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Managing Brain Metastases and Side Effects in Melanoma

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: Thursday, Sep 08, 2016



Transcript:

Keith T. Flaherty, MD:
Georgina, before we leave this data summary element for BRAF inhibitor-based therapy, I want your practice-oriented thoughts on brain metastases at presentation. So, when we talk about the high disease-burden patients, a good fraction of those will have asymptomatic brain metastases on presentation. You have a very high response rate, very high tumor regression rate with BRAF/MEK combination therapy. Do you trust that as the treatment for a patient who walks in the door with asymptomatic brain metastases, if it’s one lesion, if it’s five lesions? By trust, I mean systemic therapy alone, monitor and defer radiation, or do you still feature radiation?

Georgina Long, BSc, MBBS: Okay, that’s a great question. You can almost have a whole session just on brain metastases and how to manage brain metastases because they are heterogeneous. If a patient has one versus five versus miliary patterns, the ones that have 50 brain metastases on presentation, they are actually very different patient groups. You can have a different approach. But, in just answering your question, do I trust systemic treatment? Yes, I do. However, not for permanency. It’s not going to solve the problem forever. Basically, we have a lot of trials actually looking at other treatment approaches, combining local treatments, and immunotherapies in the brain. We still don’t actually have a response rate in untreated asymptomatic brain metastases for immunotherapies. But, yes, I do trust the targeted therapies to control brain metastases. The question is for how long, and so, depending on the number, the patient, the performance status, you may approach it differently.

Keith T. Flaherty, MD: Jeff, on the toxicity front, dabrafenib/trametinib is well known for its fever and sometimes even recurrent fever. Vemurafenib alone and in combination still has photosensitivity as a recurring and nagging problem for some patients. How do you think about upfront selection? Or, you treat a patient, they’re really having problematic toxicity. Do you keep interrupting and trying to find a dose that they can manage, or, in this era where we have two approved regimens, do you switch?

Jeffrey S. Weber, MD: Well, I’ll do both. In patients who I put on dabrafenib/trametinib who then have fevers, I’ll hang in there. I’ve had patients where I’ve gone through stop treatment, who go on Medrol Dosepak, which I’ll jump to very quickly, after the first attempt at using nonsteroidals and Tylenol—which may not work. Just give them a Medrol Dosepak. I let them self-manage. They’ll literally, as we’ve discussed, manage themselves. And after 72 hours, the fever’s gone away, they’re tapering down the Medrol Dosepak. They’ll go back on treatment, same dose. I don’t even dose reduce, because it doesn’t appear to help. As to which regimen to choose, that’s really a toss-up. I think if you play the game of overlapping the survival curves, they’d be virtually identical. Although, I will point out, and I’d love to hear some comments from my colleagues, at this ASCO there was some updated. The up-to-date median survival data was 30.6 months, I think, for coBRIM.

Georgina Long, BSc, MBBS: No, phase I.

Jeffrey S. Weber, MD: This was probably from the BRIM…

Keith T. Flaherty, MD: BRIM7.

Jeffrey S. Weber, MD: From BRIM7. So, in BRIM7, the treatment-naïve patients were a small number. Interestingly, 30-month median versus for the whole group in coBRIM, and I think the COMBI-v, COMBI-d, and the original phase I/II trial, it’s about 24/25 months. I wonder, is there really a difference there?

Keith T. Flaherty, MD: We need more time. The vemurafenib/cobimetinib phase III trial was about a year delayed in time. Just to say that we don’t have confident 2-year and 3-year insights, which I think will then allow you to do this overall survival tracing experiment.

Georgina Long, BSc, MBBS: And we still need to establish the activity of that combination in brain. The other thing is we got published data now with dabrafenib as a single agent. The trial of dabrafenib/trametinib in the brain is just about complete. So, we’ve got a lot more data and confidence about brain activity. And that’s an area that we need to understand with vemurafenib/cobimetinib as well.

Jeffrey S. Weber, MD: Because, dabrafenib/trametinib was approved well before vemurafenib/cobimetinib. I think most oncologists were simply used to dealing with the frankly modest side effects. We’re used to using the regimen, so I would suspect in the United States, most oncologists are still using dabrafenib/trametinib.

Georgina Long, BSc, MBBS: So, fever, it’s very common as Jason said. I’d put it up near 70%, but there is a subgroup that get that really, really bad recalcitrant recurrent fever. And in that group, you may consider wanting to change treatment where you’ve tried the prednisone. You’ve gone up to 25 mg, 50 mg. You’ve had them on that for 2 months, and they still get a few breakthrough as you taper down. But, there is that group that’s difficult.

Jeffrey S. Weber, MD: It’s interesting that you quote 70%. I think by the numbers that’s probably correct. But, in my personal experience, and we’re talking a fair number of patients in the triple digits, you don’t hear much about it. You obviously hear about the bad fevers of 103, the fatigue, and the lethargy. But, the low-grade fevers, which is what most of them are presumably, I tend not to hear about it from the patients. Do you? Do they call you with these low-grade fevers?

Georgina Long, BSc, MBBS: Yes.

Jason J. Luke, MD: I feel like I hear about it.

Georgina Long, BSc, MBBS: Yes, I hear about it. My nurse is constantly managing it and keeping me out of it, but will update me.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
Georgina, before we leave this data summary element for BRAF inhibitor-based therapy, I want your practice-oriented thoughts on brain metastases at presentation. So, when we talk about the high disease-burden patients, a good fraction of those will have asymptomatic brain metastases on presentation. You have a very high response rate, very high tumor regression rate with BRAF/MEK combination therapy. Do you trust that as the treatment for a patient who walks in the door with asymptomatic brain metastases, if it’s one lesion, if it’s five lesions? By trust, I mean systemic therapy alone, monitor and defer radiation, or do you still feature radiation?

Georgina Long, BSc, MBBS: Okay, that’s a great question. You can almost have a whole session just on brain metastases and how to manage brain metastases because they are heterogeneous. If a patient has one versus five versus miliary patterns, the ones that have 50 brain metastases on presentation, they are actually very different patient groups. You can have a different approach. But, in just answering your question, do I trust systemic treatment? Yes, I do. However, not for permanency. It’s not going to solve the problem forever. Basically, we have a lot of trials actually looking at other treatment approaches, combining local treatments, and immunotherapies in the brain. We still don’t actually have a response rate in untreated asymptomatic brain metastases for immunotherapies. But, yes, I do trust the targeted therapies to control brain metastases. The question is for how long, and so, depending on the number, the patient, the performance status, you may approach it differently.

Keith T. Flaherty, MD: Jeff, on the toxicity front, dabrafenib/trametinib is well known for its fever and sometimes even recurrent fever. Vemurafenib alone and in combination still has photosensitivity as a recurring and nagging problem for some patients. How do you think about upfront selection? Or, you treat a patient, they’re really having problematic toxicity. Do you keep interrupting and trying to find a dose that they can manage, or, in this era where we have two approved regimens, do you switch?

Jeffrey S. Weber, MD: Well, I’ll do both. In patients who I put on dabrafenib/trametinib who then have fevers, I’ll hang in there. I’ve had patients where I’ve gone through stop treatment, who go on Medrol Dosepak, which I’ll jump to very quickly, after the first attempt at using nonsteroidals and Tylenol—which may not work. Just give them a Medrol Dosepak. I let them self-manage. They’ll literally, as we’ve discussed, manage themselves. And after 72 hours, the fever’s gone away, they’re tapering down the Medrol Dosepak. They’ll go back on treatment, same dose. I don’t even dose reduce, because it doesn’t appear to help. As to which regimen to choose, that’s really a toss-up. I think if you play the game of overlapping the survival curves, they’d be virtually identical. Although, I will point out, and I’d love to hear some comments from my colleagues, at this ASCO there was some updated. The up-to-date median survival data was 30.6 months, I think, for coBRIM.

Georgina Long, BSc, MBBS: No, phase I.

Jeffrey S. Weber, MD: This was probably from the BRIM…

Keith T. Flaherty, MD: BRIM7.

Jeffrey S. Weber, MD: From BRIM7. So, in BRIM7, the treatment-naïve patients were a small number. Interestingly, 30-month median versus for the whole group in coBRIM, and I think the COMBI-v, COMBI-d, and the original phase I/II trial, it’s about 24/25 months. I wonder, is there really a difference there?

Keith T. Flaherty, MD: We need more time. The vemurafenib/cobimetinib phase III trial was about a year delayed in time. Just to say that we don’t have confident 2-year and 3-year insights, which I think will then allow you to do this overall survival tracing experiment.

Georgina Long, BSc, MBBS: And we still need to establish the activity of that combination in brain. The other thing is we got published data now with dabrafenib as a single agent. The trial of dabrafenib/trametinib in the brain is just about complete. So, we’ve got a lot more data and confidence about brain activity. And that’s an area that we need to understand with vemurafenib/cobimetinib as well.

Jeffrey S. Weber, MD: Because, dabrafenib/trametinib was approved well before vemurafenib/cobimetinib. I think most oncologists were simply used to dealing with the frankly modest side effects. We’re used to using the regimen, so I would suspect in the United States, most oncologists are still using dabrafenib/trametinib.

Georgina Long, BSc, MBBS: So, fever, it’s very common as Jason said. I’d put it up near 70%, but there is a subgroup that get that really, really bad recalcitrant recurrent fever. And in that group, you may consider wanting to change treatment where you’ve tried the prednisone. You’ve gone up to 25 mg, 50 mg. You’ve had them on that for 2 months, and they still get a few breakthrough as you taper down. But, there is that group that’s difficult.

Jeffrey S. Weber, MD: It’s interesting that you quote 70%. I think by the numbers that’s probably correct. But, in my personal experience, and we’re talking a fair number of patients in the triple digits, you don’t hear much about it. You obviously hear about the bad fevers of 103, the fatigue, and the lethargy. But, the low-grade fevers, which is what most of them are presumably, I tend not to hear about it from the patients. Do you? Do they call you with these low-grade fevers?

Georgina Long, BSc, MBBS: Yes.

Jason J. Luke, MD: I feel like I hear about it.

Georgina Long, BSc, MBBS: Yes, I hear about it. My nurse is constantly managing it and keeping me out of it, but will update me.

Transcript Edited for Clarity
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