Immunotherapy Options in Refractory CRC


John L. Marshall, MD: All right, let’s shift gears back to the sense of hope that’s out there and the new therapies that are emerging in refractory and other lines of therapy. Everybody’s favorite topic is, of course, immunotherapy. Johanna, you’re carrying the flag for us. Among other things that are out there, we know about our microsatellite instability data. At this meeting, you’ve got some new evidence of some combination therapy in that patient?

Johanna C. Bendell, MD: For the MSI patients, we’re seeing more long-term follow-up from the single-agent checkpoint inhibitors—pointedly, nivolumab. We’re going to see some survival data. There is a 33% response rate and very good long-term overall survival. And when you look at the curves—I encourage folks to take a look at those curves—when you see the Kaplan-Meier curve, it goes down, and then it stays and just plateaus. So, it shows that benefit and the long-term benefit that patients are getting.

John L. Marshall, MD: Thirty-three percent does not seem as high as I was sort of hoping. We think that this is the perfect drug or the perfect setting. So, that’s a good response rate for this setting?

Johanna C. Bendell, MD: It’s a good response rate. There’s also a lot of stable disease within that setting because that’s the other part of that curve. But, then, the big focus of research is that with these microsatellite instable tumors, it’s supposed to be a slam dunk, right? You give them a checkpoint inhibitor, and everybody is going to be good. But now the big focus is with these rapid progressors—the people with microsatellite instability who progress through the checkpoint therapy. How can we stop that? Do we have to augment the immune system in another way to get them to respond?

John L. Marshall, MD: Just like with everything else, nivolumab/ipilimumab looks even better?

Michael A. Morse, MD: Well, it does. Obviously, there are the toxicity concerns with dual checkpoint therapy. So, it’s not for everybody. But clearly, the response rates are higher. You pointed out stable disease. I think it’s important to mention that there are people who will eventually respond. And so, the expectation that this is going to cause tumors to melt away instantaneously has to be tempered with the fact that it may eventually do that. We’ve had people, on the CheckMate-142 trial, who have demonstrated that and eventually even had complete remissions.

John L. Marshall, MD: So, what do you think, Dale, about MSI? Any cancer? We’ve been talking about colon cancer. Do you need to know about every metastatic patient and their MSI status?

Dale R. Shepard, MD, PhD, FACP: We have increasingly been doing that, just in terms of looking for options. This is a legitimate option, so we’re trying to look for MSI in everyone. I think that it makes good sense. Clearly, the patients are happy. It seems like every single patient wants to know whether they can be on an immunotherapy. They see the TV ads. They come in and say, “Why can’t I have this?” There’s a lot of false hope. Again, you have to have discussions with patients. You have to make sure that they’re aware that it’s not likely that they’re going to be MSI-high.

John L. Marshall, MD: For that MSS patient, what do you say to them when they say, “Can I have immunotherapy?”

Dale R. Shepard, MD, PhD, FACP: It’s just like with any other treatment that they come in asking about. If there aren’t good data to support it, we’re not going to subject them to that.

John L. Marshall, MD: Mike, does it change over time? Should I repeat biopsy?

Michael A. Morse, MD: I’m not aware of scenarios where that changes. We were talking about mutational burden, and that’s somewhat of an unknown quantity right now, in terms of colon cancer, anyway. If somebody does have an increase in their mutational burden, might they become sensitive to it? I just don’t think we have any data for that yet.

John L. Marshall, MD: Two checkpoint inhibitors are approved in this space, now, if you’re MSI-high.

Cathy Eng, MD, FACP: Right.

John L. Marshall, MD: Is there one that is better than the other?

Cathy Eng, MD, FACP: I don’t think so, from what we can tell, at this time. But, you’re correct—pembrolizumab is approved for all MSI-high cancers, whereas nivolumab is only specifically for colorectal cancer.

John L. Marshall, MD: So, in this space, we’ve got a choice, and you can pick your favorite?

Cathy Eng, MD, FACP: I think we’re going to learn some more, eventually. There might be some subtle differences. It’s still early.

Johanna C. Bendell, MD: I think there are some good data being presented on nivolumab that say that it doesn’t matter what your RAS status is. You still do well. It doesn’t matter whether you’re somatic or germline mutation. It doesn’t matter. You still do just as well. Your PD-L1 status doesn’t matter. You still do just as well.

Cathy Eng, MD, FACP: In colon.

Johanna C. Bendell, MD: In colon. But the other thing is, if you get treated earlier—and we saw this with gastric cancer data from pembrolizumab as well—the earlier you treat, the better you probably do. This is an important message. A lot of times, people ask for the immunotherapies at the last line. They think the tumor is going to melt away. Immunotherapies take time to work, so the responses are seen later. Patients have to be in better shape to allow that time.

John L. Marshall, MD: But you do see rapid responders, too?

Johanna C. Bendell, MD: You have some, but you also want to give the immune therapy, for whatever patients, so that they’ll have time to actually respond to it.

John L. Marshall, MD: So, we just recommend that to everybody, right? From day 1, you get their MSI status. So, you’ve known it in this patient for a couple of years. When do you want to pull that trigger on giving them a checkpoint inhibitor outside a clinical trial?

Michael A. Morse, MD: This is an important point that Johanna just brought up. Data that come out of the CheckMate-142 trial suggest that people who got more than the 2 lines of therapy don’t seem to have as much of a response as people who got the FOLFOX and FOLFIRI types of regimens.

John L. Marshall, MD: So, when do I give it? Maintenance?

Michael A. Morse, MD: Well, I think this is going to be something that pushes the envelope a little bit.

Cathy Eng, MD, FACP: Off protocol.

John L. Marshall, MD: Off protocol?

Cathy Eng, MD, FACP: Currently, the National Comprehensive Cancer Network guidelines state that you either have to be unhealthy or have to have had at least 1 prior therapy.

John L. Marshall, MD: So, maintenance?

Johanna C. Bendell, MD: Call that your 1 prior?

John L. Marshall, MD: Well, that’s it. You could also document that the patient doesn’t want chemotherapy. That would probably do it, too.

Cathy Eng, MD, FACP: That’s true. You can probably do that as well.

Johanna C. Bendell, MD: And aren’t all of us unhealthy?

John L. Marshall, MD: Yes.

Cathy Eng, MD, FACP: But I think it’s important. There is a trial for treatment-naïve metastatic patients. It is open, now, specifically across the Cooperative Groups.

Dale R. Shepard, MD, PhD, FACP: I’m not sure about maintenance. Usually, in my mind, maintenance is continuing a therapy that they were previously on. And so, that would really be more early second-line, if you’re considering that maintenance, right?

Cathy Eng, MD, FACP: He’s utilizing it in semantics.

Dale R. Shepard, MD, PhD, FACP: I would say that if you’ve had 1 line, as your second therapy, I certainly think it’s legitimate to consider.

Transcript Edited for Clarity

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