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BRAF as a Driver in Melanoma

Insights From: Geoffrey Thomas Gibney, MD, MedStar Georgetown University Hospital; Ryan J. Sullivan, MD, Massachusetts General Hospital Cancer Center; Hussein A. Tawbi, MD, University of Texas MD Anderson Cancer Center
Published: Tuesday, Apr 30, 2019



Transcript:

Hussein A. Tawbi, MD:
Melanoma is a cancer that starts most of the time in the skin and actually gets induced, we think, by UV exposure, which leads to a lot of mutations. There are a few mutations in melanoma that are actually critical for its development, and we know that it may not be. So the BRAF mutation is a very good example of that. But there are actually other mutations that are, you know, reasonably common in melanoma like NRAS mutation and NF1 mutation.

The interesting part is almost all those 3, which actually cover about 85% of all melanomas, they all actually end up activating the same pathway, which is called the MAP kinase pathway. So while it’s not 1 gene that drives the entire kind of spectrum of all melanomas, it does seem that it’s 1 pathway that’s very important, you know?

And so from our perspective, at this point in time the only 1 that is targetable and affects whether we treat them and how we treat patients is the BRAF, mutation which ends up being about half of all patients with melanoma. But we continue our work in this field, and a lot of melanoma researchers are really working hard to figure out new treatments for the NRAS patients, for the NF1 patients, and potentially for the patients that don’t have any of these mutations but also have activation of the MAP kinase pathway.

Geoffrey Thomas Gibney, MD: So the BRAF target is a very specific mutation within a pathway, and it turns on that pathway in a very uniform predictable pattern, for the most part. If you were able to block it, it can actually be very effective in shutting down the activity of the cancer cell. We now have been able to develop very selective BRAF inhibitors that inhibit just the mutant protein kinase and the BRAF and have very little off-target effect, which makes it a very selective targeted therapy that can be blocked within a tumor cell. The tumor cell—when it is blocked, those that harbor the BRAF mutation actually shut down cell proliferations—and tumors in experimental models as well as in people can be seen to shrink very dramatically.

Hussein A. Tawbi, MD: Identifying the BRAF gene as a very important gene for melanoma is something that happened at kind of the tail of the human genome project and when we started being able to sequence tumors. So actually, in 2002, there was a seminal paper that identified the BRAF as 1 of the recurrent mutations in melanoma that at the time kind of realized that it’s about half of all melanomas that have that mutation.

Well, all of us, when we do cancer research, the first question we ask is, How does the cancer work? And the second question is, How can we use that to treat patients, right? As soon as that mutation was identified, you know the search was on for ways to actually block that mutation and prove that we can actually help patients with melanoma that have that mutation. And so, again, this was early 2000s, and so immediately we started looking at drugs that may possibly target that pathway.

And so 1 of the early drugs was called sorafenib. And if you see, those drugs are actually named what they inhibit, so the raf part in sorafenib is actually the fact that it inhibits RAF. Interestingly enough, sorafenib wasn’t very specific to BRAF. It inhibits ARAF and BRAF and CRAF and not actually to a very great degree. It also did not inhibit; it inhibits BRAF whether it’s mutated or not. And so still it was basically the best tool that we had, and it was actually tried in clinical trials. There were some studies actually adding that drug to chemotherapy, specifically carboplatin and paclitaxel. And the early phased trials showed really interesting results, and there were response rates of almost 40%, which we had never heard of in melanoma. The best responses we used to get are closer to 10% or 15%, so 40% was quite significant.

And that led to actually 2 large phase III trials that tried to prove that adding sorafenib to chemotherapy was more effective than chemotherapy alone. Unfortunately, you know about 1000 patients later, after those patients were randomized, it did not prove to be the case. And sorafenib alone, or sorafenib added to carboplatin and paclitaxel wasn’t actually enough to increase the rate of response or the progression-free survival, or the overall survival of patients with metastatic melanoma.

So that was obviously disappointing but it taught us a lot about the fact that we may be needing to inhibit the BRAF mutation in a much more specific way, and that’s exactly what actually happened. There was a drug, or a company, called Lexicon Pharmaceuticals that really was working on a very specific molecule that inhibits the BRAF-mutated protein, and it actually really fits very well within the BRAF V600E mutation, which was obviously the most common mutation by far.

So when that rock came to phase I trials, it was actually quite impressive that it managed to actually block the pathway, kind of block all of the signaling, through the map kinase pathway very effectively, and that very quickly translated into patients responding to treatment. So that was quite transformative to find a drug that the response rates were actually, I would say, almost 70% of patients would actually have shrinkage of their tumors; 50% of the time it was considered a partial response or better, or what we call objective response rate. So that happened in 2010, and it transformed the care of patients with BRAF-mutated melanoma.


Transcript Edited for Clarity
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Transcript:

Hussein A. Tawbi, MD:
Melanoma is a cancer that starts most of the time in the skin and actually gets induced, we think, by UV exposure, which leads to a lot of mutations. There are a few mutations in melanoma that are actually critical for its development, and we know that it may not be. So the BRAF mutation is a very good example of that. But there are actually other mutations that are, you know, reasonably common in melanoma like NRAS mutation and NF1 mutation.

The interesting part is almost all those 3, which actually cover about 85% of all melanomas, they all actually end up activating the same pathway, which is called the MAP kinase pathway. So while it’s not 1 gene that drives the entire kind of spectrum of all melanomas, it does seem that it’s 1 pathway that’s very important, you know?

And so from our perspective, at this point in time the only 1 that is targetable and affects whether we treat them and how we treat patients is the BRAF, mutation which ends up being about half of all patients with melanoma. But we continue our work in this field, and a lot of melanoma researchers are really working hard to figure out new treatments for the NRAS patients, for the NF1 patients, and potentially for the patients that don’t have any of these mutations but also have activation of the MAP kinase pathway.

Geoffrey Thomas Gibney, MD: So the BRAF target is a very specific mutation within a pathway, and it turns on that pathway in a very uniform predictable pattern, for the most part. If you were able to block it, it can actually be very effective in shutting down the activity of the cancer cell. We now have been able to develop very selective BRAF inhibitors that inhibit just the mutant protein kinase and the BRAF and have very little off-target effect, which makes it a very selective targeted therapy that can be blocked within a tumor cell. The tumor cell—when it is blocked, those that harbor the BRAF mutation actually shut down cell proliferations—and tumors in experimental models as well as in people can be seen to shrink very dramatically.

Hussein A. Tawbi, MD: Identifying the BRAF gene as a very important gene for melanoma is something that happened at kind of the tail of the human genome project and when we started being able to sequence tumors. So actually, in 2002, there was a seminal paper that identified the BRAF as 1 of the recurrent mutations in melanoma that at the time kind of realized that it’s about half of all melanomas that have that mutation.

Well, all of us, when we do cancer research, the first question we ask is, How does the cancer work? And the second question is, How can we use that to treat patients, right? As soon as that mutation was identified, you know the search was on for ways to actually block that mutation and prove that we can actually help patients with melanoma that have that mutation. And so, again, this was early 2000s, and so immediately we started looking at drugs that may possibly target that pathway.

And so 1 of the early drugs was called sorafenib. And if you see, those drugs are actually named what they inhibit, so the raf part in sorafenib is actually the fact that it inhibits RAF. Interestingly enough, sorafenib wasn’t very specific to BRAF. It inhibits ARAF and BRAF and CRAF and not actually to a very great degree. It also did not inhibit; it inhibits BRAF whether it’s mutated or not. And so still it was basically the best tool that we had, and it was actually tried in clinical trials. There were some studies actually adding that drug to chemotherapy, specifically carboplatin and paclitaxel. And the early phased trials showed really interesting results, and there were response rates of almost 40%, which we had never heard of in melanoma. The best responses we used to get are closer to 10% or 15%, so 40% was quite significant.

And that led to actually 2 large phase III trials that tried to prove that adding sorafenib to chemotherapy was more effective than chemotherapy alone. Unfortunately, you know about 1000 patients later, after those patients were randomized, it did not prove to be the case. And sorafenib alone, or sorafenib added to carboplatin and paclitaxel wasn’t actually enough to increase the rate of response or the progression-free survival, or the overall survival of patients with metastatic melanoma.

So that was obviously disappointing but it taught us a lot about the fact that we may be needing to inhibit the BRAF mutation in a much more specific way, and that’s exactly what actually happened. There was a drug, or a company, called Lexicon Pharmaceuticals that really was working on a very specific molecule that inhibits the BRAF-mutated protein, and it actually really fits very well within the BRAF V600E mutation, which was obviously the most common mutation by far.

So when that rock came to phase I trials, it was actually quite impressive that it managed to actually block the pathway, kind of block all of the signaling, through the map kinase pathway very effectively, and that very quickly translated into patients responding to treatment. So that was quite transformative to find a drug that the response rates were actually, I would say, almost 70% of patients would actually have shrinkage of their tumors; 50% of the time it was considered a partial response or better, or what we call objective response rate. So that happened in 2010, and it transformed the care of patients with BRAF-mutated melanoma.


Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
Medical Crossfire®: What Does Data Tell Us About How to Optimize Checkpoint Inhibitor Strategies Across Lines of Care for Patients with Melanoma?Nov 30, 20191.5
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