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Treating Melanoma Patients With BRAF/MEK Dual-Targeted Therapy

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: Monday, May 13, 2019



Transcript:

Ryan J. Sullivan, MD: I was an investigator on the phase I trial of the combination of encorafenib and binimetinib. And so I’ve seen the adverse effects in the efficacy outcomes from all hosts of the various different doses of encorafenib with binimetinib. I’ve seen as low as 50 mg a day and I’ve seen as high as 800 mg a day. And the data that we generated on the phase I study and the phase II study led to the phase III trial, which has been pretty consistent throughout. As you get to higher doses, there’s definitely more toxicity.

The dose that was settled upon was actually going to be 1 of 2 doses—either 600 mg a day or 450 mg a day—both of which are, are significantly higher than the 300 mg a day that was tolerated as a single agent. The reason that the single agent dose is lower is it’s more toxic as a single agent than in combination, which is very interesting. So you can get away with giving more drugs in combination than you could as a single agent.

The other 2 regimens weren’t tested that way, so I can’t say for sure that we couldn’t get away with more dabrafenib or more vemurafenib in combination with, respectively, trametinib and cobimetinib. But using those regimens, I’m not sure you could. But you can get away with more encorafenib in combination than as a single agent.

The adverse-effect profile is pretty consistent. We see definitely fatigue and nausea, and occasionally we see achiness. We occasionally see a rise in liver function testing, and that was seen in phase I, that was seen in phase III. We don’t see the photosensitivity. We don’t tend to see fever, although I’ve had a few develop fever. And we also had seen some pain syndrome. I’ve seen a few patients who had been treated off trial and on label, who have developed discomfort who actually have required dose holds and occasionally dose reductions.

When we use the drug after patients have already been on a BRAF-targeted therapy, sometimes we actually see the same exact toxicity that was problematic with, say, for example, dabrafenib-trametinib. As I mentioned before, dabrafenib-trametinib causes a fair amount of fever. Over 50% of patients will develop fever in the setting in dabrafenib and trametinib. A number of our patients have required drastic dose reductions or dose hesitations or weird kinds of strategies to give them the most drug we think they can tolerate but still potentially have benefit and survive and function.

And what we’ve clearly seen is with encorafenib-binimetinib in patients who’ve had severe febrile syndromes with dabrafenib-trametinib, that some of those patients will develop severe febrile syndromes. It’s as if the dabrafenib and trametinib brought it out in them and that a similar type of drug strategy can cause the same adverse effect that was happening before. We haven’t seen that with photosensitivity; it’s really only been with the fever. But it wasn’t an adverse effect we were expecting. We thought from our experience in the earlier trials, and from the data that have been published in the COLUMBUS study, that fever wasn’t going to be a big deal in it. So it was a little bit interesting and happened more frequently than we would have predicted to see that type of toxicity. It just seemed that some patients who had severe adverse effects from dabrafenib-trametinib were primed to have severe adverse effects from encorafenib-binimetinib, but certainly not all. And we’ve had a number of patients who’ve had a tough time with a different regimen who have done well with that regimen.

Geoffrey Thomas Gibney, MD: The use of BRAF-targeted therapy in frontline BRAF-mutant melanoma patients, I have seen in my experience to be very effective. This includes encorafenib-binimetinib, dabrafenib-trametinib, and vemurafenib-cobimetinib. All 3 regimens have been studied in the frontline. We know response rates can be very high, up to 70%. In my experience, I’ve seen very similar results. The question has been the durability. But this has been a very effective strategy for patients as a frontline option or at least 1 of the options that we now have available for patients.

Hussein A. Tawbi, MD: When we prescribe encorafenib and binimetinib for patients with BRAF-mutated melanoma in the first-line setting, you know my current experience with that particular population is that they do seem to have more tolerance for this combination than my experience has been with dabrafenib and trametinib, mostly because, again, the fevers are much less significant. We still experience some fevers, and we still need to do some dose interruptions, but they seem to be easier to tolerate. I think my patients have indicated to me a couple of things that they particularly like about that combination. One is actually the fact that they don’t have to refrigerate the MEK inhibitor, which really makes it easier for them to travel and other things.

The other piece is that they don’t have to be fasting when they take their medications, which are 2 issues that kind of affect the quality of life I would say of patients. And then kind of just how they manage their own treatment.

On the other hand, you know there are some issues that people bring up. One is actually that some adverse effects are related to vision. So patients do have some blurry vision really early on in their treatment. And that can obviously make a patient quite concerned, because you know they’re not seeing as clearly as they normally do. So our experience with this has been that the vast majority of patients actually do relatively well. Sometimes we don’t even have to hold the drugs, and that just kind of improves on its own over a couple of weeks.

But the other thing that patients do bring up that may be a challenge with this combination is the fact that they have to take a lot of pills to be able to get the effective dose. But all in all it seems to be a well-tolerated combination that seems to have potentially a more effective profile as well. So we have been using it more frequently in this population.

Geoffrey Thomas Gibney, MD: The agents that I’ve used include encorafenib-binimetinib, as well as dabrafenib-trametinib and vemurafenib-cobimetinib strategies. In the second line I’ve seen these to be very effective, and tolerability is similar to what we see in the frontline setting. Now when we do have a patient on 1 of the BRAF/MEK combinations, as I alluded to previously, there can be adverse effects that arise regarding dose modification or interruption. There are some scenarios in which it would make sense to try an alternative BRAF/MEK inhibitor combination. For example, if a patient is having significant pyrexia or photosensitivity with 1 of the earlier approved regimens, switching to a regimen with encorafenib-binimetinib may be more successful in the sense that there are fewer adverse effects related to pyrexia or photosensitivity. Now patients on encorafenib and binimetinib still can have adverse effects, and the patients still need to be monitored vigilantly, even switching between the BRAF classes.

Hussein A. Tawbi, MD: With the approval of encorafenib and binimetinib, and now having a new combination in our hands, we actually have sometimes switched patients who have already been on other combinations like dabrafenib-trametinib or vemurafenib and cobimetinib. But I have to say that I’ve only done that in the setting of patients who have experienced kind of significant toxicities and were either at really low doses of the other BRAF/MEK inhibitors, which is always uncomfortable to an oncologist—you know, that if you’re giving a lower dose, you may be kind of breeding resistance or getting less efficacy. So for those patients, we’ve made the switch, and I have to say that it’s been a bit more tolerated. I wouldn’t say that it wasn’t 100% always across the board; it’s an easier thing to handle. But I’ve had patients who were on less than half the dose of BRAF and MEK inhibitors who have managed now to get full dose on this, which obviously we really like. But there are some patients who have experienced equally challenging toxicities as well. So it’s, I think, it’s a reasonable strategy, but it’s not going to work 100% of the time.

Transcript Edited for Clarity.
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Transcript:

Ryan J. Sullivan, MD: I was an investigator on the phase I trial of the combination of encorafenib and binimetinib. And so I’ve seen the adverse effects in the efficacy outcomes from all hosts of the various different doses of encorafenib with binimetinib. I’ve seen as low as 50 mg a day and I’ve seen as high as 800 mg a day. And the data that we generated on the phase I study and the phase II study led to the phase III trial, which has been pretty consistent throughout. As you get to higher doses, there’s definitely more toxicity.

The dose that was settled upon was actually going to be 1 of 2 doses—either 600 mg a day or 450 mg a day—both of which are, are significantly higher than the 300 mg a day that was tolerated as a single agent. The reason that the single agent dose is lower is it’s more toxic as a single agent than in combination, which is very interesting. So you can get away with giving more drugs in combination than you could as a single agent.

The other 2 regimens weren’t tested that way, so I can’t say for sure that we couldn’t get away with more dabrafenib or more vemurafenib in combination with, respectively, trametinib and cobimetinib. But using those regimens, I’m not sure you could. But you can get away with more encorafenib in combination than as a single agent.

The adverse-effect profile is pretty consistent. We see definitely fatigue and nausea, and occasionally we see achiness. We occasionally see a rise in liver function testing, and that was seen in phase I, that was seen in phase III. We don’t see the photosensitivity. We don’t tend to see fever, although I’ve had a few develop fever. And we also had seen some pain syndrome. I’ve seen a few patients who had been treated off trial and on label, who have developed discomfort who actually have required dose holds and occasionally dose reductions.

When we use the drug after patients have already been on a BRAF-targeted therapy, sometimes we actually see the same exact toxicity that was problematic with, say, for example, dabrafenib-trametinib. As I mentioned before, dabrafenib-trametinib causes a fair amount of fever. Over 50% of patients will develop fever in the setting in dabrafenib and trametinib. A number of our patients have required drastic dose reductions or dose hesitations or weird kinds of strategies to give them the most drug we think they can tolerate but still potentially have benefit and survive and function.

And what we’ve clearly seen is with encorafenib-binimetinib in patients who’ve had severe febrile syndromes with dabrafenib-trametinib, that some of those patients will develop severe febrile syndromes. It’s as if the dabrafenib and trametinib brought it out in them and that a similar type of drug strategy can cause the same adverse effect that was happening before. We haven’t seen that with photosensitivity; it’s really only been with the fever. But it wasn’t an adverse effect we were expecting. We thought from our experience in the earlier trials, and from the data that have been published in the COLUMBUS study, that fever wasn’t going to be a big deal in it. So it was a little bit interesting and happened more frequently than we would have predicted to see that type of toxicity. It just seemed that some patients who had severe adverse effects from dabrafenib-trametinib were primed to have severe adverse effects from encorafenib-binimetinib, but certainly not all. And we’ve had a number of patients who’ve had a tough time with a different regimen who have done well with that regimen.

Geoffrey Thomas Gibney, MD: The use of BRAF-targeted therapy in frontline BRAF-mutant melanoma patients, I have seen in my experience to be very effective. This includes encorafenib-binimetinib, dabrafenib-trametinib, and vemurafenib-cobimetinib. All 3 regimens have been studied in the frontline. We know response rates can be very high, up to 70%. In my experience, I’ve seen very similar results. The question has been the durability. But this has been a very effective strategy for patients as a frontline option or at least 1 of the options that we now have available for patients.

Hussein A. Tawbi, MD: When we prescribe encorafenib and binimetinib for patients with BRAF-mutated melanoma in the first-line setting, you know my current experience with that particular population is that they do seem to have more tolerance for this combination than my experience has been with dabrafenib and trametinib, mostly because, again, the fevers are much less significant. We still experience some fevers, and we still need to do some dose interruptions, but they seem to be easier to tolerate. I think my patients have indicated to me a couple of things that they particularly like about that combination. One is actually the fact that they don’t have to refrigerate the MEK inhibitor, which really makes it easier for them to travel and other things.

The other piece is that they don’t have to be fasting when they take their medications, which are 2 issues that kind of affect the quality of life I would say of patients. And then kind of just how they manage their own treatment.

On the other hand, you know there are some issues that people bring up. One is actually that some adverse effects are related to vision. So patients do have some blurry vision really early on in their treatment. And that can obviously make a patient quite concerned, because you know they’re not seeing as clearly as they normally do. So our experience with this has been that the vast majority of patients actually do relatively well. Sometimes we don’t even have to hold the drugs, and that just kind of improves on its own over a couple of weeks.

But the other thing that patients do bring up that may be a challenge with this combination is the fact that they have to take a lot of pills to be able to get the effective dose. But all in all it seems to be a well-tolerated combination that seems to have potentially a more effective profile as well. So we have been using it more frequently in this population.

Geoffrey Thomas Gibney, MD: The agents that I’ve used include encorafenib-binimetinib, as well as dabrafenib-trametinib and vemurafenib-cobimetinib strategies. In the second line I’ve seen these to be very effective, and tolerability is similar to what we see in the frontline setting. Now when we do have a patient on 1 of the BRAF/MEK combinations, as I alluded to previously, there can be adverse effects that arise regarding dose modification or interruption. There are some scenarios in which it would make sense to try an alternative BRAF/MEK inhibitor combination. For example, if a patient is having significant pyrexia or photosensitivity with 1 of the earlier approved regimens, switching to a regimen with encorafenib-binimetinib may be more successful in the sense that there are fewer adverse effects related to pyrexia or photosensitivity. Now patients on encorafenib and binimetinib still can have adverse effects, and the patients still need to be monitored vigilantly, even switching between the BRAF classes.

Hussein A. Tawbi, MD: With the approval of encorafenib and binimetinib, and now having a new combination in our hands, we actually have sometimes switched patients who have already been on other combinations like dabrafenib-trametinib or vemurafenib and cobimetinib. But I have to say that I’ve only done that in the setting of patients who have experienced kind of significant toxicities and were either at really low doses of the other BRAF/MEK inhibitors, which is always uncomfortable to an oncologist—you know, that if you’re giving a lower dose, you may be kind of breeding resistance or getting less efficacy. So for those patients, we’ve made the switch, and I have to say that it’s been a bit more tolerated. I wouldn’t say that it wasn’t 100% always across the board; it’s an easier thing to handle. But I’ve had patients who were on less than half the dose of BRAF and MEK inhibitors who have managed now to get full dose on this, which obviously we really like. But there are some patients who have experienced equally challenging toxicities as well. So it’s, I think, it’s a reasonable strategy, but it’s not going to work 100% of the time.

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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