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Adjuvant PD-(L)1 Inhibitors 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 14, 2016


Transcript:

Jeffrey Weber, MD, PhD:
Do you think that ipilimumab will have its time and then be surpassed by PD-1 blockade? So, Reinhard, what can you tell us about upcoming trials whose data I assume will be available in the next year to 2 years?

Reinhard Dummer, MD: Though we are interested by the ipilimumab data, we all are aware that anti–PD-1 therapy has such a beneficial adverse event profile. Therefore, anti–PD-1 agents are more or less the favored drugs in the adjuvant setting. There is far less toxicity. And, from the stage IV data we know, and this has been shown in several prospective randomized trials, anti–PD-1 therapy has better efficacy. So, to investigate this in the adjuvant setting, it’s essential, and I think this has already been done now. We have the comparison ipilimumab 10 mg/kg versus anti–PD-1. And, we have the EORTC study comparing a placebo to ant–-PD-1 therapy. Unfortunately, it will take another 4 to 5 years until we know whether anti–PD-1 therapy will be really as effective.

Dirk Schadendorf, MD: In terms of overall survival.

Reinhard Dummer, MD: Of overall survival. We still have to keep in mind that the anti–PD-1 mode of action depends on the presence of tumor cells. And, in a disease where you have a minimal residual disease, there might be some drawbacks and feedback mechanisms that reduce the efficacy.

Jeffrey Weber, MD, PhD: Although, is that urban legend or is that reality? Axel, do you really buy into that idea that you need a tumor microenvironment for PD-1 blockade to work?

Axel Hauschild, MD: From the theoretical standpoint, Reinhard is absolutely correct. But, on the other hand, you know it’s an activation of T cells, which is independent from any PD-ligand–1 expression on tumor cells, which we know from stage IV melanoma. Therefore, I’m very hopeful, and I think we are speaking about the same expectations that PD-1 antibodies will soon replace ipilimumab simply because they are more efficacious and less toxic in stage VI. I strongly believe the same will be seen in stage III. Also, I want to point out that there might be an alternative for ipilimumab. You know ipilimumab 10 mg/kg versus 3 was tested in the US compared to high-dose interferon. So, I believe it’s a very important trial, the intergroup study, because it’s not only the dose of 10 mg/kg, which is tested again, but it’s also the testing for only one year compared to ipilimumab 3 mg/kg for 1 year and high-dose interferon, as approved. It’s not telling us if this is superior to just a placebo. It’s telling us if this is superior for so-called standard of care in US and Europe.

Jeffrey Weber, MD, PhD: Yes, but won’t that take a long time to become mature? You have 2 active regimens: ipilimumab 3 mg/kg and ipilimumab 10 mg/kg. That could take a long time.

Caroline Robert, MD, PhD: Yes. Plus, now it’s much more difficult to analyze because we have drugs that are impacting overall survival afterwards when patients relapse. So, it will be now, the trials that are running now, because a patient when they relapse will have a treatment that has some efficacy, which was not the case before. So, we have to be ready to change our ways to analyze the results.

Axel Hauschild, MD: I don’t think that overall survival is the endpoint of the future because we have so many active drugs for disease in most of the trials, with only one exception, you know, relapse-free survival (RFS) as the endpoint. And, this is not impacted by subsequent treatment modalities. Therefore, in terms of RFS, because we can see the results earlier, I think that we will have clear results.

Jeffrey Weber, MD, PhD: To close out the book on the adjuvant discussion, it sounds like RFS will be the endpoint of the future, not OS, which I think we all agree with.

Transcript Edited for Clarity
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Transcript:

Jeffrey Weber, MD, PhD:
Do you think that ipilimumab will have its time and then be surpassed by PD-1 blockade? So, Reinhard, what can you tell us about upcoming trials whose data I assume will be available in the next year to 2 years?

Reinhard Dummer, MD: Though we are interested by the ipilimumab data, we all are aware that anti–PD-1 therapy has such a beneficial adverse event profile. Therefore, anti–PD-1 agents are more or less the favored drugs in the adjuvant setting. There is far less toxicity. And, from the stage IV data we know, and this has been shown in several prospective randomized trials, anti–PD-1 therapy has better efficacy. So, to investigate this in the adjuvant setting, it’s essential, and I think this has already been done now. We have the comparison ipilimumab 10 mg/kg versus anti–PD-1. And, we have the EORTC study comparing a placebo to ant–-PD-1 therapy. Unfortunately, it will take another 4 to 5 years until we know whether anti–PD-1 therapy will be really as effective.

Dirk Schadendorf, MD: In terms of overall survival.

Reinhard Dummer, MD: Of overall survival. We still have to keep in mind that the anti–PD-1 mode of action depends on the presence of tumor cells. And, in a disease where you have a minimal residual disease, there might be some drawbacks and feedback mechanisms that reduce the efficacy.

Jeffrey Weber, MD, PhD: Although, is that urban legend or is that reality? Axel, do you really buy into that idea that you need a tumor microenvironment for PD-1 blockade to work?

Axel Hauschild, MD: From the theoretical standpoint, Reinhard is absolutely correct. But, on the other hand, you know it’s an activation of T cells, which is independent from any PD-ligand–1 expression on tumor cells, which we know from stage IV melanoma. Therefore, I’m very hopeful, and I think we are speaking about the same expectations that PD-1 antibodies will soon replace ipilimumab simply because they are more efficacious and less toxic in stage VI. I strongly believe the same will be seen in stage III. Also, I want to point out that there might be an alternative for ipilimumab. You know ipilimumab 10 mg/kg versus 3 was tested in the US compared to high-dose interferon. So, I believe it’s a very important trial, the intergroup study, because it’s not only the dose of 10 mg/kg, which is tested again, but it’s also the testing for only one year compared to ipilimumab 3 mg/kg for 1 year and high-dose interferon, as approved. It’s not telling us if this is superior to just a placebo. It’s telling us if this is superior for so-called standard of care in US and Europe.

Jeffrey Weber, MD, PhD: Yes, but won’t that take a long time to become mature? You have 2 active regimens: ipilimumab 3 mg/kg and ipilimumab 10 mg/kg. That could take a long time.

Caroline Robert, MD, PhD: Yes. Plus, now it’s much more difficult to analyze because we have drugs that are impacting overall survival afterwards when patients relapse. So, it will be now, the trials that are running now, because a patient when they relapse will have a treatment that has some efficacy, which was not the case before. So, we have to be ready to change our ways to analyze the results.

Axel Hauschild, MD: I don’t think that overall survival is the endpoint of the future because we have so many active drugs for disease in most of the trials, with only one exception, you know, relapse-free survival (RFS) as the endpoint. And, this is not impacted by subsequent treatment modalities. Therefore, in terms of RFS, because we can see the results earlier, I think that we will have clear results.

Jeffrey Weber, MD, PhD: To close out the book on the adjuvant discussion, it sounds like RFS will be the endpoint of the future, not OS, which I think we all agree with.

Transcript Edited for Clarity
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