When Immunotherapy Can Replace Surgery

Chuck: This is the Good News About Cancer. I'm Dr. Chuck Ryan. Alicia: And I’m Dr. Alicia Morgans.

Chuck: We're oncologists, and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than there ever has been, and we're here to share that with you.

Alicia: In each episode of this show, we talk with one of our colleagues about a promising development in oncology. We'll break down what's new, why it matters, and how it points the way forward.

Andrea: What we ended up seeing was, you know, just really incredible results, in that every single patient's tumor melted completely to just immunotherapy, to just Dostarlimab. No one needed chemo, chemoradiation, or surgery.

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Chuck: You know, one of the things that surprised me during recording and planning for Season One was how I kind of sat down and we came up with a list of good news stories we wanted to tell. We didn't get through that list, not even close, because news was coming out at the time. We would read a paper, we would see something in even like the New York Times.

And so it just tells us that A, there's a lot of good news that's out there that just hasn't really been told, and B, we can't even keep up to some extent with some

of the good news that's coming out even as we're going day to day and week to week.

Alicia: Well, I know that you and I are both here to do our best to try to keep up anyway, so let's get started! Let's dive right into the first episode of Season Two.

Chuck: Well, you know, we're going to start Season Two paradoxically, perhaps, with a little bit of bad news. And that's that colorectal cancer is on the rise for younger individuals. There's been a lot of press about this, and we really don't know why that's happening.

Alicia: You know, the other issue is that treatment for colorectal cancer, especially for people with really low rectal cancers, is something that changes their lives in many ways.

So people have to undergo treatments like chemotherapy, which can cause side effects of fatigue and nausea and low blood counts. But sometimes they also need to have big surgeries that end up leaving them with a colostomy bag, or a bag where their stool is actually collected, rather than being able to have bowel movement normally. So these big changes are hard physically and emotionally, and certainly things that we want to try to limit in any way that we possibly can.

Chuck: Remember last season we talked about infertility and its effect from breast cancer treatment? Colorectal cancer treatment can similarly cause infertility because of radiation that is frequently delivered. And that can damage the uterus and those tissues and make them incapable of carrying a child. So that's another big one that we're concerned about.

But the good news part of this is that despite all of these problems associated with standard treatment, we are pushing the boundaries of what we can do with different types of treatments. And most notably, we've seen a significant advance recently in the application of immune therapy to colorectal cancer.

Alicia: Yeah, I think this is one of the most exciting advances for people who have certain types of colorectal cancer. There are developments with the use of immunotherapy that seem to take away the need for people to undergo these major surgeries and long-term treatments with radiation.

And we had such a wonderful opportunity to speak with Dr. Andrea Cercek, who works where you do, at Memorial Sloan Kettering Cancer Center, where she's really pushing the boundaries in this way with this drug that she was looking into called Dostarlimab. And this is an immunotherapy drug that is

hopefully helpful, as she'll tell us, in people with certain types of colorectal cancer.

Chuck: She's a physician scientist and head of the colorectal section at Memorial Sloan Kettering Cancer Center. She's also the co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers. So you can really think of nobody better to tell this story and to be doing this type of research.

Alicia: Great. Well, let's get into it. ___________

Alicia: Andrea, thank you so much for being here. We're really excited to talk with you and about all of the innovation that you and your team have been witness to, and have been party to, and have been really championing.

I wonder if you could – before we kind of dive into these advances for those patients with colorectal cancer who have this special form of colorectal cancer – just set the stage. Tell us about colorectal cancer. Is this something that we in the United States should worry about? Is it something we think about?

Andrea: Absolutely. Colorectal cancer is a very common cancer, not just in the United States, but throughout the world. And most commonly this cancer occurs kind of in the 60, 70 to 80-year-old group.

But what we're really starting to see, and we've been seeing this now for the last few decades, actually, is a rise in young adults. And now we're seeing individuals in their twenties, thirties, and forties with this disease.

And it's occurring all over the world. It's really every country that has a registry is seeing this phenomenon. And we really don't know why it's happening.

But there is a really urgent need to kind of not only raise awareness, you know, for diagnosis, but also to improve care of all patients with colorectal cancer, but especially these young adults.

Chuck: And give us a little bit of a sense as to the standard treatment, for most people around the world. What do they experience? What, what do they go through?

Andrea: Typically colorectal cancer, when it's diagnosed in an early stage – so that's any stage one through three before it metastasizes or spreads outside of the colon and the surrounding lymph nodes – is treated with local therapy.

So for colon cancer, because it's located in the abdomen outside of the pelvis, the first intervention is surgery. So the tumor is resected, and then we look at it under the microscope and then decide if the person needs chemotherapy or not. And then typically after chemotherapy, if they need it, they're done and they undergo just observation.

For rectal cancer, it's a little bit different. So the rectum is located in the pelvis, so it's the bottom part of the large intestine, but because it's located in the pelvis, the treatment usually involves chemotherapy, radiation usually with chemotherapy as well. And then surgery.

And we do the treatment of chemotherapy and radiation before surgery to kind of try to improve surgical outcomes, just because it's more complicated because it's down there in between the pelvic bones.

Chuck: And so typically a patient after undergoing chemotherapy, radiation and surgery is left with a normal gastrointestinal tract for the most part? Or, what are the sort of implications of going through all of that treatment?

Andrea: Yeah, so the trouble with the treatment is, you know, every treatment always has some toxicity associated with it, right?

So with chemotherapy, we give a short amount of chemotherapy about three to four months. Typically very little in terms of long-term effects, but there can be neuropathy. It's not, you know, completely insignificant. Patients can have kind of a numbness and tingling. And there's other issues that can happen with chemotherapy as well.

But most of the toxicity from rectal cancer treatment really comes from the radiation. Because when we radiate the tumor, there are many structures that are in the way. And so patients often have some degree of bowel dysfunction, bladder dysfunction because the bladder is right there, the urethra is right in the area of the radiation.

And then most difficult, especially for these young adults, is sexual health. The vaginal canal, you know, you can develop erectile dysfunction, as well as infertility. And this is now becoming an increasing problem for us, especially with all of these young adults that I just mentioned that are developing colon

cancer, because what I didn't mention actually is that the most common location of this young adult colorectal cancer is in the rectum.

So most of these young adults that we're seeing have rectal cancer. And because the ovaries are in the field of radiation, as is the uterus, it causes – if the ovaries stay in the field – immediate menopause. And then the uterus is actually incapable of carrying a baby because of the blood vessels that are kind of scarred during the process.

And then of course, surgery can be tricky as well. It depends on the location of the tumor, right? So the lower you go, the closer it is to what's called the sphincter or the muscle that really enables us to hold our bowel function. And so if the tumor is located very low, then when it's resected, the colon can't be reattached, the rectum can't be reattached. And so about 30% of patients with rectal cancer need a permanent bag or what's called a permanent colostomy.

And so the treatment is curative, people live – obviously that's our number one goal, but there are all these, you know, important side effects or toxicities that we have to keep in mind.

Chuck: So obvious opportunity for improvement in outcome in terms of, survivorship outcomes and, quality of life, et cetera. And in order to do that, you began to focus on MMR deficient rectal cancer, which is not the standard. Tell us a little bit about MMR deficient colorectal cancer. What does that mean, and why does it make it different?

Andrea: So we noticed actually, when we were treating our patients with rectal cancer, we would start with chemotherapy first, and most patients responded very nicely to that, and then went on to radiation and surgery. But a proportion of patients actually didn't respond or developed really rapid recurrence.

So the cancer would, you know, respond a little bit and then grow back very quickly. And when we looked at those patients, we noticed that they had “mismatch repair deficiency.” And it basically means that the tumors develop many, many, many thousands and thousands of mutations.

So what we learned is that these tumors look very foreign or abnormal to the immune system. Meaning that, you know, when we get, let's say we get strep throat or you know, some bacterial infection, the way that our bodies fight it is because the immune system sees the bacteria, chews it up, we get better. Sometimes we need a little bit of help from antibiotics, but for the most part, it's

really our immune system that does that because the bacteria is not supposed to be there.

So these tumors are kind of like that. They just look very, very unusual to the immune system. So the immune system is already trying to sort of chew them up. Except cancer's very smart. And so what cancer does is it puts up what are called checkpoint blockades. So they put up these little like, kind of like arms, to prevent the immune system from being able to get to it.

So around this time, what we noticed – and this was work by Luis Diaz and Yung Lee, who were at Hopkins at the time – that these tumors that are mismatch repair deficient, or what are called MSI-high or hyper mutated, responded amazingly well to immunotherapy in advanced disease.

And so all immunotherapy is, is it's called checkpoint blockade. So it basically gets rid of those checkpoints, breaks that bond, and then allows the immune system to attack tumor, but then also to recruit basically like an army of immune cells that can then really attack and effectively kind of chew up and get rid of the tumor completely.

So patients that had metastatic disease that had exhausted all standard treatments, when they received immunotherapy and had this type of tumor had just incredible responses.

And so that led us to this idea of: what if we took the subset of tumors, which are about 5% or so of all early stage rectal cancers, if we identified them early, and instead of starting with chemotherapy, we introduced immunotherapy first.

Alicia: Just to, just to recap: in about 5% of people who have these rectal tumors, they have something different about the genetics of the cancer that makes it cause all of these mistakes or mutations to happen and allows them to kind of flourish there.

So if we can unmask these mistakes and get the immune system to wake up, recognize them, and attack, we might be able to get that immune system to really take care of the cancer, get rid of those cells, instead of using things like chemotherapy and other treatments like radiation or surgery. Is that what you're saying?

Andrea: Yeah, that's exactly right, Alicia.

So the, you know, the idea was could we just start with immunotherapy on a clinical trial? And basically exactly as you said, see you know, what we can get away with, could we omit chemo? Could we omit chemotherapy and radiation?

Or could we omit chemotherapy, radiation, and surgery? And basically replace the standard of care with just immunotherapy in this subset of patients with mismatch repair deficient tumors.

Alicia: That's fantastic. And it really speaks to our ability to break down what seems like a single type of cancer into these subgroups, these subtypes that might have unique and special vulnerabilities or weaknesses that we in oncology or in cancer care can harness to really make a huge difference.

And I know you want to get into the trial and really share what you did and exactly what you found with that study.

Andrea: The idea was really very simple. It was: let's give six months of immunotherapy and see what happens. And of course, we wanted to cure the patient, so we followed them really closely. We weren't going to omit any standard treatments, but we were just kind of trying to see if we did six months, what would happen?

If the tumor was still there then they could get standard of care treatment with radiation. And then if the tumor was still there, they needed surgery. But if they responded completely to just immunotherapy, then we would follow them with what's called non-operative management, meaning they just get the immunotherapy, the tumor's gone, we would just observe them. No further treatment.

And so we used a drug called Dostarlimab, which is what's called a PD-1 monoclonal antibody. So just one drug. And, you know, patients received it every three weeks for nine treatments total. So six months.

And what we ended up seeing was, you know, just really incredible results in that every single patient's tumor melted completely to just immunotherapy, to just Dostarlimab. No one needed chemo, chemoradiation, or surgery.

They were able to have completely normal bowel and bladder function, normal sexual function, as well as fertility. And we now have, I'm really excited to say actually, five babies from the patients on study. So that's been really, really exciting.

Chuck: So these are astounding results and they exceeded your expectations, but has it become the standard of care yet? If a person is diagnosed, they're not at Memorial Sloan Kettering Cancer Center, they're not on a clinical trial, are they going to get the immunotherapy and avoid surgery? Or are we, are we not there yet?

Andrea: I think we're close. It's not, you know, what we're seeing is that it's definitely in the guidelines. It's obviously not– Dostarlimab or PD-1 blockade – is not FDA approved yet, but most people are aware of the data and are aware of the treatment. But there are of course nuances and sort of comfort that needs to happen with non-operative management.

So what I'm seeing in some cases is, “Oh, we're seeing these amazing responses now, time for surgery.” And it's like, actually no! If the tumor's responding, let's keep going with this because this is, you know, the end result can be omission of everything, including surgery. So I think there is, of course, with everything else, still a learning point there.

Alicia: Andrea, can I ask you just a little bit more about that? Because there are patients and people who think about enrolling in clinical trials. There are young doctors and researchers, and- and old ones too who are around the country, around the world, who are trying to make a difference and make a change.

And one of the hardest things when we try to really disrupt the standard of care or change the way that we do things– it can be really hard. How do you think about that? How do you encourage people to continue innovating? To continue participating in clinical trials? Or for yourself and your own practice, how do you think about making those leaps, which can seem really daunting sometimes?

Andrea: I think certainly on our study, I have to say kudos to the patients that took a chance and enrolled on the study, you know, where basically we had a curative therapy, you know, we said, “You're sitting in front of us, we can cure you with this treatment, but let's try this and see what happens.”

So I think certainly the first several patients were incredibly brave. And I tell my patients that all the time. We always thank our patients and their caregivers and their families, first and foremost, right? For trusting in science and, and taking a risk. But that's really how progress is made.

And I think that goes the same for clinical investigators, for basic sciences, for everyone, it’s like, you have to kind of, take a little bit of a leap of faith and try

something a little bit out there to really make big progress. And when it happens, it's obviously amazing for everyone. But especially, you know, our patients.

Chuck: I was just talking to a patient yesterday who was on a clinical trial and really struggling with some things, not side effects, but just struggling with the uncertainties of being on the trial. And I said, “Someday there's going to be an academic presentation at some big meeting, and the principal investigator of this trial is going to get up and present the data, and then they're going to say thank you to all the patients and their families who participated in this trial.”

And I said, “I'm just going to say that to you today because you're not going to be at that academic presentation, because patients don't go to them.” You know?

Andrea: Right.

Chuck: And it's a really remarkable thing, I mean, to put yourself in the face of the uncertainty where you have a curative therapy but you chose to go something experimental.

If only this could be applied to the other 95% of patients with rectal cancer. And I know that your team has been doing some work along those lines. It's a high bar, but you're trying to figure out ways to convert some of these tumors that don't respond to immunotherapy into those that do. I wonder if you could speak about that a little bit.

Andrea: As a completely sort of honest, but very optimistic opinion, I think we're gonna get there. You know, I think we're starting to see a lot of progress in that area.

So the issue with the other 95%, as you said, is that the tumors are hiding from the immune system. So they have very smart ways to put up blockades and put this little sort of cloak on. So the immune system just doesn't see it.

And what we're doing is just figuring out different ways to get rid of that, you know, invisible cloak that they have, right? Because once again, once that happens, then you give immunotherapy and there's nothing more powerful than the immune system.

And so there are several ongoing studies, looking at that in advanced disease and stage four disease and MSS tumors or what are called microsatellite stable or MMR-proficient tumors. And then we have a study actually in early stage

rectal cancer where we're giving a combination of a PD-1 monoclonal antibody Balstilimab, and an anti-CTLA-4, drug called, Botensilimab.

With a similar idea that we introduce that first and see how much of a response we can get. But obviously, you know, continuing with, with curative intent therapy on that study. And I'm, you know, super excited because I think in the next couple years we're going to see huge progress in this area for sure.

Chuck: We really are. And we should also point out that mismatch repair deficient tumors occur in many other organs. In fact, Alicia and I both treat prostate cancer, and it's also about five to 7% of prostate cancers will have this. And we have seen some dramatic responses to immunotherapy in the setting of advanced prostate cancer.

We don't typically, I don't think, see it in the early stage like this, where we're able to avoid the surgery. That study has either not been done or is still ongoing, but it is, it is something that occurs in other cancers.

Andrea: Once we saw the amazing responses in mismatch repair deficient rectal cancer, we actually opened our study. We opened a second cohort of mismatch repair deficient sort of any solid tumor, so including esophagus, stomach, pancreas, liver, as well as genitourinary.

So we had urothelial patients as well as a couple patients with mismatch repair deficient prostate cancer, and then GYN endometrial cancer as well. And we published those data, so we had 54 patients. All-comers. And we did see very significant responses. It was about 68% of those that didn't need surgery.

But there is still, to your point, a bit more work that needs to be done in some of the other solid tumors. So our prostate patients, for example, they both had stable disease, but they didn't have enough of a response. And you know, the thinking there probably is that they need a little bit extra, they, they need a little bit extra help.

Similarly with stomach cancer as well, many did respond, but not kind of as, you know, robustly as the patients with rectal cancer, or urothelial actually was an amazing response, that we saw in patients with urothelial cancer.

So really the bottom line is that these tumors are so exquisitely sensitive to the immune system. Some of them might need a little bit longer treatment or, or maybe combination. But we really can think about non-operative management in a lot of these early stage cancers.

Chuck: Remarkable.

Alicia: It's, it's so important, I think, obviously we think about this from the doctor's perspective. And we want to try to cure more people and help them live longer and feel better.

But I wonder, Andrea, you see these people, they come into your clinics, they talk about their lives. What difference has it made for them in their day-to-day and their survivorship experience, which, you know, lasts a lifetime after that diagnosis?

Andrea: It really was a learning curve for me initially as kind of a, a young oncologist seeing all of these young patients, where you realize very quickly that it doesn't stop with the cure.

You know, as oncologists, our goal is cure, right? And we think, you know, this is it, it's gone. The cancer's gone. That’s great, but there's a human sitting there with a whole life ahead of them. And obviously you never forget that you have cancer. It stays with you forever. And it affects people in many different ways. So we can't ignore that, and we can't take that away.

But if we can take away some of the toxicity and let them live as, best and unaffected lives as possible in survivorship, and I mentioned the, the babies and, you know, families and continuing into the next generation or simply just living a normal life without needing to map out where the bathrooms are or without needing to manage, a colostomy.

Certainly all of that is part of cancer survivorship, but if we can minimize that as much as possible, I think that is, you know, that's the most rewarding thing.

Alicia: So when you think about this, all of this progress, and all of the work that you continue to do, what would you say to families, to people who are taking care of themselves or dealing with, colorectal cancer in terms of the future and where we go from here and what hope might you have for them?

Andrea: There are so many exciting things going on in colorectal cancer treatment, drug development, you know, not only immunotherapy-based. We've been mostly focusing on immunotherapy, but I think just in general with targeted therapies, there have been a lot of advances in advanced disease. And now we're thinking about it in early-stage disease as well.

So I am, you know, always optimistic and excited, but I think the last several years we've seen this like huge acceleration in improvement in outcomes for patients, both with early stage as well as with advanced disease. So the future's definitely bright.

Chuck: Andrea, congratulations on this remarkable study and its outcomes and the impact it will have on current and future generations of patients with colorectal cancer. Thank you for joining us.

Andrea: Thank you very much for having me.

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Chuck: That was a great conversation, Alicia. I think, you know, the thing that strikes me is: although this is a subset of patients, they did something where the rates of cure, the rates of complete response, are higher, and it didn't come at a cost of greater intensity. The patients actually got less treatment and they had a better outcome, and that's exactly what we hope to do with many other cancers.

Alicia: I agree, and I think that there may be ways to take people who don't necessarily have the opportunity to use this type of a treatment approach in the future, to potentially give them the opportunity to still benefit by turning on different pathways or utilizing different combinations that make them also sensitive to this type of a treatment paradigm. And that to me is also extremely exciting.

Chuck: Right, and we need to acknowledge as, as she did, that this is a subset of patients. This is not the most common scenario that we're going to see in colorectal cancer, but it's a window into the future.

Alicia: Well, and there certainly will be a lot more for us to talk about in the future as we consider this and all of the other good news that is to come.

Chuck: So, although we started out by saying there's kind of a bad news story here in the increased incidence of colorectal cancer, there is definitely progress being made.

Alicia: Absolutely. Thank you so much for listening to the Good News About Cancer. I'm Dr. Alicia Morgans at Dana-Farber Cancer Institute in Boston.

Chuck: And I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work.

Alicia: Thanks to Lilly for support of the show. Our production partner for this series is CitizenRacecar. This episode was produced by Anna Van Dine with post-production by Alex Brouwer.

Chuck: And there's a whole lot more good news to talk about, so make sure you subscribe to this wherever you listen to your podcasts. And if you like the show, share it with someone you think might find it interesting.

Alicia: We’ll be back again soon with some more good news about cancer.