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Options for NRAS-Mutant Melanoma

Panelists: Jeffrey S. Weber, MD, PhD, NYU Langone Medical Center; Robert H. I. Andtbacka, MD, CM, Huntsman Cancer Institute; Georgina Long, MD, PhD, Melanoma Institute of Australia at the University of Sydney; Michael A. Davies, MD, PhD, University of Texas MD Anderson Cancer Center; Jason J. Luke, MD, University of Chicago
Published: Wednesday, Jul 19, 2017



Transcript:

Jeffrey S. Weber, MD, PhD:
What can you tell us about managing the toxicities of the BRAF/MEK inhibitor combinations? There are 3 of them that are out there: 2 combinations are approved; 1 is still in the experimental investigational trials. We know lots about treating ipilimumab, nivolumab, and pembrolizumab toxicity, but what can you tell us about treating the toxicity of patients who get BRAF/MEK inhibitors?

Jason J. Luke, MD: It’s worth understanding the differences between these 2 approved and 1 coming combinations, because it can really come down to a patient-level selection about which toxicities they might be more prone to or would be more worrisome in terms of choosing. So, for the combination of dabrafenib and trametinib, which was the first combination that was approved, the major toxicity that I think of and I think most think of is the pyrexia syndrome, or fever syndrome, that patients can have. It can range from chills all the way up to relapsing fevers at 105°.

Really, that’s the one I’m mostly looking for, and what I tell my patients is that for any signs of disproportionate fatigue, definitely fever, or anything, just stop taking the drugs. Call our clinic and let us know. And usually, if we let it wash out, the patient can restart and do quite well. I really reinforce the idea that a couple of days off the drug is going to have no impact whatsoever on whether or not the drug works, and that’s really important for them to understand.

In the vemurafenib and cobimetinib combinations, toxicities are slightly different. We see more cutaneous toxicities associated with vemurafenib, as well as some more GI toxicities. So, again, how these might play with comorbid disease in any individual patient is really important to take home. The final combination of encorafenib and binimetinib is likely to be coming in the relatively near future. There’s a little bit of pyrexia in both and a little bit of these other side effects, although I have to say, based on the data that we’ve seen so far, it looks like that regimen doesn’t quite have the more obvious toxicities we’re going to look for. I think broadly speaking, they’re going to look fairly similar in terms of their benefits, so choosing one for an individual patient will come down to knowing that patient and knowing what other comorbidities they might have to be on the lookout for.

Jeffrey S. Weber, MD, PhD: Let’s go back to Mike, because another issue is not just BRAF-mutated melanoma. There’s also another common mutation, the NRAS mutation, in maybe 15% or 20% of metastatic patients. Do you routinely look at your patients who are NRAS-mutated and try to pick NRAS-mutated specific therapy for them, or do you lump them in with the BRAF wild-type population?

Michael A. Davies, MD, PhD: Just before I talk about that, one other test that I do think is worth considering, particularly in patients with acral lentiginous melanoma or mucosal melanoma, is to look for c-KIT mutations. Because we do know that those subtypes and cutaneous melanomas, at a lower rate, can have targetable c-KIT mutations, and there’s very good documentation of the response rates ranging from 10% to 50%, depending on the common mutations that are present. And so, in our molecular testing, that’s the other mutation that we consider looking for. It’s very clear that NRAS mutations are a driver of growth in melanoma. That’s supported quite well by functional studies.

The challenge we have in melanoma, like all other diseases, is how to overcome it. It’s really a struggle that goes across all different types of cancer. So, at this point, there have been clinical trials showing that MEK inhibitor therapy actually has superior response rates and slight improvement in progression-free survival versus chemotherapy, but they did not result in a benefit in overall survival. And indeed, those differences were relatively small and transient. I do think that there’s probably a rationale for clinical trials moving forward with a MEK inhibitor backbone combined with other agents.

The other interesting data that are out there that have been reported by a couple different groups, including our own, involve patients with NRAS mutations seeming to have better outcomes with immunotherapy than patients with a BRAF mutation or other genotypes. It may be related to total mutation burden overall being somewhat higher in those patients, but it’s one of those things where, to be honest, when we see an NRAS mutation, even though we know we don’t have a great targeted therapy option for those patients, we’re actually quite optimistic about immunotherapy working in those patients.

Jeffrey S. Weber, MD, PhD: So, you think not only does immunotherapy work in those patients, but it also works better than in non-NRAS-mutated patients. Do you think you have enough patients to make that conclusion?

Michael A Davies, MD, PhD: Well, I think that it’s, at this point, data that are intriguing. And it was really quite surprising. So, data we had seen before were that before the era of the common immunotherapies, when we looked at overall survival in patients with stage 4 disease, we had seen that both patients with BRAF mutations and with NRAS mutations had worse overall survival in stage 4 compared with the BRAF/NRAS wild-type patients. We saw a marked shift in the outcomes of the BRAF patients with the onset of the BRAF-targeted therapies. And so, with our historical database of outcomes with chemotherapy and biochemotherapy, it was pretty striking that the NRAS patients were doing worse. Actually, this observation that we’ve seen with interleukin-2 and that other groups have seen with checkpoint inhibitors that suggests the NRAS patients are doing better was promising, if not absolutely definitive.

Georgina Long, MD, PhD: Just to support that, at ASCO this year, we looked at V600E versus V600K mutations, and biologically, they’re very different. With immunotherapy, patients with the V600K mutation did a heap better than patients with the V600E mutation. We know from the clinical trials that the reverse is true for V600K and E4, BRAF, and MEK inhibitors.

Jeffrey S. Weber, MD, PhD: And what is your explanation?

Georgina Long, MD, PhD: Again, the V600K mutation, similar to NRAS mutation associated with chronic sun damage, has high mutational burden. And the genetic profile of these tumors—they have a lot more other somatic mutations in the tumors, but they do extremely well with immune therapies.

Jeffrey S. Weber, MD, PhD: Back to Robert. You have the broad perspective on melanoma therapy, in my view. Do you see NRAS-mutated therapies or therapies specific for the NRAS-mutated population coming up in the future? Meaning, will there be a trial that will develop with a registration strategy that’s going to get these drugs approved by the FDA?

Robert H.I. Andtbacka, MD, CM: I think there may be, but I think that we’re still very early in all of that to determine what drugs we are going to use, how effective they are going to be, if we are going to use monotherapy for those, and if they will be in combination—and if so, what combination will be used. I think back to Mike’s point earlier, as well: Will this be a combination of the targeted therapy as well as immunotherapy in this setting, since we know that these patients may respond a bit better to immunotherapy? So, I think that we don’t yet know where we stand with this.

There’s an additional point that I’d like to add, which Jason actually touched on here. I think that we’re talking about targeted therapy, and we’re talking about the majority of patients responding very well to the BRAF/MEK inhibitor combinations. But I think what we see, or what I see increasingly as a surgeon, is that the majority of lesions are responding, but then you have clonal selection and 1 area that is then growing. The question then becomes, what do we do at that point in time? And we are increasingly doing a surgical resection of those clones that are growing and then continuing the therapy. The other thing to think about is to switch therapy at that point in time—and switch to immunotherapy.

Additionally, we also have clinical trials ongoing right now trying to answer the question: Should we have continuous treatment for BRAF/MEK therapy, or do we need to cycle this and have intermittent treatment? There’s a SWOG trial ongoing right now looking at continuous therapy versus intermittent therapy, so I think there are many questions in terms of the potential resistance and how we deal with that for these patients.

Jeffrey S. Weber, MD, PhD: The final issue with BRAF/MEK inhibition is whether or not it’s active in the brain. Actually, Mike presented some very nice data today. So, why don’t you tell us, if you see a patient with mutation and brain metastases, will you want to put them on BRAF/MEK inhibition, or would you want to put them, in view of data that we’ll discuss later also presented in your session, on immunotherapy?

Michael A. Davies, MD, PhD: As not to spoil the data we’ll talk about later, the results we presented today were from the COMBI-MB study, a phase II trial of patients with BRAF-mutant metastatic melanoma with brain metastases. And we treated different cohorts of patients, depending on what type of BRAF mutation they had and whether or not they’d had prior therapies directed to the brain. What we saw consistently across those groups was a very high initial response rate—response rates in the 60% range—and disease control rates of approximately 80%.

These are actually very comparable to what we’ve seen in patients with extracranial disease, albeit a little bit lower. What was striking, though, is that the duration of the responses we saw in the patients with brain metastases, and specifically in the brain metastases, were much shorter than what we’ve seen in other clinical trials with dabrafenib/trametinib. So, on average, the duration of response we were seeing with dabrafenib/trametinib was about 6 months, as opposed to approximately 12 months that we’ve seen in trials of patients with extracranial disease only.

I think there’s a clear signal of activity there, but there clearly is something different about the activity of dabrafenib/trametinib in brain metastases, compared with extracranial disease. That was even seen within the patients within the trial. The most common pattern of progression was progression in the brain only—without progressing outside of the brain. The real question that we have to figure out is what it is that’s driving that differential response and how do we build upon these results to do better.

Transcript Edited for Clarity

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Transcript:

Jeffrey S. Weber, MD, PhD:
What can you tell us about managing the toxicities of the BRAF/MEK inhibitor combinations? There are 3 of them that are out there: 2 combinations are approved; 1 is still in the experimental investigational trials. We know lots about treating ipilimumab, nivolumab, and pembrolizumab toxicity, but what can you tell us about treating the toxicity of patients who get BRAF/MEK inhibitors?

Jason J. Luke, MD: It’s worth understanding the differences between these 2 approved and 1 coming combinations, because it can really come down to a patient-level selection about which toxicities they might be more prone to or would be more worrisome in terms of choosing. So, for the combination of dabrafenib and trametinib, which was the first combination that was approved, the major toxicity that I think of and I think most think of is the pyrexia syndrome, or fever syndrome, that patients can have. It can range from chills all the way up to relapsing fevers at 105°.

Really, that’s the one I’m mostly looking for, and what I tell my patients is that for any signs of disproportionate fatigue, definitely fever, or anything, just stop taking the drugs. Call our clinic and let us know. And usually, if we let it wash out, the patient can restart and do quite well. I really reinforce the idea that a couple of days off the drug is going to have no impact whatsoever on whether or not the drug works, and that’s really important for them to understand.

In the vemurafenib and cobimetinib combinations, toxicities are slightly different. We see more cutaneous toxicities associated with vemurafenib, as well as some more GI toxicities. So, again, how these might play with comorbid disease in any individual patient is really important to take home. The final combination of encorafenib and binimetinib is likely to be coming in the relatively near future. There’s a little bit of pyrexia in both and a little bit of these other side effects, although I have to say, based on the data that we’ve seen so far, it looks like that regimen doesn’t quite have the more obvious toxicities we’re going to look for. I think broadly speaking, they’re going to look fairly similar in terms of their benefits, so choosing one for an individual patient will come down to knowing that patient and knowing what other comorbidities they might have to be on the lookout for.

Jeffrey S. Weber, MD, PhD: Let’s go back to Mike, because another issue is not just BRAF-mutated melanoma. There’s also another common mutation, the NRAS mutation, in maybe 15% or 20% of metastatic patients. Do you routinely look at your patients who are NRAS-mutated and try to pick NRAS-mutated specific therapy for them, or do you lump them in with the BRAF wild-type population?

Michael A. Davies, MD, PhD: Just before I talk about that, one other test that I do think is worth considering, particularly in patients with acral lentiginous melanoma or mucosal melanoma, is to look for c-KIT mutations. Because we do know that those subtypes and cutaneous melanomas, at a lower rate, can have targetable c-KIT mutations, and there’s very good documentation of the response rates ranging from 10% to 50%, depending on the common mutations that are present. And so, in our molecular testing, that’s the other mutation that we consider looking for. It’s very clear that NRAS mutations are a driver of growth in melanoma. That’s supported quite well by functional studies.

The challenge we have in melanoma, like all other diseases, is how to overcome it. It’s really a struggle that goes across all different types of cancer. So, at this point, there have been clinical trials showing that MEK inhibitor therapy actually has superior response rates and slight improvement in progression-free survival versus chemotherapy, but they did not result in a benefit in overall survival. And indeed, those differences were relatively small and transient. I do think that there’s probably a rationale for clinical trials moving forward with a MEK inhibitor backbone combined with other agents.

The other interesting data that are out there that have been reported by a couple different groups, including our own, involve patients with NRAS mutations seeming to have better outcomes with immunotherapy than patients with a BRAF mutation or other genotypes. It may be related to total mutation burden overall being somewhat higher in those patients, but it’s one of those things where, to be honest, when we see an NRAS mutation, even though we know we don’t have a great targeted therapy option for those patients, we’re actually quite optimistic about immunotherapy working in those patients.

Jeffrey S. Weber, MD, PhD: So, you think not only does immunotherapy work in those patients, but it also works better than in non-NRAS-mutated patients. Do you think you have enough patients to make that conclusion?

Michael A Davies, MD, PhD: Well, I think that it’s, at this point, data that are intriguing. And it was really quite surprising. So, data we had seen before were that before the era of the common immunotherapies, when we looked at overall survival in patients with stage 4 disease, we had seen that both patients with BRAF mutations and with NRAS mutations had worse overall survival in stage 4 compared with the BRAF/NRAS wild-type patients. We saw a marked shift in the outcomes of the BRAF patients with the onset of the BRAF-targeted therapies. And so, with our historical database of outcomes with chemotherapy and biochemotherapy, it was pretty striking that the NRAS patients were doing worse. Actually, this observation that we’ve seen with interleukin-2 and that other groups have seen with checkpoint inhibitors that suggests the NRAS patients are doing better was promising, if not absolutely definitive.

Georgina Long, MD, PhD: Just to support that, at ASCO this year, we looked at V600E versus V600K mutations, and biologically, they’re very different. With immunotherapy, patients with the V600K mutation did a heap better than patients with the V600E mutation. We know from the clinical trials that the reverse is true for V600K and E4, BRAF, and MEK inhibitors.

Jeffrey S. Weber, MD, PhD: And what is your explanation?

Georgina Long, MD, PhD: Again, the V600K mutation, similar to NRAS mutation associated with chronic sun damage, has high mutational burden. And the genetic profile of these tumors—they have a lot more other somatic mutations in the tumors, but they do extremely well with immune therapies.

Jeffrey S. Weber, MD, PhD: Back to Robert. You have the broad perspective on melanoma therapy, in my view. Do you see NRAS-mutated therapies or therapies specific for the NRAS-mutated population coming up in the future? Meaning, will there be a trial that will develop with a registration strategy that’s going to get these drugs approved by the FDA?

Robert H.I. Andtbacka, MD, CM: I think there may be, but I think that we’re still very early in all of that to determine what drugs we are going to use, how effective they are going to be, if we are going to use monotherapy for those, and if they will be in combination—and if so, what combination will be used. I think back to Mike’s point earlier, as well: Will this be a combination of the targeted therapy as well as immunotherapy in this setting, since we know that these patients may respond a bit better to immunotherapy? So, I think that we don’t yet know where we stand with this.

There’s an additional point that I’d like to add, which Jason actually touched on here. I think that we’re talking about targeted therapy, and we’re talking about the majority of patients responding very well to the BRAF/MEK inhibitor combinations. But I think what we see, or what I see increasingly as a surgeon, is that the majority of lesions are responding, but then you have clonal selection and 1 area that is then growing. The question then becomes, what do we do at that point in time? And we are increasingly doing a surgical resection of those clones that are growing and then continuing the therapy. The other thing to think about is to switch therapy at that point in time—and switch to immunotherapy.

Additionally, we also have clinical trials ongoing right now trying to answer the question: Should we have continuous treatment for BRAF/MEK therapy, or do we need to cycle this and have intermittent treatment? There’s a SWOG trial ongoing right now looking at continuous therapy versus intermittent therapy, so I think there are many questions in terms of the potential resistance and how we deal with that for these patients.

Jeffrey S. Weber, MD, PhD: The final issue with BRAF/MEK inhibition is whether or not it’s active in the brain. Actually, Mike presented some very nice data today. So, why don’t you tell us, if you see a patient with mutation and brain metastases, will you want to put them on BRAF/MEK inhibition, or would you want to put them, in view of data that we’ll discuss later also presented in your session, on immunotherapy?

Michael A. Davies, MD, PhD: As not to spoil the data we’ll talk about later, the results we presented today were from the COMBI-MB study, a phase II trial of patients with BRAF-mutant metastatic melanoma with brain metastases. And we treated different cohorts of patients, depending on what type of BRAF mutation they had and whether or not they’d had prior therapies directed to the brain. What we saw consistently across those groups was a very high initial response rate—response rates in the 60% range—and disease control rates of approximately 80%.

These are actually very comparable to what we’ve seen in patients with extracranial disease, albeit a little bit lower. What was striking, though, is that the duration of the responses we saw in the patients with brain metastases, and specifically in the brain metastases, were much shorter than what we’ve seen in other clinical trials with dabrafenib/trametinib. So, on average, the duration of response we were seeing with dabrafenib/trametinib was about 6 months, as opposed to approximately 12 months that we’ve seen in trials of patients with extracranial disease only.

I think there’s a clear signal of activity there, but there clearly is something different about the activity of dabrafenib/trametinib in brain metastases, compared with extracranial disease. That was even seen within the patients within the trial. The most common pattern of progression was progression in the brain only—without progressing outside of the brain. The real question that we have to figure out is what it is that’s driving that differential response and how do we build upon these results to do better.

Transcript Edited for Clarity
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