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Triplet Regimens for BRAF V600E-Positive mCRC

Panelists: Howard Hochster, MD, FACP, Rutgers Cancer Institute; Joleen Hubbard, MD, Mayo Clinic; Christopher Lieu, MD, University of Colorado School of Medicine; John Marshall, MD, Georgetown University Hospital; Tony Saab, MD, Mayo Clinic
Published: Friday, Mar 01, 2019



Transcript: 

Howard S. Hochster, MD, FACP:
Most of the trials that have looked at the cetuximab sequence show that it kind of has the same activity if you use it in second-line and third-line therapy. So maybe by pushing it further back you haven’t lost that much, but some people will drop off, or will get too sick on regorafenib. So that’s really the question. I think this trial was underpowered and there was an imbalance in the people who crossed over that led to some of the findings in the REVERCE trial.

John L. Marshall, MD: Remind me, how many patients were on that study?

Tanios S. Bekaii-Saab, MD: It ended up being close to 100.

John L. Marshall, MD: About 50 in each arm?

Tanios S. Bekaii-Saab, MD: Fifty in each arm.

John L. Marshall, MD: So here’s a 50 in each arm study—you know where I’m going with this—that doesn’t quite make it for us in a practice changing, randomized trial. Chris, what about targeting BRAF? Where are we with that? And how come that’s practice changing? But this is fascinating and all. So we set this up perfectly.

Christopher Lieu, MD: I’m going to answer your question in 2 parts. The first one is in the frontline setting, right? This is why we at least need BRAF testing up front. Because if you know that your patient has a BRAF V600E mutation, for that specific mutation their overall survival is essentially a third of what we would expect in a normal patient population with metastatic colorectal cancer [mCRC].

So any intervention here that may improve this group’s overall survival is critical. The problem with BRAF mutations in metastatic colorectal cancer is they’re relatively rare, which means that the data that we have to extrapolate from studies are fairly slim. What data do exist suggest that the use of FOLFOXIRI [folinic acid/fluorouracil/oxaliplatin/irinotecan], that triplet combination of chemotherapy, may improve overall survival for these patients.

John L. Marshall, MD: Not over normal people, I always have to explain this, better than if you didn’t use it, right?

Christopher Lieu, MD: Correct. So if you imagine some retrospective studies, the median overall survival is as low as 10.7 months, and then in the FOLFOXIRI arm when we’ve looked retrospectively, that median overall survival seems to have doubled. And so, in good performance status patients, there’s some evidence to suggest that maybe we should be starting with a much more aggressive regimen. That’s the key to knowing the BRAF status before you start therapy.

In the second-line setting, there’s a study that’s been presented now several years ago on the use of irinotecan with cetuximab and vemurafenib. Again, to your point, a small study, right? Around 100 patients.

John L. Marshall, MD: I love this study though. I love it.

Christopher Lieu, MD: Where they’re randomized to receive IRI [irinotecan]/cetuximab/vemurafenib versus IRI and CETUX [cetuximab]. Again, a very difficult patient population to treat because all of the patients universally don’t do very well. But the study was powered for progression-free survival. It’s expanded to have a better look at overall survival. There was a statistically significant difference between the 2 arms. Progression-free survival in the standard of care arm, the IRI/cetuximab arm, was 2 months? The first time you look with a CT [computed tomography] scan they progress, in the vemurafenib/irinotecan/cetuximab arm, the treatment arm, a little bit over 4 months. So that’s an improvement.

When you look at the overall survival difference, now there was crossover allowed in the study, right? So that’s a very important key here. Even with crossover you can see a trend towards an overall survival improvement. So despite the fact that it’s a small study, I think, number 1, it proves that this combination is effective. It met its primary endpoint in terms of progression-free survival. The overall survival difference really did near statistical significance, even with a small proportion of patients. And this is truly a group that needs better treatment options, and that’s why the study is so powerful.

Howard S. Hochster, MD, FACP: John, this was a SWOG 1406 study that Scott Kopetz, MD, PhD, ran and the manuscript should be submitted for publication pretty soon. We’re working on the final revisions. But the fact is, it’s a known biology. It was a drug that was already out there for other diseases with the BRAF V600E mutation, and everything went in the direction that we would have expected without having any other treatment options for these patients. So I think that was the reason that the NCCN [National Comprehensive Cancer Network] Colon Committee voted to include that in the guidelines. Even though it’s only a 110-patient study, it still fit the biology and all the clinical data lined up that way.

And, again, we did not want to not allow patients access if we knew they had this bad mutation, that they could still get vemurafenib. So with the crossover, it’s really hard to say that you have a survival difference. We really didn’t expect one.

John L. Marshall, MD: Whatever we think of the design of the BEACON clinical trial though, that NCCN decision killed the BEACON trial in the United States because everybody was voting with their feet and putting patients on the triplet therapy. You know, it’s the way drug development is going today, Joleen, is that you don’t actually have to have FDA approval if the drugs are already approved out there for something else. What you need is guideline approval. And it can’t be an easy decision for you guys to make—to vote, as Howard said, for NCCN to approve that.

Joleen M. Hubbard, MD: Yes. Chris pointed out that this is a patient population with such an unmet need. Their survival was poor. I think that weighed in on the decision to have these in the NCCN guidelines. And also, the fact that it was randomized data, and you can’t argue with the statistical significance of that data. So I think it was to provide an opportunity for patients. Unfortunately, it did affect the BEACON study, but I think we’ll still have good results from the BEACON study as well.


Transcript Edited for Clarity

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Transcript: 

Howard S. Hochster, MD, FACP:
Most of the trials that have looked at the cetuximab sequence show that it kind of has the same activity if you use it in second-line and third-line therapy. So maybe by pushing it further back you haven’t lost that much, but some people will drop off, or will get too sick on regorafenib. So that’s really the question. I think this trial was underpowered and there was an imbalance in the people who crossed over that led to some of the findings in the REVERCE trial.

John L. Marshall, MD: Remind me, how many patients were on that study?

Tanios S. Bekaii-Saab, MD: It ended up being close to 100.

John L. Marshall, MD: About 50 in each arm?

Tanios S. Bekaii-Saab, MD: Fifty in each arm.

John L. Marshall, MD: So here’s a 50 in each arm study—you know where I’m going with this—that doesn’t quite make it for us in a practice changing, randomized trial. Chris, what about targeting BRAF? Where are we with that? And how come that’s practice changing? But this is fascinating and all. So we set this up perfectly.

Christopher Lieu, MD: I’m going to answer your question in 2 parts. The first one is in the frontline setting, right? This is why we at least need BRAF testing up front. Because if you know that your patient has a BRAF V600E mutation, for that specific mutation their overall survival is essentially a third of what we would expect in a normal patient population with metastatic colorectal cancer [mCRC].

So any intervention here that may improve this group’s overall survival is critical. The problem with BRAF mutations in metastatic colorectal cancer is they’re relatively rare, which means that the data that we have to extrapolate from studies are fairly slim. What data do exist suggest that the use of FOLFOXIRI [folinic acid/fluorouracil/oxaliplatin/irinotecan], that triplet combination of chemotherapy, may improve overall survival for these patients.

John L. Marshall, MD: Not over normal people, I always have to explain this, better than if you didn’t use it, right?

Christopher Lieu, MD: Correct. So if you imagine some retrospective studies, the median overall survival is as low as 10.7 months, and then in the FOLFOXIRI arm when we’ve looked retrospectively, that median overall survival seems to have doubled. And so, in good performance status patients, there’s some evidence to suggest that maybe we should be starting with a much more aggressive regimen. That’s the key to knowing the BRAF status before you start therapy.

In the second-line setting, there’s a study that’s been presented now several years ago on the use of irinotecan with cetuximab and vemurafenib. Again, to your point, a small study, right? Around 100 patients.

John L. Marshall, MD: I love this study though. I love it.

Christopher Lieu, MD: Where they’re randomized to receive IRI [irinotecan]/cetuximab/vemurafenib versus IRI and CETUX [cetuximab]. Again, a very difficult patient population to treat because all of the patients universally don’t do very well. But the study was powered for progression-free survival. It’s expanded to have a better look at overall survival. There was a statistically significant difference between the 2 arms. Progression-free survival in the standard of care arm, the IRI/cetuximab arm, was 2 months? The first time you look with a CT [computed tomography] scan they progress, in the vemurafenib/irinotecan/cetuximab arm, the treatment arm, a little bit over 4 months. So that’s an improvement.

When you look at the overall survival difference, now there was crossover allowed in the study, right? So that’s a very important key here. Even with crossover you can see a trend towards an overall survival improvement. So despite the fact that it’s a small study, I think, number 1, it proves that this combination is effective. It met its primary endpoint in terms of progression-free survival. The overall survival difference really did near statistical significance, even with a small proportion of patients. And this is truly a group that needs better treatment options, and that’s why the study is so powerful.

Howard S. Hochster, MD, FACP: John, this was a SWOG 1406 study that Scott Kopetz, MD, PhD, ran and the manuscript should be submitted for publication pretty soon. We’re working on the final revisions. But the fact is, it’s a known biology. It was a drug that was already out there for other diseases with the BRAF V600E mutation, and everything went in the direction that we would have expected without having any other treatment options for these patients. So I think that was the reason that the NCCN [National Comprehensive Cancer Network] Colon Committee voted to include that in the guidelines. Even though it’s only a 110-patient study, it still fit the biology and all the clinical data lined up that way.

And, again, we did not want to not allow patients access if we knew they had this bad mutation, that they could still get vemurafenib. So with the crossover, it’s really hard to say that you have a survival difference. We really didn’t expect one.

John L. Marshall, MD: Whatever we think of the design of the BEACON clinical trial though, that NCCN decision killed the BEACON trial in the United States because everybody was voting with their feet and putting patients on the triplet therapy. You know, it’s the way drug development is going today, Joleen, is that you don’t actually have to have FDA approval if the drugs are already approved out there for something else. What you need is guideline approval. And it can’t be an easy decision for you guys to make—to vote, as Howard said, for NCCN to approve that.

Joleen M. Hubbard, MD: Yes. Chris pointed out that this is a patient population with such an unmet need. Their survival was poor. I think that weighed in on the decision to have these in the NCCN guidelines. And also, the fact that it was randomized data, and you can’t argue with the statistical significance of that data. So I think it was to provide an opportunity for patients. Unfortunately, it did affect the BEACON study, but I think we’ll still have good results from the BEACON study as well.


Transcript Edited for Clarity
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