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Optimizing Frontline Chemotherapy in mCRC

Panelists:Tanios Bekaii-Saab, MD, Ohio State University – James Cancer Hospital; Johanna Bendell, MD, Sarah Cannon Research Institute; Charles S. Fuchs, MD, Dana-Farber Cancer Institute; Richard Kim, MD, Moffitt Cancer Center; John L. Marshall, MD, Georgetown University Hospital
Published: Tuesday, Apr 12, 2016


Transcript:

Johanna Bendell, MD:
TRIBE looked at FOLFIRI/bevacizumab versus FOLFOXIRI/bevacizumab, saw an improvement in response rate, an improvement in progression-free survival, and what looks like an improvement in overall survival in all the data.

John L. Marshall, MD: Why didn’t we do this? It’s a JCO paper. It’s an OS benefit. Why didn’t we adopt this then? That’s what, two years ago that paper?

Johanna Bendell, MD: I think it was fear, to be honest with you.

John L. Marshall, MD: Toxicity or are we uncomfortable with the regimen?

Johanna Bendell, MD: We weren’t used to FOLFIRINOX. Now we’re more used to FOLFIRINOX. We were worried about the toxicity in the regimen. The other thing is, something people don’t understand completely about FOLFOXIRI, is that the way the regimen was given in that study was for 4 to 6 months, and then they went on maintenance. A lot of my folks that call me, they’re like, why would I give FOLFOXIRI? It’s using all the bullets in my gun at once. It’s actually not because you’re only giving it for a certain period of time and then you’re backing off. So you can still use those agents again.

John L. Marshall, MD: And sure, those agents are still on the table for a recycle.

Charles S. Fuchs, MD: But to answer your question, one other thing that did temper the enthusiasm was in a subanalysis; they looked at the ability of FOLFOXIRI to get you to a curative liver resection, and there was no difference. You weren’t more likely if you got that kitchen sink approach to get it. But I know a number of oncologists said to me, I’m not doing it because it doesn’t improve your likelihood of getting a curative metastasectomy.

John L. Marshall, MD: That’s the one place I do regularly use it in because it is a slightly higher response rate.

Charles S. Fuchs, MD: But the study didn’t show it.

John L. Marshall, MD: I understand. But if response is what I’ve got to get, that’s a fairly reproducible response. But anyway, this study is different though.

Johanna Bendell, MD: The STEAM study is a little bit different. This was looking at a US-based population as opposed to the European-based population. This was looking at FOLFOXIRI versus what we call a sequential, where you got two cycles of FOLFOX and two cycles of FOLFIRI, back and forth versus FOLFOX, all of them with bevacizumab, all of them with maintenance therapy after 4 months to 6 months, depending.

John L. Marshall, MD: And the maintenance was?

Johanna Bendell, MD: 5-FU or capecitabine plus bevacizumab. It was dealer’s choice. The primary endpoint of this was looking at both response rate as well as progression-free survival. And what we saw is that you did get an improved response rate with the FOLFOXIRI versus the FOLFOX. We also saw an improved number of patients going to liver resection. As opposed to the TRIBE data, where we saw that about twice as many people went to potentially curative liver resection in the FOLFOXIRI arms versus the FOLFOX arms.

John L. Marshall, MD: Were the patients stratified by whether we thought they might be resectable?

Johanna Bendell, MD: No, they weren’t stratified. It was just all-comers across the board. Now, when we look at the analysis, it looks like about the same number had liver-only disease versus extrahepatic disease. The other thing it looked at was the progression-free survival. And certainly, when you gave FOLFOXIRI concurrently, you got what looks to be a better progression-free survival than if you used FOLFOX plus bevacizumab alone. So, I think it’s saying maybe we should start thinking about using this triplet regimen, not only for our BRAF mutated patients, but is it something viable for more patients globally.

John L. Marshall, MD: And the alternating schedule?

Johanna Bendell, MD: The alternating schedule didn’t seem to be as good as the concurrent, so I don’t think I would do the alternating schedule, but more the concurrent schedule.

John L. Marshall, MD: They may be synergistic, oxaliplatin and irinotecan, is that what that’s saying a little bit? There’s been some debate. Do we deconstruct FOLFOXIRI or FOLFIRINOX in pancreatic cancer, for example, or is there some magic…

Charles S. Fuchs, MD: We don’t have to be synergistic if they’re additive, if they work better together.

John L. Marshall, MD: I was thinking if you gave one and then the other, that you’d still see your additive benefit, but maybe not. Maybe they need to be on board.

Tanios Bekaii-Saab, MD: The interesting component of this is the sequential approach with giving FOLFOX and FOLFIRI, not in terms of necessarily a strategy to adopt, but more that it’s telling that you don’t really need to throw in the kitchen sink. You can get away with exposing patients sequentially with treatment. It may be more merciful on patients. The other thing, the PFS in the FOLFOXIRI doesn’t look any different than the PFS with your other study, with FOLFIRI alone versus FOLFOX.

Johanna Bendell, MD: Well, don’t forget, in the TRIBE study it was better.

John L. Marshall, MD: Yeah, it was better.

Tanios Bekaii-Saab, MD: No, I understand but still, you’re hitting the wall of one year, which is pretty much close to the 11 to 12 month you see with FOLFIRI/Avastin. The point of the matter is there is a certain patient population that is likely to benefit from the triplet yet to be determined. But I would not take a blank statement and say that FOLFOXIRI plus bevacizumab should become standard for most patients.

John L. Marshall, MD: I’ve got a recipe here. I’ve got choices. And Richard, this is a little unfair. I recognize that because all of this is pretty fresh. I’ve got a frontline, let’s say, asymptomatic metastatic colon patient. My choices are everything from 5-FU/bevacizumab or capecitabine/bevacizumab, which we see pretty good data with, right? So a simple, easy regimen all the way to a much more intensive combination regimen. Could we figure out the right person in the absence of a biomarker? What do I do?

Richard Kim, MD: Well, it has to be really individualized on the patients. You have to look at patient’s age, patient’s performance status, and tumor burden. Does the patient have a large, 10-centimeter lesion or does the patient have a few sub-centimeter lesions in the liver? So the decision of what you use up front would depend upon those multifactorial, including the biomarkers as well. In terms of using FOLFOXIRI up front, the main concern is some patients are a little bit older, the toxicity is a concern of those patients. However, in a subset population, it definitely seems like those patients may benefit from FOLFOXIRI, especially with a BRAF mutation or if you are trying to downstage a patient for surgery, that’s why we go back to the multi-disciplinary approach. You have to present the case at tumor boards to talk about, could this potentially become resectable later on? So, that becomes a key point.

John L. Marshall, MD: Well, our patients do want to be aggressive frontline. They want to push hard. Maybe it is ‘slam the cancer,’ but being cognizant that you want to back off and do maintenance, because this is a maintenance study, where you showed there was some difference from that initial approach. Charlie?

Charles S. Fuchs, MD: One thing that I think is really interesting about Johanna’s presentation of STEAM is the fact that you do improve their ability to get a metastasectomy, to get a resection. That’s what I wanted to see from these regimens. And the fact that you’re demonstrating that, I’m going to think twice. When I see a patient who’s resectable or more borderline resectable, I may very well do it.

Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
TRIBE looked at FOLFIRI/bevacizumab versus FOLFOXIRI/bevacizumab, saw an improvement in response rate, an improvement in progression-free survival, and what looks like an improvement in overall survival in all the data.

John L. Marshall, MD: Why didn’t we do this? It’s a JCO paper. It’s an OS benefit. Why didn’t we adopt this then? That’s what, two years ago that paper?

Johanna Bendell, MD: I think it was fear, to be honest with you.

John L. Marshall, MD: Toxicity or are we uncomfortable with the regimen?

Johanna Bendell, MD: We weren’t used to FOLFIRINOX. Now we’re more used to FOLFIRINOX. We were worried about the toxicity in the regimen. The other thing is, something people don’t understand completely about FOLFOXIRI, is that the way the regimen was given in that study was for 4 to 6 months, and then they went on maintenance. A lot of my folks that call me, they’re like, why would I give FOLFOXIRI? It’s using all the bullets in my gun at once. It’s actually not because you’re only giving it for a certain period of time and then you’re backing off. So you can still use those agents again.

John L. Marshall, MD: And sure, those agents are still on the table for a recycle.

Charles S. Fuchs, MD: But to answer your question, one other thing that did temper the enthusiasm was in a subanalysis; they looked at the ability of FOLFOXIRI to get you to a curative liver resection, and there was no difference. You weren’t more likely if you got that kitchen sink approach to get it. But I know a number of oncologists said to me, I’m not doing it because it doesn’t improve your likelihood of getting a curative metastasectomy.

John L. Marshall, MD: That’s the one place I do regularly use it in because it is a slightly higher response rate.

Charles S. Fuchs, MD: But the study didn’t show it.

John L. Marshall, MD: I understand. But if response is what I’ve got to get, that’s a fairly reproducible response. But anyway, this study is different though.

Johanna Bendell, MD: The STEAM study is a little bit different. This was looking at a US-based population as opposed to the European-based population. This was looking at FOLFOXIRI versus what we call a sequential, where you got two cycles of FOLFOX and two cycles of FOLFIRI, back and forth versus FOLFOX, all of them with bevacizumab, all of them with maintenance therapy after 4 months to 6 months, depending.

John L. Marshall, MD: And the maintenance was?

Johanna Bendell, MD: 5-FU or capecitabine plus bevacizumab. It was dealer’s choice. The primary endpoint of this was looking at both response rate as well as progression-free survival. And what we saw is that you did get an improved response rate with the FOLFOXIRI versus the FOLFOX. We also saw an improved number of patients going to liver resection. As opposed to the TRIBE data, where we saw that about twice as many people went to potentially curative liver resection in the FOLFOXIRI arms versus the FOLFOX arms.

John L. Marshall, MD: Were the patients stratified by whether we thought they might be resectable?

Johanna Bendell, MD: No, they weren’t stratified. It was just all-comers across the board. Now, when we look at the analysis, it looks like about the same number had liver-only disease versus extrahepatic disease. The other thing it looked at was the progression-free survival. And certainly, when you gave FOLFOXIRI concurrently, you got what looks to be a better progression-free survival than if you used FOLFOX plus bevacizumab alone. So, I think it’s saying maybe we should start thinking about using this triplet regimen, not only for our BRAF mutated patients, but is it something viable for more patients globally.

John L. Marshall, MD: And the alternating schedule?

Johanna Bendell, MD: The alternating schedule didn’t seem to be as good as the concurrent, so I don’t think I would do the alternating schedule, but more the concurrent schedule.

John L. Marshall, MD: They may be synergistic, oxaliplatin and irinotecan, is that what that’s saying a little bit? There’s been some debate. Do we deconstruct FOLFOXIRI or FOLFIRINOX in pancreatic cancer, for example, or is there some magic…

Charles S. Fuchs, MD: We don’t have to be synergistic if they’re additive, if they work better together.

John L. Marshall, MD: I was thinking if you gave one and then the other, that you’d still see your additive benefit, but maybe not. Maybe they need to be on board.

Tanios Bekaii-Saab, MD: The interesting component of this is the sequential approach with giving FOLFOX and FOLFIRI, not in terms of necessarily a strategy to adopt, but more that it’s telling that you don’t really need to throw in the kitchen sink. You can get away with exposing patients sequentially with treatment. It may be more merciful on patients. The other thing, the PFS in the FOLFOXIRI doesn’t look any different than the PFS with your other study, with FOLFIRI alone versus FOLFOX.

Johanna Bendell, MD: Well, don’t forget, in the TRIBE study it was better.

John L. Marshall, MD: Yeah, it was better.

Tanios Bekaii-Saab, MD: No, I understand but still, you’re hitting the wall of one year, which is pretty much close to the 11 to 12 month you see with FOLFIRI/Avastin. The point of the matter is there is a certain patient population that is likely to benefit from the triplet yet to be determined. But I would not take a blank statement and say that FOLFOXIRI plus bevacizumab should become standard for most patients.

John L. Marshall, MD: I’ve got a recipe here. I’ve got choices. And Richard, this is a little unfair. I recognize that because all of this is pretty fresh. I’ve got a frontline, let’s say, asymptomatic metastatic colon patient. My choices are everything from 5-FU/bevacizumab or capecitabine/bevacizumab, which we see pretty good data with, right? So a simple, easy regimen all the way to a much more intensive combination regimen. Could we figure out the right person in the absence of a biomarker? What do I do?

Richard Kim, MD: Well, it has to be really individualized on the patients. You have to look at patient’s age, patient’s performance status, and tumor burden. Does the patient have a large, 10-centimeter lesion or does the patient have a few sub-centimeter lesions in the liver? So the decision of what you use up front would depend upon those multifactorial, including the biomarkers as well. In terms of using FOLFOXIRI up front, the main concern is some patients are a little bit older, the toxicity is a concern of those patients. However, in a subset population, it definitely seems like those patients may benefit from FOLFOXIRI, especially with a BRAF mutation or if you are trying to downstage a patient for surgery, that’s why we go back to the multi-disciplinary approach. You have to present the case at tumor boards to talk about, could this potentially become resectable later on? So, that becomes a key point.

John L. Marshall, MD: Well, our patients do want to be aggressive frontline. They want to push hard. Maybe it is ‘slam the cancer,’ but being cognizant that you want to back off and do maintenance, because this is a maintenance study, where you showed there was some difference from that initial approach. Charlie?

Charles S. Fuchs, MD: One thing that I think is really interesting about Johanna’s presentation of STEAM is the fact that you do improve their ability to get a metastasectomy, to get a resection. That’s what I wanted to see from these regimens. And the fact that you’re demonstrating that, I’m going to think twice. When I see a patient who’s resectable or more borderline resectable, I may very well do it.

Transcript Edited for Clarity
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