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Emerging Therapies for BRAF-Mutated NSCLC

Insights From: Bruce E. Johnson, MD, Dana-Farber Cancer Institute
Published: Monday, Oct 28, 2019



Transcript: 

Bruce E. Johnson, MD:
One of the things that’s been very promising in melanoma is the combinations of the BRAF and MEK inhibitors, which are very active in those patients. The majority of people respond and respond for a year, or even years. In addition, the checkpoint inhibitors are very active in that group. And so, it’s somewhat of an ongoing discussion about whether you should use one or the other first, and what the sequence should be.

The obvious thing that people are doing is combining the 2. There have been combinations of atezolizumab with vemurafenib and cobimetinib. In the early reports of these—there are not large trials yet—they have found that up to two-thirds of the patients have somewhat severe adverse effects. It looks like the time that it works goes from about 10 months to 16 months. So it looks like if you can get it in and get it in safely, they may be doing it a bit better. They’ve also taken a look at dabrafenib, trametinib, plus pembrolizumab. You see the same thing. You’re seeing relatively high adverse effects as well, but you’re also beginning to see some early hints that if they do tolerate it, it may work a bit longer. Whether this can be applied in large populations in randomized phase III trials and what the outcomes will be are unknown in melanoma.

The combination of BRAF inhibitors with checkpoint inhibitors will be somewhat of a challenge in lung cancer because only 1% or 2% of the advanced lung cancer patients have BRAF mutations. So being able to focus on this is somewhat of a challenge. In addition, so far when they have tried to combine checkpoint inhibition with the other targeted agents it hasn’t been terribly effective, and it hasn’t been wildly adopted. So the BRAF mutations would end up being a bit of a different story than what we’ve seen from some of the other more common ones—combining checkpoint inhibitors with epidermal growth factor receptor inhibitors, and the ALK inhibitors.

The research that’s ongoing with the BRAF-mutated population in non–small cell lung cancer is testing the other combinations that haven’t been reported yet. That is vemurafenib plus cobimetinib, and binimetinib plus encorafenib. We don’t have a lot of other studies adding a third agent to that regimen.

There is work developing novel agents to try to do more with the RAF kinase family. There are 3 different RAFs. There’s ARAF, BRAF, and CRAF; and they dimerize. And so, there’s work that’s ongoing trying to prevent the dimerization with the other RAF proteins to try to cut down on the feedback. Because typically if you try to inhibit one of the RAF kinases, you may end up getting an increased signaling through the other RAF family members. So if we can prevent the dimerization with the other RAF inhibitors, we may be able to be more effective in blocking the signal through the RAF proteins.

Mostly, these are experiments going on in the laboratory, getting candidate molecules that are working the way that they hypothesize. And then, being able to translate these into real medicines and move them into treatment for patients.

The largest unmet need is increasing the duration of response. It turns out there are a subset of patients who are responding for 2 or even 3 years. One of the unmet needs is to define who those patients are, so we know about it ahead of time. This is particularly true if the checkpoint inhibitors are effective so we know which patients should go on the BRAF/MEK inhibitors, and which patients we should think more about using the checkpoint inhibitors in.

The second thing is that we need better drugs to extend the duration of response. Currently, it’s 10 months. We’ve seen other things where with the ALK inhibitors they’ve been able to work going from 10 months to nearly 3 years. And we have EGFR inhibitors that have gone from an initial 10 months now up to approaching 2 years with the next-generation agents. So we would like to see more effective agents developed against both BRAF and MEK to try to extend that response duration.

And lastly, and one of the things we hope, is that by being more effective in inhibiting either the BRAF family of kinases, or by being able to more effectively inhibit MEK, and by blocking multiple pathways, you can actually potentially cure the patients, which is what our ultimate goal is.


Transcript Edited for Clarity 
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Transcript: 

Bruce E. Johnson, MD:
One of the things that’s been very promising in melanoma is the combinations of the BRAF and MEK inhibitors, which are very active in those patients. The majority of people respond and respond for a year, or even years. In addition, the checkpoint inhibitors are very active in that group. And so, it’s somewhat of an ongoing discussion about whether you should use one or the other first, and what the sequence should be.

The obvious thing that people are doing is combining the 2. There have been combinations of atezolizumab with vemurafenib and cobimetinib. In the early reports of these—there are not large trials yet—they have found that up to two-thirds of the patients have somewhat severe adverse effects. It looks like the time that it works goes from about 10 months to 16 months. So it looks like if you can get it in and get it in safely, they may be doing it a bit better. They’ve also taken a look at dabrafenib, trametinib, plus pembrolizumab. You see the same thing. You’re seeing relatively high adverse effects as well, but you’re also beginning to see some early hints that if they do tolerate it, it may work a bit longer. Whether this can be applied in large populations in randomized phase III trials and what the outcomes will be are unknown in melanoma.

The combination of BRAF inhibitors with checkpoint inhibitors will be somewhat of a challenge in lung cancer because only 1% or 2% of the advanced lung cancer patients have BRAF mutations. So being able to focus on this is somewhat of a challenge. In addition, so far when they have tried to combine checkpoint inhibition with the other targeted agents it hasn’t been terribly effective, and it hasn’t been wildly adopted. So the BRAF mutations would end up being a bit of a different story than what we’ve seen from some of the other more common ones—combining checkpoint inhibitors with epidermal growth factor receptor inhibitors, and the ALK inhibitors.

The research that’s ongoing with the BRAF-mutated population in non–small cell lung cancer is testing the other combinations that haven’t been reported yet. That is vemurafenib plus cobimetinib, and binimetinib plus encorafenib. We don’t have a lot of other studies adding a third agent to that regimen.

There is work developing novel agents to try to do more with the RAF kinase family. There are 3 different RAFs. There’s ARAF, BRAF, and CRAF; and they dimerize. And so, there’s work that’s ongoing trying to prevent the dimerization with the other RAF proteins to try to cut down on the feedback. Because typically if you try to inhibit one of the RAF kinases, you may end up getting an increased signaling through the other RAF family members. So if we can prevent the dimerization with the other RAF inhibitors, we may be able to be more effective in blocking the signal through the RAF proteins.

Mostly, these are experiments going on in the laboratory, getting candidate molecules that are working the way that they hypothesize. And then, being able to translate these into real medicines and move them into treatment for patients.

The largest unmet need is increasing the duration of response. It turns out there are a subset of patients who are responding for 2 or even 3 years. One of the unmet needs is to define who those patients are, so we know about it ahead of time. This is particularly true if the checkpoint inhibitors are effective so we know which patients should go on the BRAF/MEK inhibitors, and which patients we should think more about using the checkpoint inhibitors in.

The second thing is that we need better drugs to extend the duration of response. Currently, it’s 10 months. We’ve seen other things where with the ALK inhibitors they’ve been able to work going from 10 months to nearly 3 years. And we have EGFR inhibitors that have gone from an initial 10 months now up to approaching 2 years with the next-generation agents. So we would like to see more effective agents developed against both BRAF and MEK to try to extend that response duration.

And lastly, and one of the things we hope, is that by being more effective in inhibiting either the BRAF family of kinases, or by being able to more effectively inhibit MEK, and by blocking multiple pathways, you can actually potentially cure the patients, which is what our ultimate goal is.


Transcript Edited for Clarity 
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