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Immunotherapy in CRC

Panelists: John Marshall, MD, Georgetown University; Cathy Eng, MD, Vanderbilt University; Tanios Bekaii-Saab, MD, Mayo Clinic; Dustin Deming, MD, University of Wisconsin; Michael Morse, MD, Duke Cancer Institute
Published: Thursday, Aug 22, 2019



Transcript: 

John Marshall, MD: We just have a few more minutes left, and we still have something to talk about regarding immunotherapy. Mike, remind everybody where we are with approvals in colorectal cancer, and where you see the field going.

Michael Morse, MD: Obviously with MSI [microsatellite instability]-high cancers in general, we have pembrolizumab, for MSI-high colon cancer—nivolumab, nivolumab plus ipilimumab. The data are very consistent from study to study concerning the MSI-high benefits.

John Marshall, MD: If you knew that right from the beginning, what line of therapy would you use?

Michael Morse, MD: Right now, of course, the approvals are based on people who have been previously treated, so there might be insurance challenges. The second thing is, we don’t really know in the first line how it’s going to compare with chemotherapy. That’s being tested right now, and do you already know what’s going to happen in KEYNOTE-177?

Tanios Bekaii-Saab, MD: No, I care about the study, but I don’t care at the same time, because in all frankness, I’ve had patients who have never seen a drop of chemotherapy for 5 years.

John Marshall, MD: Yes, but these are patients from your study. They’re Lynch syndrome patients.

Tanios Bekaii-Saab, MD: No, I totally get it. For many patients, they may not even need that chemotherapy.

John Marshall, MD: Mike’s point is that the approval was in patients who have had all the prior treatments. Are you going to give them regorafenib before you’re going to give them a checkpoint inhibitor, if you knew their MSI status? Where do you draw the line? Your argument is frontline, then?

Michael Morse, MD: It’s at least 1 prior line. I think the approvals would say it’s essentially 2, but….

Tanios Bekaii-Saab, MD: See, I’d say no more than 1 line of therapy, if you can afford it.

Michael Morse, MD: The other thing that is true is, it would appear that the response rates are a little better if it’s given earlier.

Cathy Eng, MD: Front line.

Michael Morse, MD: Right, exactly.

Cathy Eng, MD: There were those interesting data.

Michael Morse, MD: Yes, that would argue for why not do to it front line.

Cathy Eng, MD: There are even data in the neoadjuvant setting for colon, so that’s impressive, as well.

Tanios Bekaii-Saab, MD: I think response rate is a bit deceiving with chemotherapy versus PD-1 [programmed cell death protein 1], because a lot of the responses continue to convert over time with the PD-1 inhibitors. With chemotherapy, they actually tend to be fleeting and short-lived, whatever you call short-lived, it could be 10 months or a year for those patients. For those with PD-1 inhibitors who are MSI-high, they continue to have that depth of response, which is probably just that tumor that continues to shrivel.

John Marshall, MD: For our excitement on 1 side, there are some patients who develop toxicities that are significant and have to come off, and not everybody responds. That’s the unusual MSI patient; let’s talk about the more common patient. Cathy, I’ll pick on you. What are the efforts going on now to try and convert MSS [microsatellite stable] patients?

Cathy Eng, MD: I think there are a lot of interesting data looking at the role of tumor mutation burden [TMB]. Granted, that is a very small percentage of patients, but there appear to be some positive data that there may be a correlation and you may benefit, potentially.

John Marshall, MD: The only way you’re going to get that is through a broader and next-generation kind of approach, so arguing back to our original discussion about doing that.

Cathy Eng, MD: Correct.

John Marshall, MD: You know that. If you had a patient with a TMB of 22, but MSS, are you calling the Aetna guy to see if you can get it approved?

Cathy Eng, MD: I think it’s not unreasonable if you’re running out of options for that patient, as long as they still have a good performance status.

Michael Morse, MD: The interesting thing is, though….

Cathy Eng, MD: It’s still early.

Michael Morse, MD: Yes, and even in the MSI-high patients, where there’s been a suggestion that even their tumor mutational burden may separate patients, the separation occurs at something like 30 to 40 mutations. I think, for the patient who has 8, 9, 10, or 12, it’s hard to say that that person is likely to….

Cathy Eng, MD: Weren’t the SWOG 80405 data though based upon greater than 8?

Michael Morse, MD: Right, and that’s prognostic data, but you’re right, even at 8. Now, how you get to these numbers, often it’s….

Cathy Eng, MD: That’s the problem. Exactly.

Michael Morse, MD: It’s the median that’s chosen.

Tanios Bekaii-Saab, MD: This is the one you like to draw a line onto because it looks nicer on a publication. Who knows, right now?

Michael Morse, MD: What should be the cutoff?

John Marshall, MD: You know we published some data, Mohammed Salem, MD was the lead author, looking at the different MSI mismatch repair proteins and showing that there are different tumor mutational burdens depending on which ones you’re missing. They’re not all even created equally. We’re going to start to subdivide those. Is there ever a role, Dustin, to throw that Hail Mary—that patient who’s refractory, is still good performance status, MSS? Should I just try some checkpoint anyway, or is that really a foul?

Dustin Deming, MD: I think that’s a foul. In my mind, the odds of benefit for that patient are extremely low. I would much rather look for a clinical trial for that patient than try that.

Tanios Bekaii-Saab, MD: There’s nothing wrong with calling it quits at the right point, frankly. Why not? We know from studies that, when the time is right, if you initiate the palliative care and comfort care options sooner rather than later, those patients actually end up passing, when they get to that point, with more dignity and more comfort than if we keep on hammering them down because we just don’t want to give up. In fact, you’ve given up on them in a different way.

Cathy Eng, MD: I think you’re talking going off on a completely different tangent.

Tanios Bekaii-Saab, MD: No, that’s the Hail Mary effect. I think it’s not a completely different tangent. The Hail Mary effect is, essentially, when you don’t have any other option and you say, “I’m going to try immune therapy.”

Cathy Eng, MD: Yes, I agree. I wouldn’t do immunotherapy either. I’m just saying that, obviously, I think all of us would agree that you should consider palliative care early on in all patients.

Tanios Bekaii-Saab, MD: No, I’m talking about palliative care as part of the end-of-life care, that’s hospice care, comfort care, not necessarily palliative care, because chemotherapy all the way through is palliative for most of these patients, anyway.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: We just have a few more minutes left, and we still have something to talk about regarding immunotherapy. Mike, remind everybody where we are with approvals in colorectal cancer, and where you see the field going.

Michael Morse, MD: Obviously with MSI [microsatellite instability]-high cancers in general, we have pembrolizumab, for MSI-high colon cancer—nivolumab, nivolumab plus ipilimumab. The data are very consistent from study to study concerning the MSI-high benefits.

John Marshall, MD: If you knew that right from the beginning, what line of therapy would you use?

Michael Morse, MD: Right now, of course, the approvals are based on people who have been previously treated, so there might be insurance challenges. The second thing is, we don’t really know in the first line how it’s going to compare with chemotherapy. That’s being tested right now, and do you already know what’s going to happen in KEYNOTE-177?

Tanios Bekaii-Saab, MD: No, I care about the study, but I don’t care at the same time, because in all frankness, I’ve had patients who have never seen a drop of chemotherapy for 5 years.

John Marshall, MD: Yes, but these are patients from your study. They’re Lynch syndrome patients.

Tanios Bekaii-Saab, MD: No, I totally get it. For many patients, they may not even need that chemotherapy.

John Marshall, MD: Mike’s point is that the approval was in patients who have had all the prior treatments. Are you going to give them regorafenib before you’re going to give them a checkpoint inhibitor, if you knew their MSI status? Where do you draw the line? Your argument is frontline, then?

Michael Morse, MD: It’s at least 1 prior line. I think the approvals would say it’s essentially 2, but….

Tanios Bekaii-Saab, MD: See, I’d say no more than 1 line of therapy, if you can afford it.

Michael Morse, MD: The other thing that is true is, it would appear that the response rates are a little better if it’s given earlier.

Cathy Eng, MD: Front line.

Michael Morse, MD: Right, exactly.

Cathy Eng, MD: There were those interesting data.

Michael Morse, MD: Yes, that would argue for why not do to it front line.

Cathy Eng, MD: There are even data in the neoadjuvant setting for colon, so that’s impressive, as well.

Tanios Bekaii-Saab, MD: I think response rate is a bit deceiving with chemotherapy versus PD-1 [programmed cell death protein 1], because a lot of the responses continue to convert over time with the PD-1 inhibitors. With chemotherapy, they actually tend to be fleeting and short-lived, whatever you call short-lived, it could be 10 months or a year for those patients. For those with PD-1 inhibitors who are MSI-high, they continue to have that depth of response, which is probably just that tumor that continues to shrivel.

John Marshall, MD: For our excitement on 1 side, there are some patients who develop toxicities that are significant and have to come off, and not everybody responds. That’s the unusual MSI patient; let’s talk about the more common patient. Cathy, I’ll pick on you. What are the efforts going on now to try and convert MSS [microsatellite stable] patients?

Cathy Eng, MD: I think there are a lot of interesting data looking at the role of tumor mutation burden [TMB]. Granted, that is a very small percentage of patients, but there appear to be some positive data that there may be a correlation and you may benefit, potentially.

John Marshall, MD: The only way you’re going to get that is through a broader and next-generation kind of approach, so arguing back to our original discussion about doing that.

Cathy Eng, MD: Correct.

John Marshall, MD: You know that. If you had a patient with a TMB of 22, but MSS, are you calling the Aetna guy to see if you can get it approved?

Cathy Eng, MD: I think it’s not unreasonable if you’re running out of options for that patient, as long as they still have a good performance status.

Michael Morse, MD: The interesting thing is, though….

Cathy Eng, MD: It’s still early.

Michael Morse, MD: Yes, and even in the MSI-high patients, where there’s been a suggestion that even their tumor mutational burden may separate patients, the separation occurs at something like 30 to 40 mutations. I think, for the patient who has 8, 9, 10, or 12, it’s hard to say that that person is likely to….

Cathy Eng, MD: Weren’t the SWOG 80405 data though based upon greater than 8?

Michael Morse, MD: Right, and that’s prognostic data, but you’re right, even at 8. Now, how you get to these numbers, often it’s….

Cathy Eng, MD: That’s the problem. Exactly.

Michael Morse, MD: It’s the median that’s chosen.

Tanios Bekaii-Saab, MD: This is the one you like to draw a line onto because it looks nicer on a publication. Who knows, right now?

Michael Morse, MD: What should be the cutoff?

John Marshall, MD: You know we published some data, Mohammed Salem, MD was the lead author, looking at the different MSI mismatch repair proteins and showing that there are different tumor mutational burdens depending on which ones you’re missing. They’re not all even created equally. We’re going to start to subdivide those. Is there ever a role, Dustin, to throw that Hail Mary—that patient who’s refractory, is still good performance status, MSS? Should I just try some checkpoint anyway, or is that really a foul?

Dustin Deming, MD: I think that’s a foul. In my mind, the odds of benefit for that patient are extremely low. I would much rather look for a clinical trial for that patient than try that.

Tanios Bekaii-Saab, MD: There’s nothing wrong with calling it quits at the right point, frankly. Why not? We know from studies that, when the time is right, if you initiate the palliative care and comfort care options sooner rather than later, those patients actually end up passing, when they get to that point, with more dignity and more comfort than if we keep on hammering them down because we just don’t want to give up. In fact, you’ve given up on them in a different way.

Cathy Eng, MD: I think you’re talking going off on a completely different tangent.

Tanios Bekaii-Saab, MD: No, that’s the Hail Mary effect. I think it’s not a completely different tangent. The Hail Mary effect is, essentially, when you don’t have any other option and you say, “I’m going to try immune therapy.”

Cathy Eng, MD: Yes, I agree. I wouldn’t do immunotherapy either. I’m just saying that, obviously, I think all of us would agree that you should consider palliative care early on in all patients.

Tanios Bekaii-Saab, MD: No, I’m talking about palliative care as part of the end-of-life care, that’s hospice care, comfort care, not necessarily palliative care, because chemotherapy all the way through is palliative for most of these patients, anyway.

Transcript Edited for Clarity
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