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mCRC: Right-Side vs Left-Side Tumors

Panelists: John L. Marshall, MD, Georgetown University; Bert H. ONeil, MD, Indiana University School of Medicine; Marwan Fakih, MD, City of Hope Comprehensive Care Center; Gabriela Chiorean, MD, University of Washington School of Medicine; Wells A. Messersmith, MD, FACP, University of Colorado Cancer Center
Published: Friday, Sep 07, 2018



Transcript:
John L. Marshall, MD: Yes, I think it’s really hard for us to just keep pushing. Our European colleagues, of course, have embraced this. They’ve said that if I’ve got the right patient, it’s targeted therapy. I’m going to use it and justify it based on that. They’re not as convinced on the right, left. You want to give us a quick summary on right, left to make sure everybody out there is up to speed?

Gabriela Chiorean, MD: Well, I think it’s really the most important thing we’ve learned about colon cancer in the past couple of years, it’s left and right. And we have more and more explanations of the differences between really the genetics, the molecular signatures, even the CMS classifications, how it shifts from a CMS class 1 to a 4, etc, as you move along the colon. I think that clearly the rectals and the sigmoids have better prognosis overall as a site. And then if they are KRAS wild-type, they benefit even more. And I think that nowadays, we know that the transverse colon should not be considered, a right should be considered a left. So we learn more and more things, and I think these things are extremely valid about the location of the cancer, both prognostically as well as predictively when we are to use EGFR-targeted therapies.

John L. Marshall, MD: Bert, as we see new data and new evidence coming forward, in our circles, we ask, “Well, what RAS enrichment did they do? What left, right enrichment?” In some studies, we’re going to have that being presented. But most of these studies were done before we knew this, and so we’re asked to interpret it in light of some patients probably inappropriately receiving therapy and the like. Does that weaken the value? Should we wait on that sort of enrichment before we make any new clinical conclusions of new data that are coming forward? What’s your take on that?

Bert H. O’Neil, MD: You know, it is a tough question because you can easily have imbalance of a factor like that in a study that affects result. It can be either a left-right imbalance or, you know, did they do it, did this occur in the extended RAS period versus just checking CODON-2, and might you have excessive RAS mutations you weren’t aware of in one arm or the other? So I think when evaluating a study, you just need to keep those things in mind. I don’t know that I would not believe the results of the study. Also, you kind of have to assume that these things will randomize themselves out for the most part.

John L. Marshall, MD: We’re going to do a quick review of sidedness, all right? We have now new data around right side and left side. I want us to talk very specifically about the data around biologics. Let’s start with 80405. Bert, start there. So 80405, reanalysis by Alan Venook, tells us what about left-sided colon cancers?

Bert H. O’Neil, MD: Tells us several things. As you all know, the study overall was a negative one in terms of equivalence of bevacizumab and cetuximab in addition to chemotherapy. With analysis of sidedness, we learned a few things, one that we already knew, which is that patients with left-sided tumors had longer survival than those with origin on the right side. But perhaps more surprisingly, we found that patients with right-sided tumors who were RAS wild-type appeared not to do very well with EGFR antibody. Whereas on the left side, it appeared that patients did better with an EGFR antibody than they did if they started out with bevacizumab. And this is interesting because essentially, all patients in this study eventually crossed over to the other therapy type.

John L. Marshall, MD: So, Gabby, if I’ve got a right-sided RAS wild-type, BRAF wild-type patient, should I not give EGFR therapy in the first-line setting?

Gabriela Chiorean, MD: Correct. I would not use an EGFR-targeted therapy in the first-line setting if you are a right-sided KRAS wild type, BRAF wild type. I would use a FOLFOX or FOLFIRI plus bevacizumab.

John L. Marshall, MD: Marwan, on the other side of things, if I’ve got a left-sided RAS wild-type, BRAF wild-type patient, should I be giving EGFR-targeted therapy to that patient?

Marwan Fakih, MD: I think it should be a strong consideration based on the difference in overall survival that we see both on FIRE-3 in those patients as well as on 80405. Because even on 80405, the difference in OS was statistically significant for the RAS wild-type left colon patients who received cetuximab versus bevacizumab. And I think that trend is also supported by the CRYSTAL trial and the PRIME trial, where you see a significant advantage in that patient population, whether it’s response rate or overall survival. So in our practice, we certainly consider anti-EGFR therapy for those patients in the frontline setting.

John L. Marshall, MD: So, Wells, we went from all patients getting EGFR therapy to then the RAS, which I guess cuts it down to about 40%. BRAF knocks maybe another 10% off that. Sidedness, I’m down to about 20% or 30% of patients who are even candidates for EGFR therapy in the frontline setting. What do you do with all the others? Is bevacizumab appropriate for all the others?

Wells A. Messersmith, MD, FACP: Yes. I would say, first of all, I think in 80405, there’s a fairly strong trend I’m not sure quite reached statistical significance, and the difference was somewhat marginal. Actually, we save the EGFR, because of rash and other considerations, for second-line therapy. Although I agree there are other studies and other indications that it might be. But I’m still comfortable with bevacizumab in the first-line setting even for that subset. But you’re right: it starts to get chopped down fairly quickly to a small patient population. And I think talking through with the patients, I’m amazed at how different patients value or devalue rash, just as some patients value or devalue hair loss. It really depends on a lot of these personal issues.

John L. Marshall, MD: So the punch line here is that you’ve got to put in the correct ICD-10 code to know what the correct biologic option is for our patients with frontline metastatic disease.

Transcript Edited for Clarity

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Transcript:
John L. Marshall, MD: Yes, I think it’s really hard for us to just keep pushing. Our European colleagues, of course, have embraced this. They’ve said that if I’ve got the right patient, it’s targeted therapy. I’m going to use it and justify it based on that. They’re not as convinced on the right, left. You want to give us a quick summary on right, left to make sure everybody out there is up to speed?

Gabriela Chiorean, MD: Well, I think it’s really the most important thing we’ve learned about colon cancer in the past couple of years, it’s left and right. And we have more and more explanations of the differences between really the genetics, the molecular signatures, even the CMS classifications, how it shifts from a CMS class 1 to a 4, etc, as you move along the colon. I think that clearly the rectals and the sigmoids have better prognosis overall as a site. And then if they are KRAS wild-type, they benefit even more. And I think that nowadays, we know that the transverse colon should not be considered, a right should be considered a left. So we learn more and more things, and I think these things are extremely valid about the location of the cancer, both prognostically as well as predictively when we are to use EGFR-targeted therapies.

John L. Marshall, MD: Bert, as we see new data and new evidence coming forward, in our circles, we ask, “Well, what RAS enrichment did they do? What left, right enrichment?” In some studies, we’re going to have that being presented. But most of these studies were done before we knew this, and so we’re asked to interpret it in light of some patients probably inappropriately receiving therapy and the like. Does that weaken the value? Should we wait on that sort of enrichment before we make any new clinical conclusions of new data that are coming forward? What’s your take on that?

Bert H. O’Neil, MD: You know, it is a tough question because you can easily have imbalance of a factor like that in a study that affects result. It can be either a left-right imbalance or, you know, did they do it, did this occur in the extended RAS period versus just checking CODON-2, and might you have excessive RAS mutations you weren’t aware of in one arm or the other? So I think when evaluating a study, you just need to keep those things in mind. I don’t know that I would not believe the results of the study. Also, you kind of have to assume that these things will randomize themselves out for the most part.

John L. Marshall, MD: We’re going to do a quick review of sidedness, all right? We have now new data around right side and left side. I want us to talk very specifically about the data around biologics. Let’s start with 80405. Bert, start there. So 80405, reanalysis by Alan Venook, tells us what about left-sided colon cancers?

Bert H. O’Neil, MD: Tells us several things. As you all know, the study overall was a negative one in terms of equivalence of bevacizumab and cetuximab in addition to chemotherapy. With analysis of sidedness, we learned a few things, one that we already knew, which is that patients with left-sided tumors had longer survival than those with origin on the right side. But perhaps more surprisingly, we found that patients with right-sided tumors who were RAS wild-type appeared not to do very well with EGFR antibody. Whereas on the left side, it appeared that patients did better with an EGFR antibody than they did if they started out with bevacizumab. And this is interesting because essentially, all patients in this study eventually crossed over to the other therapy type.

John L. Marshall, MD: So, Gabby, if I’ve got a right-sided RAS wild-type, BRAF wild-type patient, should I not give EGFR therapy in the first-line setting?

Gabriela Chiorean, MD: Correct. I would not use an EGFR-targeted therapy in the first-line setting if you are a right-sided KRAS wild type, BRAF wild type. I would use a FOLFOX or FOLFIRI plus bevacizumab.

John L. Marshall, MD: Marwan, on the other side of things, if I’ve got a left-sided RAS wild-type, BRAF wild-type patient, should I be giving EGFR-targeted therapy to that patient?

Marwan Fakih, MD: I think it should be a strong consideration based on the difference in overall survival that we see both on FIRE-3 in those patients as well as on 80405. Because even on 80405, the difference in OS was statistically significant for the RAS wild-type left colon patients who received cetuximab versus bevacizumab. And I think that trend is also supported by the CRYSTAL trial and the PRIME trial, where you see a significant advantage in that patient population, whether it’s response rate or overall survival. So in our practice, we certainly consider anti-EGFR therapy for those patients in the frontline setting.

John L. Marshall, MD: So, Wells, we went from all patients getting EGFR therapy to then the RAS, which I guess cuts it down to about 40%. BRAF knocks maybe another 10% off that. Sidedness, I’m down to about 20% or 30% of patients who are even candidates for EGFR therapy in the frontline setting. What do you do with all the others? Is bevacizumab appropriate for all the others?

Wells A. Messersmith, MD, FACP: Yes. I would say, first of all, I think in 80405, there’s a fairly strong trend I’m not sure quite reached statistical significance, and the difference was somewhat marginal. Actually, we save the EGFR, because of rash and other considerations, for second-line therapy. Although I agree there are other studies and other indications that it might be. But I’m still comfortable with bevacizumab in the first-line setting even for that subset. But you’re right: it starts to get chopped down fairly quickly to a small patient population. And I think talking through with the patients, I’m amazed at how different patients value or devalue rash, just as some patients value or devalue hair loss. It really depends on a lot of these personal issues.

John L. Marshall, MD: So the punch line here is that you’ve got to put in the correct ICD-10 code to know what the correct biologic option is for our patients with frontline metastatic disease.

Transcript Edited for Clarity
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