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Sequencing for BRAF+, RAS+, HER2- Left-Sided CRC

Insights From: John L. Marshall, MD, MedStar Georgetown University Hospital; Tanios S. Bekaii-Saab, MD, Mayo Clinic
Published: Friday, Apr 05, 2019



Transcript: 

John L. Marshall, MD:
Right-sided colon cancer is now pretty well established. Kind of known it a while that they have a worse prognosis. Left-sided seems to be better. We don’t really know why. Certainly some of the bad markers track one side or the other, but that’s clearly not the only explanation. So this is influencing our decision making. We’ve got it down to where left-side cancers with RAS wild-type, BRAF wild-type are the ones where EGFR therapies are really very effective—first, second or third line—and it falls on us to decide when to use that. All the other cancers, so the 80% of the rest of them, [that therapy] really doesn’t work very well.

And so in some ways that makes our decision making easier for right-sided cancers, apart from say BRAF where we need to know that. Because that might influence our initial lines of therapy. But I think probably the most heated discussion going on right now is in that 20%, with some analyses, retrospective analyses looking at those patients who are RAS wild-type, BRAF wild-type, left-sided. Is that a group? Is that the patient we should be using EGFR therapy in? And I have to say, I’m increasingly struggling with not doing it. It’s easier for me in the bulky tumors, the big bulky tumors where I need a response, but you know these curves are being pretty consistent that that initial line of therapy is worth it. Not there in everybody, but I’m leaning that way. You?

Tanios S. Bekaii-Saab, MD: So I would say, John, the way I would think, now take those 2 studies—FIRE-3 and CALGB 80405—and I think, what was the primary outcome of these studies? They were negative. These are 2 negative studies that we’ve been literally….

John L. Marshall, MD: Basically meaning no difference.

Tanios S. Bekaii-Saab, MD: No, no, they were negative. FIRE-3 was supposed to be a superiority.

John L. Marshall, MD: Superiority.

Tanios S. Bekaii-Saab, MD: And it ended up being a wash. CALGB 80405 was also a superiority study for the cetuximab arm, and it ended up being a wash. This is where I get concerned. I don’t see these curves so separated all the way through in my mind to say that it’s definitely an improvement. FIRE-3 was started with a primary endpoint that doesn’t make a lot of sense, response rate. It makes some kind of sense, but even on that EGFR inhibitor that supposedly induces a better response, did not win.

Then we ended up doing an analysis on survival, which essentially the curve of overall survival only separated after 2 years, whereby patients progressed at 1 year on average. So it makes you wonder what’s going on there. CALGB 80405 took 10-plus years to accrue. A lot of things changed every year over the last 10 years. I have difficulties actually making sense out of this data. It’s not very clear-cut.

Now, that said, I think in my mind your lines of therapy are first line, second line, and then the rest. In those first 2 lines of therapy, you have for that BRAF wild-type, RAS wild-type, left sided, HER2 nonamplified patient, I would consider an EGFR inhibitor in the first line as an option. But if I don’t expose them into the first line, which for the most I don’t, then I use in second line; I wouldn’t wait for the third line. They have to have in the first or second line.

John L. Marshall, MD: See I’m a little different, interesting. So we play the chess game differently.

Tanios S. Bekaii-Saab, MD: Yes.

John L. Marshall, MD: I might, in that patient if I’ve decided not to use it first, I’m not going to play it till I need a response. I’m not going to cure them. So if they’re asymptomatic in the second line, I might fiddle there knowing that I’ve got a really good salvage card to play later. But that’s the point I think of this, is that you’ve got to know the rules of the chess game, and there’s more than one way to play the chess game.

Tanios S. Bekaii-Saab, MD: But the other option, John, is you have the option of FOLFOXIRI [folinic acid/fluorouracil/oxaliplatin/irinotecan] and bevacizumab, which does have historically a higher response rate than a doublet.

John L. Marshall, MD: So why don’t we do that in everybody, right? That’s a positive study. Why don’t we do it to everybody?

Tanios S. Bekaii-Saab, MD: I’ve been doing more of it, and I’ll tell you why. I look at this as an outlook. If I see a patient that I want to do FOLFOXIRI/bevacizumab, I know that within 3 months I can switch them to capecitabine. So I give them the promise, “I’m gonna hit you hard.”

John L. Marshall, MD: We’re only going to do this for a little bit.

Tanios S. Bekaii-Saab, MD: For 2 to 3 months, and then I’m going to tone it down to capecitabine and bevacizumab.

John L. Marshall, MD: What about the guys who say, and gals who say, you know I’m burning all my drugs, so I don’t want to use all of them in frontline?

Tanios S. Bekaii-Saab, MD: Well, I don’t think you are because for most patients you expose them to 3 months and then they go on capecitabine/bevacizumab. They progress within 3 months; that’s really a bad omen.

John L. Marshall, MD: Yes.

Tanios S. Bekaii-Saab, MD: If they actually take more than 3 months, you can do whatever you want. You can do the FOLFOX [folinic acid/fluorouracil/oxaliplatin], you can do the FOLFIRI [folinic acid/fluorouracil/irinotecan], you can go back to the FOLFOXIRI. So you’re not burning that many bridges. Plus, when we look at the study, the survival may be a little bit better than FOLFIRI or FOLFOX alone. And then if you have all these other agents, depending on the profiling and the sidedness of the tumor and all this, we’re talking here about RAS wild-type, BRAF wild-type, you know, HER2 nonamplified, left-sided tumor, you can still go to EGFR inhibitors with FOLFIRI, or irinotecan. And you still have regorafenib and TAS-102. I think you don’t burn as many bridges. In fact, if anything….

John L. Marshall, MD: But you can burn a trial eligibility for example if you wanted to.

Tanios S. Bekaii-Saab, MD: You could, you could.

John L. Marshall, MD: There aren’t that many second-line studies.

Tanios S. Bekaii-Saab, MD: Unfortunately, not good ones at least.

John L. Marshall, MD: Do you think we’re obligated? Let’s say you sent the test and you got back that they have a V600E, and maybe you’ve had a couple of cycles already, and they look OK. I don’t feel obligated to put drug in at that point.

Tanios S. Bekaii-Saab, MD: No, I would keep a close eye on them. The response rate, you know, with a doublet is very minimal and very dismal, and tends to essentially be unsure.

I’ve had patients who started on FOLFIRI. I start FOLFIRI on all my patients in the first line; FOLFIRI with bevacizumab, and they turned out to have a BRAF V600E, and I kept them; within 4 months typically they progress, most of them do. There’s a small group of patients that doesn’t really, does incredibly much better than expected. So with those patients who actually start progressing, I add the oxaliplatin till they’ll go on FOLFOXIRI. And if you started with FOLFOXIRI, I’d add the irinotecan.

John L. Marshall, MD: So you would add it in downstream.

Tanios S. Bekaii-Saab, MD: Yes. It’s more difficult to add it when you’re starting with FOLFOX because you run out of FOLFOX after 4 to 5 months. It’s much easier to do it with FOLFIRI because you know you can still expose those patients to....

John L. Marshall, MD: Do molecular markers at all influence your maintenance?

Tanios S. Bekaii-Saab, MD: So the molecular, at this point of time they don’t.

John L. Marshall, MD: And so we share this, that we kind of stop our induction in frontline therapy, intensive therapy, after around 3 months, in that ballpark. Not much more response after that; it’s before you’re getting cumulative neuropathy.

Tanios S. Bekaii-Saab, MD: You hit that plateau.

John L. Marshall, MD: And maybe your first scan’s at 3 months even. Some people are 2 and 4, which is fine.

Tanios S. Bekaii-Saab, MD: I think 3 is; I think you get stuck with the 4 when you’re like wired to do your scans every 2 months. But if you can rewire some of this and say 3 months, knowing that 95% of the patients will have some form of response.

John L. Marshall, MD: Watching markers, maybe seeing how they’re doing, reassuring the patient.

Tanios S. Bekaii-Saab, MD: Absolutely. Then you can do a 3-month and then take that decision then about the maintenance; they don’t need that additional month after the third. The only reason why that ends up being a 4-month induction strategy is because you scan every 2 months.

John L. Marshall, MD: Right. And avoiding that. I always say neuropathy’s our fault not oxaliplatin’s fault.

Tanios S. Bekaii-Saab, MD: Exactly. You know all these studies that looked at trying to find a way to tone down the neurotoxicity or neuropathy from oxaliplatin, the easiest way to do it is not to expose them, or to minimize the exposure at the end of the day.


Transcript Edited for Clarity
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Transcript: 

John L. Marshall, MD:
Right-sided colon cancer is now pretty well established. Kind of known it a while that they have a worse prognosis. Left-sided seems to be better. We don’t really know why. Certainly some of the bad markers track one side or the other, but that’s clearly not the only explanation. So this is influencing our decision making. We’ve got it down to where left-side cancers with RAS wild-type, BRAF wild-type are the ones where EGFR therapies are really very effective—first, second or third line—and it falls on us to decide when to use that. All the other cancers, so the 80% of the rest of them, [that therapy] really doesn’t work very well.

And so in some ways that makes our decision making easier for right-sided cancers, apart from say BRAF where we need to know that. Because that might influence our initial lines of therapy. But I think probably the most heated discussion going on right now is in that 20%, with some analyses, retrospective analyses looking at those patients who are RAS wild-type, BRAF wild-type, left-sided. Is that a group? Is that the patient we should be using EGFR therapy in? And I have to say, I’m increasingly struggling with not doing it. It’s easier for me in the bulky tumors, the big bulky tumors where I need a response, but you know these curves are being pretty consistent that that initial line of therapy is worth it. Not there in everybody, but I’m leaning that way. You?

Tanios S. Bekaii-Saab, MD: So I would say, John, the way I would think, now take those 2 studies—FIRE-3 and CALGB 80405—and I think, what was the primary outcome of these studies? They were negative. These are 2 negative studies that we’ve been literally….

John L. Marshall, MD: Basically meaning no difference.

Tanios S. Bekaii-Saab, MD: No, no, they were negative. FIRE-3 was supposed to be a superiority.

John L. Marshall, MD: Superiority.

Tanios S. Bekaii-Saab, MD: And it ended up being a wash. CALGB 80405 was also a superiority study for the cetuximab arm, and it ended up being a wash. This is where I get concerned. I don’t see these curves so separated all the way through in my mind to say that it’s definitely an improvement. FIRE-3 was started with a primary endpoint that doesn’t make a lot of sense, response rate. It makes some kind of sense, but even on that EGFR inhibitor that supposedly induces a better response, did not win.

Then we ended up doing an analysis on survival, which essentially the curve of overall survival only separated after 2 years, whereby patients progressed at 1 year on average. So it makes you wonder what’s going on there. CALGB 80405 took 10-plus years to accrue. A lot of things changed every year over the last 10 years. I have difficulties actually making sense out of this data. It’s not very clear-cut.

Now, that said, I think in my mind your lines of therapy are first line, second line, and then the rest. In those first 2 lines of therapy, you have for that BRAF wild-type, RAS wild-type, left sided, HER2 nonamplified patient, I would consider an EGFR inhibitor in the first line as an option. But if I don’t expose them into the first line, which for the most I don’t, then I use in second line; I wouldn’t wait for the third line. They have to have in the first or second line.

John L. Marshall, MD: See I’m a little different, interesting. So we play the chess game differently.

Tanios S. Bekaii-Saab, MD: Yes.

John L. Marshall, MD: I might, in that patient if I’ve decided not to use it first, I’m not going to play it till I need a response. I’m not going to cure them. So if they’re asymptomatic in the second line, I might fiddle there knowing that I’ve got a really good salvage card to play later. But that’s the point I think of this, is that you’ve got to know the rules of the chess game, and there’s more than one way to play the chess game.

Tanios S. Bekaii-Saab, MD: But the other option, John, is you have the option of FOLFOXIRI [folinic acid/fluorouracil/oxaliplatin/irinotecan] and bevacizumab, which does have historically a higher response rate than a doublet.

John L. Marshall, MD: So why don’t we do that in everybody, right? That’s a positive study. Why don’t we do it to everybody?

Tanios S. Bekaii-Saab, MD: I’ve been doing more of it, and I’ll tell you why. I look at this as an outlook. If I see a patient that I want to do FOLFOXIRI/bevacizumab, I know that within 3 months I can switch them to capecitabine. So I give them the promise, “I’m gonna hit you hard.”

John L. Marshall, MD: We’re only going to do this for a little bit.

Tanios S. Bekaii-Saab, MD: For 2 to 3 months, and then I’m going to tone it down to capecitabine and bevacizumab.

John L. Marshall, MD: What about the guys who say, and gals who say, you know I’m burning all my drugs, so I don’t want to use all of them in frontline?

Tanios S. Bekaii-Saab, MD: Well, I don’t think you are because for most patients you expose them to 3 months and then they go on capecitabine/bevacizumab. They progress within 3 months; that’s really a bad omen.

John L. Marshall, MD: Yes.

Tanios S. Bekaii-Saab, MD: If they actually take more than 3 months, you can do whatever you want. You can do the FOLFOX [folinic acid/fluorouracil/oxaliplatin], you can do the FOLFIRI [folinic acid/fluorouracil/irinotecan], you can go back to the FOLFOXIRI. So you’re not burning that many bridges. Plus, when we look at the study, the survival may be a little bit better than FOLFIRI or FOLFOX alone. And then if you have all these other agents, depending on the profiling and the sidedness of the tumor and all this, we’re talking here about RAS wild-type, BRAF wild-type, you know, HER2 nonamplified, left-sided tumor, you can still go to EGFR inhibitors with FOLFIRI, or irinotecan. And you still have regorafenib and TAS-102. I think you don’t burn as many bridges. In fact, if anything….

John L. Marshall, MD: But you can burn a trial eligibility for example if you wanted to.

Tanios S. Bekaii-Saab, MD: You could, you could.

John L. Marshall, MD: There aren’t that many second-line studies.

Tanios S. Bekaii-Saab, MD: Unfortunately, not good ones at least.

John L. Marshall, MD: Do you think we’re obligated? Let’s say you sent the test and you got back that they have a V600E, and maybe you’ve had a couple of cycles already, and they look OK. I don’t feel obligated to put drug in at that point.

Tanios S. Bekaii-Saab, MD: No, I would keep a close eye on them. The response rate, you know, with a doublet is very minimal and very dismal, and tends to essentially be unsure.

I’ve had patients who started on FOLFIRI. I start FOLFIRI on all my patients in the first line; FOLFIRI with bevacizumab, and they turned out to have a BRAF V600E, and I kept them; within 4 months typically they progress, most of them do. There’s a small group of patients that doesn’t really, does incredibly much better than expected. So with those patients who actually start progressing, I add the oxaliplatin till they’ll go on FOLFOXIRI. And if you started with FOLFOXIRI, I’d add the irinotecan.

John L. Marshall, MD: So you would add it in downstream.

Tanios S. Bekaii-Saab, MD: Yes. It’s more difficult to add it when you’re starting with FOLFOX because you run out of FOLFOX after 4 to 5 months. It’s much easier to do it with FOLFIRI because you know you can still expose those patients to....

John L. Marshall, MD: Do molecular markers at all influence your maintenance?

Tanios S. Bekaii-Saab, MD: So the molecular, at this point of time they don’t.

John L. Marshall, MD: And so we share this, that we kind of stop our induction in frontline therapy, intensive therapy, after around 3 months, in that ballpark. Not much more response after that; it’s before you’re getting cumulative neuropathy.

Tanios S. Bekaii-Saab, MD: You hit that plateau.

John L. Marshall, MD: And maybe your first scan’s at 3 months even. Some people are 2 and 4, which is fine.

Tanios S. Bekaii-Saab, MD: I think 3 is; I think you get stuck with the 4 when you’re like wired to do your scans every 2 months. But if you can rewire some of this and say 3 months, knowing that 95% of the patients will have some form of response.

John L. Marshall, MD: Watching markers, maybe seeing how they’re doing, reassuring the patient.

Tanios S. Bekaii-Saab, MD: Absolutely. Then you can do a 3-month and then take that decision then about the maintenance; they don’t need that additional month after the third. The only reason why that ends up being a 4-month induction strategy is because you scan every 2 months.

John L. Marshall, MD: Right. And avoiding that. I always say neuropathy’s our fault not oxaliplatin’s fault.

Tanios S. Bekaii-Saab, MD: Exactly. You know all these studies that looked at trying to find a way to tone down the neurotoxicity or neuropathy from oxaliplatin, the easiest way to do it is not to expose them, or to minimize the exposure at the end of the day.


Transcript Edited for Clarity
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