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Future Outlook: Treating Advanced Melanoma

Panelists: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Michael A. Davies, MD, PhD UT MD Anderson Cancer Center; Jason J. Luke, MD, FACP, University of Chicago; Caroline Robert, MD, PhD Gustave-Roussy; Merrick I. Ross, MD UT MD Anderson Cancer Center
Published: Friday, Dec 21, 2018



Transcript: 

Axel Hauschild, MD:
At the end of our discussion, I want to touch on 2 new components with different modes of action. There is the NKTR component, which is called NKTR-214. There was a trial released at ASCO [American Society of Clinical Oncology Annual Meeting] on this. Merrick, are you familiar with this data?

Merrick I. Ross, MD: No.

Axel Hauschild, MD: How about you, Jason?

Jason J. Luke, MD, FACP: Yes.

Axel Hauschild, MD: May I ask you to briefly explain the mode of action and then give us your sense of the interpretation of the data? This is very likely to become the next clinical trial in a phase III setting for first-line patients.

Jason J. Luke, MD, FACP: So NKTR-214 is an interesting molecule. It’s a pegylated IL-2 [interleukin-2] that sways toward the beta aspect of the IL-2 receptor. For those who remember, going back to the days of high-dose IL-2, the major upside or downside limitation of high-dose IL-2 is that it drives regulatory T cells, which was thought to cap the benefit in many patients. It was also highly toxic. The take here was to pegylate this molecule and then direct it more toward the beta aspect of the IL-2 receptor to try to drive more toward CD8 T cells—more of the effector approach—and to limit that toxicity.

And so in the clinical trial it was combined with nivolumab. In early studies, there was a striking effect. The response rate was very high. Initially it was about 80%, coming down now toward 50% to 60%. But in observation, several patients who were deemed to be PD-L1 [programmed death-ligand 1]–negative at baseline—actually, more than several—experienced very deep responses. This proposed the idea that maybe adding an IL-2 would sort of supercharge T cells that were unblocked by anti–PD-1 [anti–programmed cell death protein 1] therapy. This is a mechanism that we have been familiar with for decades. And so, there’s a lot of hope that this could be highly effective. The data set, to date, has been somewhat small. There was a fair amount of concern of that large drop in the response rate. There are putative mechanistic reasons why that might be the case, so we’re going to have to wait and see.

Axel Hauschild, MD: And it went down to 50%.

Jason J. Luke, MD, FACP: Yes. I think that a lot of people were struck by the translational data, which really showed a massive upregulation in the tumor microenvironment of interferon gamma-associated genes, which is the kind of immune response we want. A number of CD8 cells were going up. So I think there is hope. People know about IL-2, and we think that is something that can work in melanoma. So maybe it can be effective.

Axel Hauschild, MD: It’s too early to draw any conclusions right now. We need to wait for more clinical trial data.

Michael A. Davies, MD, PhD: I think we’ve learned that lesson based on the IDO [indoleamine 2, 3-dioxygenase] inhibitor experience. Even with very promising results in early phase clinical studies, we really need to wait for randomized clinical trial data.

Axel Hauschild, MD: Yes, or for randomized phase II clinical trial data preceding the phase III trials, right?

So the last point, Caroline, is a personal neoantigen vaccine—NEO-PV-01. It has been published in a high-ranking journal. Honestly, I forgot whether it was published in Nature or Science. This idea of combining anti–PD-1 with a vaccine is not really new, but it comes back to the point that we now have some checkpoint inhibitors.

Caroline Robert, MD, PhD: With all of the new drugs, we need to revisit our old ideas and our old drugs. Vaccination for melanoma and renal cell cancer failed before. But that was not because it wasn’t a good idea; it was because we didn’t know which antigen to use and which way to administer and how to design that. We also now have drugs that can be very good as adjuvant therapy, in fact. So we now know that the real tumor-associated antigens that really play a role are not very large in number. There are only a few of them. That’s why, when we have a large tumor burden, we increase the chance to have the good ones. But in reality, the ones that really play a role in rejection of the tumor—there are very few of them. The problem is that they are usually very personal. So here there is this approach with some personally derived neoantigen combined with anti–PD-1. It’s very promising. I’m not sure whether this approach will be the definitive one. Probably not, but we think it may be the way to go.

Axel Hauschild, MD: Thank you very much. Before we end this interesting discussion, I would like to ask every expert at the table for his or her highlight of ESMO [European Society for Medical Oncology] 2018 [Congress] and melanoma. I’d like to start with Merrick.

Merrick I. Ross, MD: I think the highlight is the CheckMate 511 trial. The fact that you can have similar efficacy with a flip-dosing of ipilimumab and avoid significant toxicity is a huge advance, and I think it will be the framework for our future investigations.

Axel Hauschild, MD: Thanks a lot. Jason?

Jason J. Luke, MD, FACP: I wanted to highlight a downer. There was an abstract about ipilimumab and nivolumab for uveal melanoma that didn’t get a lot of press but really showed a response rate that was not impressive—around 11%. It can’t be emphasized enough that these patients need to be referred for clinical trials because we do not have effective therapies for them.

Axel Hauschild, MD: Mike?

Michael A. Davies, MD, PhD: Again, hearing this update on the COMBI-AD results adds a lot to the conversation we have with patients about the relative benefits of adjuvant targeted therapy and adjuvant immunotherapy. I think it’s a very important result and is very exciting.

Caroline Robert, MD, PhD: And I would say that in so many fields we have to fight against our maybe preconceived ideas. We are in a period of paradigm shaking. We have to be very, very fluid in our strategies.

Axel Hauschild, MD: My personal highlight was seeing more on COMBI-AD and, also, the update of CheckMate 067. In both clinical trials, for the adjuvant arena as well as for the stage IV arena, we have long-lasting responses and long-lasting relapse-free survival, which is excellent and is good news for our patients.
So thank you very much. This was very enjoyable and very informative. It was a great pleasure for me to be your moderator. Thank you for your contributions, and thank you for the invitation.


Transcript Edited for Clarity
 

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Transcript: 

Axel Hauschild, MD:
At the end of our discussion, I want to touch on 2 new components with different modes of action. There is the NKTR component, which is called NKTR-214. There was a trial released at ASCO [American Society of Clinical Oncology Annual Meeting] on this. Merrick, are you familiar with this data?

Merrick I. Ross, MD: No.

Axel Hauschild, MD: How about you, Jason?

Jason J. Luke, MD, FACP: Yes.

Axel Hauschild, MD: May I ask you to briefly explain the mode of action and then give us your sense of the interpretation of the data? This is very likely to become the next clinical trial in a phase III setting for first-line patients.

Jason J. Luke, MD, FACP: So NKTR-214 is an interesting molecule. It’s a pegylated IL-2 [interleukin-2] that sways toward the beta aspect of the IL-2 receptor. For those who remember, going back to the days of high-dose IL-2, the major upside or downside limitation of high-dose IL-2 is that it drives regulatory T cells, which was thought to cap the benefit in many patients. It was also highly toxic. The take here was to pegylate this molecule and then direct it more toward the beta aspect of the IL-2 receptor to try to drive more toward CD8 T cells—more of the effector approach—and to limit that toxicity.

And so in the clinical trial it was combined with nivolumab. In early studies, there was a striking effect. The response rate was very high. Initially it was about 80%, coming down now toward 50% to 60%. But in observation, several patients who were deemed to be PD-L1 [programmed death-ligand 1]–negative at baseline—actually, more than several—experienced very deep responses. This proposed the idea that maybe adding an IL-2 would sort of supercharge T cells that were unblocked by anti–PD-1 [anti–programmed cell death protein 1] therapy. This is a mechanism that we have been familiar with for decades. And so, there’s a lot of hope that this could be highly effective. The data set, to date, has been somewhat small. There was a fair amount of concern of that large drop in the response rate. There are putative mechanistic reasons why that might be the case, so we’re going to have to wait and see.

Axel Hauschild, MD: And it went down to 50%.

Jason J. Luke, MD, FACP: Yes. I think that a lot of people were struck by the translational data, which really showed a massive upregulation in the tumor microenvironment of interferon gamma-associated genes, which is the kind of immune response we want. A number of CD8 cells were going up. So I think there is hope. People know about IL-2, and we think that is something that can work in melanoma. So maybe it can be effective.

Axel Hauschild, MD: It’s too early to draw any conclusions right now. We need to wait for more clinical trial data.

Michael A. Davies, MD, PhD: I think we’ve learned that lesson based on the IDO [indoleamine 2, 3-dioxygenase] inhibitor experience. Even with very promising results in early phase clinical studies, we really need to wait for randomized clinical trial data.

Axel Hauschild, MD: Yes, or for randomized phase II clinical trial data preceding the phase III trials, right?

So the last point, Caroline, is a personal neoantigen vaccine—NEO-PV-01. It has been published in a high-ranking journal. Honestly, I forgot whether it was published in Nature or Science. This idea of combining anti–PD-1 with a vaccine is not really new, but it comes back to the point that we now have some checkpoint inhibitors.

Caroline Robert, MD, PhD: With all of the new drugs, we need to revisit our old ideas and our old drugs. Vaccination for melanoma and renal cell cancer failed before. But that was not because it wasn’t a good idea; it was because we didn’t know which antigen to use and which way to administer and how to design that. We also now have drugs that can be very good as adjuvant therapy, in fact. So we now know that the real tumor-associated antigens that really play a role are not very large in number. There are only a few of them. That’s why, when we have a large tumor burden, we increase the chance to have the good ones. But in reality, the ones that really play a role in rejection of the tumor—there are very few of them. The problem is that they are usually very personal. So here there is this approach with some personally derived neoantigen combined with anti–PD-1. It’s very promising. I’m not sure whether this approach will be the definitive one. Probably not, but we think it may be the way to go.

Axel Hauschild, MD: Thank you very much. Before we end this interesting discussion, I would like to ask every expert at the table for his or her highlight of ESMO [European Society for Medical Oncology] 2018 [Congress] and melanoma. I’d like to start with Merrick.

Merrick I. Ross, MD: I think the highlight is the CheckMate 511 trial. The fact that you can have similar efficacy with a flip-dosing of ipilimumab and avoid significant toxicity is a huge advance, and I think it will be the framework for our future investigations.

Axel Hauschild, MD: Thanks a lot. Jason?

Jason J. Luke, MD, FACP: I wanted to highlight a downer. There was an abstract about ipilimumab and nivolumab for uveal melanoma that didn’t get a lot of press but really showed a response rate that was not impressive—around 11%. It can’t be emphasized enough that these patients need to be referred for clinical trials because we do not have effective therapies for them.

Axel Hauschild, MD: Mike?

Michael A. Davies, MD, PhD: Again, hearing this update on the COMBI-AD results adds a lot to the conversation we have with patients about the relative benefits of adjuvant targeted therapy and adjuvant immunotherapy. I think it’s a very important result and is very exciting.

Caroline Robert, MD, PhD: And I would say that in so many fields we have to fight against our maybe preconceived ideas. We are in a period of paradigm shaking. We have to be very, very fluid in our strategies.

Axel Hauschild, MD: My personal highlight was seeing more on COMBI-AD and, also, the update of CheckMate 067. In both clinical trials, for the adjuvant arena as well as for the stage IV arena, we have long-lasting responses and long-lasting relapse-free survival, which is excellent and is good news for our patients.
So thank you very much. This was very enjoyable and very informative. It was a great pleasure for me to be your moderator. Thank you for your contributions, and thank you for the invitation.


Transcript Edited for Clarity
 
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TitleExpiration DateCME Credits
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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