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Adjuvant Therapy for 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: Monday, Nov 07, 2016


Transcript:

Jeffrey Weber, MD, PhD:
Let’s go beyond the sentinel node. Let’s say you have your patient with stage III disease. What’s the approach to adjuvant therapy? In other words, we just heard at this ESMO 2016 the first survival data. So, can you just recap, Axel, the survival data on the ipilimumab trial and tell me, will this change the way you talk to patients about possible adjuvant therapy?

Axel Hauschild, MD: When Lex Eggermont presented this trial for the first time at ASCO, and 2 years ago already, there was rumor in the room because relapse-free survival looked very promising, but overall survival data were not available, and there was a lot of toxicity. Everybody was saying, well, does this toxicity outweigh the benefits of the treatment? And, now that we have a positive trial in terms of significant improvement of overall survival by 28%, so, hazard ratio is 0.72 for what I call high-dose ipilimumab compared to placebo, there is certainly a good reason to explain this to the patients. It’s certainly not a drug which can be given at this high dose to every patient, and there is substantial toxicity, but, I think, we need to discuss it and certainly there’s the issue of whether, in the future, we can use lower dosages of ipilimumab or other checkpoint inhibitors. But, at the moment, it’s the best data which are available. But, Jeff, you are from the US, we are from Europe; in Europe, there is much more competition because it’s not only high-dose interferon which is approved for this setting of stage III patients, it’s also the low-dose interferon, which was, in Germany, much more popular to use in the adjuvant setting than high-dose interferon because high dose was so toxic.

Jeffrey Weber, MD, PhD: Although, in the US there’s little penetration of low-dose or pegylated interferon use in the US, and less and less interferon, and I think, especially, in view of the survival data, there will be perhaps more penetration. But, Reinhard, how do you look at patients getting high-dose ipilimumab? I mean, what do you tell them?

Reinhard Dummer, MD: Until now, interferon was the only drug available, and actually, in Switzerland, we have pegylated interferon on the market. And, I have to say that I have restricted the use of pegylated interferon to patients with an ulcerated primary plus micrometastases. And, for patients with nodal disease, with a major nodal disease, actually, I say interferon makes no sense. Certainly we’ve tried to bring them in clinical trials. But, unfortunately, this was not always possible. And, this is the patient population today that has another option. So, with the data that we have now out there with ipilimumab, this is a patient population with a high risk for relapse, and with a 28% improvement in survival. I think this is an option that you have to offer to the patient. The discussion about the risk–benefit will be a tough one because we will have to face a number of significant toxicities, the acute toxicities with colitis that might may become life-threatening, especially if not well handled. And, then, we have the life, probably lifelong problems with endocrine function.

Caroline Robert, MD, PhD: Yes, which is not that easy. I mean in the metastatic setting it’s easier to accept. But, in the adjuvant setting, to take pills every day because you are hormone insufficient, it’s not that easy.

Jeffrey Weber, MD, PhD: Yes. So, Dirk, how do you risk adjust this?

Dirk Schadendorf, MD: For high-risk patients, stage IIIc, I think there’s no option. We have complained for decades about no true evidence that interferon will translate into an overall survival benefit. I think that there is also clear evidence that interferon, if it works at all, works best in patients with minimal tumor load in the sentinel. Now, for the first time, actually, we have clear data showing and convincing long-term overall survival benefit with ipilimumab. Nevertheless, I agree with Reinhard. I think for high-dose ipilimumab, we need patients who are compliant. We need an educated environment so that actual actions can be taken early on.

You need a good working network in order to be safe, yourself, and your patient is safe. The patient needs to actually be involved in the decision making, and you need to discuss the risk–benefit ratio with the patient. If the patient is accepting that, I think you can go for that. I think their attitude, the cultural differences, will also drive some of the decision. In some parts of the US, I think high-dose interferon with its toxicity was also much better accepted than in some parts of Europe. I think there are differences in perception of the risk–benefit ratio. But, I clearly believe that this is a step forward.

Axel Hauschild, MD: I’d like to make one comment. If you go to the details of the EORTC study, which was presented at ESMO here, and published in the New England Journal of Medicine yesterday, you see that the best patients are still those patients with low tumor load on the sentinel node, which means in one population, the stage IIb/c patients—the ones with relatively low tumor load. Whereas the patients with bulky lymph node disease, macroscopically lymph node–positive patients, are doing less well, comparatively.

Jeffrey Weber, MD, PhD: Although, unlike in some of the interferon trials, though, there appears to be, with the Eggermont presentation, a benefit both for the bulky patients and for the low-disease burden.

Axel Hauschild, MD: I agree. But, still, there’s a difference, right? So, the patients with low tumor load always do better. I believe there’s still a very high medical need if we are talking about prospectives for those patients with the high risk of relapse and the risk for very early relapse, which means it could be one day that these patients are more or less treated as stage IV melanoma patients. Because you know the risk for relapse is so high, and the relapse comes within weeks or just a couple of months, and these tumors are considered as having the behavior and metastatic spread pattern like stage IV patients.

Caroline Robert, MD, PhD: Because most of them are, indeed, already.

Axel Hauschild, MD: It could be, you know, the approach of hit it hard in the adjuvant setting, as well.

Transcript Edited for Clarity
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Transcript:

Jeffrey Weber, MD, PhD:
Let’s go beyond the sentinel node. Let’s say you have your patient with stage III disease. What’s the approach to adjuvant therapy? In other words, we just heard at this ESMO 2016 the first survival data. So, can you just recap, Axel, the survival data on the ipilimumab trial and tell me, will this change the way you talk to patients about possible adjuvant therapy?

Axel Hauschild, MD: When Lex Eggermont presented this trial for the first time at ASCO, and 2 years ago already, there was rumor in the room because relapse-free survival looked very promising, but overall survival data were not available, and there was a lot of toxicity. Everybody was saying, well, does this toxicity outweigh the benefits of the treatment? And, now that we have a positive trial in terms of significant improvement of overall survival by 28%, so, hazard ratio is 0.72 for what I call high-dose ipilimumab compared to placebo, there is certainly a good reason to explain this to the patients. It’s certainly not a drug which can be given at this high dose to every patient, and there is substantial toxicity, but, I think, we need to discuss it and certainly there’s the issue of whether, in the future, we can use lower dosages of ipilimumab or other checkpoint inhibitors. But, at the moment, it’s the best data which are available. But, Jeff, you are from the US, we are from Europe; in Europe, there is much more competition because it’s not only high-dose interferon which is approved for this setting of stage III patients, it’s also the low-dose interferon, which was, in Germany, much more popular to use in the adjuvant setting than high-dose interferon because high dose was so toxic.

Jeffrey Weber, MD, PhD: Although, in the US there’s little penetration of low-dose or pegylated interferon use in the US, and less and less interferon, and I think, especially, in view of the survival data, there will be perhaps more penetration. But, Reinhard, how do you look at patients getting high-dose ipilimumab? I mean, what do you tell them?

Reinhard Dummer, MD: Until now, interferon was the only drug available, and actually, in Switzerland, we have pegylated interferon on the market. And, I have to say that I have restricted the use of pegylated interferon to patients with an ulcerated primary plus micrometastases. And, for patients with nodal disease, with a major nodal disease, actually, I say interferon makes no sense. Certainly we’ve tried to bring them in clinical trials. But, unfortunately, this was not always possible. And, this is the patient population today that has another option. So, with the data that we have now out there with ipilimumab, this is a patient population with a high risk for relapse, and with a 28% improvement in survival. I think this is an option that you have to offer to the patient. The discussion about the risk–benefit will be a tough one because we will have to face a number of significant toxicities, the acute toxicities with colitis that might may become life-threatening, especially if not well handled. And, then, we have the life, probably lifelong problems with endocrine function.

Caroline Robert, MD, PhD: Yes, which is not that easy. I mean in the metastatic setting it’s easier to accept. But, in the adjuvant setting, to take pills every day because you are hormone insufficient, it’s not that easy.

Jeffrey Weber, MD, PhD: Yes. So, Dirk, how do you risk adjust this?

Dirk Schadendorf, MD: For high-risk patients, stage IIIc, I think there’s no option. We have complained for decades about no true evidence that interferon will translate into an overall survival benefit. I think that there is also clear evidence that interferon, if it works at all, works best in patients with minimal tumor load in the sentinel. Now, for the first time, actually, we have clear data showing and convincing long-term overall survival benefit with ipilimumab. Nevertheless, I agree with Reinhard. I think for high-dose ipilimumab, we need patients who are compliant. We need an educated environment so that actual actions can be taken early on.

You need a good working network in order to be safe, yourself, and your patient is safe. The patient needs to actually be involved in the decision making, and you need to discuss the risk–benefit ratio with the patient. If the patient is accepting that, I think you can go for that. I think their attitude, the cultural differences, will also drive some of the decision. In some parts of the US, I think high-dose interferon with its toxicity was also much better accepted than in some parts of Europe. I think there are differences in perception of the risk–benefit ratio. But, I clearly believe that this is a step forward.

Axel Hauschild, MD: I’d like to make one comment. If you go to the details of the EORTC study, which was presented at ESMO here, and published in the New England Journal of Medicine yesterday, you see that the best patients are still those patients with low tumor load on the sentinel node, which means in one population, the stage IIb/c patients—the ones with relatively low tumor load. Whereas the patients with bulky lymph node disease, macroscopically lymph node–positive patients, are doing less well, comparatively.

Jeffrey Weber, MD, PhD: Although, unlike in some of the interferon trials, though, there appears to be, with the Eggermont presentation, a benefit both for the bulky patients and for the low-disease burden.

Axel Hauschild, MD: I agree. But, still, there’s a difference, right? So, the patients with low tumor load always do better. I believe there’s still a very high medical need if we are talking about prospectives for those patients with the high risk of relapse and the risk for very early relapse, which means it could be one day that these patients are more or less treated as stage IV melanoma patients. Because you know the risk for relapse is so high, and the relapse comes within weeks or just a couple of months, and these tumors are considered as having the behavior and metastatic spread pattern like stage IV patients.

Caroline Robert, MD, PhD: Because most of them are, indeed, already.

Axel Hauschild, MD: It could be, you know, the approach of hit it hard in the adjuvant setting, as well.

Transcript Edited for Clarity
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