Immunotherapy and MSI Status in Colorectal Cancer

Transcript:John L. Marshall, MD: Let’s talk a little bit about immuno-oncology, because for a long time, I was feeling like we were left behind. It’s been science that I’ve been working on for a long time. Actually, the group out of Hopkins, in a multi-center study, said let’s look at the MSI-high tumors. There was lure, I think, that this might be an attractive target. Johanna, maybe you start on the studies and the results at GI ASCO. I think one of the lead authors has three oral presentations on using immuno-oncology in GI cancer. So set the stage for our folks.

Johanna Bendell, MD: This was such impressive data that we saw. They looked at folks with MSI-high colon cancer. But they also looked at MSI-high other tumors, which I think we can get to at another point. But this is all associated with the Lynch syndrome. What they saw was, when they gave checkpoint inhibitors—this was a PD-1 inhibitor—to patients with MSI-high colon cancer, they saw between a 60% to 70% response rate. People were joking that this is like ALK for non—small cell lung cancer. And these responses were durable. Even more importantly than that, it gives folks such a difference in terms of treatment options for their cancer.

John L. Marshall, MD: So has anybody found one of these patients and done this yet?

Tanios Bekaii-Saab, MD: Yes. So, we were part of that study that was published in The New England Journal of Medicine, and actually I have a number of patients on that trial—we’re talking about colorectal—including a pancreatic cancer patient who had a CR, which is pretty amazing. I’ve never seen a CR in pancreatic cancer with just a single modality agent. It was very impressive. I think these effects are real, as Johanna alluded to, not just that you see a depth of response, but you see also those responses being durable. So, a very exciting time. Of course, there are limitations to this study. There is no randomized portion.

John L. Marshall, MD: Do you need one?

Tanios Bekaii-Saab, MD: You know, yes and no. It’s exciting as it is, but, yes, you do.

John L. Marshall, MD: So I think the study that’s been done basically is frontline metastatic colon, single agent.

Tanios Bekaii-Saab, MD: The patients have failed.

John L. Marshall, MD: No, there’s a frontline study of chemotherapy versus single-agent checkpoint.

Tanios Bekaii-Saab, MD: No, no, I’m sorry. Yes, a study is ongoing. But this was in refractory disease. And, again, the effect is likely to halt, but you’d like to have some control over the set.

John L. Marshall, MD: Charlie…

Charles S. Fuchs, MD: It’s really exciting, and it’s obviously real. The one caveat is, when I read the paper, I noticed that in the colon patients, virtually all or almost all the patients with MSI had Lynch syndrome, realizing that in our practice, often times, the patients with microsatellite instability don’t have familial colon cancer; they just have it sporadically.

John L. Marshall, MD: And just for our audience, my number in my head is I say, oh, maybe 15% are MSI high, with 5% of those having Lynch syndrome and 10% having acquired. Is that a rough number that people use?

Johanna Bendell, MD: Yes.

Charles S. Fuchs, MD: It’s about right.

John L. Marshall, MD: So you’d get MSI high back, some of whom have Lynch syndrome, some of whom don’t.

Charles S. Fuchs, MD: So, I’m just curious. Is this a Lynch phenomenon or is this really an MSI phenomenon?

Tanios Bekaii-Saab, MD: And again, that’s where the question lies. It could be certainly a Lynch phenomenon. But there’s a good rationale to think about it as just an MSI, and not a Lynch phenomenon, because of the presence of, as you said, multiple mutations that expose these cells to benefit from these immune-directed therapies. I think, again, those numbers were relatively small. We’re still dealing with only 4% to 5% of all our colorectal cancer patients, and even less when you go to non—colorectal cancer patients. So a lot of these confirmatory studies are underway, and I think we’ll have more data. But, as Johanna said, this was like an ALK effect. You don’t see the depth of response and the durability of these responses unless you have a real drug that’s actually working in such a significant way.

John L. Marshall, MD: So measure this: you do MSI testing on patients and then when they come back positive, find a trial? Get compassionate use? Is this the message out there? And there’s a lot of trials. Everybody here got one open? And you can pick more than one? It’s a fascinating world. There’s a space race, more than one. And slots and different drugs and different combinations being tested. So the message out here, I think, is that there is access. You can get it, so it’s not a just make-believe, there are no trials.

Charles S. Fuchs, MD: And I’m sure you’re hearing this, too. I’m hearing about patients who are getting compassionate release of the drugs who are MSI high, and perhaps the payers are paying for it. I don’t know, but I’m certainly hearing about it.

John L. Marshall, MD: No, I think that’s true.

Johanna Bendell, MD: I actually have three patients that we did, because we had a trial that we were in between, and they were able to get compassionate use.

John L. Marshall, MD: Richard?

Richard Kim, MD: Same. I think we do have several trials, I think probably more trials than the patient right now currently at this time. And I’ve gotten one or two patients on compassionate use, as well. So patients with colon cancer, we test for MSI. In case they’re MSI high, we can offer the therapy off- or on-label.

John L. Marshall, MD: For a patient on first or second-line therapy, you don't have enough tissue to do this, pause, do a biopsy, send it?

Charles S. Fuchs, MD: I think we know the genetics of these tumors.

John L. Marshall, MD: We need to know, right?

Johanna Bendell, MD: Yes.

Tanios Bekaii-Saab, MD: Yes. That’s key.

John L. Marshall, MD: I want to be clear.

Transcript Edited for Clarity