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Considering Chemotherapy's Value in Melanoma

Panelists: Jeffrey S. Weber, MD, PhD, NYU Langone Health; Reinhard G. Dummer, MD, University Hospital of Zurich; Axel Hauschild, MD, PhD, University Hospital Schleswig-Holstein; Michael A. Postow, MD, Memorial Sloan Kettering Cancer Center; Caroline Robert, MD, PhD, Gustave-Roussy
Published: Monday, Oct 30, 2017



Transcript: 

Axel Hauschild, MD, PhD: I need to say that we always have a bias. We have the good cases in mind forever: surprising responses to chemotherapy, complete responses. I saw some cases that were long-lasting. I guess that they were cured with chemotherapy.

Caroline Robert, MD, PhD: Yes.

Axel Hauschild, MD, PhD: But you forget the bad cases, and they are the vast majority, 90% or 95%, of the cases. We’ve seen some late responses, particularly with PD-1 antibodies. You can see a shift very late from stable disease to partial or complete responses. So, it could be a late response, but the patient does not care about that. The patient is getting a nice response, which is hopefully long-lasting. The patient is not asking for the mode of action. We are asking for it, because we are surprised. But chemotherapy for me is still a last-line treatment, and I would call it a bridging therapy, Reinhard. I like this term.

I would like to make one point. The only convincing data that I have seen in patients who have received ipilimumab, ipilimumab plus nivolumab, and all of these treatments are on adoptive T-cell transfer. This 32% rate of complete response is published by the Rosenberg group, and the cases by Jacob Schachter from Tel Aviv University are really convincing. The only issue with adoptive T-cell transfer and tumor infiltrating lymphocytes I have is that these are highly selective patients. Are they taking just the best of the best patients with positive predictive factors? And now, because we do not have as many trials as Paris, I had the offer to be part of a clinical trial of TIL cells. And there’s a trial coming to Germany with multiple centers where the TILs are produced professionally, outside of the centers, and we can take part. This is a wonderful option for my patients, because all of my patients can be included, whether they have had 1, 2, or 3 lines of treatment. This is the ideal scenario for the BRAF wild-type patients.

Jeffrey S. Weber, MD, PhD: Are you telling me that IL-2 [interleukin-2] is not dead?

Axel Hauschild, MD, PhD: IL-2 is dead because it was never alive in Europe, because it was never approved. I don’t know any clinical center in Europe that is using IL-2. There is 1 exception in Denmark. In Denmark, surprisingly, it’s not approved but used. The combination with interferon-alpha.

Jeffrey S. Weber, MD, PhD: Really? Michael, do you ever use high-dose IL-2? It’s actually, in the United States, the one approved treatment for metastatic melanoma that we haven’t discussed at all.

Michael A. Postow, MD: Exactly, and it’s interesting. Some of our historical treatments like IL-2 have, I think, been supplanted by a lot of our new treatments that we’ve been talking about: the BRAF/MEK inhibitors, immune checkpoint inhibitors. But the reality is that they don’t work any less well now than they ever did in the past even though we have new drugs that might be better. I think there could still be a role for some of these treatments, including IL-2 and chemotherapy. Of course, we want to try to recruit patients for clinical trials. But with IL-2, absolutely, there’s that group of patients who can have those long-term complete responses now. It’s not as many people as we would want—between 5% and 10%, unfortunately—but there is still a signal. There is still some efficacy, and, if patients have difficult times accessing clinical trials and they’ve had checkpoint inhibitors and BRAF and MEK inhibitors, I think this is something that still enters into the discussion.

Just to make a comment on chemotherapy as well, there is still a response rate with chemotherapy, and I think that it’s worth talking to patients about that, especially if they’re having difficulties accessing clinical trials. There are a number of eligibility restrictions on clinical trials. Sometimes, patients geographically cannot participate in clinical trials. Chemotherapy still may have a role for those patients after they’ve had other drugs like the checkpoint inhibitors, IL-2, or BRAF and MEK inhibitors. It doesn’t work any less well now because we’ve had other drugs that have shown better benefit.

Jeffrey S. Weber, MD, PhD: What you’re saying is that if Dr. Van Winkle would wake up from his 50-year sleep, he might actually be familiar with some of the treatments we’re using.

Caroline Robert, MD, PhD: Yes, but we also have to be careful, because now some physicians say, “Chemotherapy doesn’t work, let’s forget it. I will give you immunotherapy or targeted therapy.” We have to be careful, because if the patient does not respond to anything and you end up saying that you have nothing or chemotherapy, then how does he feel or how does she feel? Because you said before that it doesn’t work. So, you have to be careful.

Jeffrey S. Weber, MD, PhD: Those are the patients who should be going on a trial.

Caroline Robert, MD, PhD: It’s not always possible.

Jeffrey S. Weber, MD, PhD: That’s true, not all patients are eligible for trials. Although, at least in the United States, I think eligibility criteria are loosening up, which has always been a problem. It used to be that you could never put an ocular melanoma patient on trials. It used to be that having brain metastases at any point in their disease course was an exclusion, but that’s not always true.

Axel Hauschild, MD, PhD: Jeff, honestly, regarding clinical trial access, you are living in a paradise in the United States. Very many of the phase I trials for patients who had received every treatment, who were refractory, are going to the United States and not to Europe. With Zurich, we are discussing a luxury situation, but for the vast majority of countries in Europe, there are no clinical trials available and there are none of the new drugs available.

I’m bringing this up here just to mention it, because there was a nice survey from Lidija Sekulovic from Serbia, and she was figuring out that 5000 metastatic melanoma patients, stage 4, have no access to any of the new drugs. This was brought to European Journal of Cancer, to the European Parliament, and to an ESMO press conference last year. It’s really a nightmare in the vast majority of countries in Europe. So, we are talking about the best of the best centers, the core centers. But still, with chemotherapy, if you explain to these patients that chemotherapy is not of any value, you are taking away the only treatment opportunity in these countries.

Transcript Edited for Clarity 

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Transcript: 

Axel Hauschild, MD, PhD: I need to say that we always have a bias. We have the good cases in mind forever: surprising responses to chemotherapy, complete responses. I saw some cases that were long-lasting. I guess that they were cured with chemotherapy.

Caroline Robert, MD, PhD: Yes.

Axel Hauschild, MD, PhD: But you forget the bad cases, and they are the vast majority, 90% or 95%, of the cases. We’ve seen some late responses, particularly with PD-1 antibodies. You can see a shift very late from stable disease to partial or complete responses. So, it could be a late response, but the patient does not care about that. The patient is getting a nice response, which is hopefully long-lasting. The patient is not asking for the mode of action. We are asking for it, because we are surprised. But chemotherapy for me is still a last-line treatment, and I would call it a bridging therapy, Reinhard. I like this term.

I would like to make one point. The only convincing data that I have seen in patients who have received ipilimumab, ipilimumab plus nivolumab, and all of these treatments are on adoptive T-cell transfer. This 32% rate of complete response is published by the Rosenberg group, and the cases by Jacob Schachter from Tel Aviv University are really convincing. The only issue with adoptive T-cell transfer and tumor infiltrating lymphocytes I have is that these are highly selective patients. Are they taking just the best of the best patients with positive predictive factors? And now, because we do not have as many trials as Paris, I had the offer to be part of a clinical trial of TIL cells. And there’s a trial coming to Germany with multiple centers where the TILs are produced professionally, outside of the centers, and we can take part. This is a wonderful option for my patients, because all of my patients can be included, whether they have had 1, 2, or 3 lines of treatment. This is the ideal scenario for the BRAF wild-type patients.

Jeffrey S. Weber, MD, PhD: Are you telling me that IL-2 [interleukin-2] is not dead?

Axel Hauschild, MD, PhD: IL-2 is dead because it was never alive in Europe, because it was never approved. I don’t know any clinical center in Europe that is using IL-2. There is 1 exception in Denmark. In Denmark, surprisingly, it’s not approved but used. The combination with interferon-alpha.

Jeffrey S. Weber, MD, PhD: Really? Michael, do you ever use high-dose IL-2? It’s actually, in the United States, the one approved treatment for metastatic melanoma that we haven’t discussed at all.

Michael A. Postow, MD: Exactly, and it’s interesting. Some of our historical treatments like IL-2 have, I think, been supplanted by a lot of our new treatments that we’ve been talking about: the BRAF/MEK inhibitors, immune checkpoint inhibitors. But the reality is that they don’t work any less well now than they ever did in the past even though we have new drugs that might be better. I think there could still be a role for some of these treatments, including IL-2 and chemotherapy. Of course, we want to try to recruit patients for clinical trials. But with IL-2, absolutely, there’s that group of patients who can have those long-term complete responses now. It’s not as many people as we would want—between 5% and 10%, unfortunately—but there is still a signal. There is still some efficacy, and, if patients have difficult times accessing clinical trials and they’ve had checkpoint inhibitors and BRAF and MEK inhibitors, I think this is something that still enters into the discussion.

Just to make a comment on chemotherapy as well, there is still a response rate with chemotherapy, and I think that it’s worth talking to patients about that, especially if they’re having difficulties accessing clinical trials. There are a number of eligibility restrictions on clinical trials. Sometimes, patients geographically cannot participate in clinical trials. Chemotherapy still may have a role for those patients after they’ve had other drugs like the checkpoint inhibitors, IL-2, or BRAF and MEK inhibitors. It doesn’t work any less well now because we’ve had other drugs that have shown better benefit.

Jeffrey S. Weber, MD, PhD: What you’re saying is that if Dr. Van Winkle would wake up from his 50-year sleep, he might actually be familiar with some of the treatments we’re using.

Caroline Robert, MD, PhD: Yes, but we also have to be careful, because now some physicians say, “Chemotherapy doesn’t work, let’s forget it. I will give you immunotherapy or targeted therapy.” We have to be careful, because if the patient does not respond to anything and you end up saying that you have nothing or chemotherapy, then how does he feel or how does she feel? Because you said before that it doesn’t work. So, you have to be careful.

Jeffrey S. Weber, MD, PhD: Those are the patients who should be going on a trial.

Caroline Robert, MD, PhD: It’s not always possible.

Jeffrey S. Weber, MD, PhD: That’s true, not all patients are eligible for trials. Although, at least in the United States, I think eligibility criteria are loosening up, which has always been a problem. It used to be that you could never put an ocular melanoma patient on trials. It used to be that having brain metastases at any point in their disease course was an exclusion, but that’s not always true.

Axel Hauschild, MD, PhD: Jeff, honestly, regarding clinical trial access, you are living in a paradise in the United States. Very many of the phase I trials for patients who had received every treatment, who were refractory, are going to the United States and not to Europe. With Zurich, we are discussing a luxury situation, but for the vast majority of countries in Europe, there are no clinical trials available and there are none of the new drugs available.

I’m bringing this up here just to mention it, because there was a nice survey from Lidija Sekulovic from Serbia, and she was figuring out that 5000 metastatic melanoma patients, stage 4, have no access to any of the new drugs. This was brought to European Journal of Cancer, to the European Parliament, and to an ESMO press conference last year. It’s really a nightmare in the vast majority of countries in Europe. So, we are talking about the best of the best centers, the core centers. But still, with chemotherapy, if you explain to these patients that chemotherapy is not of any value, you are taking away the only treatment opportunity in these countries.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Vignette Series: 34th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow®Feb 28, 20182.0
Community Practice Connections™: 13th Annual International Symposium on Melanoma and Other Cutaneous Malignancies®Apr 28, 20182.0
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