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Novel Approaches in Melanoma

Panelists:Keith T. Flaherty, MD Massachusetts General Hospital;Georgina Long, BSc, MBBS, FRACP, Melanoma Institute of Australia;Jason J. Luke, MD, FACP, University of Chicago;Jeffrey S. Weber, MD, NYU Langone Medical Center;Jonathan S. Zager, MD, Moffitt Cancer Center
Published: Wednesday, Sep 28, 2016



Transcript:

Keith T. Flaherty, MD:
Jason, a patient has had immunotherapy and, let’s say, exhausted all available immunotherapies, and they have a BRAF mutation. They’re on BRAF inhibitor-based treatment. They’ve responded for a time, they’re now starting to progress. Is there treatment beyond progression? Without available FDA-approved therapies to reach for otherwise, is that a reasonable proposition for most patients or all patients?

Jason J. Luke, MD: With a BRAF inhibitor?

Keith T. Flaherty, MD: Yes.

Jason J. Luke, MD: I think it’s an individual patient-level decision. What is the progression? If you have an instance where you can intervene somehow on that tumor, then absolutely. If it’s widespread systemic progression, it’s not like immunotherapy where we think there might be a little something here. But, absolutely intervene in the context of an isolated lesion or a couple of lesions. At our site, we have a very active radiation oncology group who will do multisites, stereotactic, body radiotherapy. Even if a couple metastases start to grow, we can get them, so I think that’s very reasonable. But, again, I think that’s a patient-level consideration. Unfortunately, we have many patients who get past PD-1, they progress systemically on BRAF inhibitor, and we still have to employ chemotherapy in some of these patients. And, I don’t think it should be lost sight that that does still happen sometimes for some patients.

Keith T. Flaherty, MD: Just a quick last point. If a patient had a BRAF mutation, received BRAF/MEK up-front therapy, ultimately progresses, moves to immunotherapy, ultimately progresses, any role to go back to BRAF inhibitor?

Jason J. Luke, MD: Absolutely, absolutely. So, this is something that we do in clinical practice quite a bit with my network of folks that I work with. We have patients who are BRAF mutation where we know that works. The question is, how are we going to use that optimally? We often will use it to maximum benefit and take patients off if they’ve already progressed through other things with the hope of getting them on a study, knowing we can go back. And, we will do this intermittently with the idea to try to keep the patient in good shape, as long as we can to give them as many chances as we can to other options?

Keith T. Flaherty, MD: That’s great. Of course, we need targeted therapy options for other patients. We’re starting to get a little bit of a glimmer. Maybe we can get a foot in the door there. So, how do you look at this emerging binimetinib, MEK inhibitor monotherapy data, Georgina, in NRAS-mutant patients? Is that a therapy that is interesting and maybe building a cornerstone for combination? Is it actually a therapy that, based on the emerging evidence, actually could be endorsed in practice?

Georgina Long, BSc, MBBS: Based on the emerging evidence in the NEMO study, the phase III trial of only Q61 NRAS-mutant melanoma that randomized patients to dacarbazine versus binimetinib, the MEK inhibitor, I don’t think this trial will change clinical practice at all. There’s a benefit with progression-free survival, there’s a benefit with response, but there’s no benefit with survival. But, it is a wonderful foundation because there’s definitely a signal there. It’s a wonderful foundation for combinations. And, I think MEK inhibition is a good basis because the MAP kinase pathway is constitutively active in the majority of melanomas, even if they’re not BRAF mutated. So, I think it’s a good foundation. It is a building block. There is definite PFS and response rate advantage. It’s something we now need to understand more. As we started this whole discussion with, when we were talking about mutations, we need to understand better the pathways and how to inhibit them. But, a MEK inhibitor is a good foundation to add things on to.

Jason J. Luke, MD: Because we raised it in the very beginning about other molecular targets, one that we didn’t discuss—it isn’t quite ready for prime-time in melanoma but maybe is in breast cancer—is CDK4. So, there were data here at ASCO around CDK4 being important in some of the other melanoma subtypes. But, again, as an add-on in the NRAS space, it looks like regulation of the cell cycle machinery as a secondary threshold in most melanomas is a good combinatorial partner. And building on these MEK data in RAS-mutant tumors, I think that’s the obvious next step. We have some data already in this space, and I think that you’ll see that coming forward very soon.

Georgina Long, BSc, MBBS: And, CDK2NA, which is another inhibitor, that whole cell cycling mechanism is quite common in melanoma. I agree. I think the combination of a MEK inhibitor and CDK4/6 inhibitor, which has been explored in a phase I in NRAS, could be extended to other types of melanomas other than just NRAS. But, it’s definitely something to watch.

Transcript Edited for Clarity

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Transcript:

Keith T. Flaherty, MD:
Jason, a patient has had immunotherapy and, let’s say, exhausted all available immunotherapies, and they have a BRAF mutation. They’re on BRAF inhibitor-based treatment. They’ve responded for a time, they’re now starting to progress. Is there treatment beyond progression? Without available FDA-approved therapies to reach for otherwise, is that a reasonable proposition for most patients or all patients?

Jason J. Luke, MD: With a BRAF inhibitor?

Keith T. Flaherty, MD: Yes.

Jason J. Luke, MD: I think it’s an individual patient-level decision. What is the progression? If you have an instance where you can intervene somehow on that tumor, then absolutely. If it’s widespread systemic progression, it’s not like immunotherapy where we think there might be a little something here. But, absolutely intervene in the context of an isolated lesion or a couple of lesions. At our site, we have a very active radiation oncology group who will do multisites, stereotactic, body radiotherapy. Even if a couple metastases start to grow, we can get them, so I think that’s very reasonable. But, again, I think that’s a patient-level consideration. Unfortunately, we have many patients who get past PD-1, they progress systemically on BRAF inhibitor, and we still have to employ chemotherapy in some of these patients. And, I don’t think it should be lost sight that that does still happen sometimes for some patients.

Keith T. Flaherty, MD: Just a quick last point. If a patient had a BRAF mutation, received BRAF/MEK up-front therapy, ultimately progresses, moves to immunotherapy, ultimately progresses, any role to go back to BRAF inhibitor?

Jason J. Luke, MD: Absolutely, absolutely. So, this is something that we do in clinical practice quite a bit with my network of folks that I work with. We have patients who are BRAF mutation where we know that works. The question is, how are we going to use that optimally? We often will use it to maximum benefit and take patients off if they’ve already progressed through other things with the hope of getting them on a study, knowing we can go back. And, we will do this intermittently with the idea to try to keep the patient in good shape, as long as we can to give them as many chances as we can to other options?

Keith T. Flaherty, MD: That’s great. Of course, we need targeted therapy options for other patients. We’re starting to get a little bit of a glimmer. Maybe we can get a foot in the door there. So, how do you look at this emerging binimetinib, MEK inhibitor monotherapy data, Georgina, in NRAS-mutant patients? Is that a therapy that is interesting and maybe building a cornerstone for combination? Is it actually a therapy that, based on the emerging evidence, actually could be endorsed in practice?

Georgina Long, BSc, MBBS: Based on the emerging evidence in the NEMO study, the phase III trial of only Q61 NRAS-mutant melanoma that randomized patients to dacarbazine versus binimetinib, the MEK inhibitor, I don’t think this trial will change clinical practice at all. There’s a benefit with progression-free survival, there’s a benefit with response, but there’s no benefit with survival. But, it is a wonderful foundation because there’s definitely a signal there. It’s a wonderful foundation for combinations. And, I think MEK inhibition is a good basis because the MAP kinase pathway is constitutively active in the majority of melanomas, even if they’re not BRAF mutated. So, I think it’s a good foundation. It is a building block. There is definite PFS and response rate advantage. It’s something we now need to understand more. As we started this whole discussion with, when we were talking about mutations, we need to understand better the pathways and how to inhibit them. But, a MEK inhibitor is a good foundation to add things on to.

Jason J. Luke, MD: Because we raised it in the very beginning about other molecular targets, one that we didn’t discuss—it isn’t quite ready for prime-time in melanoma but maybe is in breast cancer—is CDK4. So, there were data here at ASCO around CDK4 being important in some of the other melanoma subtypes. But, again, as an add-on in the NRAS space, it looks like regulation of the cell cycle machinery as a secondary threshold in most melanomas is a good combinatorial partner. And building on these MEK data in RAS-mutant tumors, I think that’s the obvious next step. We have some data already in this space, and I think that you’ll see that coming forward very soon.

Georgina Long, BSc, MBBS: And, CDK2NA, which is another inhibitor, that whole cell cycling mechanism is quite common in melanoma. I agree. I think the combination of a MEK inhibitor and CDK4/6 inhibitor, which has been explored in a phase I in NRAS, could be extended to other types of melanomas other than just NRAS. But, it’s definitely something to watch.

Transcript Edited for Clarity
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