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New Therapy Options for BRAF-Mutated 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: Tuesday, Aug 13, 2019



Transcript: 

John Marshall, MD: Let’s drill down on a pretty hot topic in colorectal cancer, which is this BRAF-mutated group of patients. Tony, you’re going to get the lead on this to set the stage in a transformative approach to research, to getting things on guidelines, and share some of the progress that’s been made in BRAF targeting.

Tanios Bekaii-Saab, MD: In terms of getting things on guidelines, too fast does hurt a good study. Fortunately, BEACON did complete with the ex-US [United States].

John Marshall, MD: How did we get to BEACON? Start with Scott Kopetz, MD, PhD’s study.

Tanios Bekaii-Saab, MD: It started actually with Scott, and others as well, working in their laboratories, asking the right questions, and understanding what drives a BRAF-mutated colon cancer. We’ve always known that these tumors behave so badly. Those patients’ average survivals were actually what we saw with 5-FU [fluorouracil] 20 years ago. The question is, how do you target those patients? Of course, a lot of the learned experience started indicating that this may behave like melanoma. We’ll just throw a BRAF inhibitor in there and we’re going to see some nice responses. It turns out that only 5% of those patients respond, and their responses are a fraction of 7+ [chemotherapy].

They were trying to understand what happens. It actually has to do with the fact that you block BRAF, and then you have more complex pathways within the cell that essentially make EGFR relevant again. It turns out that you have to actually block EGFR when in the presence of the mutation itself, because EGFR on its own doesn’t work. Now, you put the 2 together, and then you have more activity. In the SWOG study with vemurafenib, irinotecan, and cetuximab, it did show an improvement in outcome.

John Marshall, MD: This is counterintuitive to me, Mike, that you’re hitting the same pathway twice. It’s like cutting a wire twice, and somehow that increases your benefit.

Michael Morse, MD: As Tony brought up, though, these are dynamic pathways, and there are feedback loops. One thing you were alluding to is that ERK [extracellular signal-regulated kinase pathway] may have some feedback against EGFR. When you inhibit signaling to ERK, now you lose the feedback, and EGFR becomes relevant.

There’s also the PI3 kinase/mTOR pathway that becomes active as well. It becomes a little clearer why colon cancer is different than melanoma when we bring in the importance of EGFR targeting.

John Marshall, MD: Cathy, I think of you as a traditionalist, in some ways.

No, this is good. It keeps us honest, and I don’t mean that in any teasing way. I think it adds balance to things. Is it appropriate for us, based on 50 patients, to change our NCCN [National Comprehensive Cancer Network] guidelines?

Cathy Eng, MD: Well, it was originally 30 patients.

John Marshall, MD: For Scott’s study, it was 50 on that arm, right?

Cathy Eng, MD: Are you taking about the original SWOG study?

John Marshall, MD: The SWOG study, yes.

Cathy Eng, MD: Because the BRAF-mutated patients have such a poor prognosis, I think it was changed early on because it gave them an alternative.

John Marshall, MD: These were already approved drugs. That’s what made this even possible.

Cathy Eng, MD: Right, but if you look at the control arm, which was just the irinotecan/CETUX [cetuximab], the progression-free survival is 2 months, which is the time that you were restaged. That really indicated how poorly these patients do with the standard of care.

John Marshall, MD: They could argue that it was also equally informative of not giving that regimen.

Tanios Bekaii-Saab, MD: Cetuximab.

Cathy Eng, MD: Correct.

John Marshall, MD: To BRAF-mutated patients.

Cathy Eng, MD: It was very important to get that information out to the community.

John Marshall, MD: Why is one of the arms in BEACON fat?

Cathy Eng, MD: The control? I think we all know that.

Tanios Bekaii-Saab, MD: That’s a regular 3-arm.

Cathy Eng, MD: Correct.

Tanios Bekaii-Saab, MD: You couldn’t get away without having that arm. Unfortunately, in some ways, what we learned from this arm mostly comes from ex-US patients. Our US patients didn’t have to suffer through it, apparently. What we learned is that, indeed, FOLFIRI [folinic acid/fluorouracil/irinotecan]-cetuximab has almost no activity.

John Marshall, MD: In the BRAF.

Tanios Bekaii-Saab, MD: Or no activity in the BRAF-mutated patients. That argument is done, and we don’t even have to bring it up again. Cetuximab or panitumumab, with BRAF V600E should not be an option now.

John Marshall, MD: That’s what the studies also did for us. We have to acknowledge the positive.
Tanios Bekaii-Saab, MD: Yes, we learned. I think these studies are important. That’s how we learn. We know from experience that a 30- or 40-patient study can look very shiny in the early stages, and then when they go to the phase III battle, they end up being even detrimental, sometimes.

Dustin Deming, MD: This was a different setting. This was in a setting where we had an evolution of trials over about 10 years, where we had started with BRAF inhibitors alone, and then the BRAF inhibitors plus the anti-EGFR. And there were other….

Cathy Eng, MD: Stepwise progress.

Dustin Deming, MD: There were other anti-EGFR triplet combinations that were done and showed significant activity. In many ways, I think the other studies helped validate the early results of the BEACON study, allowing it to influence the standard of care.

Cathy Eng, MD: Very good point.

Tanios Bekaii-Saab, MD: I still don’t think that the guidelines should adopt those quickly, before the study is completed.

John Marshall, MD: What if you were a patient with a BRAF V600E mutation?

Cathy Eng, MD: Yes.

Tanios Bekaii-Saab, MD: I totally get it, but here’s the problem. That, again, brings on a lot of disparity, because even if it’s in the guidelines, those who can afford it, are going to get it. Those who cannot, do not. Those who can afford it, will afford it either way, whether it’s in the guidelines or not.

John Marshall, MD: Well the guidelines do, for the most part, support insurance coverage.

Tanios Bekaii-Saab, MD: In all frankness, if you look at the vemurafenib, irinotecan, EGFR—so cetuximab—data, it’s interesting, but the delta is still small. What you’re seeing with the encorafenib, binimetinib, and cetuximab on the BEACON is actually a much—in a phase III study where you actually end up being less selective—the delta is actually quite significant. The response rate goes from 26% with the 3 agents, to 2%.

John Marshall, MD: I honestly wanted more.

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: It’s better than what we had before, but now, let’s remind everybody what we’re doing here.

Tanios Bekaii-Saab, MD: Better than 2%.

John Marshall, MD: Instead of cutting the cable twice, we’re now cutting it a third time, and adding a MEK inhibitor.

Cathy Eng, MD: Which has its own adverse effects.

John Marshall, MD: It has its own adverse effects. We now have 2 of these different regimens that have come forward. The BEACON study, and then some other agents have been tested in this space, as well. We have a press release. Are they here to stay? These triplets, now cut the cord 3 times, are fine?

Tanios Bekaii-Saab, MD: Historically, if you look at all the studies, the triplets seem to perform the best in terms of response rate, and perhaps, PFS [progression-free survival]. I’m not sure about OS [overall survival] yet.

John Marshall, MD: This was without chemotherapy, right. There’s no irinotecan in this one?

Tanios Bekaii-Saab, MD: No, BEACON has a….

John Marshall, MD: One arm.

Tanios Bekaii-Saab, MD: It has a more simplified arm that we haven’t heard about yet. We’ll see the results.

Dustin Deming, MD: The other exciting thing with the idea of cutting the pathway in 3 parts is that it also prevents a lot of the toxicity that comes with this regimen. When I had previously done phase 1 studies with MEK inhibitors and anti-EGFR inhibitors—horrible rash.

John Marshall, MD: Spicy, wasn’t it?

Dustin Deming, MD: Yes. People’s skin was peeling off, and that’s not what’s happening with the triplet regimen. Blocking the pathway in multiple places is actually blocking some of those things that result in adverse events to these drugs.

John Marshall, MD: I have to say, that was one of the striking pieces of this. The TOX [toxicity] table really didn’t show too much.

Dustin Deming, MD: Right.

John Marshall, MD: I was expecting to see a lot, and it seemed like it was a pretty well-tolerated regimen.

Tanios Bekaii-Saab, MD: That’s true in melanoma, as well. It’s interesting. They tend to abrogate each other’s toxicities. That’s definitely a plus, and probably more activity, as well. This is a very welcome addition in a space that has suffered incredibly in terms of the paucity of good options.

John Marshall, MD: To be fair, on the flip side, we only just recently started finding these people, right?

Cathy Eng, MD: Correct.

John Marshall, MD: I’m old enough. We weren’t doing BRAF testing until fairly recently. Mike, what if I catch some other BRAF mutation, not the V600E? Are they the same? Do I apply the same logic, or is this unique to this target?

Michael Morse, MD: If you can extrapolate from melanoma, there can be responses in others. I don’t think we know well enough here. There’s been some analysis, but the others are very uncommon.

John Marshall, MD: They are uncommon, and I think we’ve got a little bit of data that maybe they do, and maybe they don’t. Cathy, what would you do with a non-V600E mutation?

Cathy Eng, MD: There have been some data, mostly retrospective. I don’t think we really know what else to utilize for the patients right now.

John Marshall, MD: You’re not going to use this, though, and just hope?

Cathy Eng, MD: I don’t think we’re comfortable yet.

Tanios Bekaii-Saab, MD: No. It’s this space that needs to be explored.

Cathy Eng, MD: Agreed.

Tanios Bekaii-Saab, MD: That’s another 3% to 4% of the patients, so it’s not an insignificant number. They do a little bit better, but that doesn’t mean that we can’t think about targeting those patients.

Dustin Deming, MD: We really have to know what mutation it is. If it’s a class 3 BRAF mutation that affects dimerization, hitting it with a BRAF inhibitor like encorafenib is not going to do anything. The cetuximab plus a MEK inhibitor may actually do something, and in fact, there are some data that says cetuximab alone is fine for that population. They tend to have a much better prognosis than patients with a V600 alteration.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: Let’s drill down on a pretty hot topic in colorectal cancer, which is this BRAF-mutated group of patients. Tony, you’re going to get the lead on this to set the stage in a transformative approach to research, to getting things on guidelines, and share some of the progress that’s been made in BRAF targeting.

Tanios Bekaii-Saab, MD: In terms of getting things on guidelines, too fast does hurt a good study. Fortunately, BEACON did complete with the ex-US [United States].

John Marshall, MD: How did we get to BEACON? Start with Scott Kopetz, MD, PhD’s study.

Tanios Bekaii-Saab, MD: It started actually with Scott, and others as well, working in their laboratories, asking the right questions, and understanding what drives a BRAF-mutated colon cancer. We’ve always known that these tumors behave so badly. Those patients’ average survivals were actually what we saw with 5-FU [fluorouracil] 20 years ago. The question is, how do you target those patients? Of course, a lot of the learned experience started indicating that this may behave like melanoma. We’ll just throw a BRAF inhibitor in there and we’re going to see some nice responses. It turns out that only 5% of those patients respond, and their responses are a fraction of 7+ [chemotherapy].

They were trying to understand what happens. It actually has to do with the fact that you block BRAF, and then you have more complex pathways within the cell that essentially make EGFR relevant again. It turns out that you have to actually block EGFR when in the presence of the mutation itself, because EGFR on its own doesn’t work. Now, you put the 2 together, and then you have more activity. In the SWOG study with vemurafenib, irinotecan, and cetuximab, it did show an improvement in outcome.

John Marshall, MD: This is counterintuitive to me, Mike, that you’re hitting the same pathway twice. It’s like cutting a wire twice, and somehow that increases your benefit.

Michael Morse, MD: As Tony brought up, though, these are dynamic pathways, and there are feedback loops. One thing you were alluding to is that ERK [extracellular signal-regulated kinase pathway] may have some feedback against EGFR. When you inhibit signaling to ERK, now you lose the feedback, and EGFR becomes relevant.

There’s also the PI3 kinase/mTOR pathway that becomes active as well. It becomes a little clearer why colon cancer is different than melanoma when we bring in the importance of EGFR targeting.

John Marshall, MD: Cathy, I think of you as a traditionalist, in some ways.

No, this is good. It keeps us honest, and I don’t mean that in any teasing way. I think it adds balance to things. Is it appropriate for us, based on 50 patients, to change our NCCN [National Comprehensive Cancer Network] guidelines?

Cathy Eng, MD: Well, it was originally 30 patients.

John Marshall, MD: For Scott’s study, it was 50 on that arm, right?

Cathy Eng, MD: Are you taking about the original SWOG study?

John Marshall, MD: The SWOG study, yes.

Cathy Eng, MD: Because the BRAF-mutated patients have such a poor prognosis, I think it was changed early on because it gave them an alternative.

John Marshall, MD: These were already approved drugs. That’s what made this even possible.

Cathy Eng, MD: Right, but if you look at the control arm, which was just the irinotecan/CETUX [cetuximab], the progression-free survival is 2 months, which is the time that you were restaged. That really indicated how poorly these patients do with the standard of care.

John Marshall, MD: They could argue that it was also equally informative of not giving that regimen.

Tanios Bekaii-Saab, MD: Cetuximab.

Cathy Eng, MD: Correct.

John Marshall, MD: To BRAF-mutated patients.

Cathy Eng, MD: It was very important to get that information out to the community.

John Marshall, MD: Why is one of the arms in BEACON fat?

Cathy Eng, MD: The control? I think we all know that.

Tanios Bekaii-Saab, MD: That’s a regular 3-arm.

Cathy Eng, MD: Correct.

Tanios Bekaii-Saab, MD: You couldn’t get away without having that arm. Unfortunately, in some ways, what we learned from this arm mostly comes from ex-US patients. Our US patients didn’t have to suffer through it, apparently. What we learned is that, indeed, FOLFIRI [folinic acid/fluorouracil/irinotecan]-cetuximab has almost no activity.

John Marshall, MD: In the BRAF.

Tanios Bekaii-Saab, MD: Or no activity in the BRAF-mutated patients. That argument is done, and we don’t even have to bring it up again. Cetuximab or panitumumab, with BRAF V600E should not be an option now.

John Marshall, MD: That’s what the studies also did for us. We have to acknowledge the positive.
Tanios Bekaii-Saab, MD: Yes, we learned. I think these studies are important. That’s how we learn. We know from experience that a 30- or 40-patient study can look very shiny in the early stages, and then when they go to the phase III battle, they end up being even detrimental, sometimes.

Dustin Deming, MD: This was a different setting. This was in a setting where we had an evolution of trials over about 10 years, where we had started with BRAF inhibitors alone, and then the BRAF inhibitors plus the anti-EGFR. And there were other….

Cathy Eng, MD: Stepwise progress.

Dustin Deming, MD: There were other anti-EGFR triplet combinations that were done and showed significant activity. In many ways, I think the other studies helped validate the early results of the BEACON study, allowing it to influence the standard of care.

Cathy Eng, MD: Very good point.

Tanios Bekaii-Saab, MD: I still don’t think that the guidelines should adopt those quickly, before the study is completed.

John Marshall, MD: What if you were a patient with a BRAF V600E mutation?

Cathy Eng, MD: Yes.

Tanios Bekaii-Saab, MD: I totally get it, but here’s the problem. That, again, brings on a lot of disparity, because even if it’s in the guidelines, those who can afford it, are going to get it. Those who cannot, do not. Those who can afford it, will afford it either way, whether it’s in the guidelines or not.

John Marshall, MD: Well the guidelines do, for the most part, support insurance coverage.

Tanios Bekaii-Saab, MD: In all frankness, if you look at the vemurafenib, irinotecan, EGFR—so cetuximab—data, it’s interesting, but the delta is still small. What you’re seeing with the encorafenib, binimetinib, and cetuximab on the BEACON is actually a much—in a phase III study where you actually end up being less selective—the delta is actually quite significant. The response rate goes from 26% with the 3 agents, to 2%.

John Marshall, MD: I honestly wanted more.

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: It’s better than what we had before, but now, let’s remind everybody what we’re doing here.

Tanios Bekaii-Saab, MD: Better than 2%.

John Marshall, MD: Instead of cutting the cable twice, we’re now cutting it a third time, and adding a MEK inhibitor.

Cathy Eng, MD: Which has its own adverse effects.

John Marshall, MD: It has its own adverse effects. We now have 2 of these different regimens that have come forward. The BEACON study, and then some other agents have been tested in this space, as well. We have a press release. Are they here to stay? These triplets, now cut the cord 3 times, are fine?

Tanios Bekaii-Saab, MD: Historically, if you look at all the studies, the triplets seem to perform the best in terms of response rate, and perhaps, PFS [progression-free survival]. I’m not sure about OS [overall survival] yet.

John Marshall, MD: This was without chemotherapy, right. There’s no irinotecan in this one?

Tanios Bekaii-Saab, MD: No, BEACON has a….

John Marshall, MD: One arm.

Tanios Bekaii-Saab, MD: It has a more simplified arm that we haven’t heard about yet. We’ll see the results.

Dustin Deming, MD: The other exciting thing with the idea of cutting the pathway in 3 parts is that it also prevents a lot of the toxicity that comes with this regimen. When I had previously done phase 1 studies with MEK inhibitors and anti-EGFR inhibitors—horrible rash.

John Marshall, MD: Spicy, wasn’t it?

Dustin Deming, MD: Yes. People’s skin was peeling off, and that’s not what’s happening with the triplet regimen. Blocking the pathway in multiple places is actually blocking some of those things that result in adverse events to these drugs.

John Marshall, MD: I have to say, that was one of the striking pieces of this. The TOX [toxicity] table really didn’t show too much.

Dustin Deming, MD: Right.

John Marshall, MD: I was expecting to see a lot, and it seemed like it was a pretty well-tolerated regimen.

Tanios Bekaii-Saab, MD: That’s true in melanoma, as well. It’s interesting. They tend to abrogate each other’s toxicities. That’s definitely a plus, and probably more activity, as well. This is a very welcome addition in a space that has suffered incredibly in terms of the paucity of good options.

John Marshall, MD: To be fair, on the flip side, we only just recently started finding these people, right?

Cathy Eng, MD: Correct.

John Marshall, MD: I’m old enough. We weren’t doing BRAF testing until fairly recently. Mike, what if I catch some other BRAF mutation, not the V600E? Are they the same? Do I apply the same logic, or is this unique to this target?

Michael Morse, MD: If you can extrapolate from melanoma, there can be responses in others. I don’t think we know well enough here. There’s been some analysis, but the others are very uncommon.

John Marshall, MD: They are uncommon, and I think we’ve got a little bit of data that maybe they do, and maybe they don’t. Cathy, what would you do with a non-V600E mutation?

Cathy Eng, MD: There have been some data, mostly retrospective. I don’t think we really know what else to utilize for the patients right now.

John Marshall, MD: You’re not going to use this, though, and just hope?

Cathy Eng, MD: I don’t think we’re comfortable yet.

Tanios Bekaii-Saab, MD: No. It’s this space that needs to be explored.

Cathy Eng, MD: Agreed.

Tanios Bekaii-Saab, MD: That’s another 3% to 4% of the patients, so it’s not an insignificant number. They do a little bit better, but that doesn’t mean that we can’t think about targeting those patients.

Dustin Deming, MD: We really have to know what mutation it is. If it’s a class 3 BRAF mutation that affects dimerization, hitting it with a BRAF inhibitor like encorafenib is not going to do anything. The cetuximab plus a MEK inhibitor may actually do something, and in fact, there are some data that says cetuximab alone is fine for that population. They tend to have a much better prognosis than patients with a V600 alteration.

Transcript Edited for Clarity
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