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Melanoma: Nuances of BRAF/MEK Combinations in the Front line

Panelists: Robert H.I. Andtbacka, MD, CM, Huntsman Cancer Institute; Michael A. Davies, MD, PhD, MD Anderson Cancer Center; Antoni Ribas, MD, PhD, University of California Los Angeles; Georgina Long, MD, Melanoma Institute of Australia; Michael Postow, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Jan 17, 2017


Transcript:

Robert H.I. Andtbacka, MD, CM:
In terms of the BRAF/MEK combinations that we have, we have 2 approved combinations: dabrafenib and trametinib versus vemurafenib and cobimetinib. I’d like to take a few moments to talk about choosing one over the other, in terms of response, but also in terms of toxicity. Are there certain patient features that make you choose one over the other? Tony, which one should we choose?

Antoni Ribas, MD, PhD: We’ll go back to the obvious, which is we don’t have randomized data. We cannot answer that.

Robert H.I. Andtbacka, MD, CM: We never compared them head to head.

Antoni Ribas, MD, PhD: I think there’s got to be a comparison head to head. I don’t think anybody will do that. The totality of the data suggest they are very similar combinations. The dabrafenib/trametinib and vemurafenib/cobimetinib give roughly the same rate of responses, and the progression-free survival, and overall survival seems to be within the margin of error of clinical trials. They do have some peculiar toxicities that are different, even though they’re both BRAF and MEK inhibitors, and when they’re given together, the theory is that some of the side effects go down. The side effects that are induced by BRAF inhibitors inducing paradoxical MAP kinase activation are decreased with the MEK inhibitor.

Robert H.I. Andtbacka, MD, CM: Which ones are those, Tony? Can you give some examples?

Antoni Ribas, MD, PhD: Skin rashes go down, as do joint pains, which are induced by the BRAF inhibitor acting on cells that are wild type for BRAF. They have normal BRAF mutations, but the BRAF inhibitor binding to the wild-type BRAF transactivates the MAP kinase signaling. In the skin and in the joints, it leads to side effects. Then, the BRAF inhibitor decreases one of the main side effects from the MEK inhibitor, which is acneiform skin rash, something I don’t think we have a direct explanation for. But, that’s a socially limiting toxicity for MEK inhibitors that decreases in frequency when given together with a BRAF inhibitor. So, those toxicities seem to go side by side with the 2 pairs. But, whenever vemurafenib is used, it has a peculiar toxicity, which is being photosensitive where patients can have sunburns with minimal sun exposure. In southern California where I practice, and maybe more where Georgina practices, these patients try to avoid the sun continuously, and they have to be covered all the time. Even indirect sun can lead to a sunburn, which is something that makes them change their lifestyle. But, if we go to the other combination, dabrafenib/trametinib, dabrafenib brings a very peculiar toxicity, which is fever and sometimes hypertension. Fevers can be high, there can be chills, and they can happen at any time. So, those are patients that may live their life worrying whether that would happen in a situation where it would be unwanted or that this toxicity may lead to having to adjust doses. Georgina was one of the first investigators working with dabrafenib and dabrafenib/trametinib, but has come up with a series of ways to mitigate that. But, it continues to be an effect that is limiting to patients.

So, if I see a patient where we’re going to decide to start a BRAF plus MEK inhibitor, I talk about both combinations. We go over the pros and cons of each one of them. Honestly, I still haven’t made up my mind which one to use.

Michael A. Davies, MD, PhD: The one thing, just to add to that, is that in addition to the combination reducing the risk of rash that we see with single-agent BRAF inhibitor, the other side effects that have decreased are the cutaneous squamous cell carcinomas or keretoacanthomas. They are also significantly decreased with the combination.

Robert H.I. Andtbacka, MD, CM: Georgina, Tony mentioned that you worked with dabrafenib and got a way to mitigate this toxicity. So, tell us a bit about what you tell patients if they have some of these toxicities. How do you mitigate them? Dose reductions? Switching therapies?

Georgina Long, MD: Dabrafenib and trametinib—with the fever, first of all, we know that dose reduction actually does not help, but an intermittent treatment strategy may. Having said that, we’ve not prospectively proven that intermittent—so a full dose for a number of weeks or a few days and then off, going on/off, on/off—actually is better than continuous dosing in humans. We have not proven that. But, the concept and the hypothesis is that we are inhibiting the MAP kinase pathway, so if you’re going to bother to inhibit it, to stop the cell from dividing and causing apoptosis or death of the cell, do it properly. And we already know that from our randomized trials that with single-agent BRAF, you add 1 mg of trametinib onto dabrafenib, it improves things a bit. But, if you add 2 mg of trametinib, it’s even better. So, we do know that there is a dose response with inhibition of the MAP kinase pathway. I avoid dose reductions at all costs. I’m happy to do some intermittent treatment, but, ultimately I would like to keep the MAP kinase properly inhibited for as long as possible. And sometimes, we have to revert to steroids in a small number of patients. Often though, if you can get patients through the first 3 to 5 months where they’ve had quite significant fevers, you can then start to withdraw the steroids. It’s really only 10% to 20% of patients where you actually have to use steroids for that 3-month period.

Robert H.I. Andtbacka, MD, CM: I guess then, back to your point, would you ever use monotherapy BRAF treatment?

Georgina Long, MD: No.

Robert H.I. Andtbacka, MD, CM: Anyone else use monotherapy?

Michael A. Postow, MD: No.

Michael A. Davies, MD, PhD: No.

Antoni Ribas, MD, PhD: No.

Robert H.I. Andtbacka, MD, CM: So, we have consensus here among the melanoma experts: no monotherapy with BRAF.

Georgina Long, MD: And don’t dose reduce. Use other strategies, do not dose reduce.

Michael A. Postow, MD: And no monotherapy with a MEK inhibitor either. BRAF is the important drug in the combination, but, certainly, you have added efficacy with adding MEK to the BRAF.

Robert H.I. Andtbacka, MD, CM: What about the duration of therapy? How long do we treat with the combination BRAF/MEK therapy for this?

Georgina Long, MD: I’m happy to quickly deal with this because we have a little bit of data on that, and it tends to be continuous, for as long as it’s tolerated and the patients haven’t progressed. Unlike what we saw with the phase I KEYNOTE-001 pembrolizumab data, what we have seen generally—and it’s not as large of a data set as the KEYNOTE-001—is that if you have a complete response on dabrafenib and trametinib or a BRAF/MEK combination and you stop, small numbers consistently have all shown that about 50% of patients will recur. And it tends to recur in the first 3 months. There’s no doubt that there is half of them that have a CR that you don’t need the treatment, but we can’t pick them. So, we end up just continuing treatment.

Robert H.I. Andtbacka, MD, CM: Mike, when would you switch over to immunotherapy for these patients who have BRAF mutations who are on a BRAF/MEK combination? When do you switch to immunotherapy for them?

Michael A. Davies, MD, PhD: Honestly, I don’t know. I think that that’s probably the honest answer is that, again, we’ve talked about the fact that although there’s a rationale for this, we don’t know. One thing I would say is that we don’t have data in this space, but I know I’ve had patients who were on targeted therapy with a BRAF or BRAF/MEK inhibitor who progressed. They went on to immunotherapy, responded quite nicely, but then progressed. And, in those patients, we’ve re-challenged with targeted therapy and often have gotten very nice responses. And so, this interesting phenomenon that the resistance selected with continuous treatment, if the patients go off to a different therapy, it’s not clear that that resistant phenotype is there anymore. So, it is actually possible to go back to that therapy, and it’s challenging a lot of the dogma that we’ve had, as we have both effective targeted therapies and immune therapies. Do you really treat with an agent all the way to resistance or do you switch as your question suggested?

And I have to say, at this point, I don’t know that anybody has a correct answer for that question. I will say that one of the things that’s quite challenging is I have seen some patients who have gotten to a complete response, and then have been switched to immune therapy where there’s really nothing to follow to let you know if the immune therapy is helping at that point or not. And I think that that’s a very challenging way to manage a patient in terms of knowing what to do. So, again, at this point with the data that we have about patients who have achieved a complete response with targeted therapy or the more follow-up we have, it’s becoming very clear that many of those patients are doing well for a very long time, and at this point are continuing on treatment. For patients who achieve a CR, I’m certainly keeping those patients on targeted therapy. I think when we see patients who have a very nice initial response but then somewhat plateau, there’s the question of whether or not that’s a window of time to change. But, again, it’s a data-free zone, which really goes again back to the gestalt question of how you feel with those patients.

The other thing I would say is I have had patients who, for one reason or another, have really wanted to make that switch. I have had some patients who have then subsequently responded quite nicely to immunotherapy, and other ones who have not responded at all. And so, there’s a real heterogeneity there that we really don’t understand at this point.

Transcript Edited for Clarity
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Transcript:

Robert H.I. Andtbacka, MD, CM:
In terms of the BRAF/MEK combinations that we have, we have 2 approved combinations: dabrafenib and trametinib versus vemurafenib and cobimetinib. I’d like to take a few moments to talk about choosing one over the other, in terms of response, but also in terms of toxicity. Are there certain patient features that make you choose one over the other? Tony, which one should we choose?

Antoni Ribas, MD, PhD: We’ll go back to the obvious, which is we don’t have randomized data. We cannot answer that.

Robert H.I. Andtbacka, MD, CM: We never compared them head to head.

Antoni Ribas, MD, PhD: I think there’s got to be a comparison head to head. I don’t think anybody will do that. The totality of the data suggest they are very similar combinations. The dabrafenib/trametinib and vemurafenib/cobimetinib give roughly the same rate of responses, and the progression-free survival, and overall survival seems to be within the margin of error of clinical trials. They do have some peculiar toxicities that are different, even though they’re both BRAF and MEK inhibitors, and when they’re given together, the theory is that some of the side effects go down. The side effects that are induced by BRAF inhibitors inducing paradoxical MAP kinase activation are decreased with the MEK inhibitor.

Robert H.I. Andtbacka, MD, CM: Which ones are those, Tony? Can you give some examples?

Antoni Ribas, MD, PhD: Skin rashes go down, as do joint pains, which are induced by the BRAF inhibitor acting on cells that are wild type for BRAF. They have normal BRAF mutations, but the BRAF inhibitor binding to the wild-type BRAF transactivates the MAP kinase signaling. In the skin and in the joints, it leads to side effects. Then, the BRAF inhibitor decreases one of the main side effects from the MEK inhibitor, which is acneiform skin rash, something I don’t think we have a direct explanation for. But, that’s a socially limiting toxicity for MEK inhibitors that decreases in frequency when given together with a BRAF inhibitor. So, those toxicities seem to go side by side with the 2 pairs. But, whenever vemurafenib is used, it has a peculiar toxicity, which is being photosensitive where patients can have sunburns with minimal sun exposure. In southern California where I practice, and maybe more where Georgina practices, these patients try to avoid the sun continuously, and they have to be covered all the time. Even indirect sun can lead to a sunburn, which is something that makes them change their lifestyle. But, if we go to the other combination, dabrafenib/trametinib, dabrafenib brings a very peculiar toxicity, which is fever and sometimes hypertension. Fevers can be high, there can be chills, and they can happen at any time. So, those are patients that may live their life worrying whether that would happen in a situation where it would be unwanted or that this toxicity may lead to having to adjust doses. Georgina was one of the first investigators working with dabrafenib and dabrafenib/trametinib, but has come up with a series of ways to mitigate that. But, it continues to be an effect that is limiting to patients.

So, if I see a patient where we’re going to decide to start a BRAF plus MEK inhibitor, I talk about both combinations. We go over the pros and cons of each one of them. Honestly, I still haven’t made up my mind which one to use.

Michael A. Davies, MD, PhD: The one thing, just to add to that, is that in addition to the combination reducing the risk of rash that we see with single-agent BRAF inhibitor, the other side effects that have decreased are the cutaneous squamous cell carcinomas or keretoacanthomas. They are also significantly decreased with the combination.

Robert H.I. Andtbacka, MD, CM: Georgina, Tony mentioned that you worked with dabrafenib and got a way to mitigate this toxicity. So, tell us a bit about what you tell patients if they have some of these toxicities. How do you mitigate them? Dose reductions? Switching therapies?

Georgina Long, MD: Dabrafenib and trametinib—with the fever, first of all, we know that dose reduction actually does not help, but an intermittent treatment strategy may. Having said that, we’ve not prospectively proven that intermittent—so a full dose for a number of weeks or a few days and then off, going on/off, on/off—actually is better than continuous dosing in humans. We have not proven that. But, the concept and the hypothesis is that we are inhibiting the MAP kinase pathway, so if you’re going to bother to inhibit it, to stop the cell from dividing and causing apoptosis or death of the cell, do it properly. And we already know that from our randomized trials that with single-agent BRAF, you add 1 mg of trametinib onto dabrafenib, it improves things a bit. But, if you add 2 mg of trametinib, it’s even better. So, we do know that there is a dose response with inhibition of the MAP kinase pathway. I avoid dose reductions at all costs. I’m happy to do some intermittent treatment, but, ultimately I would like to keep the MAP kinase properly inhibited for as long as possible. And sometimes, we have to revert to steroids in a small number of patients. Often though, if you can get patients through the first 3 to 5 months where they’ve had quite significant fevers, you can then start to withdraw the steroids. It’s really only 10% to 20% of patients where you actually have to use steroids for that 3-month period.

Robert H.I. Andtbacka, MD, CM: I guess then, back to your point, would you ever use monotherapy BRAF treatment?

Georgina Long, MD: No.

Robert H.I. Andtbacka, MD, CM: Anyone else use monotherapy?

Michael A. Postow, MD: No.

Michael A. Davies, MD, PhD: No.

Antoni Ribas, MD, PhD: No.

Robert H.I. Andtbacka, MD, CM: So, we have consensus here among the melanoma experts: no monotherapy with BRAF.

Georgina Long, MD: And don’t dose reduce. Use other strategies, do not dose reduce.

Michael A. Postow, MD: And no monotherapy with a MEK inhibitor either. BRAF is the important drug in the combination, but, certainly, you have added efficacy with adding MEK to the BRAF.

Robert H.I. Andtbacka, MD, CM: What about the duration of therapy? How long do we treat with the combination BRAF/MEK therapy for this?

Georgina Long, MD: I’m happy to quickly deal with this because we have a little bit of data on that, and it tends to be continuous, for as long as it’s tolerated and the patients haven’t progressed. Unlike what we saw with the phase I KEYNOTE-001 pembrolizumab data, what we have seen generally—and it’s not as large of a data set as the KEYNOTE-001—is that if you have a complete response on dabrafenib and trametinib or a BRAF/MEK combination and you stop, small numbers consistently have all shown that about 50% of patients will recur. And it tends to recur in the first 3 months. There’s no doubt that there is half of them that have a CR that you don’t need the treatment, but we can’t pick them. So, we end up just continuing treatment.

Robert H.I. Andtbacka, MD, CM: Mike, when would you switch over to immunotherapy for these patients who have BRAF mutations who are on a BRAF/MEK combination? When do you switch to immunotherapy for them?

Michael A. Davies, MD, PhD: Honestly, I don’t know. I think that that’s probably the honest answer is that, again, we’ve talked about the fact that although there’s a rationale for this, we don’t know. One thing I would say is that we don’t have data in this space, but I know I’ve had patients who were on targeted therapy with a BRAF or BRAF/MEK inhibitor who progressed. They went on to immunotherapy, responded quite nicely, but then progressed. And, in those patients, we’ve re-challenged with targeted therapy and often have gotten very nice responses. And so, this interesting phenomenon that the resistance selected with continuous treatment, if the patients go off to a different therapy, it’s not clear that that resistant phenotype is there anymore. So, it is actually possible to go back to that therapy, and it’s challenging a lot of the dogma that we’ve had, as we have both effective targeted therapies and immune therapies. Do you really treat with an agent all the way to resistance or do you switch as your question suggested?

And I have to say, at this point, I don’t know that anybody has a correct answer for that question. I will say that one of the things that’s quite challenging is I have seen some patients who have gotten to a complete response, and then have been switched to immune therapy where there’s really nothing to follow to let you know if the immune therapy is helping at that point or not. And I think that that’s a very challenging way to manage a patient in terms of knowing what to do. So, again, at this point with the data that we have about patients who have achieved a complete response with targeted therapy or the more follow-up we have, it’s becoming very clear that many of those patients are doing well for a very long time, and at this point are continuing on treatment. For patients who achieve a CR, I’m certainly keeping those patients on targeted therapy. I think when we see patients who have a very nice initial response but then somewhat plateau, there’s the question of whether or not that’s a window of time to change. But, again, it’s a data-free zone, which really goes again back to the gestalt question of how you feel with those patients.

The other thing I would say is I have had patients who, for one reason or another, have really wanted to make that switch. I have had some patients who have then subsequently responded quite nicely to immunotherapy, and other ones who have not responded at all. And so, there’s a real heterogeneity there that we really don’t understand at this point.

Transcript Edited for Clarity
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