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Targeting NRAS Mutations in Metastatic 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: Tuesday, Oct 17, 2017



Transcript: 

Jeffrey S. Weber, MD, PhD: Another issue is that Michael talked about how at his institution, they’re doing genetic profiling on every patient with stage 3 and 4 disease. You will find out if people have other mutations than BRAF. You will find out if they’re KIT-mutated or NRAS-mutated. So, Reinhard, does knowing about the NRAS mutation in about 15% to 20% of patients have an impact on your treatment decision? And have you been involved in any NRAS-targeted therapy trials?

Reinhard G. Dummer, MD: In general, I think we should do more genetic testing. I’m not really a friend of complete exome sequencing, because it is too time consuming and the information is not really helpful. But I think a reasonable targeted sequencing approach would help us, and I’m sure that we will be able to identify a number of mutations in tumor suppressive genes that might help us to say how long the response duration will be. We can really read a lot out of all of this, and we will learn this is what we need. We need more information that we first have to collect and then bring together in databases.

For the NRAS situations, I think there are a lot of myths around NRAS. For example, that these patients have more aggressive disease, but I think the data are not so convincing. There are patients with NRAS mutations who actually have really good behavior, and immunotherapy works nicely. There are even reports that suggest they respond better to immunotherapy. I would say the patients are typically older, though there are other factors involved, like a high mutational burden.

And obviously, NRAS-mutated patients have a good chance to respond to MEK inhibition. This was investigated in the NEMO trial, and the results of the study meet a primary endpoint, but I think the data are not strong enough to convince us that we should use this. So, we have to continue, I think. A MEK inhibitor could be a good backbone, but we have to select other molecules like a CDK4 inhibitor or a MDM2 inhibitor or anything else, maybe based on the mutational profile that we see in the individual patient, to increase this.

Jeffrey S. Weber, MD, PhD: We haven’t heard much about CDK4 plus MEK inhibition in that population. Is there any information that you have?

Reinhard G. Dummer, MD: The combination is quite toxic and difficult to manage, and you probably should have a genetic basis to use it. Maybe CDKN2A mutations or mutations in this area would help. There are preclinical data that suggest the NRAS mutation results in a very strong activation of cyclin-dependent kinases. So, by this, it is justified to use this combination. But I think we really have to learn more, especially in the clinic.

Jeffrey S. Weber, MD, PhD: Axel, is the NRAS mutation a surrogate for someone who is going to do well with immunotherapy? This was out there several years ago.

Axel Hauschild, MD, PhD: That was discussed in the frame of ipilimumab development and that the NRAS patients are doing a bit better. In our days, it’s not playing an important role. This is a group of BRAF wild-type patients, and there are 2 clinical trials coming up very soon, 2 randomized phase III trials, to approve a MEK inhibitor. Plus, on one clinical trial, there’s a PD-L1 antibody, and on the other clinical trial, there’s a PD-1 antibody. They are targeting just the BRAF wild-type patients, who include the vast majority of NRAS-mutated patients, so that might be something in the future.

I want to give a very brief comment on combining MAP kinase pathway inhibitors, like BRAF/MEK inhibitors, with PI3 kinase inhibitors. The data I have seen on triple regimens are not really exciting. The response rates appear not to be higher, but look even lower than for BRAF plus MEK inhibition alone and with a substantial add-on of toxicity. And therefore, it’s not an easy task to combine 3 targeted agents, and I’m not sure if this is the future. I think the future lies in combining targeted therapies with immunotherapies. Neglecting immunotherapies for melanoma as part of a combination is maybe not the right way to go in the future.

Jeffrey S. Weber, MD, PhD: It’s my feeling that the field of clinical development of multiple targeted therapies appears to have stagnated. Do you think it’s because we’re now adding immunotherapy to targeted therapy?

Axel Hauschild, MD, PhD: I believe it’s because immunotherapies are very strong. It’s more or less a backbone therapy for metastatic melanoma, and there are also the toxicity issues of targeted agents.

Reinhard G. Dummer, MD: But I think the issue is that we need better patient selection. A good example is the BRAF/MEK combination plus a cyclin-dependent kinase. These data have been presented at the ASCO. Actually, I have treated a number of patients, and there were some of them that had extraordinary and exciting long-lasting responses. I think if we do a complete genetic profiling, there would be a good chance that we would identify patients with cyclin-D amplifications or mutations in P15 or P16 that really will help us. So, I think these trials need molecular guidance, and then targeted therapy can be further developed.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: Another issue is that Michael talked about how at his institution, they’re doing genetic profiling on every patient with stage 3 and 4 disease. You will find out if people have other mutations than BRAF. You will find out if they’re KIT-mutated or NRAS-mutated. So, Reinhard, does knowing about the NRAS mutation in about 15% to 20% of patients have an impact on your treatment decision? And have you been involved in any NRAS-targeted therapy trials?

Reinhard G. Dummer, MD: In general, I think we should do more genetic testing. I’m not really a friend of complete exome sequencing, because it is too time consuming and the information is not really helpful. But I think a reasonable targeted sequencing approach would help us, and I’m sure that we will be able to identify a number of mutations in tumor suppressive genes that might help us to say how long the response duration will be. We can really read a lot out of all of this, and we will learn this is what we need. We need more information that we first have to collect and then bring together in databases.

For the NRAS situations, I think there are a lot of myths around NRAS. For example, that these patients have more aggressive disease, but I think the data are not so convincing. There are patients with NRAS mutations who actually have really good behavior, and immunotherapy works nicely. There are even reports that suggest they respond better to immunotherapy. I would say the patients are typically older, though there are other factors involved, like a high mutational burden.

And obviously, NRAS-mutated patients have a good chance to respond to MEK inhibition. This was investigated in the NEMO trial, and the results of the study meet a primary endpoint, but I think the data are not strong enough to convince us that we should use this. So, we have to continue, I think. A MEK inhibitor could be a good backbone, but we have to select other molecules like a CDK4 inhibitor or a MDM2 inhibitor or anything else, maybe based on the mutational profile that we see in the individual patient, to increase this.

Jeffrey S. Weber, MD, PhD: We haven’t heard much about CDK4 plus MEK inhibition in that population. Is there any information that you have?

Reinhard G. Dummer, MD: The combination is quite toxic and difficult to manage, and you probably should have a genetic basis to use it. Maybe CDKN2A mutations or mutations in this area would help. There are preclinical data that suggest the NRAS mutation results in a very strong activation of cyclin-dependent kinases. So, by this, it is justified to use this combination. But I think we really have to learn more, especially in the clinic.

Jeffrey S. Weber, MD, PhD: Axel, is the NRAS mutation a surrogate for someone who is going to do well with immunotherapy? This was out there several years ago.

Axel Hauschild, MD, PhD: That was discussed in the frame of ipilimumab development and that the NRAS patients are doing a bit better. In our days, it’s not playing an important role. This is a group of BRAF wild-type patients, and there are 2 clinical trials coming up very soon, 2 randomized phase III trials, to approve a MEK inhibitor. Plus, on one clinical trial, there’s a PD-L1 antibody, and on the other clinical trial, there’s a PD-1 antibody. They are targeting just the BRAF wild-type patients, who include the vast majority of NRAS-mutated patients, so that might be something in the future.

I want to give a very brief comment on combining MAP kinase pathway inhibitors, like BRAF/MEK inhibitors, with PI3 kinase inhibitors. The data I have seen on triple regimens are not really exciting. The response rates appear not to be higher, but look even lower than for BRAF plus MEK inhibition alone and with a substantial add-on of toxicity. And therefore, it’s not an easy task to combine 3 targeted agents, and I’m not sure if this is the future. I think the future lies in combining targeted therapies with immunotherapies. Neglecting immunotherapies for melanoma as part of a combination is maybe not the right way to go in the future.

Jeffrey S. Weber, MD, PhD: It’s my feeling that the field of clinical development of multiple targeted therapies appears to have stagnated. Do you think it’s because we’re now adding immunotherapy to targeted therapy?

Axel Hauschild, MD, PhD: I believe it’s because immunotherapies are very strong. It’s more or less a backbone therapy for metastatic melanoma, and there are also the toxicity issues of targeted agents.

Reinhard G. Dummer, MD: But I think the issue is that we need better patient selection. A good example is the BRAF/MEK combination plus a cyclin-dependent kinase. These data have been presented at the ASCO. Actually, I have treated a number of patients, and there were some of them that had extraordinary and exciting long-lasting responses. I think if we do a complete genetic profiling, there would be a good chance that we would identify patients with cyclin-D amplifications or mutations in P15 or P16 that really will help us. So, I think these trials need molecular guidance, and then targeted therapy can be further developed.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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