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Melanoma: BRAF/MEK Targeted Therapy

Panelists:Keith T. Flaherty, MD Massachusetts General Hospital;Georgina Long, BSc, MBBS, FRACP, Melanoma Institute of Australia;Jason J. Luke, MD, FACP, University of Chicago;Jeffrey S. Weber, MD, NYU Langone Medical Center;Jonathan S. Zager, MD, Moffitt Cancer Center
Published: Tuesday, Aug 30, 2016



Transcript:

Keith T. Flaherty, MD:
Georgina, I want to delve in to each of these therapies and their strengths, weaknesses, if you will. We’ll start with BRAF inhibitor–based therapy. We had two BRAF inhibitors on the market as monotherapy with a phase III trial—better than dacarbazine—and MEK inhibitor monotherapy, all in the V600 BRAF-mutant population. Now, there are three randomized phase III trials with pretty mature follow-up at this point with dabrafenib/trametinib and vemurafenib/cobimetinib. So, maybe briefly summarize how you digest the information, how you present it to patients on the strengths of the evidence regarding that therapy. Maybe tuck in there also, are there patients who you still think about BRAF inhibitor monotherapy or is it BRAF/MEK for all?

Georgina Long, BSc, MBBS: Just to answer your last question, the data are very clear. BRAF plus MEK is superior to BRAF inhibitor alone. There is no role for a single-agent BRAF inhibitor. I don’t think I’ve ever given a patient a single-agent BRAF inhibitor with those three randomized trials. So, we’re talking about COMBI-d, dabrafenib/trametinib versus dabrafenib, we’re talking COMBI-v, which is dabrafenib/trametinib versus vemurafenib, and we’re talking coBRIM, which is vemurafenib combined with cobimetinib versus vemurafenib alone.

The amazing thing is that the 1-year and 2-year overall survivals for the combinations in each of those trials was almost exactly the same. We’re talking 74%, 75%, 1-year survival in that group. These are BRAF-mutated patients. Of course, V600 and then a 2-year overall survival are in a pooled analysis of dabrafenib and trametinib; 53% in coBRIM, 48% all within a few percentage points. So, very clear benefit of the combination of a BRAF inhibitor. I do not see a role for BRAF inhibitor monotherapy at all, in any patient. Sometimes people make arguments. For example, the effect of MEK inhibitors on the heart, which is actually reversible. Even in that setting, I test it out. I test the doublet out in patients with heart failure. That’s the first important fact.

The next thing was, they’re all similar. The difference is for dabrafenib/trametinib and vemurafenib/cobimetinib, and they’ve never been compared head-to-head. That’s a really important point; it’s probably in the toxicity profile. So, for dabrafenib/trametinib, the main toxicity that is an issue is fever, pyrexia, which can be managed, but does require a bit of experience. It can be managed with intermittent treatment, so just stopping the patient. The difficult bit is the first 3 months: if you can get patients through that, they tend to be sailing well by 6 months; they’re really good. It’s the fever management for dabrafenib/trametinib, which can also be managed with steroids. And then for vemurafenib/cobimetinib, it’s the rashes and the diarrhea. Fever is not a major problem for that group. That’s really the difference between the two combinations. So, that answers your set of questions. Did you want to delve into the beneficiaries for these drugs at this point or not yet?

Keith T. Flaherty, MD: Yes. As you said, from an efficacy perspective, I think we treat the BRAF/MEK approach as a therapeutic unit. And then for argument’s sake, dabrafenib/trametinib, vemurafenib/cobimetinib, it’s hard to parse between the two. So, considering BRAF/MEK is a strategy, Jason, you were alluding to before the evidence regarding patient selection or subsets. You look at the evidence as it’s been presented for either the BRAF/MEK strategies. How do you talk to a patient with high disease burden about what your expectations are? Many people in practice have felt like BRAF inhibitor therapy, going back to BRAF inhibitor monotherapy days, was just what you had as an option at least to start with. But what’s your take and how do you present it to patients in terms of near-term to intermediate-term expectations?

Jason J. Luke, MD: Well, I feel very comfortable telling most patients we should see very quick onset of clinical benefit. And so in patients who are symptomatic and who have BRAF mutations that are identified, I tell them this is the best approach. Because you’ll feel better quickly. Getting out to high-burden patients, perhaps liver metastases or brain, that’s a question of where will we be in 6 months. But it’s an open question. I don’t think we generally have the answer to that. But I tell patients that, from my perspective, the best decision making process is, what do we have, what do we know now? If the patient is symptomatic now, then we treat the patient and then we think about what’s going to be the next step.

And this dovetails with what we discussed before. We have many active agents now, so knowing how we’re going to use them, I think, is an open question. People need experience with each one. So, in a patient, especially maybe a lower performance status patient where I’m concerned if we had a side-effect issue, start with a BRAF inhibitor. Debulk the disease at a minimum and then reassess and re-discuss what treatment options would potentially be offered. The other big one here that comes up is in the context of patients who have autoimmunity or other variants of the standard patient that you would think of. In that setting, then, I think it’s much more clear to just get the drug started quickly.

And I just want to comment very quickly about what Georgina said about the side-effect profile. My personal experience is it’s at least 50% that get the fevers, but the most important thing, just let the patient know. If you start getting chills, just stop the drugs. Because patients don’t like to stop. They think, “Oh, stop the cancer drug, it’s going to be terrible.” In reality, it doesn’t have any effect on efficacy at all and you can literally avoid hospitalizations for dehydration. Just stop the drugs for a few days. It will recover. You can go right back to it.

Georgina Long, BSc, MBBS: I would sit the patient in a separate room and they get a whole conversation. Not only with me, but in a separate room with a nurse. And the biggest thing is, contact us. If in doubt, stop the drugs and reinforcing the fact that it’s not a negative thing on your cancer to stop for 2, 3 days. In fact, it’s better because you’re not going to be stopping for a week; you’re just going to be stopping for 48 hours.

Jeffrey S. Weber, MD: But, speaking of stopping, have these discontinuous trials gotten any traction?

Keith T. Flaherty, MD: Well, the biggest trial on that point is not 2, 3 days off therapy, but a couple weeks off therapy, meaning several weeks on, 2 weeks off. And that’s a strategy that has some preclinical science behind it. We haven’t seen any evidence yet that that spares us on toxicity, prolongs overall disease control; it’s still a proactive hypothesis. But when I’ve been asked by practitioners in the community on that topic, I’d say it’s not ready for prime time in terms of a treatment strategy to build into practice now.

Georgina Long, BSc, MBBS: Can I just make a comment? Because we haven’t actually commented on the actual response rate of targeted therapies. So, the overall response rate using RECIST is near 70% across the board, but tumor reduction occurs in 95% of patients. And that’s why we’re sitting here all confidently saying, presurgery, we’d give it. If they’ve got high burden, you want quick control, we’d give it. The issue, though, is that those very patients with high burden of disease, high LDH do poorly across the board on treatments. But we know, as Jason was alluding to, that they’re probably going to progress by 4 months if they’ve got a very, very high LDH. We know that. We’ve seen the data. The progression-free survival in that subgroup is not good on any treatment. But because the dabrafenib/trametinib studies have really delved into that, we actually have the data and can say high LDH progresses very quickly.

Keith T. Flaherty, MD: Yes. I would pull out, though, from this year’s ASCO with 3-year follow-up, the high-LDH group. We had given up hope on them at the 2-year follow-up. It turns out, actually, that a 15% to 20% subset of high-LDH patients are still alive and well at 3 years.

Georgina Long, BSc, MBBS: Do you know who they are though? They’re the elevated LDH between 1 and 2.

Keith T. Flaherty, MD: Yes, they’re not so bad, right? Fair point.

Georgina Long, BSc, MBBS: They’re not the 2X the upper limit, and we saw that in the pooled analysis. When we delved into LDH, we saw a clear separation between LDH 1X2 upper limits of normal versus 2. The 3-year survival for people with LDH above 2 was 7%—that’s overall survival. Whereas, for 1 to 2, it was up near, I don’t know, 20% or something like that.

Keith T. Flaherty, MD: This is an important point, actually, right? Because, we’ve been very quick about talking about LDH.

Georgina Long, BSc, MBBS: Yes, but there’s a difference.

Keith T. Flaherty, MD: I think for those who don’t see as many melanoma patients as we do, 1.1X the upper limit of normal is not all hope lost. But, 4X the upper limit of normal, that’s the type of patient we’re talking about that’s in a really tough spot.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
Georgina, I want to delve in to each of these therapies and their strengths, weaknesses, if you will. We’ll start with BRAF inhibitor–based therapy. We had two BRAF inhibitors on the market as monotherapy with a phase III trial—better than dacarbazine—and MEK inhibitor monotherapy, all in the V600 BRAF-mutant population. Now, there are three randomized phase III trials with pretty mature follow-up at this point with dabrafenib/trametinib and vemurafenib/cobimetinib. So, maybe briefly summarize how you digest the information, how you present it to patients on the strengths of the evidence regarding that therapy. Maybe tuck in there also, are there patients who you still think about BRAF inhibitor monotherapy or is it BRAF/MEK for all?

Georgina Long, BSc, MBBS: Just to answer your last question, the data are very clear. BRAF plus MEK is superior to BRAF inhibitor alone. There is no role for a single-agent BRAF inhibitor. I don’t think I’ve ever given a patient a single-agent BRAF inhibitor with those three randomized trials. So, we’re talking about COMBI-d, dabrafenib/trametinib versus dabrafenib, we’re talking COMBI-v, which is dabrafenib/trametinib versus vemurafenib, and we’re talking coBRIM, which is vemurafenib combined with cobimetinib versus vemurafenib alone.

The amazing thing is that the 1-year and 2-year overall survivals for the combinations in each of those trials was almost exactly the same. We’re talking 74%, 75%, 1-year survival in that group. These are BRAF-mutated patients. Of course, V600 and then a 2-year overall survival are in a pooled analysis of dabrafenib and trametinib; 53% in coBRIM, 48% all within a few percentage points. So, very clear benefit of the combination of a BRAF inhibitor. I do not see a role for BRAF inhibitor monotherapy at all, in any patient. Sometimes people make arguments. For example, the effect of MEK inhibitors on the heart, which is actually reversible. Even in that setting, I test it out. I test the doublet out in patients with heart failure. That’s the first important fact.

The next thing was, they’re all similar. The difference is for dabrafenib/trametinib and vemurafenib/cobimetinib, and they’ve never been compared head-to-head. That’s a really important point; it’s probably in the toxicity profile. So, for dabrafenib/trametinib, the main toxicity that is an issue is fever, pyrexia, which can be managed, but does require a bit of experience. It can be managed with intermittent treatment, so just stopping the patient. The difficult bit is the first 3 months: if you can get patients through that, they tend to be sailing well by 6 months; they’re really good. It’s the fever management for dabrafenib/trametinib, which can also be managed with steroids. And then for vemurafenib/cobimetinib, it’s the rashes and the diarrhea. Fever is not a major problem for that group. That’s really the difference between the two combinations. So, that answers your set of questions. Did you want to delve into the beneficiaries for these drugs at this point or not yet?

Keith T. Flaherty, MD: Yes. As you said, from an efficacy perspective, I think we treat the BRAF/MEK approach as a therapeutic unit. And then for argument’s sake, dabrafenib/trametinib, vemurafenib/cobimetinib, it’s hard to parse between the two. So, considering BRAF/MEK is a strategy, Jason, you were alluding to before the evidence regarding patient selection or subsets. You look at the evidence as it’s been presented for either the BRAF/MEK strategies. How do you talk to a patient with high disease burden about what your expectations are? Many people in practice have felt like BRAF inhibitor therapy, going back to BRAF inhibitor monotherapy days, was just what you had as an option at least to start with. But what’s your take and how do you present it to patients in terms of near-term to intermediate-term expectations?

Jason J. Luke, MD: Well, I feel very comfortable telling most patients we should see very quick onset of clinical benefit. And so in patients who are symptomatic and who have BRAF mutations that are identified, I tell them this is the best approach. Because you’ll feel better quickly. Getting out to high-burden patients, perhaps liver metastases or brain, that’s a question of where will we be in 6 months. But it’s an open question. I don’t think we generally have the answer to that. But I tell patients that, from my perspective, the best decision making process is, what do we have, what do we know now? If the patient is symptomatic now, then we treat the patient and then we think about what’s going to be the next step.

And this dovetails with what we discussed before. We have many active agents now, so knowing how we’re going to use them, I think, is an open question. People need experience with each one. So, in a patient, especially maybe a lower performance status patient where I’m concerned if we had a side-effect issue, start with a BRAF inhibitor. Debulk the disease at a minimum and then reassess and re-discuss what treatment options would potentially be offered. The other big one here that comes up is in the context of patients who have autoimmunity or other variants of the standard patient that you would think of. In that setting, then, I think it’s much more clear to just get the drug started quickly.

And I just want to comment very quickly about what Georgina said about the side-effect profile. My personal experience is it’s at least 50% that get the fevers, but the most important thing, just let the patient know. If you start getting chills, just stop the drugs. Because patients don’t like to stop. They think, “Oh, stop the cancer drug, it’s going to be terrible.” In reality, it doesn’t have any effect on efficacy at all and you can literally avoid hospitalizations for dehydration. Just stop the drugs for a few days. It will recover. You can go right back to it.

Georgina Long, BSc, MBBS: I would sit the patient in a separate room and they get a whole conversation. Not only with me, but in a separate room with a nurse. And the biggest thing is, contact us. If in doubt, stop the drugs and reinforcing the fact that it’s not a negative thing on your cancer to stop for 2, 3 days. In fact, it’s better because you’re not going to be stopping for a week; you’re just going to be stopping for 48 hours.

Jeffrey S. Weber, MD: But, speaking of stopping, have these discontinuous trials gotten any traction?

Keith T. Flaherty, MD: Well, the biggest trial on that point is not 2, 3 days off therapy, but a couple weeks off therapy, meaning several weeks on, 2 weeks off. And that’s a strategy that has some preclinical science behind it. We haven’t seen any evidence yet that that spares us on toxicity, prolongs overall disease control; it’s still a proactive hypothesis. But when I’ve been asked by practitioners in the community on that topic, I’d say it’s not ready for prime time in terms of a treatment strategy to build into practice now.

Georgina Long, BSc, MBBS: Can I just make a comment? Because we haven’t actually commented on the actual response rate of targeted therapies. So, the overall response rate using RECIST is near 70% across the board, but tumor reduction occurs in 95% of patients. And that’s why we’re sitting here all confidently saying, presurgery, we’d give it. If they’ve got high burden, you want quick control, we’d give it. The issue, though, is that those very patients with high burden of disease, high LDH do poorly across the board on treatments. But we know, as Jason was alluding to, that they’re probably going to progress by 4 months if they’ve got a very, very high LDH. We know that. We’ve seen the data. The progression-free survival in that subgroup is not good on any treatment. But because the dabrafenib/trametinib studies have really delved into that, we actually have the data and can say high LDH progresses very quickly.

Keith T. Flaherty, MD: Yes. I would pull out, though, from this year’s ASCO with 3-year follow-up, the high-LDH group. We had given up hope on them at the 2-year follow-up. It turns out, actually, that a 15% to 20% subset of high-LDH patients are still alive and well at 3 years.

Georgina Long, BSc, MBBS: Do you know who they are though? They’re the elevated LDH between 1 and 2.

Keith T. Flaherty, MD: Yes, they’re not so bad, right? Fair point.

Georgina Long, BSc, MBBS: They’re not the 2X the upper limit, and we saw that in the pooled analysis. When we delved into LDH, we saw a clear separation between LDH 1X2 upper limits of normal versus 2. The 3-year survival for people with LDH above 2 was 7%—that’s overall survival. Whereas, for 1 to 2, it was up near, I don’t know, 20% or something like that.

Keith T. Flaherty, MD: This is an important point, actually, right? Because, we’ve been very quick about talking about LDH.

Georgina Long, BSc, MBBS: Yes, but there’s a difference.

Keith T. Flaherty, MD: I think for those who don’t see as many melanoma patients as we do, 1.1X the upper limit of normal is not all hope lost. But, 4X the upper limit of normal, that’s the type of patient we’re talking about that’s in a really tough spot.

Transcript Edited for Clarity
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