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Future Directions in I/O Therapy for mCRC

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: Mike, for our last comment, I know you’ve spent a lot of your career looking at combination immunotherapy, vaccines and other approaches. Do you see that those techniques might, in fact, expand the number of patients in colorectal cancer who respond to immunotherapy?

Michael Morse, MD: Obviously, that’s a huge open question. A lot of research is going on in the area. I think we need to understand more about the molecular subtypes of colon cancer and where there might be an effect. If you take what we talk about as the CMS4 [consensus molecular subtype 4] group, they have an immunosuppressed environment. There may be a role for trying to change that immunosuppression. The CMS2 and 3 groups, that’s an immune desert, so we’re going to have to find some strategies to get the T cells to the tumor so we can modulate them with checkpoint. You and I could have a conversation about all the different strategies being done to try to achieve that.

John Marshall, MD: I know, Tony, you feel strongly about this. We probably will still be left with some patients where immune therapy is just not going to do the trick.

Tanios Bekaii-Saab, MD: If you have a tumor that’s—let’s use the simple terms—incredibly cold, nothing is going to make it hot, at least with the tools we have today. With the warmer tumors, you probably would benefit more. We have a couple of fairly negative abstracts that are in the back of the proceedings, and we have a large study, IMblaze370, that also was negative. Not selecting the right patient with a reasonable strategy will end up with negative after negative.

Michael Morse, MD: There’s obviously going to be excitement. You already brought this up about the nivolumab/regorafenib, and we have to see where that goes.

Tanios Bekaii-Saab, MD: This is where I would argue that, yes, it’s exciting, but it’s still limited to a small percentage of patients. At the end of the day, and even if it’s 20% or 30%, and that translates into 10% when you go to the phase III study, or 15%, those patients benefit. How can we figure out who those patients are that we’re going to actually focus on, and then leave the really cold tumors for a different strategy?

John Marshall, MD: Just like really cold tumors, at my age, nothing is going to make me hot, either.

Tanios Bekaii-Saab, MD: You are one hot tamale.

John Marshall, MD: You guys are great. This has been an amazing discussion and really informative. I hope all of you out there feel the same way. Before we end our overall discussion, I’d like to open the floor and give each one of you a chance to give your final thoughts on this. Cathy, you get to go first. What are your overall thoughts about colorectal cancer today?

Cathy Eng, MD: Based upon all the information we discussed here, obviously there are so many things we still don’t have a definitive answer for. We still need to encourage patients to participate in clinical trials. I think that’s the key.

John Marshall, MD: Do we have clinical trials for them to participate in?

Cathy Eng, MD: There are several clinical trials all across the board, but we need patients.

John Marshall, MD: We need the trials, too. Tony?

Tanios Bekaii-Saab, MD: I think the most important thing that we need to keep reminding our physicians who care for patients with colon cancer is, we really need to have that genetic information from day 1, if possible, and at least, at minimum, the ones we discussed—BRAF, RAS, HER2, MSI [microsatellite instability], maybe NTRK fusions, and others. We have to do these reflexively, because they do affect not only how we decide to treat our patients, but also access to clinical trials.

John Marshall, MD: Dr Dustin Deming.

Dustin Deming, MD: What’s really exciting now is how we’re seeing that the more we understand about the biology of colon cancer, the better we’re able to actually develop more personalized treatment options for patients, whether that be immune therapies or targeted therapies. I’m really excited as we’re learning more and more about the biology that will continue to advance the field for patients.

John Marshall, MD: Yes, and thanks. Michael, you get the last word.

Michael Morse, MD: I have to say that immunotherapy does have a role in colon cancer, of course, and I am hopeful that it will have the role even in satellite-stable patients. We didn’t talk about the role of the microbiome, and I think as we understand not just the biology of the tumor, but the host’s response, environmental factors, and so on, I think it will all change our understanding of how to manage the disease.

John Marshall, MD: Eat more dirt; fix your microbiome. That’s the secret.

Thank you guys for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange discussion to be useful and informative.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: Mike, for our last comment, I know you’ve spent a lot of your career looking at combination immunotherapy, vaccines and other approaches. Do you see that those techniques might, in fact, expand the number of patients in colorectal cancer who respond to immunotherapy?

Michael Morse, MD: Obviously, that’s a huge open question. A lot of research is going on in the area. I think we need to understand more about the molecular subtypes of colon cancer and where there might be an effect. If you take what we talk about as the CMS4 [consensus molecular subtype 4] group, they have an immunosuppressed environment. There may be a role for trying to change that immunosuppression. The CMS2 and 3 groups, that’s an immune desert, so we’re going to have to find some strategies to get the T cells to the tumor so we can modulate them with checkpoint. You and I could have a conversation about all the different strategies being done to try to achieve that.

John Marshall, MD: I know, Tony, you feel strongly about this. We probably will still be left with some patients where immune therapy is just not going to do the trick.

Tanios Bekaii-Saab, MD: If you have a tumor that’s—let’s use the simple terms—incredibly cold, nothing is going to make it hot, at least with the tools we have today. With the warmer tumors, you probably would benefit more. We have a couple of fairly negative abstracts that are in the back of the proceedings, and we have a large study, IMblaze370, that also was negative. Not selecting the right patient with a reasonable strategy will end up with negative after negative.

Michael Morse, MD: There’s obviously going to be excitement. You already brought this up about the nivolumab/regorafenib, and we have to see where that goes.

Tanios Bekaii-Saab, MD: This is where I would argue that, yes, it’s exciting, but it’s still limited to a small percentage of patients. At the end of the day, and even if it’s 20% or 30%, and that translates into 10% when you go to the phase III study, or 15%, those patients benefit. How can we figure out who those patients are that we’re going to actually focus on, and then leave the really cold tumors for a different strategy?

John Marshall, MD: Just like really cold tumors, at my age, nothing is going to make me hot, either.

Tanios Bekaii-Saab, MD: You are one hot tamale.

John Marshall, MD: You guys are great. This has been an amazing discussion and really informative. I hope all of you out there feel the same way. Before we end our overall discussion, I’d like to open the floor and give each one of you a chance to give your final thoughts on this. Cathy, you get to go first. What are your overall thoughts about colorectal cancer today?

Cathy Eng, MD: Based upon all the information we discussed here, obviously there are so many things we still don’t have a definitive answer for. We still need to encourage patients to participate in clinical trials. I think that’s the key.

John Marshall, MD: Do we have clinical trials for them to participate in?

Cathy Eng, MD: There are several clinical trials all across the board, but we need patients.

John Marshall, MD: We need the trials, too. Tony?

Tanios Bekaii-Saab, MD: I think the most important thing that we need to keep reminding our physicians who care for patients with colon cancer is, we really need to have that genetic information from day 1, if possible, and at least, at minimum, the ones we discussed—BRAF, RAS, HER2, MSI [microsatellite instability], maybe NTRK fusions, and others. We have to do these reflexively, because they do affect not only how we decide to treat our patients, but also access to clinical trials.

John Marshall, MD: Dr Dustin Deming.

Dustin Deming, MD: What’s really exciting now is how we’re seeing that the more we understand about the biology of colon cancer, the better we’re able to actually develop more personalized treatment options for patients, whether that be immune therapies or targeted therapies. I’m really excited as we’re learning more and more about the biology that will continue to advance the field for patients.

John Marshall, MD: Yes, and thanks. Michael, you get the last word.

Michael Morse, MD: I have to say that immunotherapy does have a role in colon cancer, of course, and I am hopeful that it will have the role even in satellite-stable patients. We didn’t talk about the role of the microbiome, and I think as we understand not just the biology of the tumor, but the host’s response, environmental factors, and so on, I think it will all change our understanding of how to manage the disease.

John Marshall, MD: Eat more dirt; fix your microbiome. That’s the secret.

Thank you guys for your contributions to this discussion. On behalf of our panel, we thank you for joining us. We hope you found this Peer Exchange discussion to be useful and informative.

Transcript Edited for Clarity
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