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TRIBE-2: FOLFOX or FOLFIRI With Bevacizumab in 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: Monday, Jul 29, 2019



Transcript: 

John Marshall, MD: Talk about that TRIBE study, Cathy.

Cathy Eng, MD: TRIBE-2.

John Marshall, MD: Yes, TRIBE-2 update.

Cathy Eng, MD: The control arm is the standard regimen, FOLFOX [folinic acid, fluorouracil, oxaliplatin], and then when you progress you go on to FOLFIRI [folinic acid fluorouracil, irinotecan], and then the investigational arm was just continuing on your FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan]. The progression-free survival [PFS] was significantly improved for those individuals who received the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab] regimen. Keep in mind, they did do the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab] for their maximum of 12 cycles, then they did the maintenance. Then at progression, they reintroduced the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab]. The PFS was significantly better. I historically had been using that regimen in my healthy patients, and actually, the median age of the patients on that study was 60 in both arms. I think it’s not unreasonable.

John Marshall, MD: This is a primarily European study, right? They play the chess game differently than we do, and so, should we start playing their game?

Tanios Bekaii-Saab, MD: I think the key with all this at the end of the day, whether you’re using a doublet or a triplet, is the maintenance piece. When you want to think about whether to use [folinic acid, fluorouracil, oxaliplatin, irinotecan] or [folinic acid, fluorouracil, oxaliplatin], or what have you, 3 to 4 months of any of these regimens is probably more than enough to induce the response you need. The maintenance is what really actually matters after that. That’s why we started rethinking about using more of the [folinic acid, fluorouracil, oxaliplatin, irinotecan], because I have the capacity to move from a very aggressive 3-month regimen, where I’m probably punishing my patient a little bit, frankly. Then, very quickly, but symptomatically, they improve. Their cancer symptoms actually resolve, because the response rate is pretty high, and then move them to the maintenance phase.

Cathy Eng, MD: Yes, the response rate was close to 70%.

Tanios Bekaii-Saab, MD: Yes, absolutely.

John Marshall, MD: Well, Dustin, let me pick on you on this. If we’re going to follow this argument—I’m not sure that everybody necessarily agrees—back to left-sided, molecularly and positively enriched, the best response rates are with EGFR-targeted therapies. Yet, we’ve had a resistance even in there. Should we then, as Cathy hinted at, be applying that best response rate regimen in that left-sided patient?

Dustin Deming, MD: I think this is a pretty challenging question, and there’s a lot of things that go into this. When we’re thinking about a first-line regimen and we have multiple potential lines of therapy for patients, looking at a change in survival doesn’t necessarily always give us the correct answer. I think in relying purely on the survival endpoint for deciding first-line EGFR, or for deciding to do a triplet regimen, there’s a lot of caveats that go into a survival endpoint, and so we have to be careful there. The other thing is that when we’re talking about using EGFR therapy in the first-line setting, one thing that you have to be careful with is that there tends to be a lot more toxicity with using EGFR in that setting. Patients developing an acneiform rash can tell that, and people around them can tell that something is different about them. For many patients, FOLFOX-BEV [folinic acid, fluorouracil, oxaliplatin plus bevacizumab] is a great regimen because they don’t feel or look like a cancer patient.

Tanios Bekaii-Saab, MD: Yes, and let me add to that argument, which I absolutely agree with. One of the issues with EGFR inhibitors in the first line is the lack of solid maintenance data. For those patients who you want to maintain on EGFR inhibitors plus 5-FU [fluorouracil], we don’t have the data that compare that combo to 5-FU alone, so we don’t know really whether we need the EGFR inhibitor. The EGFR inhibitors have long-term toxicities that are equally bad. That rash may go away, but that skin never looks good, their eyelashes become that big, and their magnesium will have to be replaced on a constant basis. It’s very obnoxious.

John Marshall, MD: What if I switched my maintenance to a CAPE-BEV [capecitabine plus bevacizumab] approach?

Tanios Bekaii-Saab, MD: We don’t have the data.

John Marshall, MD: I know we don’t have the data, but there’s a lot of stuff we’re talking about here.

Tanios Bekaii-Saab, MD: Then why wouldn’t you do a [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus [bevacizumab]?

John Marshall, MD: Well, that’s just my point.

Tanios Bekaii-Saab, MD: I don’t think [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus [bevacizumab], and move to [capecitabine plus bevacizumab], or [folinic acid, fluorouracil, oxaliplatin plus bevacizumab]….

John Marshall, MD: Well, the counter-argument is that the EGFR rechallenge, if you look at the European data there, looks pretty promising. Right? You can give it for a few months.

Tanios Bekaii-Saab, MD: You don’t need to use it in the first line. You can move it to the second line.

John Marshall, MD: Well, I’m not saying you don’t need to, but what about this option of rechallenge? Mike, what do you think?

Michael Morse, MD: You need to give it enough time to do the rechallenge, because those mutations that have developed and the timeline on their disappearance could be 4 or 6 months, or even longer.

John Marshall, MD: That would argue in favor of giving it earlier, right? Then you have your time for….

Tanios Bekaii-Saab, MD: You get a good median progression-free survival from second-line EGFR inhibitors on the left side, which is beyond 4 to 6 months.

John Marshall, MD: What I’m hearing is not a consensus, but a shift toward initially more intensive therapy as a consideration, even in an asymptomatic metastatic patient. Not required….

Tanios Bekaii-Saab, MD: I don’t think I said that.

John Marshall, MD: That’s what I’m hearing. I’m a little deaf, but….

Tanios Bekaii-Saab, MD: No, let me be clear. When we were talking about the right sided-tumors, because they do incredibly badly, I would consider them RAS-mutated. For the RAS­-mutated patients, I would give it the consideration in the right patient who has symptoms. In the patient with BRAF mutation, definitely. For the good-prognosis patient with a left-sided tumor, I wouldn’t favor a triplet. I would go with a sequential approach.

John Marshall, MD: You’ve started a right-sided patient on [folinic acid, fluorouracil, oxaliplatin plus bevacizumab].

Cathy Eng, MD: Yes.

John Marshall, MD: You’ve sent off the molecular profile. A month later, it comes back. The CEA [carcinoembryonic antigen] is gone in half, and they’re BRAF-mutated. Do I add irinotecan?

Cathy Eng, MD: Oh.

John Marshall, MD: Anybody? You told me I got BRAF definitely. Do I add irinotecan? Are my CEAs coming down?

Tanios Bekaii-Saab, MD: The answer is no.

John Marshall, MD: No.

Tanios Bekaii-Saab, MD: The answer is no.

Michael Morse, MD: No? We’re responding.

Tanios Bekaii-Saab, MD: There are 2 reason why it’s a no. One is, there are 30% of those patients with V600E mutations who do incredibly well. We don’t know why, but they do. That’s the tail end, and we have patients who continue trickling through under therapy. It may be one of those patients, and I’d rather, at this point, just assess what the doublet is doing. The other point is, now we at least have options for those patients if they fail chemotherapy, which may be a very reasonable option. For that, I’m not compelled to just jump.

Cathy Eng, MD: He said the patient’s responding.

John Marshall, MD: Yes, that’s where I am. I would not add it.

Cathy Eng, MD: The patient’s responding, so….

John Marshall, MD: I would not add it at that point.

Tanios Bekaii-Saab, MD: That’s a very….

Cathy Eng, MD: CEAs dropped in half, so maybe?

John Marshall, MD: Mike, do I ever give EGFR….

Tanios Bekaii-Saab, MD: Even if he’s not responding.

John Marshall, MD: Do I ever give EGFR therapy to a right-sided colon cancer?

Michael Morse, MD: I assume you’re getting into the issue of, once you’ve run out of options. would you still?

John Marshall, MD: Second or third line; either they’re RAS wild-type, BRAF wild-type, or HER2-negative. Do I ever just do it anyway?

Dustin Deming, MD: We actually looked at this at our institution, and for the right-sided tumors that are pan wild-type, we haven’t had anybody respond to single agent, but we have had people respond to irinotecan plus anti-EGFR therapy in the setting of prior irinotecan.

John Marshall, MD: I’m doing it, but after having watched and paid attention, I don’t think we’ve seen a response in this group.

Cathy Eng, MD: When you don’t have options, for patients in the community who can’t participate in a clinical trial, sometimes you have to consider that, if you don’t have enough data, and it’s reasonable.

John Marshall, MD: It’s not crazy to try this. Is it crazy to try it? Would you give it to you?

Tanios Bekaii-Saab, MD: If I’m at the desperate….

Cathy Eng, MD: He’s speechless.

John Marshall, MD: He is speechless. I did it, finally.

Tanios Bekaii-Saab, MD: No. If I’m at the desperate point where there are no other options, the answer is yes.

John Marshall, MD: You’d give it a try.

Tanios Bekaii-Saab, MD: Yes, I’ll give it a try. To Dustin’s point, the study that looked at cetuximab versus best operative care, looked at the subgroup of patients with right versus left. What was interesting to see is that there weren’t responses. There wasn’t a PFS benefit, but for the OS [overall survival], there was a 2-month difference between the cetuximab and the best operative care on the right side.

Cathy Eng, MD: But are you really going to give single agent?

Tanios Bekaii-Saab, MD: No, but let me get to the point. The point is, I would want to go on regorafenib first.

John Marshall, MD: But no, I’m saying….

Tanios Bekaii-Saab, MD: And on TAS-102, before I actually get to cetuximab.

John Marshall, MD: Yes.

Cathy Eng, MD: Once again, we’re talking about the setting where we may not have options.

John Marshall, MD: We’re out of stuff.

Tanios Bekaii-Saab, MD: Then, at that point, the answer yes.

John Marshall, MD: Not traditionally second line. Maybe third, maybe fourth if the patient is still doing OK. You’re not excited about it, but you’re not going to withhold it if you had the opportunity.

Tanios Bekaii-Saab, MD: As a last option.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: Talk about that TRIBE study, Cathy.

Cathy Eng, MD: TRIBE-2.

John Marshall, MD: Yes, TRIBE-2 update.

Cathy Eng, MD: The control arm is the standard regimen, FOLFOX [folinic acid, fluorouracil, oxaliplatin], and then when you progress you go on to FOLFIRI [folinic acid fluorouracil, irinotecan], and then the investigational arm was just continuing on your FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan]. The progression-free survival [PFS] was significantly improved for those individuals who received the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab] regimen. Keep in mind, they did do the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab] for their maximum of 12 cycles, then they did the maintenance. Then at progression, they reintroduced the FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus BEV [bevacizumab]. The PFS was significantly better. I historically had been using that regimen in my healthy patients, and actually, the median age of the patients on that study was 60 in both arms. I think it’s not unreasonable.

John Marshall, MD: This is a primarily European study, right? They play the chess game differently than we do, and so, should we start playing their game?

Tanios Bekaii-Saab, MD: I think the key with all this at the end of the day, whether you’re using a doublet or a triplet, is the maintenance piece. When you want to think about whether to use [folinic acid, fluorouracil, oxaliplatin, irinotecan] or [folinic acid, fluorouracil, oxaliplatin], or what have you, 3 to 4 months of any of these regimens is probably more than enough to induce the response you need. The maintenance is what really actually matters after that. That’s why we started rethinking about using more of the [folinic acid, fluorouracil, oxaliplatin, irinotecan], because I have the capacity to move from a very aggressive 3-month regimen, where I’m probably punishing my patient a little bit, frankly. Then, very quickly, but symptomatically, they improve. Their cancer symptoms actually resolve, because the response rate is pretty high, and then move them to the maintenance phase.

Cathy Eng, MD: Yes, the response rate was close to 70%.

Tanios Bekaii-Saab, MD: Yes, absolutely.

John Marshall, MD: Well, Dustin, let me pick on you on this. If we’re going to follow this argument—I’m not sure that everybody necessarily agrees—back to left-sided, molecularly and positively enriched, the best response rates are with EGFR-targeted therapies. Yet, we’ve had a resistance even in there. Should we then, as Cathy hinted at, be applying that best response rate regimen in that left-sided patient?

Dustin Deming, MD: I think this is a pretty challenging question, and there’s a lot of things that go into this. When we’re thinking about a first-line regimen and we have multiple potential lines of therapy for patients, looking at a change in survival doesn’t necessarily always give us the correct answer. I think in relying purely on the survival endpoint for deciding first-line EGFR, or for deciding to do a triplet regimen, there’s a lot of caveats that go into a survival endpoint, and so we have to be careful there. The other thing is that when we’re talking about using EGFR therapy in the first-line setting, one thing that you have to be careful with is that there tends to be a lot more toxicity with using EGFR in that setting. Patients developing an acneiform rash can tell that, and people around them can tell that something is different about them. For many patients, FOLFOX-BEV [folinic acid, fluorouracil, oxaliplatin plus bevacizumab] is a great regimen because they don’t feel or look like a cancer patient.

Tanios Bekaii-Saab, MD: Yes, and let me add to that argument, which I absolutely agree with. One of the issues with EGFR inhibitors in the first line is the lack of solid maintenance data. For those patients who you want to maintain on EGFR inhibitors plus 5-FU [fluorouracil], we don’t have the data that compare that combo to 5-FU alone, so we don’t know really whether we need the EGFR inhibitor. The EGFR inhibitors have long-term toxicities that are equally bad. That rash may go away, but that skin never looks good, their eyelashes become that big, and their magnesium will have to be replaced on a constant basis. It’s very obnoxious.

John Marshall, MD: What if I switched my maintenance to a CAPE-BEV [capecitabine plus bevacizumab] approach?

Tanios Bekaii-Saab, MD: We don’t have the data.

John Marshall, MD: I know we don’t have the data, but there’s a lot of stuff we’re talking about here.

Tanios Bekaii-Saab, MD: Then why wouldn’t you do a [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus [bevacizumab]?

John Marshall, MD: Well, that’s just my point.

Tanios Bekaii-Saab, MD: I don’t think [folinic acid, fluorouracil, oxaliplatin, irinotecan] plus [bevacizumab], and move to [capecitabine plus bevacizumab], or [folinic acid, fluorouracil, oxaliplatin plus bevacizumab]….

John Marshall, MD: Well, the counter-argument is that the EGFR rechallenge, if you look at the European data there, looks pretty promising. Right? You can give it for a few months.

Tanios Bekaii-Saab, MD: You don’t need to use it in the first line. You can move it to the second line.

John Marshall, MD: Well, I’m not saying you don’t need to, but what about this option of rechallenge? Mike, what do you think?

Michael Morse, MD: You need to give it enough time to do the rechallenge, because those mutations that have developed and the timeline on their disappearance could be 4 or 6 months, or even longer.

John Marshall, MD: That would argue in favor of giving it earlier, right? Then you have your time for….

Tanios Bekaii-Saab, MD: You get a good median progression-free survival from second-line EGFR inhibitors on the left side, which is beyond 4 to 6 months.

John Marshall, MD: What I’m hearing is not a consensus, but a shift toward initially more intensive therapy as a consideration, even in an asymptomatic metastatic patient. Not required….

Tanios Bekaii-Saab, MD: I don’t think I said that.

John Marshall, MD: That’s what I’m hearing. I’m a little deaf, but….

Tanios Bekaii-Saab, MD: No, let me be clear. When we were talking about the right sided-tumors, because they do incredibly badly, I would consider them RAS-mutated. For the RAS­-mutated patients, I would give it the consideration in the right patient who has symptoms. In the patient with BRAF mutation, definitely. For the good-prognosis patient with a left-sided tumor, I wouldn’t favor a triplet. I would go with a sequential approach.

John Marshall, MD: You’ve started a right-sided patient on [folinic acid, fluorouracil, oxaliplatin plus bevacizumab].

Cathy Eng, MD: Yes.

John Marshall, MD: You’ve sent off the molecular profile. A month later, it comes back. The CEA [carcinoembryonic antigen] is gone in half, and they’re BRAF-mutated. Do I add irinotecan?

Cathy Eng, MD: Oh.

John Marshall, MD: Anybody? You told me I got BRAF definitely. Do I add irinotecan? Are my CEAs coming down?

Tanios Bekaii-Saab, MD: The answer is no.

John Marshall, MD: No.

Tanios Bekaii-Saab, MD: The answer is no.

Michael Morse, MD: No? We’re responding.

Tanios Bekaii-Saab, MD: There are 2 reason why it’s a no. One is, there are 30% of those patients with V600E mutations who do incredibly well. We don’t know why, but they do. That’s the tail end, and we have patients who continue trickling through under therapy. It may be one of those patients, and I’d rather, at this point, just assess what the doublet is doing. The other point is, now we at least have options for those patients if they fail chemotherapy, which may be a very reasonable option. For that, I’m not compelled to just jump.

Cathy Eng, MD: He said the patient’s responding.

John Marshall, MD: Yes, that’s where I am. I would not add it.

Cathy Eng, MD: The patient’s responding, so….

John Marshall, MD: I would not add it at that point.

Tanios Bekaii-Saab, MD: That’s a very….

Cathy Eng, MD: CEAs dropped in half, so maybe?

John Marshall, MD: Mike, do I ever give EGFR….

Tanios Bekaii-Saab, MD: Even if he’s not responding.

John Marshall, MD: Do I ever give EGFR therapy to a right-sided colon cancer?

Michael Morse, MD: I assume you’re getting into the issue of, once you’ve run out of options. would you still?

John Marshall, MD: Second or third line; either they’re RAS wild-type, BRAF wild-type, or HER2-negative. Do I ever just do it anyway?

Dustin Deming, MD: We actually looked at this at our institution, and for the right-sided tumors that are pan wild-type, we haven’t had anybody respond to single agent, but we have had people respond to irinotecan plus anti-EGFR therapy in the setting of prior irinotecan.

John Marshall, MD: I’m doing it, but after having watched and paid attention, I don’t think we’ve seen a response in this group.

Cathy Eng, MD: When you don’t have options, for patients in the community who can’t participate in a clinical trial, sometimes you have to consider that, if you don’t have enough data, and it’s reasonable.

John Marshall, MD: It’s not crazy to try this. Is it crazy to try it? Would you give it to you?

Tanios Bekaii-Saab, MD: If I’m at the desperate….

Cathy Eng, MD: He’s speechless.

John Marshall, MD: He is speechless. I did it, finally.

Tanios Bekaii-Saab, MD: No. If I’m at the desperate point where there are no other options, the answer is yes.

John Marshall, MD: You’d give it a try.

Tanios Bekaii-Saab, MD: Yes, I’ll give it a try. To Dustin’s point, the study that looked at cetuximab versus best operative care, looked at the subgroup of patients with right versus left. What was interesting to see is that there weren’t responses. There wasn’t a PFS benefit, but for the OS [overall survival], there was a 2-month difference between the cetuximab and the best operative care on the right side.

Cathy Eng, MD: But are you really going to give single agent?

Tanios Bekaii-Saab, MD: No, but let me get to the point. The point is, I would want to go on regorafenib first.

John Marshall, MD: But no, I’m saying….

Tanios Bekaii-Saab, MD: And on TAS-102, before I actually get to cetuximab.

John Marshall, MD: Yes.

Cathy Eng, MD: Once again, we’re talking about the setting where we may not have options.

John Marshall, MD: We’re out of stuff.

Tanios Bekaii-Saab, MD: Then, at that point, the answer yes.

John Marshall, MD: Not traditionally second line. Maybe third, maybe fourth if the patient is still doing OK. You’re not excited about it, but you’re not going to withhold it if you had the opportunity.

Tanios Bekaii-Saab, MD: As a last option.

Transcript Edited for Clarity
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