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Nuances in Antibody Selection: Left Vs Right-Sided mCRC

Panelists: John L. Marshall, MD, Georgetown University Hospital; Dirk Arnold, MD, PhD, Instituto CUF de Oncologia; University of Hamburg; Fortunato Ciardiello, MD, PhD, Seconda Università di Napoli; Paul R. Helft, MD, Indiana School of Medicine of the Indiana University Melvin and Bren Simon Cancer Center; Tanios Bekaii-Saab, MD, Mayo Clinic Cancer Center in Arizona
Published: Monday, Jul 24, 2017



Transcript:

John L. Marshall, MD:
Dirk, to my knowledge, I don’t know that we’ve gone back to the single-agent refractory trials with either cetuximab or panitumumab and looked at right versus left. Have we?

Dirk Arnold, MD, PhD: This hasn’t been done yet.

John L. Marshall, MD: But we’ve got those data in a bank somewhere? We could look at that, I would think?

Tanios Bekaii-Saab, MD: We have one.

John L. Marshall, MD: Is there one?

Tanios Bekaii-Saab, MD: Cetuximab.

John L. Marshall, MD: Single agent, right versus left?

Tanios Bekaii-Saab, MD: Single agent, yes.

John L. Marshall, MD: What did it show?

Tanios Bekaii-Saab, MD: It’s interesting. Survival is actually a little bit better with cetuximab on the right side versus best supportive care. However, the PFS was exactly the same on the right side between cetuximab and best supportive care.

It’s very intriguing. PFS overlaps, but survival is a little bit better, and this is where it gets confusing because you’re looking at a subgroup analysis that wasn’t really looked at, prospectively. How do you make sense of it? You take the benefit of the doubt and you say, “There may be that slight survival advantage.” PFS may not be affected, but those patients are actually seeing a little bit better survival on the right side.

Dirk Arnold, MD, PhD: I agree. But I don’t believe in this end point, necessarily, from the single trial. We clearly have to say that the motivation comes from the lack of other alternatives in this setting.

Tanios Bekaii-Saab, MD: But these do support.

Fortunato Ciardiello, MD, PhD: I have 2 comments. One is that the right-side tumor should be considered in the context of what the disease presentation is in the patient. If I have a patient who is relatively young with disease, and the tumor is BRAF and RAS wild-type, maybe, biologically, this is very similar to what we think about in BRAF-mutant patients? We would like to spend everything we have on first-line therapy. Maybe, in these patients, I will even try FOLFOXIRI and bevacizumab in some of these patients. Of course, I have to check to see what is right for the patient.

John L. Marshall, MD: Even without BRAF? Is that what you’re saying? I’m agreeing with you. I just want to make sure.

Fortunato Ciardiello, MD, PhD: Yes, even if it’s BRAF wild-type.

John L. Marshall, MD: We’ve got frontline data of triplet therapy with bevacizumab showing overall survival, response rate, and everything else, and we push that off to the side too. Sorry, that was one of your points.

Fortunato Ciardiello, MD, PhD: Yes. And the second point was that the study that we were discussing before, about later lines of therapy with cetuximab versus best supportive care, was a very old study—the CO.17 study. Those patients were not pretreated with bevacizumab. We don’t know, in the context of pretreatment with chemotherapy plus bevacizumab, what happens in third- or fourth-line therapy. And as all of us are saying, we have no real alternative. So in these patients, I will still try to use an anti–EGFR in the third-line or in second-line setting if first-line with antiangiogenesis didn’t work well.

When disease progresses after doublet chemotherapy plus bevacizumab, what do you do to these patients? You don’t use an antiangiogenic again. Maybe you can use an anti-EGFR? These are the patients with right-sided tumors in whom I would give an anti-EGFR—either in some patients in the second-line setting, most of the patients in the third-line setting, and very few patients in the first-line setting in a very short treatment for conversion to liver resection. But not many patients are like this. There are very, very few.

John L. Marshall, MD: Tony, the transverse colon—which side is it on?

Tanios Bekaii-Saab, MD: Transverse has not been looked at. It has been excluded.

John L. Marshall, MD: Alan Venook’s study excluded it.

Tanios Bekaii-Saab, MD: CALGB/SWOG 80405 excluded it. If it’s closer to the hepatic flexure, treat them as right-sided. If it’s closer to the splenic flexure, treat it as left-sided.

John L. Marshall, MD: Embryologically, the line is at the splenic flexure.

Tanios Bekaii-Saab, MD: Somewhere.

Dirk Arnold, MD, PhD: Embryologic gives a clear definition. The molecular biology doesn’t follow this because, in molecular biology, we learned that we have a shift of the pattern from the very right to the very left. We can see these by the percentage of patients showing BRAF-mutant status here, coming from 30% on the right side and ending in 3% on the colon. And this goes, continuously, with a continuous decrease. The profile of other things—the molecular profile and the frequency of other alterations—also gradually decreases.

John L. Marshall, MD: Great segue.

Tanios Bekaii-Saab, MD: But you’re in clinic. You’re really not going to think, “Is it 3 cm or 4 cm?” You really are just going to look at it and ask, “Is it closer to this side or closer to this side?” In a busy practice, you really have to be practical. Frankly—and we’ll talk about this later—how you treat in the first-line setting, pragmatically, is not going to really change much. It may complicate things a little.

John L. Marshall, MD: I’m putting transverse on the right. Paul?

Paul R. Helft, MD: Well, I would tend to agree with Tony. If you have one that’s really far in one direction, than the other…

John L. Marshall, MD: You pick that side?

Paul R. Helft, MD: Right. With the molecular profiles, we just don’t know yet, because there aren’t enough of them to make statistical conclusions. We give them the benefit of the doubt, in general, and put them on the left.

John L. Marshall, MD: That’s the segue that I was looking for. Do we have a gene? Do we have some molecular characteristic? Or right now, are we still stuck with anatomy?

Paul R. Helft, MD: We make the best assumptions.

John L. Marshall, MD: So it’s still anatomy? We’ve had some studies here at the 2017 ASCO Annual Meeting looking at differences in stratifications for MSI and BRAF, and an answer really didn’t come out of that. Known molecular tests don’t distinguish this, right?

Fortunato Ciardiello, MD, PhD: That’s true.

John L. Marshall, MD: It’s still anatomy. You guys have ICD-10. Do you have to code?

Fortunato Ciardiello, MD, PhD: Of course.

John L. Marshall, MD: We all hate it. It matters now, right? You have to put the correct ICD-10 code in when you’re seeing a new patient.

Transcript Edited for Clarity

Slider Left
Slider Right


Transcript:

John L. Marshall, MD:
Dirk, to my knowledge, I don’t know that we’ve gone back to the single-agent refractory trials with either cetuximab or panitumumab and looked at right versus left. Have we?

Dirk Arnold, MD, PhD: This hasn’t been done yet.

John L. Marshall, MD: But we’ve got those data in a bank somewhere? We could look at that, I would think?

Tanios Bekaii-Saab, MD: We have one.

John L. Marshall, MD: Is there one?

Tanios Bekaii-Saab, MD: Cetuximab.

John L. Marshall, MD: Single agent, right versus left?

Tanios Bekaii-Saab, MD: Single agent, yes.

John L. Marshall, MD: What did it show?

Tanios Bekaii-Saab, MD: It’s interesting. Survival is actually a little bit better with cetuximab on the right side versus best supportive care. However, the PFS was exactly the same on the right side between cetuximab and best supportive care.

It’s very intriguing. PFS overlaps, but survival is a little bit better, and this is where it gets confusing because you’re looking at a subgroup analysis that wasn’t really looked at, prospectively. How do you make sense of it? You take the benefit of the doubt and you say, “There may be that slight survival advantage.” PFS may not be affected, but those patients are actually seeing a little bit better survival on the right side.

Dirk Arnold, MD, PhD: I agree. But I don’t believe in this end point, necessarily, from the single trial. We clearly have to say that the motivation comes from the lack of other alternatives in this setting.

Tanios Bekaii-Saab, MD: But these do support.

Fortunato Ciardiello, MD, PhD: I have 2 comments. One is that the right-side tumor should be considered in the context of what the disease presentation is in the patient. If I have a patient who is relatively young with disease, and the tumor is BRAF and RAS wild-type, maybe, biologically, this is very similar to what we think about in BRAF-mutant patients? We would like to spend everything we have on first-line therapy. Maybe, in these patients, I will even try FOLFOXIRI and bevacizumab in some of these patients. Of course, I have to check to see what is right for the patient.

John L. Marshall, MD: Even without BRAF? Is that what you’re saying? I’m agreeing with you. I just want to make sure.

Fortunato Ciardiello, MD, PhD: Yes, even if it’s BRAF wild-type.

John L. Marshall, MD: We’ve got frontline data of triplet therapy with bevacizumab showing overall survival, response rate, and everything else, and we push that off to the side too. Sorry, that was one of your points.

Fortunato Ciardiello, MD, PhD: Yes. And the second point was that the study that we were discussing before, about later lines of therapy with cetuximab versus best supportive care, was a very old study—the CO.17 study. Those patients were not pretreated with bevacizumab. We don’t know, in the context of pretreatment with chemotherapy plus bevacizumab, what happens in third- or fourth-line therapy. And as all of us are saying, we have no real alternative. So in these patients, I will still try to use an anti–EGFR in the third-line or in second-line setting if first-line with antiangiogenesis didn’t work well.

When disease progresses after doublet chemotherapy plus bevacizumab, what do you do to these patients? You don’t use an antiangiogenic again. Maybe you can use an anti-EGFR? These are the patients with right-sided tumors in whom I would give an anti-EGFR—either in some patients in the second-line setting, most of the patients in the third-line setting, and very few patients in the first-line setting in a very short treatment for conversion to liver resection. But not many patients are like this. There are very, very few.

John L. Marshall, MD: Tony, the transverse colon—which side is it on?

Tanios Bekaii-Saab, MD: Transverse has not been looked at. It has been excluded.

John L. Marshall, MD: Alan Venook’s study excluded it.

Tanios Bekaii-Saab, MD: CALGB/SWOG 80405 excluded it. If it’s closer to the hepatic flexure, treat them as right-sided. If it’s closer to the splenic flexure, treat it as left-sided.

John L. Marshall, MD: Embryologically, the line is at the splenic flexure.

Tanios Bekaii-Saab, MD: Somewhere.

Dirk Arnold, MD, PhD: Embryologic gives a clear definition. The molecular biology doesn’t follow this because, in molecular biology, we learned that we have a shift of the pattern from the very right to the very left. We can see these by the percentage of patients showing BRAF-mutant status here, coming from 30% on the right side and ending in 3% on the colon. And this goes, continuously, with a continuous decrease. The profile of other things—the molecular profile and the frequency of other alterations—also gradually decreases.

John L. Marshall, MD: Great segue.

Tanios Bekaii-Saab, MD: But you’re in clinic. You’re really not going to think, “Is it 3 cm or 4 cm?” You really are just going to look at it and ask, “Is it closer to this side or closer to this side?” In a busy practice, you really have to be practical. Frankly—and we’ll talk about this later—how you treat in the first-line setting, pragmatically, is not going to really change much. It may complicate things a little.

John L. Marshall, MD: I’m putting transverse on the right. Paul?

Paul R. Helft, MD: Well, I would tend to agree with Tony. If you have one that’s really far in one direction, than the other…

John L. Marshall, MD: You pick that side?

Paul R. Helft, MD: Right. With the molecular profiles, we just don’t know yet, because there aren’t enough of them to make statistical conclusions. We give them the benefit of the doubt, in general, and put them on the left.

John L. Marshall, MD: That’s the segue that I was looking for. Do we have a gene? Do we have some molecular characteristic? Or right now, are we still stuck with anatomy?

Paul R. Helft, MD: We make the best assumptions.

John L. Marshall, MD: So it’s still anatomy? We’ve had some studies here at the 2017 ASCO Annual Meeting looking at differences in stratifications for MSI and BRAF, and an answer really didn’t come out of that. Known molecular tests don’t distinguish this, right?

Fortunato Ciardiello, MD, PhD: That’s true.

John L. Marshall, MD: It’s still anatomy. You guys have ICD-10. Do you have to code?

Fortunato Ciardiello, MD, PhD: Of course.

John L. Marshall, MD: We all hate it. It matters now, right? You have to put the correct ICD-10 code in when you’re seeing a new patient.

Transcript Edited for Clarity
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