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Dual-Targeted Therapy for BRAF-Mutant Melanoma

Panelists: Jeffrey Weber, MD, PhD, NYU Langone Medical Center; Reinhard Dummer, MD, University of Zurich Hospital;Axel Hauschild, MD, University of Kiel;Caroline Robert, MD, PhD, Gustave Roussy; Dirk Schadendorf, MD, University Hospital Essen
Published: Thursday, Dec 22, 2016


Transcript:

Jeffrey Weber, MD, PhD:
Let’s go back to your older patient who maybe has some comorbidities and who turns out to be BRAF-mutated. What criteria do you use with the BRAF-mutated patient? You have options of immunotherapy. The urban legend was always that you would get that tail in the curve only with the immunotherapy, not with the targeted therapy. But after this ESMO, I’m not so sure that’s exactly correct. So, how do you use the data to make the decision?

Reinhard Dummer, MD: Thank you for this question. And let’s stick to this patient because it was exactly the question. Actually, he’s a person who has a lot of connection to Memorial Sloan Kettering, and he also gets the opinion of Sloan Kettering. In his situation, he had extensive liver metastases, and he had extensive bone metastases. He had an LDH above 1000, and he was symptomatic.

So, he was really suffering a lot. He had incredible bone pain. We had recommended targeted therapy, a combination BRAF/MEK inhibitor, and then he got a second opinion at Sloan Kettering. Certainly, the alternative treatment would be a combination ipilimumab/nivolumab. But in the end, the colleagues at Sloan Kettering agreed because the patient had really heavy bone pain; he was on morphine. We need immediate action. And the patient was also very happy because he had the idea that he wants to go back to his office as soon as possible, which was very brave at this moment. But, actually he did. He had a wonderful response, and this response lasted for 9 months. Now, he’s on immunotherapy.

Jeffrey Weber, MD, PhD: Although paradoxically—even though, I assume we all probably agree—we would want to give the symptomatic patient with a rapid pace targeted therapy, Axel. It’s not exactly that patient who will be the one who benefits. Can you discuss some of the—I guess it was Georgina Long who published it already—dabrafenib/trametinib data on the low–disease burden patients?

Axel Hauschild, MD: Yes. There are several releases of data on the combinations of BRAF plus MEK inhibition. It’s not only for dabrafenib and trametinib, but at the EAEO meeting a couple of weeks ago, it was more or less the same data for cobimetinib and vemurafenib. It’s very clear that the patients who have the best benefit in the long run, and the longest observation period is 3 years now, are patients with low LDH with less metastatic sites involved. So, it’s the patients who are doing well, ECOG performance status of 0 or 1. And this is true for almost all drugs, including chemotherapy.

We knew from chemotherapy from the old days of DTIC already that the best patients for DTIC were patients with low tumor load, low tumor volume. I know that LDH is also discussed as more than reflecting the tumor load. It’s a biomarker. It is different biology with metastatic melanoma. But, still, it matters for all patients. And, therefore, we have a high medical need for patients with high LDH. These patients are still not doing very well, and I would make exactly the same treatment decision in your patient. For symptomatic patients—for patients with multiple brain metastases, for patients where you need the rapidly-induced response—I believe BRAF plus MEK inhibition is still my first choice, but not because the other drug’s inferior. It’s simply because the speed of the response is so impressive.

Jeffrey Weber, MD, PhD: Okay, but it brings up an interesting point. Would you then give them a brief burst of BRAF/MEK and then switch to immunotherapy? Have you ever done that?

Caroline Robert, MD, PhD: Well, that’s a big question. A lot of physicians do that, despite being totally uncontrolled, because these are data that we are going to get to have. In the community, we won’t know what to do. So, I’m strongly in favor of doing that in clinical trials. But it’s not so easy to organize quickly clinical trials to address this point. I don’t do that because of when patients respond, especially because we have these long-term responders with combination of BRAF/MEK. At 3 years, we are now having the results—45% of patients surviving. This is the same that we’re going to have with anti–PD-1 probably. But it’s true that for a population of patients with high LDH, you’re afraid that they’re going to relapse earlier, and you would like not to wait until the relapse. It is very difficult to treat with immunotherapy.

Jeffrey Weber, MD, PhD: Again, the urban legend is that you would treat the high LDH, high disease-burdened patients with targeted therapy and then you’d give the lower–disease burdened patients maybe the single-agent immunotherapy. Should we flip it, Dirk? Should it be the other way?

Dirk Schadendorf, MD: I think we have the best data actually for targeted therapy. I think we have very convincing data for patient with normal LDH. For example, patients having only one or two organ sites involved with 70% at 3 years. And I think this is very remarkable compared to 5 years ago. Whether this is achieved in patients with immunotherapy, I think it’s still open. I think we need to see these data, and this is too early for checkpoint inhibition, particularly the PD-1 antibodies.

Caroline Robert, MD, PhD: True. So, it’s actually the same population of patients that we would say, “They are good candidates for immunotherapy.” These patients with low tumor burden and low LDH, we know they do very well with combined targeted agents. We still have a problem for high LDH and very high tumor burden patients.

Dirk Schadendorf, MD: But I want to come back to Jeff’s point that starts with targeted therapy. Convert, for example, a patient with high LDH into a normal LDH patient, and then continue with checkpoint blockade. Also, this is driven by an idea, but not by data. So, I’m absolutely supporting Caroline’s notion that we need to treat these patients in clinical trials. Because, how long do we treat? To the point of best clinical response? To a normalization of LDH? For 2 months, for 3 months, for 6 months? This has gut feeling, and I think we should try to have a concept based on evidence.

Transcript Edited for Clarity
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Transcript:

Jeffrey Weber, MD, PhD:
Let’s go back to your older patient who maybe has some comorbidities and who turns out to be BRAF-mutated. What criteria do you use with the BRAF-mutated patient? You have options of immunotherapy. The urban legend was always that you would get that tail in the curve only with the immunotherapy, not with the targeted therapy. But after this ESMO, I’m not so sure that’s exactly correct. So, how do you use the data to make the decision?

Reinhard Dummer, MD: Thank you for this question. And let’s stick to this patient because it was exactly the question. Actually, he’s a person who has a lot of connection to Memorial Sloan Kettering, and he also gets the opinion of Sloan Kettering. In his situation, he had extensive liver metastases, and he had extensive bone metastases. He had an LDH above 1000, and he was symptomatic.

So, he was really suffering a lot. He had incredible bone pain. We had recommended targeted therapy, a combination BRAF/MEK inhibitor, and then he got a second opinion at Sloan Kettering. Certainly, the alternative treatment would be a combination ipilimumab/nivolumab. But in the end, the colleagues at Sloan Kettering agreed because the patient had really heavy bone pain; he was on morphine. We need immediate action. And the patient was also very happy because he had the idea that he wants to go back to his office as soon as possible, which was very brave at this moment. But, actually he did. He had a wonderful response, and this response lasted for 9 months. Now, he’s on immunotherapy.

Jeffrey Weber, MD, PhD: Although paradoxically—even though, I assume we all probably agree—we would want to give the symptomatic patient with a rapid pace targeted therapy, Axel. It’s not exactly that patient who will be the one who benefits. Can you discuss some of the—I guess it was Georgina Long who published it already—dabrafenib/trametinib data on the low–disease burden patients?

Axel Hauschild, MD: Yes. There are several releases of data on the combinations of BRAF plus MEK inhibition. It’s not only for dabrafenib and trametinib, but at the EAEO meeting a couple of weeks ago, it was more or less the same data for cobimetinib and vemurafenib. It’s very clear that the patients who have the best benefit in the long run, and the longest observation period is 3 years now, are patients with low LDH with less metastatic sites involved. So, it’s the patients who are doing well, ECOG performance status of 0 or 1. And this is true for almost all drugs, including chemotherapy.

We knew from chemotherapy from the old days of DTIC already that the best patients for DTIC were patients with low tumor load, low tumor volume. I know that LDH is also discussed as more than reflecting the tumor load. It’s a biomarker. It is different biology with metastatic melanoma. But, still, it matters for all patients. And, therefore, we have a high medical need for patients with high LDH. These patients are still not doing very well, and I would make exactly the same treatment decision in your patient. For symptomatic patients—for patients with multiple brain metastases, for patients where you need the rapidly-induced response—I believe BRAF plus MEK inhibition is still my first choice, but not because the other drug’s inferior. It’s simply because the speed of the response is so impressive.

Jeffrey Weber, MD, PhD: Okay, but it brings up an interesting point. Would you then give them a brief burst of BRAF/MEK and then switch to immunotherapy? Have you ever done that?

Caroline Robert, MD, PhD: Well, that’s a big question. A lot of physicians do that, despite being totally uncontrolled, because these are data that we are going to get to have. In the community, we won’t know what to do. So, I’m strongly in favor of doing that in clinical trials. But it’s not so easy to organize quickly clinical trials to address this point. I don’t do that because of when patients respond, especially because we have these long-term responders with combination of BRAF/MEK. At 3 years, we are now having the results—45% of patients surviving. This is the same that we’re going to have with anti–PD-1 probably. But it’s true that for a population of patients with high LDH, you’re afraid that they’re going to relapse earlier, and you would like not to wait until the relapse. It is very difficult to treat with immunotherapy.

Jeffrey Weber, MD, PhD: Again, the urban legend is that you would treat the high LDH, high disease-burdened patients with targeted therapy and then you’d give the lower–disease burdened patients maybe the single-agent immunotherapy. Should we flip it, Dirk? Should it be the other way?

Dirk Schadendorf, MD: I think we have the best data actually for targeted therapy. I think we have very convincing data for patient with normal LDH. For example, patients having only one or two organ sites involved with 70% at 3 years. And I think this is very remarkable compared to 5 years ago. Whether this is achieved in patients with immunotherapy, I think it’s still open. I think we need to see these data, and this is too early for checkpoint inhibition, particularly the PD-1 antibodies.

Caroline Robert, MD, PhD: True. So, it’s actually the same population of patients that we would say, “They are good candidates for immunotherapy.” These patients with low tumor burden and low LDH, we know they do very well with combined targeted agents. We still have a problem for high LDH and very high tumor burden patients.

Dirk Schadendorf, MD: But I want to come back to Jeff’s point that starts with targeted therapy. Convert, for example, a patient with high LDH into a normal LDH patient, and then continue with checkpoint blockade. Also, this is driven by an idea, but not by data. So, I’m absolutely supporting Caroline’s notion that we need to treat these patients in clinical trials. Because, how long do we treat? To the point of best clinical response? To a normalization of LDH? For 2 months, for 3 months, for 6 months? This has gut feeling, and I think we should try to have a concept based on evidence.

Transcript Edited for Clarity
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