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Treatment Sequencing in BRAF+ Metastatic 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: Friday, Jun 07, 2019



Transcript: 

Ryan J. Sullivan, MD: The only way you ever know if one regimen is better than another is to compare them head to head. In the absence of comparing head to head, you use lots of ancillary data. There’s a lot of extrapolation involved to figure out if one regimen is better than the other. Adverse effects are pretty consistent in terms of comparison. It’s fair to say this drug causes this. Which would you rather have? So I think we can compare across toxicities and say this is the spectrum of adverse effects with vemurafenib/cobimetinib, this is the spectrum of adverse effects of encorafenib/binimetinib. And we can compare them and say maybe we should try this because it could be a little less toxic or we don’t like the fever, or we live in Texas, we’re not going to give you vemurafenib/cobimetinib because of the photosensitivity, but we’ll try one of these other 2 regimens.

I think from an efficacy standpoint, or from a target engagement standpoint, or a potency standpoint, an argument can be made for encorafenib and binimetinib based on 2 pieces of information, maybe 3. The overall survival data from the COLUMBUS study showed that the encorafenib/binimetinib regimen of 450 mg a day of encorafenib and 45 mg BID twice a day of binimetinib was associated with the longest survival we’ve seen in a frontline BRAF-mutated population going on BRAF/MEK inhibitor combination.
 
That could be a sign of the times, meaning that trial launched after CoBRIM, after COMBI-d, after COMBI-v. And because of that, we had more therapies that were approved and it was more likely that a patient would receive PD-1 [programmed cell death protein 1] inhibitor therapy or combined PD-1, CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor therapy after their BRAF-targeted therapy. And so their overall survival might be better because there are better drugs behind it in the patient population that were on COLUMBUS versus those other trials. I don’t know if that’s true, but that’s a reasonable explanation for why the overall survival would have been better.

However, when you compare the relative survival advantage of that combination to vemurafenib versus dabrafenib/trametinib to vemurafenib or vemurafenib/cobimetinib to vemurafenib, it does seem that it’s a little bit better. So that’s one piece of information that would suggest that encorafenib/binimetinib could be a little bit more efficacious. The other piece of information is the progression-free survival data, which…the 14 or 14-1/2 months progression-free survival compared with 7 or 8 months of progression-free survival with vemurafenib, that’s compelling. But the hazard ratio isn’t that much better than the hazard ratio differences for progression-free survival with vemurafenib/cobimetinib versus vemurafenib or dabrafenib/trametinib versus vemurafenib.

However, the idea of being able to get away with more BRAF inhibitor in combination than as a single agent suggests that we have to be getting more potency hitting BRAF in the encorafenib/binimetinib combination than in vemurafenib/cobimetinib or dabrafenib/trametinib combination. We can’t prove that for sure because we don’t have wonderful BRAF inhibition assays on all these studies and all the patients who went on these studies to say, yes, we’re totally getting more robust and potent inhibition of the target. But logically it makes sense that we’re getting away with a higher dose of the BRAF inhibitor. We’re probably getting more potency.

In fact, we were able to give twice as much, 600 mg a day of encorafenib on the phase I study and treated a fair number of patients in the phase II, and we seem to still be fairly tolerable without overwhelming toxicity signal. So there even may be room to move further with that and that may be something that’s part of certain clinical trials moving forward, particularly in certain subsets of patients.
So I think there is an interesting argument to be made for efficacy that could be better with encorafenib/binimetinib, but outside of a randomized controlled trial it’s hard to say that and stand up and shout it from the mountainside. And so I think really whatever patients are comfortable receiving, whatever providers are comfortable giving, we shouldn’t be saying this is definitely the best of the 3 and you have to give this to your patients or else you’re doing them a disservice. I’m not that confident to say that.

Geoffrey Thomas Gibney, MD: Patients who are on BRAF-targeted therapy, there is some thought that it may be beneficial to treat to best response, and then if they have not seen an immuno-oncology [I/O] agent, such as nivolumab or pembrolizumab, to switch to that agent as there may be a better durability in the response. This has been recommended as a possible treatment strategy within the NCCN [National Comprehensive Cancer Network] guidelines, and I know that there are some providers that do consider offering this to patients.

In my personal practice, I have not recommended this to the majority of patients. My concern is that we don’t have strong clinical data supporting the transition, and that some patients may lose the tumor control during that transition. We also know with BRAF-targeted therapy that there is a population of patients who have very durable responses, and by switching those patients from the BRAF-targeted therapy over to an immuno-oncology agent when there’s no signs of progression, it may be premature. Those patients may have had a durable benefit lasting not just months but years. So I do discuss that with patients, and my concern is that you may have a harder time regaining that if the patient progresses down the road if you’ve switched to an I/O agent.

Hussein A. Tawbi, MD: One of the strategies that has been considered for the use of BRAF-targeted therapy in the first-line setting is to actually use it up front because we know most of the patients are going to respond. And some consider switching to immunotherapy after you get the initial response because again the data indicate the treatment with BRAF/MEK inhibitors may be limited in time in terms of its efficacy.

I am personally not in favor of this approach simply because maybe I’m a traditional oncologist, but I think that when a patient is responding to treatment, and as long as they’re responding to treatment, we really have no evidence to indicate that they will do better if we switched them to a different therapy that has not been used yet, that still has a limited impact in terms of its efficacy. Not 100% of patients will respond to immunotherapy. And I think trying to interrupt at a random time and switch to immunotherapy may actually be a risky strategy.

So at this point, as we don’t have any clinical trials that were designed that way, and any evidence that there’s a particularly magical time at which you need to switch from targeted to immunotherapy, my approach is to wait until the targeted therapy starts showing signs of losing its efficacy and then switching to immunotherapy.

Transcript Edited for Clarity
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Transcript: 

Ryan J. Sullivan, MD: The only way you ever know if one regimen is better than another is to compare them head to head. In the absence of comparing head to head, you use lots of ancillary data. There’s a lot of extrapolation involved to figure out if one regimen is better than the other. Adverse effects are pretty consistent in terms of comparison. It’s fair to say this drug causes this. Which would you rather have? So I think we can compare across toxicities and say this is the spectrum of adverse effects with vemurafenib/cobimetinib, this is the spectrum of adverse effects of encorafenib/binimetinib. And we can compare them and say maybe we should try this because it could be a little less toxic or we don’t like the fever, or we live in Texas, we’re not going to give you vemurafenib/cobimetinib because of the photosensitivity, but we’ll try one of these other 2 regimens.

I think from an efficacy standpoint, or from a target engagement standpoint, or a potency standpoint, an argument can be made for encorafenib and binimetinib based on 2 pieces of information, maybe 3. The overall survival data from the COLUMBUS study showed that the encorafenib/binimetinib regimen of 450 mg a day of encorafenib and 45 mg BID twice a day of binimetinib was associated with the longest survival we’ve seen in a frontline BRAF-mutated population going on BRAF/MEK inhibitor combination.
 
That could be a sign of the times, meaning that trial launched after CoBRIM, after COMBI-d, after COMBI-v. And because of that, we had more therapies that were approved and it was more likely that a patient would receive PD-1 [programmed cell death protein 1] inhibitor therapy or combined PD-1, CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor therapy after their BRAF-targeted therapy. And so their overall survival might be better because there are better drugs behind it in the patient population that were on COLUMBUS versus those other trials. I don’t know if that’s true, but that’s a reasonable explanation for why the overall survival would have been better.

However, when you compare the relative survival advantage of that combination to vemurafenib versus dabrafenib/trametinib to vemurafenib or vemurafenib/cobimetinib to vemurafenib, it does seem that it’s a little bit better. So that’s one piece of information that would suggest that encorafenib/binimetinib could be a little bit more efficacious. The other piece of information is the progression-free survival data, which…the 14 or 14-1/2 months progression-free survival compared with 7 or 8 months of progression-free survival with vemurafenib, that’s compelling. But the hazard ratio isn’t that much better than the hazard ratio differences for progression-free survival with vemurafenib/cobimetinib versus vemurafenib or dabrafenib/trametinib versus vemurafenib.

However, the idea of being able to get away with more BRAF inhibitor in combination than as a single agent suggests that we have to be getting more potency hitting BRAF in the encorafenib/binimetinib combination than in vemurafenib/cobimetinib or dabrafenib/trametinib combination. We can’t prove that for sure because we don’t have wonderful BRAF inhibition assays on all these studies and all the patients who went on these studies to say, yes, we’re totally getting more robust and potent inhibition of the target. But logically it makes sense that we’re getting away with a higher dose of the BRAF inhibitor. We’re probably getting more potency.

In fact, we were able to give twice as much, 600 mg a day of encorafenib on the phase I study and treated a fair number of patients in the phase II, and we seem to still be fairly tolerable without overwhelming toxicity signal. So there even may be room to move further with that and that may be something that’s part of certain clinical trials moving forward, particularly in certain subsets of patients.
So I think there is an interesting argument to be made for efficacy that could be better with encorafenib/binimetinib, but outside of a randomized controlled trial it’s hard to say that and stand up and shout it from the mountainside. And so I think really whatever patients are comfortable receiving, whatever providers are comfortable giving, we shouldn’t be saying this is definitely the best of the 3 and you have to give this to your patients or else you’re doing them a disservice. I’m not that confident to say that.

Geoffrey Thomas Gibney, MD: Patients who are on BRAF-targeted therapy, there is some thought that it may be beneficial to treat to best response, and then if they have not seen an immuno-oncology [I/O] agent, such as nivolumab or pembrolizumab, to switch to that agent as there may be a better durability in the response. This has been recommended as a possible treatment strategy within the NCCN [National Comprehensive Cancer Network] guidelines, and I know that there are some providers that do consider offering this to patients.

In my personal practice, I have not recommended this to the majority of patients. My concern is that we don’t have strong clinical data supporting the transition, and that some patients may lose the tumor control during that transition. We also know with BRAF-targeted therapy that there is a population of patients who have very durable responses, and by switching those patients from the BRAF-targeted therapy over to an immuno-oncology agent when there’s no signs of progression, it may be premature. Those patients may have had a durable benefit lasting not just months but years. So I do discuss that with patients, and my concern is that you may have a harder time regaining that if the patient progresses down the road if you’ve switched to an I/O agent.

Hussein A. Tawbi, MD: One of the strategies that has been considered for the use of BRAF-targeted therapy in the first-line setting is to actually use it up front because we know most of the patients are going to respond. And some consider switching to immunotherapy after you get the initial response because again the data indicate the treatment with BRAF/MEK inhibitors may be limited in time in terms of its efficacy.

I am personally not in favor of this approach simply because maybe I’m a traditional oncologist, but I think that when a patient is responding to treatment, and as long as they’re responding to treatment, we really have no evidence to indicate that they will do better if we switched them to a different therapy that has not been used yet, that still has a limited impact in terms of its efficacy. Not 100% of patients will respond to immunotherapy. And I think trying to interrupt at a random time and switch to immunotherapy may actually be a risky strategy.

So at this point, as we don’t have any clinical trials that were designed that way, and any evidence that there’s a particularly magical time at which you need to switch from targeted to immunotherapy, my approach is to wait until the targeted therapy starts showing signs of losing its efficacy and then switching to immunotherapy.

Transcript Edited for Clarity
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