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Additional Targets in NSCLC: BRAF V600E and BRAF Variants

Panelists: Benjamin P. Levy, MD, Sibley Memorial Hospital; Shirish M. Gadgeel, MD, University of Michigan; Lyudmila A. Bazhenova, MD, UCSD Morris Cancer Center; Anne S. Tsao, MD, MD Anderson Cancer Center; Mohammad Jahanzeb, MD, FACP, University of Miami, Miller School of Medicine
Published: Friday, Oct 26, 2018



Transcript: 

Benjamin P. Levy, MD:
For the sake of time we’re going to move on to the third section and talk about additional targets in non–small cell lung cancer. Historically, we think of the precision paradigm in non–small cell lung cancer as being limited to EGFR and ALK and possibly ROS. But all of us know that’s just the tip of the iceberg at this point. There are other mutations that are druggable. They may be rarer, but are certainly druggable, actionable, and lead to improve outcomes and response rates that we don’t normally see with chemotherapy. This is, of course, BRAF and MET and HER2, and others, NTRK. So, we’ll spend some time talking about just either approved drugs or emerging drugs over these particular molecular niches. So, MJ [Mohammad Jahanzeb, MD, FACP], let’s start out with BRAF. Discuss how one should treat BRAF, and then potentially the targeted therapy approval, and how to use it and when.

Mohammad Jahanzeb, MD, FACP: Sure. So first of all, it’s important to point out that the vast majority of oncologists are unlikely to see a single BRAF patient. It’s very rare, even more rare than ALK, maybe 1[%] to 2%. And within BRAF, there are various subtypes. It’s only BRAF V600E which seems to derive benefit from targeted therapy. And in fact, at this meeting we all saw the results where in 62 patients—only 8 of whom were previously untreated; 54 previously treated—he saw responses were about the same whether they were previously treated or not, keeping in mind the numbers are very small—37 or 38%. And PFS [progression-free survival] was longer, twice as long, in the previously untreated patients—about 12.9 months versus 6.1 month[s].

So, I think that if you have such a patient, obviously targeted therapy still beats chemotherapy. You would use it bearing in mind that the toxicities are again different—you may have pyrexia as one of the toxicities that you need to be aware of besides the usual TKI [tyrosine kinase inhibitor] toxicities. So, I think that we would use it. The question is, are there additional aspects of BRAF that we should keep in mind. You know these are not typically young never-smokers, ALK patients; they can be smokers or nonsmokers. They don’t tend to be any younger.
And the other interesting aspect in immunotherapy, is that then we get the full next-generation sequencing approach. Now we can look at these mutations and draw additional conclusions about the candidate or patient you see for immunotherapy. For example, BRAF seems to have no bearing but MET upregulates markers of immune response. STK11 downregulates markers of immune response. So, I digressed a little bit, but BRAF reminds me that now we need to pay attention to these markers, even while talking about immunotherapy.

Benjamin P. Levy, MD: Sure.

Anne S. Tsao, MD: Absolutely. So there’s some emerging data that the BRAF mutations are a unique population and they may be one of those exceptions to the oncogenic driver population, in terms of responses to immunotherapy. The jury’s still out about that. But I think for the most part, most everybody for BRAF V600E, is at least thinking about dabrafenib [Tafinlar] plus trametinib [Mekinist]. It’s the only FDA-approved regimen we have right now as a targeted agent for these patients.


Transcript Edited for Clarity
 

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Transcript: 

Benjamin P. Levy, MD:
For the sake of time we’re going to move on to the third section and talk about additional targets in non–small cell lung cancer. Historically, we think of the precision paradigm in non–small cell lung cancer as being limited to EGFR and ALK and possibly ROS. But all of us know that’s just the tip of the iceberg at this point. There are other mutations that are druggable. They may be rarer, but are certainly druggable, actionable, and lead to improve outcomes and response rates that we don’t normally see with chemotherapy. This is, of course, BRAF and MET and HER2, and others, NTRK. So, we’ll spend some time talking about just either approved drugs or emerging drugs over these particular molecular niches. So, MJ [Mohammad Jahanzeb, MD, FACP], let’s start out with BRAF. Discuss how one should treat BRAF, and then potentially the targeted therapy approval, and how to use it and when.

Mohammad Jahanzeb, MD, FACP: Sure. So first of all, it’s important to point out that the vast majority of oncologists are unlikely to see a single BRAF patient. It’s very rare, even more rare than ALK, maybe 1[%] to 2%. And within BRAF, there are various subtypes. It’s only BRAF V600E which seems to derive benefit from targeted therapy. And in fact, at this meeting we all saw the results where in 62 patients—only 8 of whom were previously untreated; 54 previously treated—he saw responses were about the same whether they were previously treated or not, keeping in mind the numbers are very small—37 or 38%. And PFS [progression-free survival] was longer, twice as long, in the previously untreated patients—about 12.9 months versus 6.1 month[s].

So, I think that if you have such a patient, obviously targeted therapy still beats chemotherapy. You would use it bearing in mind that the toxicities are again different—you may have pyrexia as one of the toxicities that you need to be aware of besides the usual TKI [tyrosine kinase inhibitor] toxicities. So, I think that we would use it. The question is, are there additional aspects of BRAF that we should keep in mind. You know these are not typically young never-smokers, ALK patients; they can be smokers or nonsmokers. They don’t tend to be any younger.
And the other interesting aspect in immunotherapy, is that then we get the full next-generation sequencing approach. Now we can look at these mutations and draw additional conclusions about the candidate or patient you see for immunotherapy. For example, BRAF seems to have no bearing but MET upregulates markers of immune response. STK11 downregulates markers of immune response. So, I digressed a little bit, but BRAF reminds me that now we need to pay attention to these markers, even while talking about immunotherapy.

Benjamin P. Levy, MD: Sure.

Anne S. Tsao, MD: Absolutely. So there’s some emerging data that the BRAF mutations are a unique population and they may be one of those exceptions to the oncogenic driver population, in terms of responses to immunotherapy. The jury’s still out about that. But I think for the most part, most everybody for BRAF V600E, is at least thinking about dabrafenib [Tafinlar] plus trametinib [Mekinist]. It’s the only FDA-approved regimen we have right now as a targeted agent for these patients.


Transcript Edited for Clarity
 
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Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Oncology Best Practice™ Decision Points in Advanced NSCLC: Assessing Treatment Options Beyond Disease ProgressionNov 30, 20181.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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