work with 8 nurse practitioners we’ve worked with in previous years at ONS. We weren’t able to figure out a way to get them here live, so we chatted with them, each one of them for about an hour, on some of the issues that we have dealt with over the years at ONS here that sort of transcend any particular tumor type. And we actually, there were — these interviews were so compelling, we decided to post all of them on the web. We’re going to also distribute — we actually produced 85 videos, all less than 90 seconds, from these nurses, and they’re posted right now. When you go back to your room, ResearchToPractice.com/ONS2024Clips. Let us know what you think about this and what else we can do with it. How can we get this kind of content out there in general, including to patients.

So today we’re going to talk about gastroesophageal cancers and colorectal cancers, but also taking care of patients in general. And we’re going to start out with, just before we sort of jump in to all the data and treatments and excitement that’s going on in these 2 cancers, or gastroesophageal cancer, let’s just talk a little bit about patients when you first encounter them who have a new diagnosis of cancer. Here’s Ms Burns, who’s a GU nurse actually, with her thoughts about it.

MS BURNS: Dealing with patients newly diagnosed with cancer is a really unique challenge and one that brings me a lot of satisfaction. I think over the years you really learn to personalize what you do and what I’ve learned is stay as close to the patient as possible. Listen, listen to what they’re asking instead of going in with an agenda. Education of new patients takes time. It’s layers and layers of interaction. So don’t intend to get all the work done the first time, just make a connection. Be calm, listen to the family, huge, hugely important in oncology nursing. And kind of give them a little bit of time to tell their story.

I think this is a huge area where oncology nurses can make an impact. The reactions to a new diagnosis of cancer are completely across the board, and sometimes very unexpected. There are times when people are very closed off and you really feel like they’re not interested. It’s just there are so many ways to cope with this type of thing and things. Their reactions change day to day, so put on your titanium suit and — but at the same time, be very open to the clues that the patient and family are giving you.

DR LOVE: So Deanna, we often think about people new to oncology or are even thinking about going into oncology, but I think everyone really needs to really think deeply about this issue. I’m curious what you’re thinking about as you’re about to go see a patient for the first time who has a new diagnosis, for example, gastroesophageal cancer.

MS GRIFFIE: Exactly what she said. I think you have to walk into that room and be open. I think it’s important not only to address — they’re obviously there to learn about their disease, to know what we’re going to do about it, how are we going to help them, how are we going to help them live longer and enjoy life more fully, but it’s also important to know what matters to them. At the end of the day, it’s not what my goal is for them. And quality of life for them may look very, very different than it does for me. And only through talking to them and learning about what’s important to their life, what are you looking forward to? Tell me one thing about you that I haven’t already read when I was prepping for your clinic today. Tell me something I need to know besides your past medical history, your past surgical history, and your current diagnosis. Tell me what makes you you. And that really starts things on a really good foot even in the worst of circumstances, because I think patients kind of drop a little bit of their anxieties because they know that I’m going to meet them on their level.

DR LOVE: Caroline, any thoughts about this? Ms Burns also mentioned the family, and they’re usually there also as well.

MS KUHLMAN: Yeah, I couldn’t agree more with what you’ve said. It is a very stressful time for patients. It is so important as providers to meet them where they are and to be a good listener as well as providing them with information, but information in ways that resonates for the patient is very important. Because you can go in there with an agenda of boxes you need to check, but it’s very important to read the room, not just for the patient but for the family, to understand those relationships, what the supports are like and what their resources are so that you can treat them as a whole person, not just as a diagnosis who’s going to get a certain kind of treatment.

DR LOVE: Alright, so let’s sort of jump into some of the medical issues that come up in these patients, and we are going to start out with gastroesophageal, so cancer of the esophagus and stomach. And in a second we’re going to hear about a patient of John’s, a 68-year-old man and what happened with him.

But Manish, maybe just get started. Can you kind of just talk a little bit about the anatomy of what we’re talking about here in terms of the esophagus, the stomach, and particularly the histology in terms of the — there’s a squamous cell cancer, more common in the esophagus. Adeno more common as you go down. Just sort of paint the global picture of where these cancers are and how they present. 

DR SHAH: Sure, absolutely. So yeah, so cancers of the upper GI tract, anywhere from basically the bottom of the neck all the way through to your navel essentially is where these would be. Esophageal cancers start at the bottom of the neck, and at the first third, or first half of the esophagus, primarily always you’ll end up getting squamous cell cancer of the esophagus. These tumors are very sensitive to chemotherapy and radiation. So that’s kind of the mode that you’re thinking about. If your tumor is really, really high up, it would be endangering the voice box, the larynx. So there, to avoid someone losing their voice by surgery, we often think about chemoradiation to avoid that. As you go further down, there’s a transition to more of a Barrett’s esophagus, which is from reflux disease and obesity and the acid coming back up into the esophagus. And that leads to a change in the esophagus, which leads to more of the adenocarcinoma subtypes. And the adenocarcinoma subtypes, they’re very similar to the top of the stomach, and they’re sort of managed very similarly. Here, we begin to think about we need to get these biomarkers, like PD-L1, or HER2, or things like that because they may affect your treatment decisions down the line. And then as you go further down, it’s true stomach cancer.

And in the stomach, you think about different types of adenocarcinoma. There’s the signet ring cell type. That’s the type that actually, like you may have heard like the rubber stomach, where the cancer’s infiltrating in the entire stomach and the patient can’t digest food. They’re losing weight, they get early satiety, and that’s because the entire wall along the entire length of the stomach has cancer infiltrating through it. But you also have intestinal types of stomach cancer as well. And then both at the GE junction, which is the location between the stomach and the esophagus, and just past the stomach, there’s a place called the antrum. That’s where the stomach narrows and then it goes into the small intestine. Both of those areas, cancer in those areas can lead to obstruction. And so you might think of dysphagia or food getting stuck, or whatever. And then often, with our current treatments, we could think about a stent or things like that to try to overcome those symptoms. So it’s — there is a change in the histology, as Dr Love went through, and the histology matters because it will affect our treatment options and how we think about the cancer.

The other thing that I would mention is that the epidemiology of the cancers are a little bit different as well. So for squamous cell cancer, the cancers develop in the setting of toxicity. Like if there’s alcohol, tobacco, or lye ingestion, or something like that, that’s a direct toxic effect to the esophagus leading to the cancer. The adenocarcinoma, that’s more from a chronic inflammation. So the reflux from Barrett’s esophagus, chronic inflammation leads to cancer. In the stomach, we’re thinking about chronic inflammation from H. pylori infection. You may have heard of that. That’s a chronic infection of a bacteria that’s widespread in the world. So these kinds of things lead to cancer in those settings.

DR LOVE: So you have to kind of like our style. But — we’re not into slides, but I love the way you, you know, this is the way you talk on rounds, right? Here, here and whatever. That’s what we’re trying to do here, to bring that back.

So John, of course a huge theme this week, everywhere in oncology, is biomarkers. We’re going to spend a lot of time going through that. We’re not going to talk about everything, but maybe just to give an initial overview of the kinds of things that we’re going to look at in the tumor.

The Current Role of Anti-PD-1/PD-L1 Antibodies in the Management of Nonmetastatic Gastroesophageal Cancers

DR STRICKLER: Yeah, so the particular case you introduced was somebody who was presenting with a locally advanced esophageal cancer.

DR LOVE: This is your 68-year-old man?

DR STRICKLER: That’s right. And in that particular case, I would be focused on only 1 biomarker. In that case, I would be interested in what we call microsatellite instability, or mismatch repair deficiency. And essentially the way to think about it is, each cell when it divides, it makes mistakes in the DNA. And so we need an editor to come in and clean up those mistakes. If there is deficient mismatch repair or microsatellite high, there’s no editor to fix the errors, so the errors multiply. So you think about the DNA being the instructions for the cell. The instructions will make no sense. And there’ll be, it will be a hypermutated tumor, and it will look foreign to the immune system as well. So those mistakes will compound to a point where it almost looks like an infection to the immune system. And we’ve learned that in these patients who have this unique type of cancer, that if you give an immune therapy, whether it be nivolumab, pembrolizumab, ipilimumab and nivolumab, that you can have pretty profound durable responses to these immunotherapies for this rare type of cancer.

So that’s one I would not want to miss. It’s rare for these types of upper GI cancers. But that’s the 1 biomarker I would look at. Now if the person presented with metastatic disease, the biomarkers I want to know right on day 1 are HER2, PD-L1 status, which we could go into detail on, and then also I would want to know MSI or mismatch repair. So those are the key biomarkers.

DR LOVE: So I want to hear about your 60 — you said he was a trucker, right?

DR STRICKLER: No, this is law enforcement.

DR LOVE: Oh, the law enforcement, right. Okay so.

DR STRICKLER: I have truckers, too, though.

DR LOVE: I want to hear about that first, but just before we go too much farther, just Deanna, just to pick back up on what we were saying about MSI, because we were talking about that. I can’t remember if it was yesterday or the day before in endometrial cancer. And in fact, MSI high is relevant in any adenocarcinoma pretty much. And again, we’ve been talking about pan tumor approvals. You have MSI high, you can get a checkpoint inhibitor because it works.

Deanna, just the theme of patient advocacy, we presented a case in a webinar a couple weeks ago of a patient who went to a doc, same story as John’s patient. The oncologist recommended chemoradiation. And the patient said, “Did you do an MSI on me?” And he hadn’t. He drew it. It was positive. And he fired his doctor and went to another doctor, who then treated him successfully. So Deanna, kind of an example of self-advocacy. So here’s the question we put out on the — sorry to spring this on you, but we put out on the webinars, what do you think the occupation was of the patient?

MS GRIFFIE: What do I think the patient — oh, wow. Um —

DR LOVE: Attorney, of course.

MS GRIFFIE: Oh, wow.

DR LOVE: And that’s what we want our patients to do. We want our patients to fight for themselves the way an attorney does. Any thoughts, though, about, can we educate patients to that level?

MS GRIFFIE: I think we can, but I think there is a very fine line there. I tell — it is at least once a week I tell a patient they really need a Googlectomy, because Google is full of terrible information and things that can really send things grossly awry, and heaven only knows what some of our patients are doing that they read from Google. So I think it’s important for them to educate themselves and be armed. But I think there needs to be such a trusting relationship with their provide and their care team, whether that be nurse practitioner, PA, doctor, or all of the above, that they can come to you and say, okay, where can I look? Can you give me this stuff? And that we’re giving them honestly what they need to know, and not just what we want them to know, not just what we want them to know now. But we do have those patients that need to look two, three steps ahead. They’re preparers, they’re planners, they need to know what the future looks like or might look like. And so it’s important for us to make sure that we have good information in their hands or share good resources with them.

DR LOVE: So John, let’s get back to your law enforcement person. What kind of symptoms did he have, and what was going on when you saw him?

DR STRICKLER: Yeah, so like so many places in America, we have a lot of rural communities in our state of North Carolina where primary care is difficult to access, and it’s difficult to find a doctor willing to look at you when you’ve got symptoms of difficulty swallowing. And so this person unfortunately presented pretty late in the disease process. Difficulty swallowing, severe dysphagia, a lot of weight loss. And I think by the time he presented, he needed a feeding tube. He had some initial conversations in his community practices and just was not comfortable with what he was hearing and wanted to go to a higher volume center, which is how he landed with us. And by the time he came into clinic, he was quite symptomatic and we were in a bit of a hurry to get him started on treatment. But he was in a tough place at the very beginning. And I will say that, in my experience that’s the majority of patients who present with a gastroesophageal cancer.

DR LOVE: Really?

DR STRICKLER: It’s rarely picked up early.

DR LOVE: Hmm, that’s interesting. So this man, where was the location, the origin, and what was the histology, the tissue diagnosis?

DR STRICKLER: So that’s right at the junction of the stomach and the esophagus. And just as Dr Shah was mentioning, this is one of the more common types of esophageal cancers in the United States, because it tends to occur in patients who are obese with chronic reflux. Over the years, they will get those adenocarcinomas right at that junction, and so that’s kind of the background. And so he was very much a prototypical case for us.

DR LOVE: So Manish, can you talk about how we think through — this is a very common scenario. GE cancer is extremely common. How we think through people who present like this, Manish?

DR SHAH: Yeah, no, absolutely. So it is the most common. I just wanted to point out just with regard to Dr Google, I point them to RTP.

DR LOVE: I mean, really, we are trying to figure out how can we do this for patients directly? Incidentally, I’ve got to say, I want to thank, someone gave me a diet Coke. Diet Coke is not approved in a Marriott country, so, appreciate that. Anyhow.

DR SHAH: Yeah, so the GE junction. So as Dr Strickler and Love mentioned, so it’s real interesting. Esophageal cancer, the epidemiology, it’s going down. Gastric cancer, the epidemiology is going down. About 70 years ago, gastric cancer was the number 2 GI cancer in the United States. It’s now number 7 or 8. GE junction, it’s going up. It’s the other direction. And the reason why is because we have an epidemic, honestly, of obesity. And so that leads to reflux, that leads to these changes. And what we’re learning now is that these tumors are not behaving like 2 esophageal cancers. They don’t respond so great to chemotherapy radiation. And they also behave a little bit differently than true stomach cancers. They’re really their own entity, and we’re trying to figure out how to best treat them. The challenge is that a lot of the studies that we rely on, they are esophageal studies and they included like GE junction as well. Or they’re gastric studies and they included GE junction as well. We really actually need to understand the GE junction.

But all that being said, the treatments that we have, we’ve made a lot of advancements over the last 5 years. And the biomarkers that were mentioned are really, really critical. The one other comment that I might make is that Dr Strickler is absolutely 100% correct. The most important biomarker for localized disease is the MSI status, microsatellite instable status. But often when you meet a patient, you don’t know, right? You don’t know if they’re localized or if the cancer’s already spread. So what we do, and it’s true everywhere — a lot of places — is that you actually get all the biomarkers right up front. Because even for GE junction cancers, you treat them with curative intent. More than half the time the cancer will come back, and you’ll need these biomarkers anyway.

So in addition to the MSI high, which is truly important for localized disease, you also need to know about HER2. That’s the same biomarker that we use in breast cancer. We need it in upper GI cancers. And also you need to know the PD-L1 CPS score. That’s for the immunotherapy. So if you get those 3, then you’re kind of set right now. In the next year that might change. But for right now, these are the things that you need to know.

The Potential Role of Immune Checkpoint Inhibitors (ICIs) as Neoadjuvant Therapy for Patients with Gastric/Gastroesophageal Junction Cancer

DR LOVE: So let’s talk about specifically managing these patients and particularly, because this patient has locally advanced disease, is not going to be amenable to having surgery. We’ve already talked about that, this kind of scenario, several times in this meeting. We’ve talked about head and neck cancer, locally advanced disease, chemoradiation therapy, cervical cancer chemoradiation, all these now bringing in immune checkpoint inhibitors, and lung cancer, chemoradiation followed by IO. So a lot of the solid tumors have strategies for this type of patient. What kind of strategy here? I guess the issue here is chemo neoadjuvantly, and then if they still have disease after chemotherapy, immunotherapy, add nivolumab.

DR STRICKLER: Right, so we essentially have 2 options in a scenario like this. A GE junction adenocarcinoma, this is the most common type of esophageal cancer you’re likely to see in the clinic. One option is more of what I would call a traditional approach, that’s the — you’ll hear it called the CROSS regimen. It’s been around for well over a decade. It’s carboplatin/paclitaxel and radiation for about 5 and a half weeks. And that is our traditional standard at Duke as well.

The alternate option is a regimen called FLOT, which is just a triplet chemotherapy cocktail. 5FU/leucovorin/oxaliplatin/docetaxel, very aggressive chemotherapy regimen. And that’s also a validated regimen for this. It’s our general approach to use the carboplatin/paclitaxel radiation because in our patient population we have a lot of experience with it and we find it to be well tolerated by most patients. And if there is residual, then the patient would complete the radiation, go to surgery, and if there is any residual disease in the surgical specimen, then the patient would receive 1 year of nivolumab, and that’s what this patient received.

DR LOVE: And how did he do?

DR STRICKLER: So thankfully — he came in quite symptomatic.

DR LOVE: Sounds like it.

DR STRICKLER: Borderline performance status, like on the verge of needing to be admitted for fluids. We were able to support him through that, started him on carbo/paclitaxel, radiation and he had a clinical response while on treatment. So that’s obviously very rewarding for the whole multidisciplinary team. When we see somebody getting stronger and stronger while on active chemoradiation, right, that is a victory for us. And he completed that, went to surgery, and down-staged the cancer successfully to a T2N0, which is a fairly early stage, when it finally was removed, so.

DR LOVE: But he still had disease?

DR STRICKLER: He did. It was still there, yep.

DR LOVE: So what’s the likelihood that he’s going to have metastatic disease in the future?

DR STRICKLER: I’d say greater — well, without nivolumab, right? Greater than 50/50 certainly, with that node positive status at the very beginning, for sure. So still, odds were not with him even at that point, but he did get the year of nivolumab and he is now a couple of years out. We just saw him back in clinic this past week, and knock on wood, no evidence of disease.

DR LOVE: Did he have any autoimmune problems from the nivolumab?

DR STRICKLER: No, thankfully not.

DR LOVE: Nothing. So Caroline, you had a patient also who got neoadjuvant therapy. Your patient got kind of a different approach where you got both FLOT and CROSS. So I’m just kind of, without getting into all the details of how it happened, I’m just kind of curious about that case, A in terms of what happened during the treatment, but also you were telling me some interesting things about what was going on in his family at that time.

MS KUHLMAN: Yes, this was a 46-year-old woman. I think in our center, there tends to be, in Massachusetts, the Boston area, a lot of access to healthcare, so they don’t tend to present as late. So she presented with your standard sort of, I feel like I have something stuck when I eat. I can’t — I choke when I eat. Not — she had those symptoms maybe for a couple of weeks before she found herself in a situation where they were able to identify a tumor. And we treated her with neoadjuvant therapy. She’s a teacher’s aide. She lives about an hour and a half from our center, so kind of a flog to get in for her treatments. She’s a mother of 2 sons, teenage, a 17-year-old and an 11-year-old. And she tolerated her therapy actually pretty well, because again, she didn’t dwindle with symptoms for months and months before she was actually identified. She got through her chemotherapy and radiation. She went to surgery. She had a path CR.

DR LOVE: So there was no tumor there?

MS KUHLMAN: No tumor. So did extremely well, and she’s 9 months out, doing well. I think the tallying point, the unique thing about her was sort of helping her navigate her treatment with teenagers, with a teenage son and an 11-year-old, and offering support around side effects from the therapy, which are not inconsequential, and still being able to maintain herself as a mother and dealing with the behavioral changes that happen with teenagers, in the setting of a serious illness, how to offer her support around communicating with her kids about her illness. She had a supportive husband, but he worked a lot, and so she was still the primary caregiver to her children. And there were several challenges in trying to support her with resources, utilizing family and friends to really support her during her treatment.

DR LOVE: So we’re going to talk a little bit more about, we’ve talked about already here this week, and we always talk about this at ONS, which is patients with minor children and grandchildren. We’ll talk a little bit more about this later.

I just want to jump back into the clinical research that’s led into the treatment of these two patients. So Manish, maybe you can talk about this study, the CheckMate 577 study, that really brought adjuvant immunotherapy into GI cancers, or into upper GI cancers.

DR SHAH: Yeah, no, absolutely. So this study was really a landmark study that was published actually in the New England Journal just a couple years back. So patients who received chemotherapy and radiation, the CROSS regimen, and then they received surgery, about 20% of the time there won’t be any tumor in the pathologic bed. But that means 80% of the time there is some residual cancer. And in that group, that 80% group, there is a high risk of recurrence. And these are patients that are really kind of beaten up. They’ve got chemoradiation, they’ve gotten an esophagectomy. They’re struggling, right? So it’s really hard to do more chemotherapy, and it’s not clear that there’s any benefit.

In esophageal cancer, immunotherapy works pretty well. And so Dr Kelly and his colleagues did this randomized trial in the group that had residual disease, that 80% group. And they randomized people to receive a year of nivolumab, or the standard, which was just supportive care, observation, and surveillance. And it was really quite remarkable. The median progression-free survival — so that’s like the average time for the cancer to come back — in the nivolumab group, was about 42 months. In the observation group, which was the standard, it was 21 months. There was a 50% improvement in the time for the cancer to come back, the median time for the cancer to come back. So just based on that, the FDA did approve the study. And it really has changed a lot of our practices. The study was done in the situation where people received chemotherapy and radiation and then they get surgery.

There are ongoing studies with FLOT and other chemotherapies, so without radiation. If you get chemotherapy and then resection, and you have residual disease, should you get adjuvant nivolumab? Right now, the NCCN guidelines or insurance companies, they won’t approve it, generally. So that’s something that we’re working on. But that might be a consideration if you’re thinking about this, because adjuvant nivolumab might be very important for your patient. So it’s a complex situation, because you have more than one option in terms of what the treatments should be for the GE junction tumors. And so arming yourself with all this information would be helpful.

DR LOVE: And we know that also there are trials that are ongoing right now, trying to see whether an immunotherapy can be brought in along with FLOT in these gastric patients. There’s a study looking at another PD-1 inhibitor, durvalumab, just presented at the European meetings last fall where they did see an improved path response CR rate. In other words, like the patient we just talked about, complete loss of tumor. But we don’t know yet whether it’s going to affect long-term outcome. There’s another study with pembrolizumab where they didn’t — they saw this path CR, but they didn’t see benefits beyond that. So I guess we’ll have to see where that goes.

But let me just sort of put our foot into the water. Something we’re going to talk a lot about today, which is putting people on checkpoint inhibitors. Deanna, we’ll just begin with a little bit of a primer from your point of view of some of the things you discuss with patients about to be given IO.

MS GRIFFIE: Oh, yeah. Most of our patients, for the most part, except for that MSI-high patient that starts with immunotherapy, it’s something that’s given a little later. And so I think people come to the room, come to the clinic expecting kind of chemotherapy related side effects and they’re vastly different. So we talk about all the itises and the fact that this is basically, in a layman’s term, this is going to release the breaks from the immune system and it’s going to kind of run through the streets at 120 miles an hour, and it’s not going to care what other cars are in the way. And so as such, it’s certainly, we think going to do a great job of cleaning up your cancer and kind of getting that under control, but there is the potential for healthy tissues to be damaged. So we really talk about all the things, or as many things as possible that we can do. I look at their med list. I see do they already have autoimmune conditions? Because that’s a big deal. And then of course we really spend time talking about the most important and the most likely to be kind of treatment-limiting, and that is uncontrolled Grade III, Grade IV diarrhea, and of course pneumonitis in the lungs. And so I tell patients every single time I see them, is this changing? What are you doing? How are you breathing? Because we don’t want that train to get ahead of us.

DR LOVE: So I want to ask about another thing. We were talking about MSI-high tumors and the fact that they’re so sensitive to immunotherapy. So along the way, people started to say well, maybe we could just give these people immunotherapy alone, no surgery, no radiation, no nothing. And this paper came out from the Memorial Sloan Kettering in New York, where they just had a small number of patients, I think 10 or 20 patients where they tried this in MSI-high rectal cancer. And John, do you want to talk about sort of what they saw, and then what that led to?

DR STRICKLER: Yeah. This is — it’s stunning to change practice off of whatever it was. It was initially 12 patients and it became 18.

DR LOVE: Right. As soon as everybody saw it, it was like yeah, that makes sense.

DR STRICKLER: Yeah. So the standard of care for somebody with locally advanced rectal cancer, independent of knowing whether they’re MSI-high or not, at least before this paper, was to do what we call usually TNT, which involves chemoradiation, maybe some chemotherapy, then going to surgery. And the folks at Memorial Sloan Kettering did a very intriguing study where they identified those very rare patients with MSI-high or mismatch repair deficient locally advanced rectal cancer. And instead of giving them chemo, and radiation, and even surgery, they gave them 6 months of dostarlimab, anti-PD-1 monoclonal antibody, and all of the patients had a complete response. None of them went to surgery, none of them went to radiation. And it was such a profound result that it actually changed practice. And if you look in the NCCN guidelines now for rectal cancer, it is listed as preferred to give an anti-PD-1 antibody for a locally advanced MSI-high rectal cancer.

DR LOVE: You can imagine why the attorney was so anxious to make sure he had an MSI done. And now this really ignited the field. And as specifically related to gastroesophageal cancer Manish, I’m hearing more and more of people when they see they’re MSI-high, again, hold off on chemoradiation, give them IO? Are you doing that?

DR SHAH: Yeah, it’s a great question. So there is some data in upper GI cancers of ipilimumab and nivolumab in the MSI-high population that’s locally advanced. And the data are very good. There’s about a 70% chance of a complete response. Not 100% that we saw in the rectal study with dostarlimab. So it’s not quite yet in the NCCN guidelines. But the activity is so tremendous that, in my practice, a lot of these patients end up being borderline resectable and I end up giving them the FOLFOX plus nivolumab, and then I drop the FOLFOX after 1 or 2 cycles and then continue the nivolumab. And I would say 2/3 to maybe 75% of them do get a complete response. And we’re talking a lot about personalized medicine and how do we care for our patients? This really does matter. I mean, I had an 80-year-old patient who had Lynch syndrome. This is 1 of the causes of MSI disease. He had multiple abdominal surgeries, prior colon cancer, and other things like that. Then he developed a gastric cancer. He was 80, 81, something like that and he truly was borderline. We gave him the chemotherapy then immunotherapy, and 2 years later he’s disease-free. He never had a gastrectomy, and he’s doing pretty well.

So knowing these biomarkers really does make a difference and you can — I think actually it opens up the idea of, how do you counsel patients? It’s not — there are examples of exceptions that can happen, and so I think we have to have hope for that.

First-Line Therapy for Metastatic Gastroesophageal Cancers

DR LOVE: So let’s move on now and talk about metastatic disease, metastatic gastroesophageal cancer. John, can you provide sort of an overview of how we look at this, both anatomically in terms of histology? And also now we’re starting to look at PD-1 levels.

DR STRICKLER: Yeah. This is actually a tough one to give me. This is extraordinarily —

DR LOVE: You can do it.

DR STRICKLER: Yeah, I can. But no, it’s an extraordinarily complicated topic because the data is now so nuanced. I think the first question that I would have is, okay, what’s the type of cancer that it is? Where did it occur? So as Dr Shah was mentioning, these proximal, high esophageal tumors tend to be squamous type. There, you think about this more as an immunotherapy sensitive cancer. We would still test for PD-L1 status, but it’s a little less important there. These tumors are very unlikely to be MSI-high, and yet they can be quite responsive to immune therapy.

So in these types of patients, the initial treatment I would be thinking about would be a combination chemo with an anti-PD-1 antibody. Further down the esophagus, you tend to get an adenocarcinoma type. And once again, you’re testing HER2, PD-L1, MSI. These are the 3 biomarkers you want to know right out of the gate. Very rare once again to have MSI-high. So HER2 and PD-L1 become quite important. If it’s HER2-positive, which is — then they would go on a combination chemo. Typically, in the United States, it would be FOLFOX together with pembrolizumab together with trastuzumab. If it’s HER2-negative, then you’re looking at that PD-L1 score. And we use the CPS score, combined positivity score. I would say if it’s 5 or greater, clearly you would want to give a chemotherapy/IO combo. Once again in the United States, we would typically give FOLFOX plus an anti-PD-1. If it’s between 1 and 5, the guidelines are kind of mixed on this. And I know Dr Shah sits on the guidelines committee. And it, truly by the data, probably there’s very limited benefit to giving IO, but I think it’s still commonly given. It’s still FDA approved in that setting. So you would give FOLFOX plus IO. If the CPS score is 0, there is no role, in my opinion, for immunotherapy whatsoever. And so that would be my approach for those lower esophageal, and gastric is much the same as lower esophageal adeno as well.

DR LOVE: So if you want to get your medical oncologist’s blood pressure up, just say, what would you do if you had a CPS of 2 in metastatic disease in the first 2 situations? And they argue for an hour about that. But we’ll sort of skip that a little bit because again, the key here is get the patient involved. If the docs aren’t clear about it, it’s even more of a reason to get patients involved.

And so let’s see how this plays out. Deanna, 67 — this is the truck driver, right.

MS GRIFFIE: Yep.

DR LOVE: 67-year-old. What happened there?

MS GRIFFIE: Yes. Okay first of all, can I give a PDS? Because I know most of the audience are nurses. I’m a nurse practitioner now, but I started as a baby nurse. It is never wrong to advocate for your patients and ask if they’ve had this testing if you don’t think they have. It’s — you have — you can push that. And you can ask, what was this patient’s MSI-high status? Or what were the biomarkers for this patient? Educate yourself enough so that the question makes sense, but don’t ever hesitate to ask the person making treatment decisions, you know, has that been factored?

DR LOVE: Is there a HER2 assay on the chart?

MS GRIFFIE: Yeah.

DR LOVE: That one is all of a sudden, that’s the question.

MS GRIFFIE: Yeah.

DR LOVE: Is there — pan-tumor.

MS GRIFFIE: Yeah. I came from a rural area where this might have been missed. So anyway. Okay, on to my topic. A 67-year-old truck driver. He’s really new to us. So this gentleman is just now starting treatment. He presented with about a 15-pound weight loss, which he was a pretty big guy to start with, or what we call in our area, Carolina petite. I think he was about 240 pounds. But he had lost some weight, was concerned. He wasn’t able to keep many foods down. He was vomiting a lot. Really, really having a hard time with nutrition. He also, interestingly enough, already has peripheral neuropathy from cardiovascular disease and claudication, so that was an issue. Also has degenerative disc disease, so there’s some sciatica going on. So he comes to us. He already has a metastatic gastroesophageal cancer in the mid lower esophagus. He also has a paraspinal mass that was positive. We did do biomarkers, biomarkers, biomarkers. He was MSI — MSS, HER2-negative.

DR LOVE: So stable. He wasn’t —

MS GRIFFIE: Yeah.

DR LOVE: MSS is the other thing.

MS GRIFFIE: MSS stable. He was proficient MMR. But his CPS score was 15. So we —

DR LOVE: So that’s elevated?

MS GRIFFIE: Yes.

DR LOVE: And also, his HER2 was negative.

MS GRIFFIE: HER2-negative.

DR LOVE: Important.

MS GRIFFIE: So we started him just recently, he will come back this next week for his second regimen, on FOLFOX and nivo. But because of his preexisting neuropathy, we did immediately dose reduce the oxali. We got him connected with vascular and, of course, have him with palliative care and a nutritionist now. So he’s really motivated at this point, has started walking and trying to do more for himself to kind of prevent this evolving neuropathy on oxaliplatin.

DR LOVE: What’s his life situation?

MS GRIFFIE: Interesting. He’s divorced, but he lives with his mother. His mother is somewhat disabled. And so he helps her when he’s not driving.

DR LOVE: Interesting.

MS GRIFFIE: Yeah.  

The Potential Role of Therapy Targeting Claudin 18.2 for Gastroesophageal Cancers

DR LOVE: Okay. Let’s talk about one of the most exciting developments in this field, a new treatment. So let’s hear a little bit about it. Manish, what is Claudin 18.2?

DR SHAH: Yeah. So this is —

DR LOVE: Another biomarker.

DR SHAH: It’s another biomarker. So Claudin 18.2 is a protein that is on the cell surface. It’s actually in the gap junction. So the gap junction is a junction between the cells in the stomach lining. And it exists to give the cells polarity. So the gap junction is like a fence that connects the 2. And it allows cells to be, you know, like an interstitial versus a luminal type of side. When cancer develops, the cancers lose their polarity, so they kind of open up. So that gap junction breaks up so then that exposes the Claudin 18.2 receptor. And because it’s unique to the lining of the stomach and you only get it when you have cancer because otherwise it’s hidden, they developed an antibody that binds to Claudin 18.2. It activates an immune response against it. And when you combine that with chemotherapy, we show that it actually improves survival. So there are 2 studies that were examining this combination of either FOLFOX with the drug was zolbetuximab or CAPOX with zolbetuximab. Altogether, over 1,000 patients were treated. And there was an improvement in survival with Claudin 18.2, about a 25% improvement in survival. So with that, the, you know, I suspect that later this year, the FDA will grant approval for zolbetuximab in the use of patients with gastric GE junction or esophageal adenocarcinoma that’s Claudin 18.2 high, 75% expression or higher. So that’s now a 4^th biomarker that we’re going to need to know about. So once again, HER2, mismatch repair, the PD-L1 score, and we score that on a scale that’s called CPS, and then now Claudin 18.2. So this is an important biomarker that we’ll need to know about.

DR LOVE: And again, a critical thing moving forward for the future if we have to. There’s another agent coming along targeting FGFR, which we were talking about this morning with biliary tract cancer. So we may have another biomarker coming along. So far, it seems like, you know, we’ve heard this before, monoclonal antibodies with target, it’s improving, maybe not everybody is getting cured, but the patients are definitely doing better. But this thing is a little bit different because this 18.2 is in the stomach. So there’s a very unusual problem. And so the day this drug gets approved, we’re going to have to, every single person who is using it is going to have to know about nausea and vomiting. Caroline, would you like to comment?

MS KUHLMAN: Yeah. So it is a unique profile. But where we often see nausea and vomiting associated with chemotherapy in the days that follow treatment, the unique thing about this drug, the zolbetuximab, is that the nausea is acute, it’s infusion-related. So typically, the first dose is a 4-hour loading dose. And usually within the first hour, probably because there’s a lot of Claudin in the stomach, the gastric mucosa, there’s a lot of activity that happens when the drug is introduced, and it causes acute nausea and vomiting despite heavy premedication with steroids, palonosetron and aprepitant.

So suggesting the fact that our standard premedication doesn’t really mitigate the nausea and vomiting, suggesting a different mechanism than chemotherapy induced.

DR LOVE: Right. So for chemo, it’s the brain.

MS KUHLMAN: Yes, it’s the brain.

DR LOVE: And here, it’s the stomach, which there’s no other drug that’s like that.

MS KUHLMAN: It’s lower. Right, right.

DR LOVE: So you had a patient. You were telling me about this 68-year-old man.

MS KUHLMAN: Well, he hasn’t actually started it.

DR LOVE: Oh, he hasn’t gotten it yet.

MS KUHLMAN: Because it’s not FDA approved yet.

DR LOVE: Okay. But, Manish, you’ve got, your 54-year-old lady, she already got the zolbetuximab?

DR SHAH: Yeah, so on a clinical trial. So yeah, we gave the zolbetuximab. And so as Caroline exactly said, it’s really quite amazing. You see the bag of zolbetuximab, you’re getting it, and you get nausea. It’s like almost 1:1. And so you really have to jump on this right away. You stop the infusion, you slow it down, you give more antiemetics. And the other thing you say is it’ll get better next time, because it’s true. Really, the first infusion is the worst, the next one is better, the next one is even better. So you’ve just got to get them through the first 1 or 2 infusions. That’s the most important thing. But this is really, really critical because we used it at all these academic centers. Once it’s available, you know, everybody is going to have this problem and they’re not going to be used to it. So this is really critical for everybody.

DR LOVE: John, I’ve heard the key thing here is to slow the infusion down. That’s really the only way you can really deal with that.

DR STRICKLER: Right.

DR LOVE: How does that sort of play out practically? And how long do these people end up being infused?

DR STRICKLER: Well, I personally don’t have experience with the drug because it’s only been given on trial in the United States. But yeah, that’s essentially the approach. But I will say that the folks in this room watching us are going to be the ones on the frontlines who have to deal with this. Even before I know about it, I know that the infusion nurses and nurse practitioners will be getting these calls. So I think this is going to be an enormous challenge to get used to this, especially since the mechanism of action of our antiemetics may not even prevent it very much. But just as was said earlier, the good news is, if there is good news, is that it appears that the worse nausea and vomiting reactions occur in the first treatment and will dissipate with each subsequent treatment. So I think that does give us some cause for hope that it’s not going to be just misery every single time they come in. It is a once every-3-week infusion. But the rate in SPOTLIGHT, I believe, of nausea was up in excess of 80%. So it’s nearly universal, something to prepare all the staff for.

DR LOVE: You don’t want your office to have a bad experience and then say, oh we’re never using the drug. Because if you think about the biomarkers, okay, so we’re getting some additional benefit but think about this. So PD1-positive, you have one thing.

DR STRICKLER: Right.

DR LOVE: But you have a lot of people who are PD-1-negative.

DR STRICKLER: Yes.

DR LOVE: And am I correct in saying most of them are Claudin-positive?

DR STRICKLER: So that’s a great question. We talked about biomarkers. So the SPOTLIGHT and GLOW studies did look at the rate of Claudin 18.2 positivity for enrollment in the trial. And that positivity rate was at 40% in both of the studies, right around 40% so not everybody. But it does appear that in this group of patients that have lower PD-L1 scores, less than 5%, there is a pretty high rate of Claudin 18.2 positivity. So I was squirming when I was explaining what we do when the PD-L1 score is under 5 because right now, we’re kind of giving the anti-PD1 when we know it’s probably not doing much.

DR LOVE: You know it’s not going to really help. Right. But now, you have something else that does work.

DR STRICKLER: That’s exactly right. So now, we’ve got an option for those patients.

DR LOVE: And the thing that was really cool about these 2 trials too was that the first report that they have, usually you only see delay in progressive disease, but they already had a survival advantage, which is very unusual for a first report of a trial. So it seems like there’s a significant benefit there. But also, Manish, any thoughts? But also, you’re going to have some people who are PD1-positive and Claudin-positive. Are you going to give them both?

DR SHAH: Right. So that’s a great question. And we don’t know the answer to that. I think that unfortunately, I’d say insurance might dictate that you get one or the other initially until the studies are done. But I just would want, just back to the nausea/vomiting and the fact that it’s really bad in the beginning. Many of you may be familiar with GI oncology drugs. When we were first using irinotecan, we were giving it weekly bolus and we would have huge diarrhea, like, 10, 12, 15 times, and we figured out how to do it. And I think now, we give it routinely. I think it’s the same thing. It’s just a matter of patient education, managing expectations, realizing that this is going to happen. And it doesn’t happen to everybody. But if everybody is aware of it, then in the few people that it happens, maybe we’ll get through it. I think that this is — I mean, there is a survival benefit. So we just need to figure out how to do it.

DR LOVE: Just slow the infusion down.

DR SHAH: Yeah.

DR LOVE: Nothing else.

Targeted Therapies for HER2-Positive Gastroesophageal Cancers

DR LOVE: So I want to move on to another form of targeted therapy that we’ve been talking about all week, but just so important to think about, which is anti-HER therapy, which has become a big part of both of these cancers that we’re talking about tonight, gastroesophageal as well as colorectal. John, can you provide a little bit of an overview of, first of all, what HER2 is, how we do HER2 testing? Here’s, again, a paper on zolbetuximab, the 2 trials. And where we are right now as we start to integrate anti-HER strategies that originally were developed in breast cancer. And now, just within the last couple of weeks, a pan-tumor approval for anti-HER antibody-drug conjugate, trastuzumab deruxtecan. So any patient with a solid tumor that’s run out of options and still wants to be treated or can be treated needs a HER2 assay because if it’s positive, they’re eligible to use this drug. And this drug works, but also has issues. And if you’ve been coming to our meetings, you know the challenge there. So, John, let’s just dive into it.

DR STRICKLER: Yeah. So HER2 is one of the best-known receptor tyrosine kinases in the oncology clinic. It’s been well-described for decades. It is what we call a receptor tyrosine kinase. It sits on the surface of the cell and drives downstream signaling, kind of helping a cancer survive, grow, spread, metastasize. And we’ve known from early on that, certainly in breast cancer and some other tumor types, that when a tumor has overexpression of HER2 or amplification of the HER2 gene, which is otherwise known as ERBB2, those cancers can be quite aggressive and they are quite prone to metastasize to the central nervous system.

The first breakthrough, of course, was trastuzumab a couple of decades ago. Probably exactly 2 decades ago when that was approved, somewhere around there. And the initial approval was in breast cancer but about 7 or 8 years later, it was found that HER2 overexpression is also found in about 15% of patients with adenocarcinoma of the upper GI tract, so specifically gastric and esophageal adenocarcinoma. So that led to the initial approval of trastuzumab with chemotherapy as a first-line treatment. And that’s been our standard for many years. And in recent years, we’ve learned that actually, somewhat surprisingly, patients who have HER2-positive disease are also likely to have high PD-L1 expression. And that’s led to some interesting work, and the name of the trial is CheckMate 811. But they found very high response rates when you combine standard chemotherapy with trastuzumab with pembrolizumab. And actually, that received an accelerated approval before they even knew the survival benefit. The response rate was over 70%. So that’s where the approval came.

And I personally have found that the responses to FOLFOX, trastuzumab, pembrolizumab can be quite durable, lasting sometimes years, particularly in patients who have IHC 3+ HER2 expression and very high PD-L1 scores. So this has opened up a whole new range of options for these patients.

And now, we have a more recent drug that’s come in called trastuzumab deruxtecan. This is an antibody-drug conjugate, trastuzumab linked to a very potent chemotherapy. And this has also been FDA approved for gastric cancer as well that’s HER2-positive. And that’s after progression on first-line therapy. So we’ve now got a range of options. When you get into what happened in the last month is that they found that trastuzumab deruxtecan is active for all solid tumors, not just breast cancer, not just gastric cancer. All solid tumors that have high levels of HER2 expression have very high response rates to this drug. So I think it’s something that increasingly, you’re going to hear patients ask for, what’s my HER2 status? And the key thing to know is if it’s IHC 3+ or high HER2, then that patient is eligible for FDA approved trastuzumab deruxtecan regardless of what tumor they have. Could be head and neck. Could be endometrial. Any cancer can get this. Yeah.

DR LOVE: I was just going to say that John really is one of the national experts in HER2-positive GI cancers. We’re going to talk in the colon section about the study he did looking at the tyrosine kinase inhibitor, tucatinib. But first, just to get back to T-DM1 because, again, you have the issue of great efficacy, but potentially troubling tolerability. What happened with your 74-year-old man, esophageal adenocarcinoma, HER2 IHC 3+? Actually, before you tell me about that, let me just point out that in breast cancer, they also see activity with HER2-low. So you don’t have to be HER2-positive, just have some HER2 and they respond really well. I don’t think right now, we know about the other tumors. Do we, John?

DR STRICKLER: It has been looked at for gastric cancer. And specifically in these HER2 intermediate category, there do appear to be some responses. But it’s not been well-described in large groups of patients yet. It hasn’t been as well-described as, say, breast cancer.

DR LOVE: So that’s really the cutting edge. Breast cancer, we went from treating 20% of the patients now to 50% of the patients because so many of them were HER2-low. So what happened with your patient? First of all, how did he tolerate — what was the situation when you started the T-DXd?

DR STRICKLER: Well, this is, once again, apparently, my patients come in quite advanced, unlike my colleagues from the Northeast. So this patient was brought into the emergency room at our hospital with, you know, falling at home, and was found to have brain metastases, so presented with brain metastases. So came to me via the neurosurgical team, treated with surgery and radiation. And he was not even known to have — he didn’t present with dysphagia at all. They only found esophageal thickening on a scan and that followed up with an EGD. That’s where they found it, and it was IHC 3+. And so that patient started up with FOLFOX, pembro and trastuzumab, and had a good run with it though was quite deconditioned from his status and eventually progressed. And then, now this story is ongoing, started on trastuzumab deruxtecan as per the FDA label as well.

But in terms of how he’s tolerating it, I’d say the main side effects are fatigue, nausea are the main side effects. But the FDA approved dose level for gastric cancer is actually higher than the dose for breast cancer. So the breast cancer dose is 5.4 mg/kg. The gastric dose is 6.4. So I actually brought that dose down, and it led to better tolerability.

DR LOVE: Yeah, I think that’s been seen in other cancers as well when you bring the dose down. But it is interesting. When you think about it, maybe I didn’t really expect, you know, the idea of an antibody-drug conjugate is it’s supposedly just targeting the chemo to the cancer cell. But at least for this drug, which has greater potency and activity, you also see, I don’t know, Deanna, what your experience is, but I think it’s actually classified as severely emetogenic. What do you see? Have you had patients get T-DXd?

MS GRIFFIE: One gentleman that I’m dealing with right now, he came to us, had horrible diarrhea on his last treatment, so he kind of started behind the 8-ball a little bit. But the diarrhea has interestingly improved since we started trastuzumab deruxtecan.

DR LOVE: T-DXd.

MS GRIFFIE: That. Thank you. But he is struggling a little bit with nausea/vomiting and taste disturbance and really struggling with nutrition. Thankfully, this is a patient who is a chemotherapy professional at this point, treatment professional. And he is very committed and very, he’s just willing to do whatever he needs to do. So he’s eating through it even though he’s really struggling. So his nutrition status is pretty good, but we’re really having to be creative in treating his nausea and vomiting. We’re using round-the-clock ondansetron. We’re using palonosetron.

We’re using that at night, 5 mg, and that’s helping a little bit with appetite. And then, of course, he’s using scopolamine patches during treatment. So we’re just really having to think outside the box. And then sometimes, having to treat the symptoms from the antiemetics. So it has been quite challenging. But at the same time, we did the first scan, and his scans look better and his numbers look amazing. Interestingly, we’re following this guy not only with CEA, but also with circulating tumor DNA testing. And we’ve seen that go from 8.59 in December and most recently, I think it was 0.52.

DR LOVE: And we’ll talk a little bit more about that later as well. We’re going to shift over in a second to colorectal cancer. But just getting back to you, Caroline. Anything else you want to say about T-DXd? Of course, the big elephant in the room, so to speak, is interstitial lung disease.

MS KUHLMAN: So I treated a gentleman who had a terrific clinical — radiographic response to T-DXd, was on it for almost a year and then developed, came in with a cough and shortness of breath. And had to come off of T-DXd due to interstitial pneumonitis, which we treated and it improved but his quality-of-life was certainly affected by his lung disease. But had quite a long time of response on T-DXd.

DR LOVE: So, Manish, we were talking about this in an earlier symposium that the breast cancer people are trying to catch this when it’s asymptomatic with just changed on x-ray. So they do screening CT scans looking for this. They want to get it before they get symptomatic. Because if you do, you stop it, give them steroids and you can keep the treatment going. Is that the paradigm you all are going to follow?

DR SHAH: Yeah, absolutely. So you hit it really on the head. When we were first developing trastuzumab deruxtecan, there were people who actually died from the pneumonitis. We call that a Grade 5 event. And the rate of that was about 1 or 2%. And what changed is actually, exactly what Dr Love said, early identification. So you might find small little wispy interstitial lung findings on a CAT scan, a cough, a little shortness of breath going up a hill, very subtle findings. That should trigger, for this drug, a CAT scan and a question, could this be ILD? If you find it early, you can stop the drug, give steroids, reverse it, and continue the benefit. The really unique thing about this drug is that the response rates in breast cancer, other solid tumors, and in colorectal cancer and even in gastric cancer are really quite high, 40 to 50%. This is in the second, third, fourth-line setting. So when the drug works, it can really shrink the tumor. So you really want the patients to get the benefit, but you need to identify this early. So the early deaths that they see, they don’t see that anymore. So a key aspect of this drug is patient education. Do you have symptoms of shortness of breath? We have to know about it.

DR LOVE: So yeah. And not only do you see a lot of responses, but they’re typically pretty long, which is, of course, terrific for the patient. And the other thing that seems to be coming out, John, related to your patient who has got brain mets is initially, they were thinking this wasn’t going to work in the brain because this is a big complex, but it seems like it actually does. And your patient has got brain mets.

DR STRICKLER: Absolutely. In somebody with an upper GI cancer that’s HER2-positive, I think that is a real win-win for that patient, right? Because this is a drug that known to be active in treating central nervous system metastases. That’s been shown out of the breast cancer literature. So this is really an outstanding choice for those patients, unfortunate patients who have that event, to have that as a therapeutic option is a nice plus.

DR LOVE: So we’re going to move on in a second to talk about colorectal cancer. But one of the things that’s so interesting about colorectal cancer is the fact that we’re seeing more and more patients who are younger. And I don’t know, Manish, if you have any thoughts. People debate about why we’re seeing this. But can you kind of put in perspective from your perspective clinically, how often that’s —

DR SHAH: Yeah.

DR LOVE: I ask people to present cases nowadays and two thirds of them are less than 50. Of course, people pick those cases out. But are you seeing this actually in your practice?

DR SHAH: Yeah, absolutely. So initially, when I was starting practice about 20 years ago, the rate of early onset colon cancer, so age less than 50, actually age less than 45 was around 1 in 20, like 8%, something like that. Now, it’s 1 in 5. About 20% of people are early onset. And there’s been a lot of work as to why that might be. There’s some suggestion that it’s related to our diet and a lot of the soda that we drink and things like that might be related. It’s not the typical risk factors. We looked into that, like tobacco. Because in an older person, you have a long time to have these environmental factors like tobacco or alcohol or diarrhea, you know, the bad Western diet. You have 20 years to 30 years to have that. And then ultimately, you develop a polyp that develops cancer. In early onset cases, the timeframe is much, much shorter. So there’s some other trigger. And we really still don’t know much about that.

The other unique thing is that early-onset colon cancers are more left-sided, like in the proximal rectum, sigmoid area, things like that. So the good news about that is that they may often be more responsive to EGFR inhibition and things like that. So the epidemiology is different. But certainly, it’s really become an epidemic. And you guys are probably all aware, that actually triggered the AGA guidelines to change when a colonoscopy should be done. We used to do colonoscopies starting at the age of 50. Now, it’s age 45 because of this early onset.

DR LOVE: So John, one of the things I hear people talk about when they try to explain this is the microbiome in the guy. I’ve heard GI people say I tell my kids to lick the doorknobs so they’ll get more microbes in their belly or something. And there’s research going on, on this where you collect fecal specimens.

DR STRICKLER: Yeah.

DR LOVE: It’s happening all across the country. Any thoughts about that?

DR STRICKLER: I think that’s an intriguing hypothesis. No, not the doorknobs.

DR LOVE: A randomized trial of teaching kids —

DR STRICKLER: So we’re always looking at what might have caused something. Was it the herbicides? Was it this? Was it that? Another possibility is it’s the absence of something that the body needs, right?

DR LOVE: That’s a good point.

DR STRICKLER: To develop and grow. And that might be why it’s so hard to solve the riddle, is because it’s maybe in this very sterile world that we live in, it might be the absence of things. When I look at my patients who are under 40 that present with colorectal cancer, it defies all stereotypes. It’s successful executives. It’s healthy, thin marathon runners who do everything right and never touch a cigarette in their life. And it’s people you would never expect to have cancer. And I do think that this is an extraordinarily complicated riddle to solve. Even just describing the microbiome is quite challenging. There was some interesting work shown at AACR in the last month proposing a model of accelerated aging to potentially explain the early onset colorectal cancer phenomenon, which I’d love to learn more about. I was not at AACR, but I found that to be a very interesting hypothesis as well. But cancer is something that grows out of inflammation, so inflammatory states whether it be that chronic reflux that causes the gastroesophageal cancer or inflammation in the colon. These are things that drive malignancy. And so we need to understand what is driving that inflammatory pattern that’s kind of causing the genesis of that cancer. And we don’t have the answers.

DR LOVE: And the other thing about these younger patients with colon cancer is that they have little kids.

DR STRICKLER: Yes, they do.

DR LOVE: And that’s the next topic. We already dealt with that a little bit. Jessica Mitchell is a GI nurse who has worked with us forever. She actually brought up this issue to us early on, many years ago. So here are her thoughts.

MS MITCHELL: Cancer doesn’t happen to an individual, cancer happens to a family system, and you have to involve everybody in that family system to try to get the best outcome for your patient and all of the other members that are going through it with that person at the same time. So to try to address those needs in a multidisciplinary fashion I think is really important in future oncological care. 

I really struggle on a daily basis, how do you incorporate the family in understanding and coping with the illness? These patients are at the prime of their life, they have young children, they are in the middle of their careers, and how do you cope with all of these responsibilities as well as your own mortality?

I think involving patients in, like, outreach sources or advocacy is critical, because I feel like so much of the available resources are for older patients, and people who are going through this at a 30-year-old stage is very different than a 60- or 70-year-old, and I think you only understand it if you’ve walked through it. So I encourage people to reach out. And now with social media, there’s so many different Facebook groups and ways for them to receive information. It’s a delicate balance between getting information that may not be applicable to your medical situation but also getting the support and understanding from someone who’s going through a similar journey.

DR LOVE: So Caroline, actually, earlier today, we were looking at a 112-page book that was written for patients on myelofibrosis that had everything you could imagine for myelofibrosis. But what about for these younger patients, whether they have colon cancer or, obviously, we see younger patients with breast cancer, et cetera? Any thoughts about how you sort of strategize as you look at the family?

MS KUHLMAN: Yeah. I think it is a unique population with a whole set of different stressors and these are people working, usually working people who have families, their families are dependent on them working, and a diagnosis of cancer throws a wrench in what is typically your most productive years, career-wise, family-wise. There’s a lot going on. At our center, we actually have a young patient’s group where we offer support to people, younger patients with new diagnoses of cancer. We’re trying to utilize resources like social media, things that are more attuned to that age group. It’s a uniquely challenging group because it’s not, you know, you’re not, you have a lot of responsibilities, not a ton of time, so you have to be very strategic about the kinds of support you offer.

DR LOVE: I’m curious, Deanna, I wouldn’t be surprised if patients would ask for your advice about what they should say to their kids.

MS GRIFFIE: Sure.

DR LOVE: And based on their age, how do you respond?

MS GRIFFIE: Yeah. First of all, we’re very fortunate that we have an amazing therapy group that subspecializes in working with children of people diagnosed with cancer. So that’s a tremendous resource if parents are willing to use that and want to connect their children. Unfortunately, you have some patients that don’t want their kids to know very much. And at the end of the day, while that’s really hard not to bring my own bias to the table, it is that patient’s decision. They get to decide how much they want their children to know and at what timepoint. But I think from me, they need me to be honest with them so then they can decide how they want to feed that to their children. And sometimes, it is just allowing whatever time during that visit they need just to spill and just to kind of vent.

And you brought up an important point. These are people that work, they need to work, they take their kids to school, they pick their kids up, they have to be at PTA meetings and whatnot. And so we really have to work very closely in their timeframe. They’re also going home with chemotherapy pumps for 2 days oftentimes. And that’s a challenge, especially when you’ve got 2 and 3-year-olds that want to crawl all over you and treat you like you’re their personal jungle gym. And you want that. That’s a very important time for a mom and baby or dad and baby. And you’re kind of interrupting that. So I think it’s important.

And the other thing that we’re seeing especially, and I think everybody is, these cancers are nasty. They’re aggressive for reasons I’m not sure we fully understand. But I think we do have to be careful in the way we approach that. Just because they’re 20-something or 30-something-year-olds, that doesn’t mean we have to hit them with the kitchen sink and make them feel terrible. I think it’s important to balance our desire to be aggressive as clinicians with what they need to carry on at home.

Selection of Appropriate Candidates with Localized Colorectal Cancer (CRC) for Adjuvant Therapy

DR LOVE: So we’re going to do a little bit of a survey in terms of taking a look at what’s going on in colorectal cancer, some highlights in colorectal cancer, some of the major advances that have occurred in the last few years because of clinical trials. And, John, you’ve been very much involved in one really important strategy that everybody in oncology is asking about, adjuvant therapy of colon cancer. Because you all really are the first ones to bring in cell-free DNA MRD as an assay. You actually did that. Can you talk about what that is, how it ties into the strategy for localized disease, and how it manifests in your practice?

DR STRICKLER: Yeah. So this idea of, you’ll hear it called MRD, some people think of it as minimal residual disease. Sometimes, it’ll be called molecular residual disease. And essentially, it’s this idea that you can detect tiny fragments of DNA from a cancer in the bloodstream when you can’t see that cancer on, say, a CT scan. So colorectal cancer, I would say, is one of the better case examples for using this MRD testing in the clinic. The reason is because if you think about somebody with Stage III disease, there, our standard of care is to give everybody adjuvant chemotherapy. And yet, over half of all patients were cured with surgery alone. So in many cases, we’re giving people a lifetime of neuropathy when they were already cured with surgery. So then that’s the question of whether we’re overtreating many patients. For Stage II disease, the standard of care for a lower-risk patient is not to give any chemotherapy at all. And there, 15% to 20% of those patients will have the cancer come back. And so we’re potentially undertreating these groups of patients. So the idea is, can we potentially bring a technology in to help us make smarter decision about who gets chemotherapy and how much chemotherapy to give so that if that person is exposed to potentially a risk of a lifetime of neuropathy, it’s appropriate to their risk of the cancer coming back. So that’s the basic idea here.

Now there have been some really intriguing studies published and presented over the last couple of years incorporating this MRD testing in the clinic. Probably the most important literature that’s come out to date has been in this lower-risk Stage II group of patients. We had an important study come out of Australia called the DYNAMIC trial where instead of the doctor just deciding if a patient would get chemo or not in a lower-risk Stage II disease, they actually randomized patients to either the doctor’s decision or get one of these MRD tests and make the decision from there. And one of the interesting findings is that patients who got randomized to having the MRD decide were half as likely to get chemo as those patients who, so the physician choice group were twice as likely, those patients were twice as likely to get chemo. But in the group of patients that had MRD-based decision making, they were more likely to get aggressive chemo. So they were higher-risk patients. They were only getting chemo if they were positive on this test, which meant they had a very high risk of the cancer coming back. So they were more likely to get aggressive chemo. When they looked at the 2-year disease-free survival, it was identical. So the lesson is if you use the MRD testing in Stage II, you’re half as likely to get chemo, but it doesn’t jeopardize your disease-free survival 2 years later. So really intriguing, provocative data.

I would say that we are now doing these types of trials here in the United States, some very important trials where we are using the tumor-informed assay to help us guide whether to give chemotherapy at all in a low-risk Stage III patient population. That data is not out yet. So for now, we’re not using the MRD testing to decide in a Stage III setting. We’re still following standard of care outside of trial. But I’d say that in our clinic, we are now increasingly using the MRD test for these Stage II patients.

DR LOVE: And I can tell you that people with all kinds of cancers are getting MRD testing because it kind of makes sense. And you can order it in patients. And the academic people say we need trials to prove it, et cetera, which is totally understandable. A lot of people out there in practice are already rock and roll, they’re ready to go. You see the tumor there, right? That’s the whole idea behind adjuvant therapy. It also gets into this issue of the advantage of so-called liquid biopsy, Manish, versus tissue. Of course, until maybe 10 years ago, it was all tissue. Then, we started to see we could look inside the blood and still see biomarkers. And here, you can do it repeatedly.

DR SHAH: Right.

DR LOVE: Where you can’t do that with tissue. Any thoughts about how this plays out?

DR SHAH: Absolutely. So a liquid biopsy basically is you take the patient’s blood sample and you, as Dr Strickler said, you look for fragments of the tumor DNA in the blood, and we can free sequence that. So some forms of MRD testing it just gives you positive or negative or gives you a percentage. But other forms gives you the mutations and you can actually track the mutations. So one thing that actually was published in the New England Journal in lung cancer when they used the tyrosine kinase inhibitor, they could track the EGFR mutation over time and reintroduce the drug in patients where it was gone again. And actually, that work is being done in colorectal as well, for example, for KRAS mutations, which is very common. Patients who have a KRAS mutation don’t benefit from mirvetux or panitumumab. And if you’re wild-type for KRAS, what can happen is that a KRAS clone could actually start to grow, developing resistance to mirvetux or panitumumab, and so then the drug doesn’t work anymore. But if you’re able to do this serial testing that Dr Love mentioned, then over time, the wild-type clones can overcome the mutant clones, and you can rechallenge the patient with mirvetux and panitumumab. And that actually has shown some evidence of efficacy. So the trials to demonstrate that that’s the right thing to do are still ongoing. But people are doing it now. They’re tracking the blood and if the clone becomes wild-type, so if the KRAS mutation kind of dies away, then you might have an opportunity to give this patient a drug that worked previously.

DR LOVE: So speaking of younger people, Caroline, 29-year-old man. That’s the way it begins. What happened?

MS KUHLMAN: Yeah. So this question around ctDNA. When I first started practicing 25 years ago and you have conversations with young patients with colon cancer, a Stage II colon cancer, you say to them you’re either in the group that’s cured with surgery alone or you’re in the group that needed chemotherapy to cure them or you were destined to recur no matter what we do. It was a very unsatisfying conversation. So the idea that we can use a marker in the blood to give us some sense of, do you need it. And you would argue in a 29-year-old, he had a T3 tumor, he had no positive nodes, and they had a good sampling, 0 of 26 nodes were positive.

DR LOVE: That’s important too, that they get enough nodes.

MS KUHLMAN: Right. So his high-risk feature is that his tumor was classified as poorly differentiated, so you could say maybe that portends a more aggressive tumor. The guy is 29, he’s a musician, he plays guitar. So the idea of saying, well you’re young and you’ve got this one feature we’re kind of worried about, we’re going to offer you FOLFOX for 6 months versus 3 months to have a test that could say you have, that’s positive, that says we can see tumor, you know fragments of your tumor in your bloodstream, is a compelling reason to actually consider it. Because it’s highly associated with the risk of recurrence.

DR LOVE: PSA, right? All the time.

MS KUHLMAN: Highly associated. And so for this gentleman, he had his surgery, we had the talk. He had, Natera, he had a blood test and it was positive. And so he went on to get FOLFOX. We followed his ctDNA blood tests serially through his adjuvant therapy. And when he cleared it, we dropped the oxaliplatin and completed his 6 months with, he got 4 cycles with oxaliplatin and then we took it out and just finished with 5-FU to reduce the amount of neuropathy he would develop. But without that information, it would have been a very different conversation.

The Current Role of ICIs in the Treatment of Metastatic CRC (mCRC)

DR LOVE: So I want to also get into the issue of immunotherapy in metastatic colorectal cancer and particularly in the so-called MSI-high patients. In MS-stable patients, it still doesn’t seem at the present time we’ve seen enough activity to justify using it. But as we were talking about earlier, MSI is a completely different story. Manish, about what fraction of patients are MSI-positive with colorectal cancer?

DR SHAH: Yeah. So it’s about, you know, it’s not too common, it’s about 5 to 10%. But actually, we think of it as a lottery ticket. No one with cancer really has a lottery ticket, but that’s how different it is. So there was an important trial called KEYNOTE-177 that actually compared for MSI-high colon cancer doing pembrolizumab immunotherapy versus chemotherapy. And chemotherapy has all the side effects of neuropathy and things like that. So this study showed a very dramatic benefit in terms of survival for, disease-free survival in terms of patients who were MSI-high and got immunotherapy from the beginning. At 2 years, there was about a 50% improvement in disease-free survival compared to — or people without progression compared to people who were on chemotherapy, which it was about only 20%. So that was a huge benefit in patients who got pembrolizumab. So based on this study, it’s actually now the first treatment out of your shelf. So if you have a patient with metastatic colon cancer, once again, you need the biomarker. If you’re MSI-high and you have metastatic disease, you should consider pembrolizumab.

And I think the one thing that we haven’t really talked about are, what are the contraindications of that? And I’m sure we’ll talk about that soon. But there are some people that have already underlying autoimmune disease like Crohn’s disease or ulcerative colitis. Particularly in the young population, they have inflammation, chronic inflammation that may feed to their colon cancer. So these are relative contraindications to immunotherapy because immunotherapy could hyperactivate their autoimmune disease and lead to more symptoms. But that being said, the majority of people tolerate pembrolizumab or nivolumab and ipilimumab really pretty well, and it can be a game-changer.

Tolerability and Other Practical Considerations with ICIs

DR LOVE: So it’s interesting, this idea of autoimmune preconditions, John, and whether, you know, because we know they can get worse with immunotherapy. But here, you have a really great benefit. In other situations, you have maybe borderline, but this is major benefit. You’re avoiding chemotherapy. What’s your sort of cutoff for how much autoimmune disease? If they have Crohn’s disease, et cetera, do you look and see whether it’s active or if they’re on treatment? Also, what about patients who had solid organ transplants? Kidney, liver, heart.

DR STRICKLER: So I have shocked myself at my willingness to kind of test the limits of this. And one of the things about autoimmune adverse reactions to this class of therapy is it’s extraordinarily unpredictable. People that I thought would sail through sometimes get horrible life-threatening autoimmune disease. Other people who I think it’s a really terrible idea that I’m giving immune therapy but I’m doing it anyway, just sail through, no problem. I have had a number of patients with a history of ulcerative colitis and Crohn’s disease who I’ve given anti-PD1 therapy to and have had no problems so far. Knock on wood. Maybe my number’s up one day. But I even had a case recently within the last year of a patient who had recurrent metastatic esophageal cancer that’s MSI-high and she had a heart transplant. And if you look at the numbers for what that person can expect with cytotoxic chemotherapy, it’s a median survival of less than a year. Now everybody in this audience knows that when you get responses to these types of therapies, they are durable. I think we’re even using the c-word in many cases, the cure word. And so I said to her, I don’t think this is a good idea to give you immune therapy if you’ve got a heart transplant. And her transplant cardiologist contacted me and said you can do this, I’ve got it, I’ll take care of the heart.

DR LOVE: Whoa.

DR STRICKLER: I’ll take care of the heart.

DR LOVE: Whoa.

DR STRICKLER: We’ll check the BNP.

DR LOVE: We heard a case of a patient who had that and had rejected it and died.

DR STRICKLER: Yeah. Yeah. So this patient said I know the risks, I’m going to do it. And the cardiologist was behind it. And she has had a durable complete response.

DR LOVE: Wow.

DR STRICKLER: The cancer is gone. The heart is healthy. She feels like a million bucks. And she was getting quite symptomatic from carcinomatosis when we started. So you hate to be painted into a corner to ever have to make that choice, but you can understand why patients look at this data and twist your arm until it breaks to give them a shot at it, right? But like I said, I’ve done things with immune therapy that I never thought I would, but you really do have to have that conversation very explicit with the patient about what they’re risking by taking this kind of a therapy. Because they see the upside, but we as providers, we know when these things go bad, they go horrible, horribly, right? And we’re not in this line of work to make people feel terrible or to harm them. So it’s a very difficult balance. I would not encourage routine use of anti-PD1 therapies in people with solid organ transplants. But it just goes to show you that, you know, I think that we have to look ourselves in the mirror and just be really careful about how we approach these issues. But thankfully, that n of 1 went okay.

DR LOVE: It’s all well and good to say well, this patient had a terrible prognosis, et cetera, et cetera, but it’s a horrible feeling if you cause a patient to die.

DR STRICKLER: Absolutely.

DR LOVE: Even if they have a terrible disease. We had a case of a patient with lung cancer, multiple sclerosis. The doc was like, you know, talk to the neurologist, et cetera. The patient wasn’t symptomatic. They treated, complete response, did great, no problem with the multiple sclerosis. PD1 was 0, incidentally. But the patient was totally informed, very into it, had seen several consultants and said okay, let’s do it. Manish?

DR SHAH: Yeah. I was just going to say that this is really a remarkable story. So whenever these drugs are developed, the clinical trial eligibility criteria, they have a hard rule, no autoimmune disease, no transplant, no whatever. And so as these drugs are now being used in the community, this is actually how we kind of explore a little bit of the boundaries. And so, in fact, although it was felt to be an absolute contraindication, it turns out that about one-third of patients, maybe even half, with an autoimmune disease can actually get the PD1 inhibitor without a severe complication from their autoimmune disease. So that is a trial that the NCI is running now specifically in patients with rheumatoid arthritis, Crohn’s disease, lupus, you name them. And actually, some are better tolerated than others. So I think that this is a really important thing. The patients have to be informed, but you also have to sort of say the data are evolving. That’s kind of how it works in oncology.

DR LOVE: And how it works in oncology is also if something looks good, then we double up on it. We were talking this morning in our HCC session about anti-CTLA4 plus PD-1, which now is an option in hepatocellular cancer.

DR SHAH: Right.

DR LOVE: So this is 2 forms of immunotherapy, one, anti-PD-1 and then a drug like ipilimumab. And I think there’s actually a big paper at ASCO on more data on looking at this more intensive therapy, more autoimmune problems. If they have a prior problem, it’s going to be more likely to be accentuated. But the initial data looks pretty impressive. We’ve been talking about hazard rate. You see up there, 0.21. The lower it is. That’s an 80% difference in the chance of survival. So at any point in time on these curves, a patient who got the IO is 80% more likely to be without disease. So that’s a huge benefit. You had a patient, Manish, who got ipi/nivo. I don’t know if it was on a trial or not. But how did the patient do in terms of autoimmune and response?

DR SHAH: Yeah. Absolutely. So as you said, this is a dual strategy to release the break on the immune system and allow the immune therapy — or the immune system to work against the cancer. There is more toxicity with the ipilimumab and nivolumab, more risk of diarrhea, more risk of rash, other things like that. And in some patients, it works really, really well. In fact, actually, we talked about MSI-high colorectal cancer and using that first and it does really, really well. Most of us stop the treatment after about 2 years. And then about half of those patients, after we stop the treatment, the cancer will come back. And at that point, there’s a debate what to do. And I don’t know, John if you have this experience, but I actually then go to ipilimumab and nivolumab in that setting. And about half the time, there’s another significant response to therapy. So these drugs really can work. In my patient that we’re talking about, he had MSI-high colorectal cancer, he got ipilimumab and nivolumab. It’s a tongue twister at 8:30 on Saturday night. And he did really, really fair well. He did have rash, worsening arthritis, and it could be managed. But the other thing that we’re learning is that we’re not afraid as much in my practice to use steroids to blunt the immune response. And that doesn’t seem to significantly outweigh the benefit from the immunotherapy as well.

DR LOVE: So I can’t resist. An 88-year-old woman.

MS GRIFFIE: I know.

DR LOVE: Go for it.

MS GRIFFIE: Alright. My story is not nearly as dramatic as Dr Strickler’s. But this was an instance where we were very reluctant to head into treatment. But we have this 88-year-old female that the doctor I work with had to do an inpatient consult. She had been admitted with a pretty bulky, obstructing tumor. She went for a right hemicolectomy. And tumor was MSI-high, MMR deficient. And so she saw us in clinic, and she basically begged us to do something. She was like, this is not what I usually look like. She really struggled to recover from surgery. She said I live alone, I’m a potter. And she is this kind of famous potter in our area. She said this is not who I am and this is not what I’ll be if you just believe in me. And so we very reluctantly started her on pembrolizumab, and honestly, just jumped off the cliff with her, and fingers crossed. She’s 16 months into it now, and peritoneal disease has gotten much, much smaller. She’s got one little ditzel in her liver that we’re still watching and we’re not seeing any lung mets anymore. So it’s just been this tremendous response. And she’s churning out pottery all the time and going to shows every weekend. And she probably does more on a weekly basis than I do. So pretty impressive. And it kind of was a lesson to us that the number that we’re seeing in that age doesn’t necessarily need to mean we’re not doing anything here.

DR LOVE: So do you find oncology depressing? Sometimes, yeah. But sometimes, no.

MS GRIFFIE: Yeah, exactly.

DR LOVE: Inspiring sometimes.

The Role of TAS-102/Bevacizumab in the Management of Relapsed/Refractory (R/R) mCRC

DR LOVE: Okay. Let’s talk about once we sort of get beyond these. And, John, can you talk about what TAS-102 is, the fact that now we’re combining it with bev, and other alternatives kind of once we get beyond chemotherapy, VEGF, et cetera?

DR STRICKLER: Yeah. So TAS-102, trifluridine/tipiracil. There you go. I can do it on a Saturday night. There you go. So this is, think of it kind of as a cousin of 5-FU. It kind of has a similar mechanism of action. So it’s a traditional cytotoxic chemotherapy. It was FDA approved, gosh, about 8, 6 to 8 years ago as a single agent in the refractory setting, so after the patient had exhausted standard front-line chemotherapy, FOLFOX, FOLFIRI, et cetera, and had a very small survival benefit, just under 2 months compared to supportive care alone. In Europe, they started to look at whether the addition of bevacizumab to TAS-102 would improve progression-free survival and overall survival. And there was some intriguing data out of Europe that, in fact, adding bevacizumab to that would, in fact, drive longer duration of benefit.

And we in the United States, we don’t need a lot to prove to us to give more bevacizumab. So we took that data and it was part of our NCCN guidelines and we’ve been doing it for years. But they then did the SUNLIGHT trial to actually prove that it, in fact, helps patients. And so it was a randomized trial of TAS-102 by itself or TAS-102 plus bevacizumab. And, in fact, it did confirm that, that combination leads to better progression-free survival and overall survival. So that is our standard of care now for TAS-102 where the patient’s eligible to take that treatment.

DR LOVE: And it’s a very interesting part of the management of colorectal, from my point of view, colorectal cancer from my point of view, because the benefits here are pretty minimal, or borderline, shall we say, but the toxicity is generally very minimal either. And patients often do want to receive treatments even if it’s not going to be the kind of benefit we just talked about, these incredible responses with MSI-high. Manish, I want to kind of get a little bit more into this. And actually, John, you have a patient I want to kind of hear how the thinking went about that. Because it’s not so much that it’s an interesting high-tech situation, it’s just an interesting human situation where it’s kind of hard to figure out what to do. But maybe, Manish, you can sort of paint the options that patients have. A lot of these patients are going to get more than 1 of these therapies. So often, it can become a question of what comes first. We had regorafenib as an alternative in this space, sort of a VEGF-directed TKI that there are a lot of tolerability problems. If anybody here has ever had a patient on regorafenib, they probably are aware, you have to deal with the dose, et cetera. But now, we have another similar agent that, I’m not sure, but it seems indirectly maybe it’s going to be less toxic, fruquintinib. So for these patients and, Manish, you’ve gotten beyond the chemotherapy, now we’re getting into really moving towards end-of-life or palliative care, how do you think about the pluses and minuses of these options?

DR SHAH: Yeah, exactly right. So I guess I have an anecdote. A lot of patients talk about, so how am I going to do, doc? What’s it look like for me? And we can, as doctors, we can tell people the numbers, and the median is sort of the average. None of my patients feel that they’re average, right? They’re all going to beat that. So the numbers don’t actually matter that much in that setting. But after 2, 3 years of treatment, patients kind of know kind of what happens. They try something, it may work for a while, it may not work. We have to deal with the side effects. And then if it doesn’t work, then there may not be something else. There may be kind of a trial that people are looking for that. So that’s the kind of population that’s ready for a TKI. The TAS-102, the fruquintinib, regorafenib. In my practice, the regorafenib, as was mentioned, really the hand-foot syndrome and the fatigue and things like that really is really challenging. So I don’t really go to that one too often. Fruquintinib just got approved 6 months ago. We’re just able to get the drug now. And it’s an oral pill, pretty well-tolerated. TAS-102 with bevacizumab is really quite a nice combination as well. And so we’re trying to manage toxicity in people who have a borderline performance status with expectations that this may or may not work.

That being said, I had recently a patient. He was a mail carrier. He was retired. He was on TAS-102 for 18 months. He was able to retire, moved down to Florida. And unfortunately, it did stop working but it did, there’s no doubt in my mind that it gave him an extra year that he wouldn’t have had. So I think although we’re a little bit sometimes not as excited about these TKIs, I think if patients have the performance status you counsel them on the side effects, there’s proven data. It’s better than best supportive care. And actually, you never know. That’s the thing. We don’t have a biomarker. You never know which patient is going to have the significant benefit. So I think we can let patients benefit it out.

DR LOVE: So Caroline, I’m curious how you see patients, how you process with patients these kinds of decisions. They may be in good condition. They may be very symptomatic. Hospice is on the table. When you look at the papers on these therapies, they don’t seem dramatically effective, but you hear cases where people really seem to have some human benefit.

MS KUHLMAN: Yeah.

DR LOVE: How do you see people processing this?

MS KUHLMAN: Yeah. I think any time you’re talking about a third-line therapy for a metastatic cancer, you really have to have an understanding of what the patient’s goals are. Once you’ve progressed on our first and second-lines, the third-line is apt, you’ve certainly seen chemotherapy, you’ve had side effects from it. You’re probably more tired, more worn down. And so those kinds of, how do you want to spend your time, right? This third-line therapy isn’t a cure. And what are your goals if you know your time is limited, is the discussion that needs to happen as you consider. If your goal is I want to spend as much time as I can traveling and I don’t really want to come to clinic much, then maybe a third-line therapy isn’t really consistent with how you hope to spend your time. But then there are patients who say, I want to do whatever I can to live as long as I can or even if the benefit is minimal, I still want to do it. So helping to understand, how do they approach a third-line therapy. I think our — I have a patient who was young, she was 56, 55 who blew through FOLFOXIRI plus bev and then got NALIRI in the second-line as got a little bit of reprieve. And then the discussion was, once she progressed on that regimen, this is an approved regimen that does improve survival. And as long as we can talk openly about what the side effects are, how do we optimally manage it so that you can continue to do the things you want to do even in the setting of ongoing treatment. And her decision was, you know, I realize I’m more apt to have low blood counts because I’m heavily pretreated. I’m probably going to have some nausea. I’m willing to do that. And so she started that therapy. She’s actually tolerated it pretty well.

DR LOVE: That’s great.

The Potential Role of KRAS-Targeted Therapy in the Management of mCRC

DR LOVE: So after 16 hours, do you think you can take 1 more biomarker? Here we go. One more. KRAS G12C. John, go for it.

DR STRICKLER: Yes. So this is our latest and greatest biomarker. And it kind of reminds me of this story. They were joking with me. The pathologist said, you know, John, our least favorite week of the year is the week after ASCO. Because there’s some new biomarker they have to worry about that everybody wants tomorrow. Right? But I’ve worked with outstanding pathologists. And if it needs to be done, they’ll get the biomarker ready.

But KRAS G12C is a mutation that interestingly, it’s most common in lung cancer. It’s seen in about 3% of colon cancer. But it is a classic driver of cancers. And, yeah, that’s my slide from a while back. KRAS as a mutation is quite common, especially in pancreas cancer, nearly 90% of pancreas cancers, about 40% to 50% of colorectal cancers. But KRAS G12C is a specific variant, a type of a KRAS mutation. It will drive resistance to our anti-EGFR therapies. And we have this new class of therapies. It was thought for many decades, in fact, when I was a fellow, which was not tremendously long ago, but it was called an undruggable target. There’s no way we’re ever going to figure out a way to attack KRAS. It’s too hard. It’s too narrow a target.

Well, thankfully, we now have KRAS inhibitors coming into the clinic. This is the very first one. There are some unique features to KRAS G12C that make it a little bit more favorable as a drug target. The bottom line is there are drugs that can lock onto KRAS G12C in a very effective way. And basically, if you think about a KRAS mutation as a light switch that just can’t turn off, this one can grab onto that light switch and finally get that light to turn off.

And so KRAS inhibitors, they’re now approved for lung cancer, KRAS G12C, adagrasib and sotorasib. And in colon cancer, it’s been a little tricky. So you would think that a KRAS inhibitor would work just as well in lung cancer as it does for colon cancer, but it’s actually not true. The response rate, if you give a KRAS inhibitor to a colon cancer patient, KRAS G12C, it’s about a 10% response rate. But in lung cancer, it’s about 40% response rate. So there’s something in the wiring of a colon cancer that keeps that light switch on even when you’ve got the KRAS G12C inhibitor doing its job. And that is this so-called feedback loop. So one of the things that unique about colon cancer is it’s a very EGFR-driven cancer. And that sits at the top of the cell surface, which you can see in the slides here, and EGFR will drive signaling down that pathway and rescue the tumor cell from the KRAS G12C inhibitor. So one of the things we’ve learned is that to effectively treat a KRAS G12C mutated colon cancer, you can’t just give a KRAS G12C inhibitor alone. You have to add an EGFR inhibitor with it. And only with the combination can you effectively turn that light switch off.

DR LOVE: And we saw a similar thing with BRAF.

DR STRICKLER: Absolutely. It’s actually the exact same model.

DR LOVE: Right.

DR STRICKLER: And, in fact, a lot of the same experts that discovered that mechanism of resistance got very involved in this same work.

DR LOVE: So I’m just kind of curious whether or not you’ve had any experience with these drugs and particularly, what kind of tolerability issues. I think you told me you had a patient who got one of these drugs.

MS GRIFFIE: Yeah. We did. Initially, it was on a trial. But then, we had to come off the trial for multiple reasons. But was doing really well on sotorasib. And so we reached out to the sponsor and got off-label approval to continue sotorasib. We have had to be very creative with dosing just for tolerability. So there have been times we’ve had to dose reduce to make that more amenable. And, of course, then added the p-mab, panitumumab, onto that later. And so far, so good. I wouldn’t say he’s thriving, but he’s surviving. And he’s happy with that. And I guess his quality-of-life at this point would not be what I would choose for myself. But as we’ve talked about, it’s what he wants. And he and his wife have been very straightforward that they want as much time as they can. They want to see their grandson graduate, and so he presses on.

DR LOVE: Manish, any difference? Again, we talked all week long about drugs within the same class. Any differences between the 2 drugs?

DR SHAH: Oh, the sotorasib and adagrasib. In fact, right before we started, I asked Dr Strickler that exact question.

DR STRICKLER: I was about to answer him and then you started talking, so I couldn’t tell him the answer.

DR LOVE: Well, now you can.

DR SHAH: I’m going to phone a friend, actually.

DR STRICKLER: Yeah. So I have a tremendous amount of experience with sotorasib and sotorasib and panitumumab. We were one of the early sites as part of that trial. So in fairness, in my own personal experience, I have a lot of experience with sotorasib. I can tell you that it’s very difficult, when sotorasib is given by itself, it’s very difficult for me to identify any adverse events or side effects related to the sotorasib, in colon cancer specifically. The story with lung cancer is a little bit more complicated. But thankfully, I don’t need to talk about that in this room today. But for colon cancer, it’s a very clean drug. I had a patient call me one time and say, Dr Strickler, my dog ate all my sotorasib pills.

DR LOVE: Wow.

DR STRICKLER: The whole bottle. And this was one of those Saturday calls that I get. And so is this something that you would worry about for your patient, right? Yes. You don’t want the dog eating all the pills. But remember, this drug only binds the mutant. It is an extremely selective drug against KRAS G12C. It has no activity against wild-type, normal KRAS. So that’s why it’s so well-tolerated. So I said to her, I’ve never heard of this scenario before, but I can’t think of any reason why this dog would get sick from this pill. And the dog was fine.

DR LOVE: Wow.

DR STRICKLER: So because it only attacks a mutant protein. So where you tend to get the side effects is when you add something else in there like —

DR LOVE: Like an EGFR antibody, for sure.

DR STRICKLER: Exactly.

DR LOVE: What do we know, again, getting back to this issue, even though you’ve had a lot of experience with sotorasib, compared to adagrasib? From what we can tell in the research, is there any difference, significant difference?

DR STRICKLER: Yeah. So I guess I avoided that one, didn’t I?

DR LOVE: I won’t let you go though.

DR STRICKLER: You tried to pin me down. So it’s interesting. The initial data that you saw, just cross-trial comparison, would hint that maybe there’s a little bit more activity with adagrasib, slightly higher response rates. They were also describing longer progression-free survival. There was also a hint that maybe there were more side effects related to adagrasib. Interestingly, they just did a large 92-patient experience with the adagrasib/cetuximab combination, and the response rate there was almost identical to the sotorasib/panitumumab. And I’ve always felt like there are 2 aspects to what makes a drug great. One is response rates and shrinking a cancer. And the other is tolerability. And when you bring a drug into the clinic, that tolerability becomes a really key factor for how long somebody can stay on something. And I think that’s really where I’ve personally had very good experience with that sotorasib/panitumumab combination. And I have that bias because we ran the trial in our area and we also happen to be in a state in the country where there’s about a 25% risk of anaphylaxis to cetuximab. So it almost forces me to give that sotorasib/panitumumab combination. But I personally, if you were to pin me down, I would say there’s no meaningful difference in activity between the 2 drugs, or tolerability. I consider them to be largely interchangeable. Now there is a new KRAS G12C inhibitor coming in the clinic called divarasib, which is not available to us yet. They have published some very intriguing response rates and PFS data. And I would love to see that data more mature because that data really was impressive.

DR LOVE: So I’ve got a dog story for you. This is for real, of a dog who grabbed a bottle of imatinib and threw it out the window while the car was going down the turnpike. So $10,000 bouncing on the — alright. So we’re going to finish out here with some video input and try to bring it all together. And particularly, again, to think about people who are just coming into the field and sort of the common question that people ask us, isn’t it depressing? Tiffany Richards is a nurse we’ve worked with many, many years in myeloma from MD Anderson. Here’s what she says.

DR RICHARDS: Yeah. I get that a lot. So in December, it’ll be 30 years since I graduated nursing school, and the majority of the time has been in oncology. And I don’t view it as depressing at all. I get to meet some incredible people that I never would have ever — sorry, I’m really getting choked up about it — I never would have had the opportunity to meet some of the amazing people that I’ve met, people that have touched me in ways that I can’t even begin to describe.

Every Christmas, I have 2 ornaments from 2 different patients back it was probably like 26 years ago. Every Christmas I put those up, and I think about those 2 women. If I wouldn’t have done oncology, I would never have had that experience. I never would have had that ability to develop those relationships.

And I think with all the progress being made in oncology now, like, it’s not how it was, like, decades ago. People are living longer. They’re living their best life even with a cancer diagnosis.  

DR LOVE: Do you want to tell me a little bit about the 2 patients?

DR RICHARDS: It was when I worked on inpatient as an RN and just had this rapport with them. And so one Christmas, they had given me an ornament, and it was a nurse angel. And so you have these moments that I would never — I just can’t imagine working in any other field in medicine.

DR LOVE: Caroline, any thoughts?

MS KUHLMAN: Well, I’ve been an oncology nurse for almost 35 years and an NP in oncology for 25 years. And I would say there are definitely moments of sadness, but what we have the opportunity to do for patients, the impact that we can make, even if it’s small, in patients that have bad disease that we can’t cure, but we can still make a difference for them. And the amount of creativity and resourcefulness and effort that you get to spend on this very important priority, you never have to ask yourself, is what I’m doing important or does it matter? I think oncology continues to grow. We are leaps and bounds ahead of where we are, particularly in GI cancers, from when I first started. And that’s every year getting better and better. So we are helping people live longer, live better. And it’s inspiring work.

DR LOVE: I mean, we’re not trying to overstate it. It is challenging as well. And I think maybe it takes a special kind of person to get gratification out of these types of situations. I guess we all have to figure out what works for us. Here’s some other thoughts from Ms Richards. Deanna, I’m curious what you think about this. Here’s Ms Richards.

Any advice to people just entering the field?

DR RICHARDS: Yeah. It’s hard because you’re going to have relationships that form, and if the patient dies it’s going to be painful, and it’s going to be sad, and you’re going to cry. But that’s okay. I don’t think we have to go around as robots. I mean on some level you do have to establish some boundaries with yourself because you can’t be super engrossed with your patients, but it’s okay to form bonds with people. And just to push yourself a little bit further than what you thought. But I would just say stick with it because at the end of the day, I think for most people, they’ll end up loving it.

DR LOVE: Deanna?

MS GRIFFIE: Absolutely. I think I could not agree with that more. And I think everybody approaches things differently, but I personally have found it to be the absolute most rewarding thing. And I knew early on as a baby nurse that I wanted to go to oncology and so I ran to get there. But it just felt more like a personal thing to me. And over the years I’ve done this, certainly, I have borne witness to great suffering, and that can take a personal toll. You’re not human and you can’t just forget those things and just put them to the side and pretend they didn’t happen. But I think it’s important if you do this work. A, I think it’s important work, and I think that what we do has immense value in so many ways. I think we meet patients at a time where they are absolutely spent, and we meet them in some of their darkest moments. And the fact that they open their arms and allow us in and entrust us with their lives and their families and their care and their future, I think that’s a tremendous honor. And so I personally leave my stuff at the door every day so that I’m worthy of that honor. But I also think it’s important to have a place to process those times of sadness and those times where it just feels heavy, every Christmas. It seems like everything goes sideways from Thanksgiving to Christmas. And so just having, whether it’s your team. And we at Duke, I’ve got to tell you, we are so blessed. We have an amazing group of providers and practitioners that we kind of bounce things off of each other and it’s a safe place to say, I am struggling because I just lost this one, and somebody will hold you and hold you up. So I think that’s important too, finding a colleague that you can kind of decompress with.

DR LOVE: So one of the comments from one of the nurses was, this is the most grateful group of people she has ever met. And this idea of the nurse angel, that’s for real. People appreciate very, very much what you do. And we appreciate you coming here. We appreciate you. Next year in Denver — 50, right, 50 years for ONS? I’m already ready with my Molly Shannon. Do you remember that? I’m 50. We’re playing those videos next year in Denver. Anyhow.

Thanks a lot. Have a great trip home. Thank you.

MS KUHLMAN: Thank you.

MS GRIFFIE: Thank you.

MS KUHLMAN: Thanks for coming.