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Metastatic CRC: Moving Into the Future

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 17, 2018



Transcript: 

John L. Marshall, MD: The world of colon cancer is clearly changing. We know about tumor sidedness and we’ll need to figure out what that’s all about. There is clearly some sort of molecular interaction. My hunch is that it may not have anything to do with us. It might have to do with our microbiome—the bacteria that live in our gastrointestinal tracts. That’s such an important part of our health but we don’t really understand it yet. We are working hard to study the microbiome to see what impact it has on colon cancer and why it might be different.

Precision medicine is having a positive impact. We now know how to better select patients for certain drugs. Molecular profiling is becoming part of the standard of care for treating metastatic colon cancer and we have therapies to go along with that. The immuno-oncology field is the same. We are working to try to expand the number of patients who are eligible for it, but we have to continue with our aggressive but cautious approach as we move forward.

I think one of the biggest areas of research that we have only just started to jump into is understanding why all of these young people are getting colon cancer. I saw an 18-year-old patient this week with colon cancer. Why is this person getting that disease? Lots of people in their 20s, 30s, and 40s are getting colon cancer. I’m unhappy with the societies that have said, “Oh, we’ll just start screening at age 45.” That doesn’t do anything to solve this problem. It is a true epidemic and it’s not just in the United States. It’s happening around the world. It’s not happening in fat people who sit on their couch and eat Big Macs all day. It is actually occurring in very fit people who are doing all of the right things and are getting this disease.

So we need to figure out what’s going on there. My hope is that whatever answers we learn there will, in fact, apply to much larger populations and have a significant and positive impact on patients in the future.

Alan Venook, MD: I’m not sure that any of the novel combinations are really going to change the game. Certainly, many of us have gone to the 4-drug combination chemotherapy, with or without a biologic. We have probably made mistakes along the way, in terms of just mixing and matching chemotherapy. Many of the studies, my study included, have just assumed that chemotherapy is indifferent to the effect of the biologics. I’m not sure that’s right. In fact, that’s probably not correct. Now, do we go all the way back and start from scratch? Probably not. I think it’s fair to say that the best combination for a given patient isn’t necessarily going to be FOLFOX [folinic acid, fluorouracil, and oxaliplatin]-based, which is how almost everybody is treated in the United States. It may very well be FOLFIRI [folinic acid, fluorouracil, and irinotecan]-based, or something else yet. It’s hard to revisit that though.

Knowing what the best new combinations will be will really depend on figuring out how we can overcome resistance. Or, for example, if our explanation of sidedness turns out to be accurate, where a VEGF inhibitor, such as bevacizumab, might be extremely valuable on right-sided tumors that might be something to think about.

Mechanistically, we have some data in our CALGB/SWOG 80405 dataset, although in small numbers, that reveal that MSI [microsatellite instability]-high patients get much more benefit from bevacizumab than they do from cetuximab. You could imagine combining bevacizumab with a checkpoint inhibitor, for example, to see if you could magnify the effect. Those seem like reasonable studies to do. In terms of new molecules and new targets, we are waiting and waiting.

We’re also hoping that some of these new vaccine strategies might work. With the checkpoint inhibitors, I think vaccines play more of a role than we thought. We have an active program there as well. So far, it’s mostly wishful thinking. The way that I put it to patients, unfortunately, is, we’re optimistic about these treatments until we’re not optimistic about them.

If we’re going to make progress, one of the things we really have to do is put patients on clinical trials. We have to collect data on all of our patients. And so, even in the absence of great ideas, collecting the information and following our patients to know who we help and who we don’t help is important. In my perspective, every patient should be poised to go on a clinical trial, certainly at the time of refractory disease. That doesn’t mean, in many cases, that we will favor a study rather than regorafenib or TAS-102 [trifluridine/tipiracil] just because we feel that we want the patients to get the option of the checkpoint inhibitor. The advances are going to require new drugs or new targets that we just don’t know about right now.

Transcript Edited for Clarity 
 
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Transcript: 

John L. Marshall, MD: The world of colon cancer is clearly changing. We know about tumor sidedness and we’ll need to figure out what that’s all about. There is clearly some sort of molecular interaction. My hunch is that it may not have anything to do with us. It might have to do with our microbiome—the bacteria that live in our gastrointestinal tracts. That’s such an important part of our health but we don’t really understand it yet. We are working hard to study the microbiome to see what impact it has on colon cancer and why it might be different.

Precision medicine is having a positive impact. We now know how to better select patients for certain drugs. Molecular profiling is becoming part of the standard of care for treating metastatic colon cancer and we have therapies to go along with that. The immuno-oncology field is the same. We are working to try to expand the number of patients who are eligible for it, but we have to continue with our aggressive but cautious approach as we move forward.

I think one of the biggest areas of research that we have only just started to jump into is understanding why all of these young people are getting colon cancer. I saw an 18-year-old patient this week with colon cancer. Why is this person getting that disease? Lots of people in their 20s, 30s, and 40s are getting colon cancer. I’m unhappy with the societies that have said, “Oh, we’ll just start screening at age 45.” That doesn’t do anything to solve this problem. It is a true epidemic and it’s not just in the United States. It’s happening around the world. It’s not happening in fat people who sit on their couch and eat Big Macs all day. It is actually occurring in very fit people who are doing all of the right things and are getting this disease.

So we need to figure out what’s going on there. My hope is that whatever answers we learn there will, in fact, apply to much larger populations and have a significant and positive impact on patients in the future.

Alan Venook, MD: I’m not sure that any of the novel combinations are really going to change the game. Certainly, many of us have gone to the 4-drug combination chemotherapy, with or without a biologic. We have probably made mistakes along the way, in terms of just mixing and matching chemotherapy. Many of the studies, my study included, have just assumed that chemotherapy is indifferent to the effect of the biologics. I’m not sure that’s right. In fact, that’s probably not correct. Now, do we go all the way back and start from scratch? Probably not. I think it’s fair to say that the best combination for a given patient isn’t necessarily going to be FOLFOX [folinic acid, fluorouracil, and oxaliplatin]-based, which is how almost everybody is treated in the United States. It may very well be FOLFIRI [folinic acid, fluorouracil, and irinotecan]-based, or something else yet. It’s hard to revisit that though.

Knowing what the best new combinations will be will really depend on figuring out how we can overcome resistance. Or, for example, if our explanation of sidedness turns out to be accurate, where a VEGF inhibitor, such as bevacizumab, might be extremely valuable on right-sided tumors that might be something to think about.

Mechanistically, we have some data in our CALGB/SWOG 80405 dataset, although in small numbers, that reveal that MSI [microsatellite instability]-high patients get much more benefit from bevacizumab than they do from cetuximab. You could imagine combining bevacizumab with a checkpoint inhibitor, for example, to see if you could magnify the effect. Those seem like reasonable studies to do. In terms of new molecules and new targets, we are waiting and waiting.

We’re also hoping that some of these new vaccine strategies might work. With the checkpoint inhibitors, I think vaccines play more of a role than we thought. We have an active program there as well. So far, it’s mostly wishful thinking. The way that I put it to patients, unfortunately, is, we’re optimistic about these treatments until we’re not optimistic about them.

If we’re going to make progress, one of the things we really have to do is put patients on clinical trials. We have to collect data on all of our patients. And so, even in the absence of great ideas, collecting the information and following our patients to know who we help and who we don’t help is important. In my perspective, every patient should be poised to go on a clinical trial, certainly at the time of refractory disease. That doesn’t mean, in many cases, that we will favor a study rather than regorafenib or TAS-102 [trifluridine/tipiracil] just because we feel that we want the patients to get the option of the checkpoint inhibitor. The advances are going to require new drugs or new targets that we just don’t know about right now.

Transcript Edited for Clarity 
 
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