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Understanding the BRAF-mutated Population in NSCLC

Insights From: Roy S. Herbst, MD, PhD, Yale Cancer Center; Bruce E. Johnson, MD, Dana-Farber Cancer Institute; Mark A. Socinski, MD, Florida Hospital Cancer Institute
Published Online: Wednesday, Dec 28, 2016



Transcript:

Bruce E. Johnson, MD:
The prevalence of BRAF mutations in non–small cell lung cancer has been defined in some relatively large studies, both in the United States and Europe. The frequency of all BRAF mutations is approximately 2% to 4%. And of those 2% to 4% that have BRAF mutations, about half of them (or 1% to 2%), will have a BRAF V600E mutation—the specific mutation for which the combination of dabrafenib and trametinib will likely be indicated.

Mark A. Socinski, MD: The BRAF population tends to be slightly younger than the average age, usually in the mid-60s, whereas the average age of lung cancer is about 70. There seems to be no predilection for men or women, about equal distribution. Most of the BRAF-mutant patients are smokers. If you look at the rate of the BRAF mutants who are true never-smokers, it’s usually in the 20% to 25% range. So, the majority have some exposure to smoking. Almost all of them have adenocarcinoma histology. At least in the lung cancer mutation consortium database, they don’t necessarily appear to be different from a prognostic point of view, although I must say I don’t know that we have enough information to really answer a lot of these prognostic, predictive aspects of a BRAF mutation.

It’s important to understand that there are a number of different BRAF mutations. The BRAF mutation, specifically, that we’re talking about is the one that we talk about in melanoma—that’s the V600E. There are certainly other ones. One needs to understand the nature of the BRAF mutation. The V600E mutation does lead to constitutive activation of the pathway, so it’s a target. The other BRAF mutations may or may not be activating mutations. So, I think the clinicians need to be aware of that.

Bruce E. Johnson, MD: The V600E mutation was discovered mostly in melanomas and then was found to occur in other tumors. Because the V600E is the predominant mutation of BRAF in melanoma, they’ve developed drugs that are specific for that V600E mutation form. They’re specifically designed to be effective with that mutation. Therefore, the drug is quite effective in those V600Es. The other types of BRAF mutants are less likely to respond to those BRAF inhibitors because it’s not designed to be active against those.

The patients who have V600E/BRAF mutations tend to be male smokers with adenocarcinoma. These are different than the patients. There are almost none where you find both a BRAF mutation as well as an EGFR, ALK, or ROS1 rearrangement. Only one of them tends to be found in a given patient. Therefore, it’s important to identify those BRAFs because they don’t have other options for targeted therapy. So, if you want to give them targeted therapy, they need to have the BRAF characterized. And they arise in ones that don’t have those oncogenic drivers that I mentioned before.

Transcript Edited for Clarity
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Transcript:

Bruce E. Johnson, MD:
The prevalence of BRAF mutations in non–small cell lung cancer has been defined in some relatively large studies, both in the United States and Europe. The frequency of all BRAF mutations is approximately 2% to 4%. And of those 2% to 4% that have BRAF mutations, about half of them (or 1% to 2%), will have a BRAF V600E mutation—the specific mutation for which the combination of dabrafenib and trametinib will likely be indicated.

Mark A. Socinski, MD: The BRAF population tends to be slightly younger than the average age, usually in the mid-60s, whereas the average age of lung cancer is about 70. There seems to be no predilection for men or women, about equal distribution. Most of the BRAF-mutant patients are smokers. If you look at the rate of the BRAF mutants who are true never-smokers, it’s usually in the 20% to 25% range. So, the majority have some exposure to smoking. Almost all of them have adenocarcinoma histology. At least in the lung cancer mutation consortium database, they don’t necessarily appear to be different from a prognostic point of view, although I must say I don’t know that we have enough information to really answer a lot of these prognostic, predictive aspects of a BRAF mutation.

It’s important to understand that there are a number of different BRAF mutations. The BRAF mutation, specifically, that we’re talking about is the one that we talk about in melanoma—that’s the V600E. There are certainly other ones. One needs to understand the nature of the BRAF mutation. The V600E mutation does lead to constitutive activation of the pathway, so it’s a target. The other BRAF mutations may or may not be activating mutations. So, I think the clinicians need to be aware of that.

Bruce E. Johnson, MD: The V600E mutation was discovered mostly in melanomas and then was found to occur in other tumors. Because the V600E is the predominant mutation of BRAF in melanoma, they’ve developed drugs that are specific for that V600E mutation form. They’re specifically designed to be effective with that mutation. Therefore, the drug is quite effective in those V600Es. The other types of BRAF mutants are less likely to respond to those BRAF inhibitors because it’s not designed to be active against those.

The patients who have V600E/BRAF mutations tend to be male smokers with adenocarcinoma. These are different than the patients. There are almost none where you find both a BRAF mutation as well as an EGFR, ALK, or ROS1 rearrangement. Only one of them tends to be found in a given patient. Therefore, it’s important to identify those BRAFs because they don’t have other options for targeted therapy. So, if you want to give them targeted therapy, they need to have the BRAF characterized. And they arise in ones that don’t have those oncogenic drivers that I mentioned before.

Transcript Edited for Clarity
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Medical Crossfire®: 3rd Annual Miami Lung Cancer Conference®May 31, 20171.5
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