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Frontline Antibody Selection in Metastatic CRC

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Tuesday, Apr 10, 2018



Transcript: 

John L. Marshall, MD: Let’s drill down on the practice implications. If you’re going to give VEGF therapy as frontline therapy, does it matter which side it is given for?

Cathy Eng, MD, FACP: It appears to not matter, in regard to left- versus right-sided tumors. But we know that the overall prognosis for survival is better on the left side. You can still give right-sided tumors anti-VEGF therapy.

John L. Marshall, MD: If you have a right-sided BRAF wild-type, KRAS wild-type tumor, I’m not giving EGFR therapy to that patient?

Johanna C. Bendell, MD: Probably not. When you look at the data, they seem to show that bevacizumab is agnostic to side. So, you get a benefit added on when you give bevacizumab. Whereas, with cetuximab or EGFR inhibitors, it may be a little different. Potentially, you see less benefit on the right side. You see more benefit on the left side. And that’s the other piece that a lot of people are debating back and forth on. When you look at the cuts of the FIRE-3 and CALGB/SWOG 80405 data, giving cetuximab to the left-sided RAS wild-type tumor actually does look better, compared with giving bevacizumab to that left-sided tumor. Now, lots of discussion can go back and forth about that—toxicity profiles of a first-line therapy with an EGFR inhibitor. But it raises that other question. In Europe, they’ve shifted.

Cathy Eng, MD, FACP: In Germany.

John L. Marshall, MD: I would think, and what I’m hearing is, Europeans are not really embracing the right-sided data as much as we are. Our guidelines changed, right?

Cathy Eng, MD, FACP: Correct.

John L. Marshall, MD: We changed guidelines to say, “If you’re right-sided, no matter what your molecular profile is, don’t do EGFR in the first-line setting. But let’s go to the opposite side. Who is that patient you would give frontline EGFR therapy to?

Michael A. Morse, MD: To me, the types of patients you want to dissect, even a little bit more, are those who might be going to surgery, for a variety of reasons. There’s the usual issue, of course, that you can’t give bevacizumab too close to a surgical procedure. The second is, if the response rates are truly higher, then there’s an opportunity to downstage more people to get to a surgery. We know that the other attempts to do that have also been successful—using multiagent therapy, like FOLFOXIRI with bevacizumab, in the OLIVIA trial. So, there is a direction in which one can go if you’re trying to get somebody to surgery to try to increase the response rate.

John L. Marshall, MD: Preoperatively.

Michael A. Morse, MD: Yes.

Johanna C. Bendell, MD: But do you argue about new EPOC data?

Cathy Eng, MD, FACP: That’s the other thing.

John L. Marshall, MD: We can pick on that. Not the negative data, but that wasn’t selected for left-sided…

Michael A. Morse, MD: Correct. Right.

John L. Marshall, MD: So, putting that aside, that may be one place in which you’d consider it, maybe?

Michael A. Morse, MD: Possibly.

John L. Marshall, MD: Dale?

Dale R. Shepard, MD, PhD, FACP: People with a thrombosis risk or people with wound healing issues—those are the people for whom I would steer more toward EGFR therapy.

John L. Marshall, MD: Left-sided, RAS wild-type, BRAF wild-type, and some sort of comorbidity?

Dale R. Shepard, MD, PhD, FACP: Comorbidity, uncontrolled hypertension, and that sort of thing.

John L. Marshall, MD: Cathy?

Cathy Eng, MD, FACP: I would agree. I also want to mention that I think it’s important to state that in CALGB/SWOG 80405, although it looks as if anti-EGFR therapy may be better on the left side, it was not powered to compare anti-VEGF versus anti-EGFR for the left side. It’s very interesting, compelling data.

John L. Marshall, MD: Enough for us to change the guidelines, though, on the other side?

Cathy Eng, MD, FACP: For the right side? Sure.

John L. Marshall, MD: It wasn’t powered for that either.

Johanna C. Bendell, MD: It wasn’t even strong data, on the right side.

Cathy Eng, MD, FACP: But the overall survival was so much less on the right side. That was also confirmed in FIRE-3, as you know.

John L. Marshall, MD: Is there anybody you’d do frontline EGFR therapy for?

Johanna C. Bendell, MD: I say all of that, and I worry about the toxicity issues. People hate having that rash for 12 months. There are probably more biomarkers that we’re missing. I think there’s a subpopulation of those left-sided RAS wild-type, BRAF wild-type, HER2-negative patients. And for regulin, epiregulin-high, I wish we could get better at measuring those. I think there is a piece. But I don’t know who they are, exactly, yet.

John L. Marshall, MD: I really struggle with this. We’re only talking about maybe 20% of all of metastatic colon cancer. There’s a 6-month delta in those analyses, in terms of overall survival. Most of those patients do get subsequent lines of therapy, at least in the United States. I get the whole toxicity profile. And so, I’m sort of feeling like I should be. Now, when you ask me if I have done it yet, the answer is no, I haven’t. I have a bulky, left-sided, symptomatic metastatic cancer patient. I want a response. I don’t really want to give FOLFIRINOX. I could. That would be my other choice—FOLFIRINOX and bevacizumab. That’s sort of my patient, which is now even fewer than 20%. But I’ve heard people say that even with asymptomatic metastatic disease, based on the overall survival delta from the underpowered study, they would do it anyway. The Europeans are saying this, right?

Johanna C. Bendell, MD: Don’t forget that there’s no response rate difference in both studies. It was an overall survival. That’s what kicked everybody into controversy.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: Let’s drill down on the practice implications. If you’re going to give VEGF therapy as frontline therapy, does it matter which side it is given for?

Cathy Eng, MD, FACP: It appears to not matter, in regard to left- versus right-sided tumors. But we know that the overall prognosis for survival is better on the left side. You can still give right-sided tumors anti-VEGF therapy.

John L. Marshall, MD: If you have a right-sided BRAF wild-type, KRAS wild-type tumor, I’m not giving EGFR therapy to that patient?

Johanna C. Bendell, MD: Probably not. When you look at the data, they seem to show that bevacizumab is agnostic to side. So, you get a benefit added on when you give bevacizumab. Whereas, with cetuximab or EGFR inhibitors, it may be a little different. Potentially, you see less benefit on the right side. You see more benefit on the left side. And that’s the other piece that a lot of people are debating back and forth on. When you look at the cuts of the FIRE-3 and CALGB/SWOG 80405 data, giving cetuximab to the left-sided RAS wild-type tumor actually does look better, compared with giving bevacizumab to that left-sided tumor. Now, lots of discussion can go back and forth about that—toxicity profiles of a first-line therapy with an EGFR inhibitor. But it raises that other question. In Europe, they’ve shifted.

Cathy Eng, MD, FACP: In Germany.

John L. Marshall, MD: I would think, and what I’m hearing is, Europeans are not really embracing the right-sided data as much as we are. Our guidelines changed, right?

Cathy Eng, MD, FACP: Correct.

John L. Marshall, MD: We changed guidelines to say, “If you’re right-sided, no matter what your molecular profile is, don’t do EGFR in the first-line setting. But let’s go to the opposite side. Who is that patient you would give frontline EGFR therapy to?

Michael A. Morse, MD: To me, the types of patients you want to dissect, even a little bit more, are those who might be going to surgery, for a variety of reasons. There’s the usual issue, of course, that you can’t give bevacizumab too close to a surgical procedure. The second is, if the response rates are truly higher, then there’s an opportunity to downstage more people to get to a surgery. We know that the other attempts to do that have also been successful—using multiagent therapy, like FOLFOXIRI with bevacizumab, in the OLIVIA trial. So, there is a direction in which one can go if you’re trying to get somebody to surgery to try to increase the response rate.

John L. Marshall, MD: Preoperatively.

Michael A. Morse, MD: Yes.

Johanna C. Bendell, MD: But do you argue about new EPOC data?

Cathy Eng, MD, FACP: That’s the other thing.

John L. Marshall, MD: We can pick on that. Not the negative data, but that wasn’t selected for left-sided…

Michael A. Morse, MD: Correct. Right.

John L. Marshall, MD: So, putting that aside, that may be one place in which you’d consider it, maybe?

Michael A. Morse, MD: Possibly.

John L. Marshall, MD: Dale?

Dale R. Shepard, MD, PhD, FACP: People with a thrombosis risk or people with wound healing issues—those are the people for whom I would steer more toward EGFR therapy.

John L. Marshall, MD: Left-sided, RAS wild-type, BRAF wild-type, and some sort of comorbidity?

Dale R. Shepard, MD, PhD, FACP: Comorbidity, uncontrolled hypertension, and that sort of thing.

John L. Marshall, MD: Cathy?

Cathy Eng, MD, FACP: I would agree. I also want to mention that I think it’s important to state that in CALGB/SWOG 80405, although it looks as if anti-EGFR therapy may be better on the left side, it was not powered to compare anti-VEGF versus anti-EGFR for the left side. It’s very interesting, compelling data.

John L. Marshall, MD: Enough for us to change the guidelines, though, on the other side?

Cathy Eng, MD, FACP: For the right side? Sure.

John L. Marshall, MD: It wasn’t powered for that either.

Johanna C. Bendell, MD: It wasn’t even strong data, on the right side.

Cathy Eng, MD, FACP: But the overall survival was so much less on the right side. That was also confirmed in FIRE-3, as you know.

John L. Marshall, MD: Is there anybody you’d do frontline EGFR therapy for?

Johanna C. Bendell, MD: I say all of that, and I worry about the toxicity issues. People hate having that rash for 12 months. There are probably more biomarkers that we’re missing. I think there’s a subpopulation of those left-sided RAS wild-type, BRAF wild-type, HER2-negative patients. And for regulin, epiregulin-high, I wish we could get better at measuring those. I think there is a piece. But I don’t know who they are, exactly, yet.

John L. Marshall, MD: I really struggle with this. We’re only talking about maybe 20% of all of metastatic colon cancer. There’s a 6-month delta in those analyses, in terms of overall survival. Most of those patients do get subsequent lines of therapy, at least in the United States. I get the whole toxicity profile. And so, I’m sort of feeling like I should be. Now, when you ask me if I have done it yet, the answer is no, I haven’t. I have a bulky, left-sided, symptomatic metastatic cancer patient. I want a response. I don’t really want to give FOLFIRINOX. I could. That would be my other choice—FOLFIRINOX and bevacizumab. That’s sort of my patient, which is now even fewer than 20%. But I’ve heard people say that even with asymptomatic metastatic disease, based on the overall survival delta from the underpowered study, they would do it anyway. The Europeans are saying this, right?

Johanna C. Bendell, MD: Don’t forget that there’s no response rate difference in both studies. It was an overall survival. That’s what kicked everybody into controversy.

Transcript Edited for Clarity 
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