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Immunotherapy in MSS Colorectal Cancer

Insights From: Alan Venook, MD, University of California San Francisco ; John L. Marshall, MD, Georgetown University ; Mark Kozloff, MD, Ingalls Cancer Care; Richard Kim, MD, Moffitt Cancer Center
Published: Monday, Dec 10, 2018



Transcript: 

John L. Marshall, MD: We need to figure out the rest of the story. We’ve talked about MSI [microsatellite instability] tumors and how I/O [immuno-oncology] works for some of those patients, but we really have not moved the bar in microsatellite stable colon cancer, which, remember, is the majority of the cancer that we see. I’ve gone around and have talked to doctors around the country. They actually say, “I’m yet to find an MSI colon cancer.” So they really want, and the patients really want a better answer for treating microsatellite stable colon cancer. We did a big randomized clinical trial. It turned out, based on some early phase I-II data, that it didn’t pan out. The combination therapy didn’t improve things over the standard of care.

One of the approaches that’s moving things forward is using vaccine-type approaches in combination with I/O. It’s possible that I/O just won’t work in these patient populations. You have to remember what I/O is: it’s basically allowing an already angry immune system to finish the job that it started. It removes a blockade. So if the tumor is not pissing off the immune system in some way, I/O won’t do anything—the current I/O therapies that we think about. A lot of the work that’s going on now is trying to stimulate the immune system, and then uses the checkpoint inhibitors to keep any resistance from forming. We are all hopeful that this kind of combination approach will, in fact, change outcomes for microsatellite stable colon cancer.

Everyone is trying anything in the immuno-oncology space. There are a lot of these drugs out there. I think there are 5 approved drugs on the market right now. You can Google and find almost any paper to support drug A plus drug B plus I/O. And so, there are an enormous number of clinical trials going on out there. I think that’s good because we don’t really understand how these things might interact. In fact, on some level, we tripped over the checkpoint inhibitors. And so, exploring this is smart.

One of the ways this is being explored is by taking traditional colon cancer therapies and combining them with I/O in the microsatellite stable patient population to see if there’s any renewed or improved outcomes. The combination of cetuximab and pembrolizumab makes total sense, just to try it. The phase I studies show some early, promising activity. But this does not mean, and this is really an important point, that doctors out there who are desperate to try anything, and patients who are desperate to try anything, should just throw these drugs out there based on these early clinical trials. I do think the toxicities, the cost, and the potential negative impact is out there as well. So this is not giving you permission to throw a Hail Mary at combining it. Wait for the data to mature to see if there’s true benefit with the combination.

Transcript Edited for Clarity 
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Transcript: 

John L. Marshall, MD: We need to figure out the rest of the story. We’ve talked about MSI [microsatellite instability] tumors and how I/O [immuno-oncology] works for some of those patients, but we really have not moved the bar in microsatellite stable colon cancer, which, remember, is the majority of the cancer that we see. I’ve gone around and have talked to doctors around the country. They actually say, “I’m yet to find an MSI colon cancer.” So they really want, and the patients really want a better answer for treating microsatellite stable colon cancer. We did a big randomized clinical trial. It turned out, based on some early phase I-II data, that it didn’t pan out. The combination therapy didn’t improve things over the standard of care.

One of the approaches that’s moving things forward is using vaccine-type approaches in combination with I/O. It’s possible that I/O just won’t work in these patient populations. You have to remember what I/O is: it’s basically allowing an already angry immune system to finish the job that it started. It removes a blockade. So if the tumor is not pissing off the immune system in some way, I/O won’t do anything—the current I/O therapies that we think about. A lot of the work that’s going on now is trying to stimulate the immune system, and then uses the checkpoint inhibitors to keep any resistance from forming. We are all hopeful that this kind of combination approach will, in fact, change outcomes for microsatellite stable colon cancer.

Everyone is trying anything in the immuno-oncology space. There are a lot of these drugs out there. I think there are 5 approved drugs on the market right now. You can Google and find almost any paper to support drug A plus drug B plus I/O. And so, there are an enormous number of clinical trials going on out there. I think that’s good because we don’t really understand how these things might interact. In fact, on some level, we tripped over the checkpoint inhibitors. And so, exploring this is smart.

One of the ways this is being explored is by taking traditional colon cancer therapies and combining them with I/O in the microsatellite stable patient population to see if there’s any renewed or improved outcomes. The combination of cetuximab and pembrolizumab makes total sense, just to try it. The phase I studies show some early, promising activity. But this does not mean, and this is really an important point, that doctors out there who are desperate to try anything, and patients who are desperate to try anything, should just throw these drugs out there based on these early clinical trials. I do think the toxicities, the cost, and the potential negative impact is out there as well. So this is not giving you permission to throw a Hail Mary at combining it. Wait for the data to mature to see if there’s true benefit with the combination.

Transcript Edited for Clarity 
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