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Triplet Regimens in BRAF-Mutant Metastatic CRC

Insights From: Alan Venook, MD, University of California San Francisco ; John L. Marshall, MD, Georgetown University ; Mark Kozloff, MD, Ingalls Cancer Care; Richard Kim, MD, Moffitt Cancer Center
Published: Tuesday, Dec 04, 2018



Transcript: 

John L. Marshall, MD: We tried to see if BRAF drugs, targeting agents, would work in BRAF-mutated colon cancer. This is the same mutation as in melanoma, so the hope was that this would work the same way. It didn’t. It really had very little activity as monotherapy, and it really took some clever clinical trial designs and thinking to actually demonstrate how to best bring BRAF inhibitors to the world of colon cancer.
Scott Kopetz, MD, PhD (The University of Texas MD Anderson Cancer Center), is really one of our major thought leaders in driving positive clinical trials forward by incorporating targeted agents in a logical way. He led the SWOG study, taking BRAF-mutated patients and enrolling them into a randomized clinical trial. It was a debate. If you just have a BRAF mutation, do the EGFR drugs work or not? Most of us thought they would be resistant. And so, the trial compared a doublet combination of irinotecan and cetuximab, which would sort of be the standard of care, versus a 3-drug combination of cetuximab, irinotecan, with vemurafenib. This randomized clinical trial, which was just a small clinical trial, first accrued very quickly, which meant that there were a lot of BRAF-mutated patients out there looking for options. So even though this was not a common mutation, it was common enough that this became a patient problem. So it accrued very quickly.

The findings of the clinical trial are incredibly important, even for a small phase II randomized study. They demonstrated an improved response rate and progression-free survival, and a trend toward an improvement in overall survival from the 3-drug combination. It showed that there really wasn’t very much benefit in using the 2-drug combination of cetuximab and irinotecan in BRAF-mutated patients.
To everyone’s surprise, except the people who were on the committee, the NCCN [National Comprehensive Cancer Network] actually adopted that study as enough evidence to go forward with that in their guidelines. If I was a patient with a BRAF mutation, I would want access to vemurafenib in that setting based on this clinical trial. But it sort of shot us in the foot. We have now struggled with accruing any new clinical trials to try and understand how to move that bar forward. And so, we need to keep pushing this forward as we attack this pathway.

Why would you combine drugs? If we really think BRAF is the driving mutation, why didn’t it work by itself? We know that the signaling pathways in metastatic colon cancer are complex. And so, if you block 1 there are routes that kind of take it around. RAS and BRAF are actually in the same pathway. And so, the logic here was that if you hit the pathway twice you would, in fact, have an improved outcome. There’s a theory and preclinical data that support this. What’s great is that the clinical trial really demonstrated that the theory was true. By hitting this pathway in 2 places, you uncover clinical activity that we didn’t get before.

If you’re thinking about using targeted therapy in colon cancer, you have to know the BRAF status. If you find a patient who has a BRAF V600E mutation, this triplet therapy may be the best option. That would usually be in the refractory setting, and the NCCN guidelines now give us permission to do this. These are all approved drugs. Be careful and watch for toxicity.

Three drugs are harder than 2. There is no question about it. But this regimen is not unmanageable. The oral medicine vemurafenib has its own issues. Cetuximab and panitumumab have their issues—mostly skin rashes and diarrhea. So you need to practice good skin-rash management. You need to watch for gastrointestinal toxicities and skin toxicities as you set forward. When you set off with this 3-drug regimen, don’t think it’ll be a piece of cake. Watch your patients closely.

Richard Kim, MD: The BEACON CRC study is a phase III study of patients with BRAF-mutant tumors who failed 1 or 2 lines of chemotherapy. It actually has 3 arms. One arm combines a BRAF inhibitor, encorafenib, plus a MEK inhibitor, binimetinib, plus an EGFR drug, cetuximab. The second arm is a combination of cetuximab with a BRAF inhibitor, and the third arm is a control arm of chemotherapy, with either FOLFIRI [folinic acid, fluorouracil, and irinotecan] or irinotecan plus cetuximab]. The primary endpoint of the study is overall survival.

The rationale behind the study is very clear. We know that patients with BRAF-mutant tumors tend to have activation of the RAS, MEK, and the MAPK pathways. In other diseases, if you block the BRAF with the MEK inhibitor, there seem to be very durable responses with improvements in overall survival. However, in colon cancer, that is not true due to the feedback activation of EGFR. So in order to overcome the resistance, you probably have to add an anti-EGFR drug on top of those doublets to overcome the resistance. That’s the rationale behind the BEACON CRC study.

The early 30-patient run-in data was presented this year. The results seem to be very promising. The triplet regimen of the BRAF inhibitor plus a MEK inhibitor plus cetuximab showed a response rate of close to 48%. In patients who failed only 1 line of chemotherapy, the response rate was as high as 62% and the progression-free survival was around 8 months. The median overall survival was not reached at the time of the presentation. In terms of the toxicity profile, in terms of the most common grade 3/4 adverse events that occurred, fatigue and anemia were seen more than 10% of the time. To my surprise, rash was not an issue. Only 1 patient developed a grade 3 rash.

For patients with BRAF-mutant tumors, after they fail first-line therapy, it is definitely reasonable to try to use the BRAF inhibitor with an EGFR drug. Based on the SWOG S1406 study, there was a trial that compared irinotecan plus cetuximab plus or minus a BRAF inhibitor. The study was very consistent with the run-in BEACON CRC study, showing that there was an improvement in overall survival, response rate, and progression-free survival by adding a BRAF inhibitor to irinotecan and cetuximab. Therefore, for patients who fail first-line therapy, if I could get a BRAF inhibitor off label, that’s what I would try to do. It is also in the NCCN guideline and is part of the compendia listing.

Transcript Edited for Clarity 
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Transcript: 

John L. Marshall, MD: We tried to see if BRAF drugs, targeting agents, would work in BRAF-mutated colon cancer. This is the same mutation as in melanoma, so the hope was that this would work the same way. It didn’t. It really had very little activity as monotherapy, and it really took some clever clinical trial designs and thinking to actually demonstrate how to best bring BRAF inhibitors to the world of colon cancer.
Scott Kopetz, MD, PhD (The University of Texas MD Anderson Cancer Center), is really one of our major thought leaders in driving positive clinical trials forward by incorporating targeted agents in a logical way. He led the SWOG study, taking BRAF-mutated patients and enrolling them into a randomized clinical trial. It was a debate. If you just have a BRAF mutation, do the EGFR drugs work or not? Most of us thought they would be resistant. And so, the trial compared a doublet combination of irinotecan and cetuximab, which would sort of be the standard of care, versus a 3-drug combination of cetuximab, irinotecan, with vemurafenib. This randomized clinical trial, which was just a small clinical trial, first accrued very quickly, which meant that there were a lot of BRAF-mutated patients out there looking for options. So even though this was not a common mutation, it was common enough that this became a patient problem. So it accrued very quickly.

The findings of the clinical trial are incredibly important, even for a small phase II randomized study. They demonstrated an improved response rate and progression-free survival, and a trend toward an improvement in overall survival from the 3-drug combination. It showed that there really wasn’t very much benefit in using the 2-drug combination of cetuximab and irinotecan in BRAF-mutated patients.
To everyone’s surprise, except the people who were on the committee, the NCCN [National Comprehensive Cancer Network] actually adopted that study as enough evidence to go forward with that in their guidelines. If I was a patient with a BRAF mutation, I would want access to vemurafenib in that setting based on this clinical trial. But it sort of shot us in the foot. We have now struggled with accruing any new clinical trials to try and understand how to move that bar forward. And so, we need to keep pushing this forward as we attack this pathway.

Why would you combine drugs? If we really think BRAF is the driving mutation, why didn’t it work by itself? We know that the signaling pathways in metastatic colon cancer are complex. And so, if you block 1 there are routes that kind of take it around. RAS and BRAF are actually in the same pathway. And so, the logic here was that if you hit the pathway twice you would, in fact, have an improved outcome. There’s a theory and preclinical data that support this. What’s great is that the clinical trial really demonstrated that the theory was true. By hitting this pathway in 2 places, you uncover clinical activity that we didn’t get before.

If you’re thinking about using targeted therapy in colon cancer, you have to know the BRAF status. If you find a patient who has a BRAF V600E mutation, this triplet therapy may be the best option. That would usually be in the refractory setting, and the NCCN guidelines now give us permission to do this. These are all approved drugs. Be careful and watch for toxicity.

Three drugs are harder than 2. There is no question about it. But this regimen is not unmanageable. The oral medicine vemurafenib has its own issues. Cetuximab and panitumumab have their issues—mostly skin rashes and diarrhea. So you need to practice good skin-rash management. You need to watch for gastrointestinal toxicities and skin toxicities as you set forward. When you set off with this 3-drug regimen, don’t think it’ll be a piece of cake. Watch your patients closely.

Richard Kim, MD: The BEACON CRC study is a phase III study of patients with BRAF-mutant tumors who failed 1 or 2 lines of chemotherapy. It actually has 3 arms. One arm combines a BRAF inhibitor, encorafenib, plus a MEK inhibitor, binimetinib, plus an EGFR drug, cetuximab. The second arm is a combination of cetuximab with a BRAF inhibitor, and the third arm is a control arm of chemotherapy, with either FOLFIRI [folinic acid, fluorouracil, and irinotecan] or irinotecan plus cetuximab]. The primary endpoint of the study is overall survival.

The rationale behind the study is very clear. We know that patients with BRAF-mutant tumors tend to have activation of the RAS, MEK, and the MAPK pathways. In other diseases, if you block the BRAF with the MEK inhibitor, there seem to be very durable responses with improvements in overall survival. However, in colon cancer, that is not true due to the feedback activation of EGFR. So in order to overcome the resistance, you probably have to add an anti-EGFR drug on top of those doublets to overcome the resistance. That’s the rationale behind the BEACON CRC study.

The early 30-patient run-in data was presented this year. The results seem to be very promising. The triplet regimen of the BRAF inhibitor plus a MEK inhibitor plus cetuximab showed a response rate of close to 48%. In patients who failed only 1 line of chemotherapy, the response rate was as high as 62% and the progression-free survival was around 8 months. The median overall survival was not reached at the time of the presentation. In terms of the toxicity profile, in terms of the most common grade 3/4 adverse events that occurred, fatigue and anemia were seen more than 10% of the time. To my surprise, rash was not an issue. Only 1 patient developed a grade 3 rash.

For patients with BRAF-mutant tumors, after they fail first-line therapy, it is definitely reasonable to try to use the BRAF inhibitor with an EGFR drug. Based on the SWOG S1406 study, there was a trial that compared irinotecan plus cetuximab plus or minus a BRAF inhibitor. The study was very consistent with the run-in BEACON CRC study, showing that there was an improvement in overall survival, response rate, and progression-free survival by adding a BRAF inhibitor to irinotecan and cetuximab. Therefore, for patients who fail first-line therapy, if I could get a BRAF inhibitor off label, that’s what I would try to do. It is also in the NCCN guideline and is part of the compendia listing.

Transcript Edited for Clarity 
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