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Immunotherapy Regimens in dMMR/MSI-High Metastatic CRC

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: 

Alan Venook, MD: Checkpoint inhibitors are obviously a big advance. For patients who are MSI [microsatellite instability]-high, both nivolumab and pembrolizumab are available. The addition of ipilimumab adds to the effectiveness of the nivolumab, but it also adds a lot to the cost and, potentially, the toxicity. So it’s something we have to be very careful with. You can put a lot of money down to get those combination treatments with a lot of risk, but the upside is, again, significant.

Our group here at UCSF [University of California, San Francisco] has not been using the combination too much in patients. Although for patients with high-burden disease, for which we don’t think we have a second chance, we are using it. In general, we start with a single-agent checkpoint inhibitor and then go from there. But I think this is a great advance. Again, how we can afford it? And the real issue is figuring out who’s going to benefit from using the drugs.

The second question is figuring out if patients don’t benefit, why? Or, if patients benefit for a period of time and then become resistant, we need to figure that out. This is very important if we’re going to expand the reach of these drugs to more patients. Right now, no more than 5% of patients with advanced colorectal cancer are candidates for these drugs. We have to do better than that.

A big study that just completed was very disappointing. This was a study that looked at atezolizumab and an MEK inhibitor, cobimetinib. This was a downright negative study that was very distressing because we thought there might be some progress there. However, there was no progress at all. So we still have a lot of work to do in that arena.

Richard Kim, MD: In patients who are mismatch repair-deficient or MSI-high, we now have options with immunotherapy. You could use a single agent, such as nivolumab or pembrolizumab, or could use the combination of a checkpoint inhibitor plus a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor. There’s no head-to-head comparison of a single-agent checkpoint inhibitor or single-agent checkpoint inhibitor plus a CTLA-4 inhibitor. However, if you look at the data, the response rate of the doublet seems to be a bit higher—maybe at 55% compared with the single agent, which can range from 30% to 50%. However, when you start combining the immunotherapy, the toxicity becomes a concern. If you look at the grade 3/4 adverse events, the rate with the doublet regimen seems to be higher.

Therefore, if a patient who’s MSI-high or mismatch repair-deficient fails 1 line of chemotherapy and has a low burden of disease—if they are asymptomatic—I would tend to go with a single checkpoint inhibitor. However, if they’re symptomatic or if the tumor is bulky and I’m trying to induce response, then I would probably use the doublet regimen of nivolumab plus ipilimumab.

We need more data on this, but, in the first-line, the combination may also be useful. There is obviously no data to support this, but in the future hopefully the data will come up and we may be able to use a more aggressive regimen as a first-line therapy in patients who are MSI-high or mismatch repair-deficient.

John L. Marshall, MD: For a long time, nobody thought immuno-oncology was ever going to make it to colon cancer. A breakthrough study actually demonstrated that pembrolizumab had activity in MSI-high–positive colon cancers. For any solid tumor that’s MSI-high, it got an unbelievable approval across all different diseases based on a molecular biomarker. And then the combination of ipilimumab and nivolumab was tested in MSI-high colon cancers and that demonstrated a slightly higher response rate and slightly higher improved outcome.

It’s important for everybody to remember that a lot of patients who are MSI-high still don’t respond to checkpoint inhibitors, whether given as a single agent or in combination. There seems to be this idea that if you have this, “Oh my goodness, it’s going to work for sure.” Well, the reality is no, it’s not. Only about half of patients respond to therapy. So we need better biomarkers. We need better combinations. It’s encouraging to see that the ipilimumab/nivolumab combination moves the bar a little bit—not a lot, but a little bit—in terms of improved response rate and improved outcomes. And so, in patients for whom you want to try the combination that is now approved, we know that there is a bit of higher toxicity, and, of course, the cost is higher. But, you get a higher response rate and a better progression-free survival.

Transcript Edited for Clarity 
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Transcript: 

Alan Venook, MD: Checkpoint inhibitors are obviously a big advance. For patients who are MSI [microsatellite instability]-high, both nivolumab and pembrolizumab are available. The addition of ipilimumab adds to the effectiveness of the nivolumab, but it also adds a lot to the cost and, potentially, the toxicity. So it’s something we have to be very careful with. You can put a lot of money down to get those combination treatments with a lot of risk, but the upside is, again, significant.

Our group here at UCSF [University of California, San Francisco] has not been using the combination too much in patients. Although for patients with high-burden disease, for which we don’t think we have a second chance, we are using it. In general, we start with a single-agent checkpoint inhibitor and then go from there. But I think this is a great advance. Again, how we can afford it? And the real issue is figuring out who’s going to benefit from using the drugs.

The second question is figuring out if patients don’t benefit, why? Or, if patients benefit for a period of time and then become resistant, we need to figure that out. This is very important if we’re going to expand the reach of these drugs to more patients. Right now, no more than 5% of patients with advanced colorectal cancer are candidates for these drugs. We have to do better than that.

A big study that just completed was very disappointing. This was a study that looked at atezolizumab and an MEK inhibitor, cobimetinib. This was a downright negative study that was very distressing because we thought there might be some progress there. However, there was no progress at all. So we still have a lot of work to do in that arena.

Richard Kim, MD: In patients who are mismatch repair-deficient or MSI-high, we now have options with immunotherapy. You could use a single agent, such as nivolumab or pembrolizumab, or could use the combination of a checkpoint inhibitor plus a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor. There’s no head-to-head comparison of a single-agent checkpoint inhibitor or single-agent checkpoint inhibitor plus a CTLA-4 inhibitor. However, if you look at the data, the response rate of the doublet seems to be a bit higher—maybe at 55% compared with the single agent, which can range from 30% to 50%. However, when you start combining the immunotherapy, the toxicity becomes a concern. If you look at the grade 3/4 adverse events, the rate with the doublet regimen seems to be higher.

Therefore, if a patient who’s MSI-high or mismatch repair-deficient fails 1 line of chemotherapy and has a low burden of disease—if they are asymptomatic—I would tend to go with a single checkpoint inhibitor. However, if they’re symptomatic or if the tumor is bulky and I’m trying to induce response, then I would probably use the doublet regimen of nivolumab plus ipilimumab.

We need more data on this, but, in the first-line, the combination may also be useful. There is obviously no data to support this, but in the future hopefully the data will come up and we may be able to use a more aggressive regimen as a first-line therapy in patients who are MSI-high or mismatch repair-deficient.

John L. Marshall, MD: For a long time, nobody thought immuno-oncology was ever going to make it to colon cancer. A breakthrough study actually demonstrated that pembrolizumab had activity in MSI-high–positive colon cancers. For any solid tumor that’s MSI-high, it got an unbelievable approval across all different diseases based on a molecular biomarker. And then the combination of ipilimumab and nivolumab was tested in MSI-high colon cancers and that demonstrated a slightly higher response rate and slightly higher improved outcome.

It’s important for everybody to remember that a lot of patients who are MSI-high still don’t respond to checkpoint inhibitors, whether given as a single agent or in combination. There seems to be this idea that if you have this, “Oh my goodness, it’s going to work for sure.” Well, the reality is no, it’s not. Only about half of patients respond to therapy. So we need better biomarkers. We need better combinations. It’s encouraging to see that the ipilimumab/nivolumab combination moves the bar a little bit—not a lot, but a little bit—in terms of improved response rate and improved outcomes. And so, in patients for whom you want to try the combination that is now approved, we know that there is a bit of higher toxicity, and, of course, the cost is higher. But, you get a higher response rate and a better progression-free survival.

Transcript Edited for Clarity 
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