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Managing Melanoma Brain Metastases

Panelists: Sanjiv S. Agarwala, MD, Temple University School of Medicine; Alexander Eggermont, MD, PhD, Institut Gustave Roussy; Caroline Robert, MD, PhD, Institut Gustave Roussy; Dirk Schadendorf, MD, PhD, West German Cancer Center at University Hospital Essen
Published: Tuesday, Aug 13, 2019



Transcript: 

Sanjiv S. Agarwala, MD: Let’s talk about melanoma brain metastases, a very big problem. And suddenly there seems to be light at the end of the tunnel, right? So, I’ll start with you, Caroline, in terms of, let’s talk about the immunotherapy data with combination therapy, which has looked exciting for a while.

Caroline Robert, MD, PhD: Yes, it’s good data but I would like to remind everybody that it’s a very selected population of patients.

Sanjiv S. Agarwala, MD: This is CheckMate-204 we’re talking about.

Caroline Robert, MD, PhD: Yes.

Sanjiv S. Agarwala, MD: In symptomatic brain metastases.

Caroline Robert, MD, PhD: They are symptomatic.

Sanjiv S. Agarwala, MD: That’s right, yes.

Caroline Robert, MD, PhD: Less than 3, I mean 3 maximum.

Sanjiv S. Agarwala, MD: Very selected patient population.

Caroline Robert, MD, PhD: These are good patients, and this is not the majority of our patients. So, it’s very good. We are very happy to see this response rate, and definitely the combination really achieved a very good result. But this is not the majority of our patients, and although there is a caveat that we are not, we have not, evaluated the combination or the sequence with the radiosurgery which we use a lot which is very effective when we have metastasis that we can treat with radiosurgery. And today in our everyday practice, we discuss all the patients with our neurology tumor board, and we initiate systemic treatment. And we also treat with radiosurgery. But we need to have some kind of controls to need to know if it’s better to do it up front or to do it later on which…

Sanjiv S. Agarwala, MD: We do the same thing at our center. Every patient is evaluated by a multidisciplinary team, includes a neurosurgeon, radiation oncologist, medical oncologist. Dirk, we had a big debate about BRAF-positive patients in the systemic melanoma setting and adjuvant as well. But, in brain metastases, do you have a different approach to a BRAF-positive patient? Let’s start with a very specific question. Asymptomatic patient with BRAF-positive disease, brain metastases, would you go with the combination immunotherapy or would you go with targeted therapy for that patient, based on all the data we have which is not randomized of course?

Dirk Schadendorf, MD, PhD: Yeah. No, I think for our symptomatic care patients, I think our approach would also be stereotactic Gamma Knife radiation and checkpoint blockade.

Sanjiv S. Agarwala, MD: Combination.

Dirk Schadendorf, MD, PhD: So that the issue which I think one has to keep in mind also with the CheckMate-204 data, that stereotactic radiation has a response rate of 100%. The duration of the response might be different and that needs to be shown. And we need to work out the combination of radiation, as Caroline said, between radiation and long-lasting control. And that’s the issue with targeted therapy. I mean, we have seen that we are getting responses, so we are using targeted therapy, BRAF/MEK combinations, particularly in symptomatic patients where we need an immediate quick onset of the response.

Sanjiv S. Agarwala, MD: You’re talking about brain symptomatic metastasis.

Dirk Schadendorf, MD, PhD: Yes, yes, yes.

Caroline Robert, MD, PhD:..... the response rate in the brain metastases is 50% but it’s not that durable.

Dirk Schadendorf, MD, PhD: Exactly.

Caroline Robert, MD, PhD: It seems not to be…

Dirk Schadendorf, MD, PhD: But, I mean if you have a symptomatic brain metastasis, I think it’s much quicker and then the question is can you complement this kind of treatment with checkpoint, can you stabilize that. I think that could also be an area which is not explored but an area for triplet therapies quickly because you have the quick onset of a therapy of the targeted component and then hopefully the long-lasting stabilization effect. But I think that needs to be shown.

Caroline Robert, MD, PhD: Yeah.

Sanjiv S. Agarwala, MD: So, do you switch someone who has symptomatic BRAF-positive disease, give them targeted therapy, make them asymptomatic, and then switch them?

Caroline Robert, MD, PhD: No, I would not switch without progression today without a clinical trial. Because the patient is doing well, you switch, they get those troughs, what do you tell the patient? If it’s not in a clinical trial I would not do it.

Sanjiv S. Agarwala, MD: I mean it’s only for the durability question but it’s not no.

Dirk Schadendorf, MD, PhD: Yeah, we would probably, in a few patients where we have urgent need, we would, possibly, off-label, we would combine already now.

Sanjiv S. Agarwala, MD: Really? That’s of course something that’s being researched in of course systemic disuse, triple combinations. Can I ask you, Caroline. We talked a lot about combination immunotherapy. What about monotherapy? There was an ASCO [American Society of Clinical Oncology] update also for monotherapy, pembrolizumab for brain metastases. Are there any patients that are BRAF wild-type, so you don’t have a choice of BRAF therapy, that you would choose monotherapy for brain metastases instead of combination?

Caroline Robert, MD, PhD: Well, first it depends of the availability of the combination.

Sanjiv S. Agarwala, MD: Assuming you have everything.

Caroline Robert, MD, PhD: So, imagine you have everything, depends on the comorbidity. If you have a patient that you think can stand the combination, you would prefer the combination. If you have a fragile patient, you would give them monotherapy. Plus, radiosurgery, we had a lot of patients where when we didn’t have access to the combination of immunotherapy, a lot of patients were treated with anti–PD-1 single agent plus radiosurgery and did really well. So not a controlled way, but we had a lot of patients treated like that. Long-term responses.

Dirk Schadendorf, MD, PhD: What is your experience? I mean, there is some rumor on of combining a checkpoint blockade.

Caroline Robert, MD, PhD: We looked at that. We published that last year, and we found that there was the same rate of radionecrosis when we had PD-1 monotherapy, anti­–PD-1 with ipilimumab/nivolumab plus radiosurgery, we did not find more radionecrosis than with radiotherapy.

Dirk Schadendorf, MD, PhD: And whole brain and checkpoint blockade, you don’t do at all?

Caroline Robert, MD, PhD: We don’t do it at the same time. We try to sequence.

Sanjiv S. Agarwala, MD: So, while we’re talking about whole brain, there was an interesting trial presented at ASCO. It was a randomized trial, whole brain radiation therapy seemed to imply that you should no longer ever do that?

Caroline Robert, MD, PhD: No.

Sanjiv S. Agarwala, MD: What are your thoughts, Dirk on that and then Alex?

Dirk Schadendorf, MD, PhD: I think we have stopped doing whole brain radiation already.

Sanjiv S. Agarwala, MD: For a long time.

Dirk Schadendorf, MD, PhD: For a long time.

Caroline Robert, MD, PhD: We did not wait for the results of this trial.

Sanjiv S. Agarwala, MD: Yeah, yeah. No, we all stopped doing it a while ago. In fact, it’s very interesting. In my clinic, the radiation oncologists don’t want to do it…

Caroline Robert, MD, PhD: In fact, no. It’s not very true for us. We do it sometimes when it’s almost last.

Sanjiv S. Agarwala, MD: When there’s nothing else left.

Caroline Robert, MD, PhD: And sometimes you have good response, or you don’t know if it’s because of that, but it seems that honestly, we do it sometimes. Maybe once every three months we have a patient who we really have is full of brain metastasis and it goes or it doesn’t go through. But we do it sometimes, and we have some survivals but it’s very rare.

Sanjiv S. Agarwala, MD: And this randomized trial was in 1 to 3 melanoma brain metastases which is very interesting, very similar to the CheckMate trial. Alex, at your center, is radiation therapy, not counting stereotactic, whole brain not done, considered, last resort?

Alexander Eggermont, MD, PhD: So, Caroline will answer that question because we are from the same.

Sanjiv S. Agarwala, MD: She did already.

Alexander Eggermont, MD, PhD: We’re from the same center. I would like to avoid contradicting Caroline because otherwise I may be in big trouble.

Caroline Robert, MD, PhD: The thing is what I’m very surprised to see, I would like to know what you think about that, I’m surprised to see some very good outcome of re-challenging with anti-BRAF/anti-MEK even in very difficult situation after a first response, then a relapse, immunotherapy, and then re-challenging. I’m very surprised by some very long good outcome in these patients.

Transcript Edited for Clarity

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Transcript: 

Sanjiv S. Agarwala, MD: Let’s talk about melanoma brain metastases, a very big problem. And suddenly there seems to be light at the end of the tunnel, right? So, I’ll start with you, Caroline, in terms of, let’s talk about the immunotherapy data with combination therapy, which has looked exciting for a while.

Caroline Robert, MD, PhD: Yes, it’s good data but I would like to remind everybody that it’s a very selected population of patients.

Sanjiv S. Agarwala, MD: This is CheckMate-204 we’re talking about.

Caroline Robert, MD, PhD: Yes.

Sanjiv S. Agarwala, MD: In symptomatic brain metastases.

Caroline Robert, MD, PhD: They are symptomatic.

Sanjiv S. Agarwala, MD: That’s right, yes.

Caroline Robert, MD, PhD: Less than 3, I mean 3 maximum.

Sanjiv S. Agarwala, MD: Very selected patient population.

Caroline Robert, MD, PhD: These are good patients, and this is not the majority of our patients. So, it’s very good. We are very happy to see this response rate, and definitely the combination really achieved a very good result. But this is not the majority of our patients, and although there is a caveat that we are not, we have not, evaluated the combination or the sequence with the radiosurgery which we use a lot which is very effective when we have metastasis that we can treat with radiosurgery. And today in our everyday practice, we discuss all the patients with our neurology tumor board, and we initiate systemic treatment. And we also treat with radiosurgery. But we need to have some kind of controls to need to know if it’s better to do it up front or to do it later on which…

Sanjiv S. Agarwala, MD: We do the same thing at our center. Every patient is evaluated by a multidisciplinary team, includes a neurosurgeon, radiation oncologist, medical oncologist. Dirk, we had a big debate about BRAF-positive patients in the systemic melanoma setting and adjuvant as well. But, in brain metastases, do you have a different approach to a BRAF-positive patient? Let’s start with a very specific question. Asymptomatic patient with BRAF-positive disease, brain metastases, would you go with the combination immunotherapy or would you go with targeted therapy for that patient, based on all the data we have which is not randomized of course?

Dirk Schadendorf, MD, PhD: Yeah. No, I think for our symptomatic care patients, I think our approach would also be stereotactic Gamma Knife radiation and checkpoint blockade.

Sanjiv S. Agarwala, MD: Combination.

Dirk Schadendorf, MD, PhD: So that the issue which I think one has to keep in mind also with the CheckMate-204 data, that stereotactic radiation has a response rate of 100%. The duration of the response might be different and that needs to be shown. And we need to work out the combination of radiation, as Caroline said, between radiation and long-lasting control. And that’s the issue with targeted therapy. I mean, we have seen that we are getting responses, so we are using targeted therapy, BRAF/MEK combinations, particularly in symptomatic patients where we need an immediate quick onset of the response.

Sanjiv S. Agarwala, MD: You’re talking about brain symptomatic metastasis.

Dirk Schadendorf, MD, PhD: Yes, yes, yes.

Caroline Robert, MD, PhD:..... the response rate in the brain metastases is 50% but it’s not that durable.

Dirk Schadendorf, MD, PhD: Exactly.

Caroline Robert, MD, PhD: It seems not to be…

Dirk Schadendorf, MD, PhD: But, I mean if you have a symptomatic brain metastasis, I think it’s much quicker and then the question is can you complement this kind of treatment with checkpoint, can you stabilize that. I think that could also be an area which is not explored but an area for triplet therapies quickly because you have the quick onset of a therapy of the targeted component and then hopefully the long-lasting stabilization effect. But I think that needs to be shown.

Caroline Robert, MD, PhD: Yeah.

Sanjiv S. Agarwala, MD: So, do you switch someone who has symptomatic BRAF-positive disease, give them targeted therapy, make them asymptomatic, and then switch them?

Caroline Robert, MD, PhD: No, I would not switch without progression today without a clinical trial. Because the patient is doing well, you switch, they get those troughs, what do you tell the patient? If it’s not in a clinical trial I would not do it.

Sanjiv S. Agarwala, MD: I mean it’s only for the durability question but it’s not no.

Dirk Schadendorf, MD, PhD: Yeah, we would probably, in a few patients where we have urgent need, we would, possibly, off-label, we would combine already now.

Sanjiv S. Agarwala, MD: Really? That’s of course something that’s being researched in of course systemic disuse, triple combinations. Can I ask you, Caroline. We talked a lot about combination immunotherapy. What about monotherapy? There was an ASCO [American Society of Clinical Oncology] update also for monotherapy, pembrolizumab for brain metastases. Are there any patients that are BRAF wild-type, so you don’t have a choice of BRAF therapy, that you would choose monotherapy for brain metastases instead of combination?

Caroline Robert, MD, PhD: Well, first it depends of the availability of the combination.

Sanjiv S. Agarwala, MD: Assuming you have everything.

Caroline Robert, MD, PhD: So, imagine you have everything, depends on the comorbidity. If you have a patient that you think can stand the combination, you would prefer the combination. If you have a fragile patient, you would give them monotherapy. Plus, radiosurgery, we had a lot of patients where when we didn’t have access to the combination of immunotherapy, a lot of patients were treated with anti–PD-1 single agent plus radiosurgery and did really well. So not a controlled way, but we had a lot of patients treated like that. Long-term responses.

Dirk Schadendorf, MD, PhD: What is your experience? I mean, there is some rumor on of combining a checkpoint blockade.

Caroline Robert, MD, PhD: We looked at that. We published that last year, and we found that there was the same rate of radionecrosis when we had PD-1 monotherapy, anti­–PD-1 with ipilimumab/nivolumab plus radiosurgery, we did not find more radionecrosis than with radiotherapy.

Dirk Schadendorf, MD, PhD: And whole brain and checkpoint blockade, you don’t do at all?

Caroline Robert, MD, PhD: We don’t do it at the same time. We try to sequence.

Sanjiv S. Agarwala, MD: So, while we’re talking about whole brain, there was an interesting trial presented at ASCO. It was a randomized trial, whole brain radiation therapy seemed to imply that you should no longer ever do that?

Caroline Robert, MD, PhD: No.

Sanjiv S. Agarwala, MD: What are your thoughts, Dirk on that and then Alex?

Dirk Schadendorf, MD, PhD: I think we have stopped doing whole brain radiation already.

Sanjiv S. Agarwala, MD: For a long time.

Dirk Schadendorf, MD, PhD: For a long time.

Caroline Robert, MD, PhD: We did not wait for the results of this trial.

Sanjiv S. Agarwala, MD: Yeah, yeah. No, we all stopped doing it a while ago. In fact, it’s very interesting. In my clinic, the radiation oncologists don’t want to do it…

Caroline Robert, MD, PhD: In fact, no. It’s not very true for us. We do it sometimes when it’s almost last.

Sanjiv S. Agarwala, MD: When there’s nothing else left.

Caroline Robert, MD, PhD: And sometimes you have good response, or you don’t know if it’s because of that, but it seems that honestly, we do it sometimes. Maybe once every three months we have a patient who we really have is full of brain metastasis and it goes or it doesn’t go through. But we do it sometimes, and we have some survivals but it’s very rare.

Sanjiv S. Agarwala, MD: And this randomized trial was in 1 to 3 melanoma brain metastases which is very interesting, very similar to the CheckMate trial. Alex, at your center, is radiation therapy, not counting stereotactic, whole brain not done, considered, last resort?

Alexander Eggermont, MD, PhD: So, Caroline will answer that question because we are from the same.

Sanjiv S. Agarwala, MD: She did already.

Alexander Eggermont, MD, PhD: We’re from the same center. I would like to avoid contradicting Caroline because otherwise I may be in big trouble.

Caroline Robert, MD, PhD: The thing is what I’m very surprised to see, I would like to know what you think about that, I’m surprised to see some very good outcome of re-challenging with anti-BRAF/anti-MEK even in very difficult situation after a first response, then a relapse, immunotherapy, and then re-challenging. I’m very surprised by some very long good outcome in these patients.

Transcript Edited for Clarity
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