ONCAlert | Upfront Therapy for mRCC

Case 1: Treatment of BRAF-Mutated Colorectal Cancer

Targeted Oncology
Published Online:1:28 PM, Thu November 8, 2018

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Shubham Pant, MD:
Richard, the SWOG S1406 study was irinotecan, vemurafenib, and cetuximab. BEACON is a combination with a MEK inhibitor. Do you think that makes a difference—like BRAF, MEK, and EGFR inhibition? There’s no chemotherapy backbone to that.

Richard Kim, MD: Right. If you look at the preclinical rationale, patients with BRAF-mutant tumors tend to have the RAS, MEK, and MAP [mitogen-activated protein] kinase overactivated. In the melanoma data, you show that you could use a MEK inhibitor plus a BRAF inhibitor and have a very good outcome. In colon cancer, that’s probably not true because of the feedback activation to EGFR. To overcome the resistance, the importance is probably not in the chemotherapy but in the EGFR drug.

The BEACON study doesn’t add chemotherapy to the backbone of the targeted therapy, but, if you look at the rationale, I think it is important to add the EGFR drug on top of the MEK and BRAF inhibitors. So the triplet regimen—I think there’s a good rationale behind it. Obviously we’ll wait to see the results of the BEACON study, but so far so good, in terms of what has been presented.

Shubham Pant, MD: Before, these patients had very poor options. Right now, what would you treat them with, Mike? What’s your frontline regimen for patients who come in with a BRAF mutation?

Michael Morse, MD: As Richard pointed out, because they respond so poorly and have a very short progression-free survival with standard treatment—such as this patient, getting FOLFIRI [folinic acid, fluorouracil (5-FU), and irinotecan] plus bevacizumab—if somebody can tolerate it, I would agree that FOLFOXIRI [folinic acid, 5-FU, oxaliplatin, and irinotecan] is probably preferred. Now, I don’t think that the TRIBE trial that used FOLFOXIRI plus bevacizumab necessarily proves that it is a regimen uniquely suited to BRAF-mutated tumors. However, people tended to do better. If they had a BRAF-mutated tumor, they tended to do better with that combination versus the 2-drug chemotherapy regimen. This suggests that a very aggressive chemotherapy combination is probably needed for people with a very aggressive cancer.

Shubham Pant, MD: Can you tell us a bit about the TRIBE study, Richard?

Richard Kim, MD: TRIBE was a randomized study comparing FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab. The progression-free survival of FOLFOXIRI plus bevacizumab was over 12 months. This is one of the rare studies for which you have a progression-free survival that’s greater than 1 year.

In the subset analysis, they looked at patients with BRAF-mutant cancer. In that study, the patients who got FOLFOXIRI plus bevacizumab tended to do better compared with those who received FOLFIRI plus bevacizumab, so there was a slight advantage. Once again, this was not the primary endpoint of the study, but, based on that, it seems like because this type of patient tends to be more aggressive, tumor-wise, we tend to go with a more aggressive approach. There are other data that show that the triplet regimen plus bevacizumab seems to be better than the doublet plus bevacizumab in the small subset population.

Shubham Pant, MD: Mike, when you use it, what is the regimen? 

Michael Morse, MD: It’s 5-FU, leucovorin, irinotecan, and oxaliplatin. This is not to be confused with FOLFIRINOX, which combines the same drugs but with slight differences in the dosing. The challenge for many people, like this older individual, is obviously that there is greater toxicity. There is more of a risk for neutropenia. There is more of a risk for diarrhea and so on. So it’s not ideal for every patient. Like anything else, you have to look at comorbidities and performance status before using it.

Shubham Pant, MD: So if you were not using FOLFOXIRI, Richard, what would you use in the frontline? Let’s say they are not a candidate, in your clinical judgment, for FOLFOXIRI. What else would you use?

Michael Morse, MD: In the first-line setting, I still think chemotherapy is the answer. If the patient is not a candidate for the triplet regimen, I would probably still go with either FOLFOX or FOLFIRI plus bevacizumab. I would not use EGFR drugs. A lot of data coming out suggest that patients with BRAF-mutant tumors tend to be resistant to EGFR drugs. So I would definitely not use it in the first-line setting. I think either FOLFOX or FOLFIRI plus bevacizumab will be my choice in patients who cannot tolerate FOLFOXIRI.

Shubham Pant, MD: Would that be the same for you, Mike?

Michael Morse, MD: I agree.

Shubham Pant, MD: For our physicians/clinicians out there, we’ll talk a lot more about tumor sidedness, microsatellite instability [MSI], and patients who don’t have any molecular alterations later on in our discussion. But specifically for patients with BRAF-mutant colorectal cancer, what I’m hearing is, if a patient comes to us, we have to sit down and explain to them that there are no data for treating them in the frontline with a better drug that inhibits the BRAF pathway. What we do is give them FOLFOXIRI with bevacizumab, or FOLFOX or FOLFIRI with bevacizumab, depending on the tolerability in the clinical scenario. If they then feel that we should try, at least in the second-line setting, to think about combining them—similar to the SWOG study…We eagerly await the BEACON results to see if we can get a great combination therapy for our patients.

Michael Morse, MD: I would agree. You mentioned 2 key points. First, you have to test for it. If you don’t know about the BRAF status, you can’t determine whether this is an option for them. I still see patients who get RAS testing but never had BRAF testing done. Secondly — and we’ll be talking about MSI later — a certain fraction of patients who have BRAF mutations are also MSI-high, and we’ve managed those people differently.

Shubham Pant, MD: Richard, before we end, what about atypical BRAFs? What are your thoughts about atypical BRAFs that are not BRAF V600E?

Richard Kim, MD: About 10% of the patients have a BRAF mutation. I think one-fifth of that percentage are probably not BRAF V600E. Those have been looked at in small studies with, obviously, very small numbers. So the prognostic value is unclear. Actually, there are data that suggest that non–BRAF V600E–mutant patients tend to have a better prognosis than patients who have BRAF V600E mutations.

But in terms of whether there’s a predictive value to EGFR inhibitors or not is unclear. This has not been studied yet. Right now, I think it’s too premature. I think we could say that, at least from the data we have, there is probably a better prognosis. However, the predictive nature of this non BRAF V600E mutation to the EGFR drug or this BRAF combination or MEK inhibitor is unclear because the trial only included patient with BRAF V600E mutations.

Shubham Pant, MD: Greg, it’s also important, as a pathologist, that you look at the second part of all mutations. Just because it says BRAF doesn’t mean that you don’t need to look at the second part of it.

Gregory Riedlinger, MD, PhD: Yes. Generally, 3 classes of BRAF mutations have been described. We know of the canonical BRAF V600 mutations, where BRAF is signaling as a monomer. And then there are other BRAF-activating mutations that theoretically function as a dimer through CRAF, which is RAF1. And then there are the so-called class 3 BRAF mutations, which are actually inactivated or are kinase dead. Knowing the differences between those and the different treatment options is obviously important.

Shubham Pant, MD: Thank you so much. This has been a great discussion. So our take-home points are: Test for these mutations that we’ve talked about. Don’t just go and look at BRAF and go “I can treat this with a BRAF inhibitor,” because it’s not approved for that. It’s only approved for BRAF V600E mutations. In the frontline, you can choose FOLFOXIRI with bevacizumab, or FOLFIRI or FOLFOX with bevacizumab, or chemotherapy, depending on the clinical status of the patient.

In the second-line setting, once they’ve failed, based on the SWOG data and the NCCN [National Comprehensive Cancer Center] guidelines, we can try to combine it with a BRAF inhibitor, such as vemurafenib. We are really waiting on the results of the BEACON trial, but this is an exciting era for our patients. Two years back, we really did not have anything for our patients. It’s a great step forward. Thank you so much.

Transcript edited for clarity.
 

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Shubham Pant, MD:
Richard, the SWOG S1406 study was irinotecan, vemurafenib, and cetuximab. BEACON is a combination with a MEK inhibitor. Do you think that makes a difference—like BRAF, MEK, and EGFR inhibition? There’s no chemotherapy backbone to that.

Richard Kim, MD: Right. If you look at the preclinical rationale, patients with BRAF-mutant tumors tend to have the RAS, MEK, and MAP [mitogen-activated protein] kinase overactivated. In the melanoma data, you show that you could use a MEK inhibitor plus a BRAF inhibitor and have a very good outcome. In colon cancer, that’s probably not true because of the feedback activation to EGFR. To overcome the resistance, the importance is probably not in the chemotherapy but in the EGFR drug.

The BEACON study doesn’t add chemotherapy to the backbone of the targeted therapy, but, if you look at the rationale, I think it is important to add the EGFR drug on top of the MEK and BRAF inhibitors. So the triplet regimen—I think there’s a good rationale behind it. Obviously we’ll wait to see the results of the BEACON study, but so far so good, in terms of what has been presented.

Shubham Pant, MD: Before, these patients had very poor options. Right now, what would you treat them with, Mike? What’s your frontline regimen for patients who come in with a BRAF mutation?

Michael Morse, MD: As Richard pointed out, because they respond so poorly and have a very short progression-free survival with standard treatment—such as this patient, getting FOLFIRI [folinic acid, fluorouracil (5-FU), and irinotecan] plus bevacizumab—if somebody can tolerate it, I would agree that FOLFOXIRI [folinic acid, 5-FU, oxaliplatin, and irinotecan] is probably preferred. Now, I don’t think that the TRIBE trial that used FOLFOXIRI plus bevacizumab necessarily proves that it is a regimen uniquely suited to BRAF-mutated tumors. However, people tended to do better. If they had a BRAF-mutated tumor, they tended to do better with that combination versus the 2-drug chemotherapy regimen. This suggests that a very aggressive chemotherapy combination is probably needed for people with a very aggressive cancer.

Shubham Pant, MD: Can you tell us a bit about the TRIBE study, Richard?

Richard Kim, MD: TRIBE was a randomized study comparing FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab. The progression-free survival of FOLFOXIRI plus bevacizumab was over 12 months. This is one of the rare studies for which you have a progression-free survival that’s greater than 1 year.

In the subset analysis, they looked at patients with BRAF-mutant cancer. In that study, the patients who got FOLFOXIRI plus bevacizumab tended to do better compared with those who received FOLFIRI plus bevacizumab, so there was a slight advantage. Once again, this was not the primary endpoint of the study, but, based on that, it seems like because this type of patient tends to be more aggressive, tumor-wise, we tend to go with a more aggressive approach. There are other data that show that the triplet regimen plus bevacizumab seems to be better than the doublet plus bevacizumab in the small subset population.

Shubham Pant, MD: Mike, when you use it, what is the regimen? 

Michael Morse, MD: It’s 5-FU, leucovorin, irinotecan, and oxaliplatin. This is not to be confused with FOLFIRINOX, which combines the same drugs but with slight differences in the dosing. The challenge for many people, like this older individual, is obviously that there is greater toxicity. There is more of a risk for neutropenia. There is more of a risk for diarrhea and so on. So it’s not ideal for every patient. Like anything else, you have to look at comorbidities and performance status before using it.

Shubham Pant, MD: So if you were not using FOLFOXIRI, Richard, what would you use in the frontline? Let’s say they are not a candidate, in your clinical judgment, for FOLFOXIRI. What else would you use?

Michael Morse, MD: In the first-line setting, I still think chemotherapy is the answer. If the patient is not a candidate for the triplet regimen, I would probably still go with either FOLFOX or FOLFIRI plus bevacizumab. I would not use EGFR drugs. A lot of data coming out suggest that patients with BRAF-mutant tumors tend to be resistant to EGFR drugs. So I would definitely not use it in the first-line setting. I think either FOLFOX or FOLFIRI plus bevacizumab will be my choice in patients who cannot tolerate FOLFOXIRI.

Shubham Pant, MD: Would that be the same for you, Mike?

Michael Morse, MD: I agree.

Shubham Pant, MD: For our physicians/clinicians out there, we’ll talk a lot more about tumor sidedness, microsatellite instability [MSI], and patients who don’t have any molecular alterations later on in our discussion. But specifically for patients with BRAF-mutant colorectal cancer, what I’m hearing is, if a patient comes to us, we have to sit down and explain to them that there are no data for treating them in the frontline with a better drug that inhibits the BRAF pathway. What we do is give them FOLFOXIRI with bevacizumab, or FOLFOX or FOLFIRI with bevacizumab, depending on the tolerability in the clinical scenario. If they then feel that we should try, at least in the second-line setting, to think about combining them—similar to the SWOG study…We eagerly await the BEACON results to see if we can get a great combination therapy for our patients.

Michael Morse, MD: I would agree. You mentioned 2 key points. First, you have to test for it. If you don’t know about the BRAF status, you can’t determine whether this is an option for them. I still see patients who get RAS testing but never had BRAF testing done. Secondly — and we’ll be talking about MSI later — a certain fraction of patients who have BRAF mutations are also MSI-high, and we’ve managed those people differently.

Shubham Pant, MD: Richard, before we end, what about atypical BRAFs? What are your thoughts about atypical BRAFs that are not BRAF V600E?

Richard Kim, MD: About 10% of the patients have a BRAF mutation. I think one-fifth of that percentage are probably not BRAF V600E. Those have been looked at in small studies with, obviously, very small numbers. So the prognostic value is unclear. Actually, there are data that suggest that non–BRAF V600E–mutant patients tend to have a better prognosis than patients who have BRAF V600E mutations.

But in terms of whether there’s a predictive value to EGFR inhibitors or not is unclear. This has not been studied yet. Right now, I think it’s too premature. I think we could say that, at least from the data we have, there is probably a better prognosis. However, the predictive nature of this non BRAF V600E mutation to the EGFR drug or this BRAF combination or MEK inhibitor is unclear because the trial only included patient with BRAF V600E mutations.

Shubham Pant, MD: Greg, it’s also important, as a pathologist, that you look at the second part of all mutations. Just because it says BRAF doesn’t mean that you don’t need to look at the second part of it.

Gregory Riedlinger, MD, PhD: Yes. Generally, 3 classes of BRAF mutations have been described. We know of the canonical BRAF V600 mutations, where BRAF is signaling as a monomer. And then there are other BRAF-activating mutations that theoretically function as a dimer through CRAF, which is RAF1. And then there are the so-called class 3 BRAF mutations, which are actually inactivated or are kinase dead. Knowing the differences between those and the different treatment options is obviously important.

Shubham Pant, MD: Thank you so much. This has been a great discussion. So our take-home points are: Test for these mutations that we’ve talked about. Don’t just go and look at BRAF and go “I can treat this with a BRAF inhibitor,” because it’s not approved for that. It’s only approved for BRAF V600E mutations. In the frontline, you can choose FOLFOXIRI with bevacizumab, or FOLFIRI or FOLFOX with bevacizumab, or chemotherapy, depending on the clinical status of the patient.

In the second-line setting, once they’ve failed, based on the SWOG data and the NCCN [National Comprehensive Cancer Center] guidelines, we can try to combine it with a BRAF inhibitor, such as vemurafenib. We are really waiting on the results of the BEACON trial, but this is an exciting era for our patients. Two years back, we really did not have anything for our patients. It’s a great step forward. Thank you so much.

Transcript edited for clarity.
 
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