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Alternative Approaches to Treating 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, Nov 06, 2017



Transcript: 

Jeffrey S. Weber, MD, PhD: What about direct injection? I’ve been approached by many people asking if we had an interest in getting involved in a trial where you would be directly injecting various substances: other viruses or TLR agonists. Have you heard much about those?

Caroline Robert, MD, PhD: Yes. I think it’s an interesting approach that might initiate a response at one place that would after be more diffuse. And we have these TLR agonist results that have been presented at ASCO. It was last year, and it was quite interesting, although very preliminary. So, let’s not shut ourselves out of anything that could help us.

Axel Hauschild, MD, PhD: And PV-10, the Provectus drug, is going to phase III, or it was. I think the first patient is already in, so there are at least 6 injectable agents which are going to phase II and III now. There is a lot of room for this. The problem is that maybe not every medical oncologist is willing to invest so much time for the technical equipment, because you need to inject it under ultrasound guidance into lymph nodes and subcutaneous metastases. So, that’s a question of logistics. And not everybody who is a conservative physician, which means they’re not operating every day, is treating patients intralesionally. It’s for the surgical oncologists. In the United States, that’s an issue, but we don’t have these sorts of surgical oncologists in Germany, so it’s done by us as dermato-oncologists. So, it’s a logistics question for intralesional agents.

Reinhard G. Dummer, MD: What really convinced me is that you see clear systemic effects of the local injection, and this is also in the phase Ib trial with the T-VEC/pembrolizumab combination. There is a phase where you just use T-VEC and see an activation in peripheral blood. You also see that noninjected lesions are more infiltrated, this is documented, and have a dominant interferon-gamma signal. And this shows that intralesional therapy is different with systemic therapy.

Jeffrey S. Weber, MD, PhD: You can make a cold tumor into a hot tumor, it sounds like, even at a distance, which is why I assume people are pursuing these strategies. But, lastly, in thinking about trials, there have been data presented with a novel targeted combination. So, Reinhard, can you tell us about the COLUMBUS study?

Reinhard G. Dummer, MD: This is an investigation, a clinical trial, that is focusing on encorafenib/binimetinib. These are 2 new targeted agents. Encorafenib is a BRAF inhibitor. I would really call it second generation, because it is a very sticky molecule and has a long dissociation time. This means it combines to the catalytic domain of BRAF and stays there for 20 hours. So, this is 5 to 10 times longer than conventional BRAF inhibitors.

You get a very profound inhibition of BRAF, and this is combined with binimetinib, which is an allosteric inhibitor of MEK1/2. Actually, with this combination, you can dose encorafenib quite high, 450 mg, together with binimetinib. This was compared to a conventional BRAF inhibitor, vemurafenib, encorafenib monotherapy, and a lower dose of the BRAF inhibitor and the MEK inhibitor. So, 300 mg of encorafenib instead of 450. And we saw, in summary, in this very complex clinical trial, that we can say there is an increase in PFS with vemurafenib at 7 months, whereas it was 9 months with encorafenib, 12 months with encorafenib low-dose plus binimetinib, and 14.9 months for the highest combination. This is very interesting, because it shows that the harder you hit the pathway, the better the results, and this is demonstrated in PFS but also in response duration. So, I think this gives new insight to the potential of BRAF/MEK strategies.

Jeffrey S. Weber, MD, PhD: I think a lot of us thought that, exactly what you said: that if you would only be able to increase the dose, do a better job of blocking the catalytic domain, and then have a slower off-rate, you’d probably have a better drug. So, this combination may now give us a third option for treating BRAF-mutated patients.

Transcript Edited for Clarity 

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Transcript: 

Jeffrey S. Weber, MD, PhD: What about direct injection? I’ve been approached by many people asking if we had an interest in getting involved in a trial where you would be directly injecting various substances: other viruses or TLR agonists. Have you heard much about those?

Caroline Robert, MD, PhD: Yes. I think it’s an interesting approach that might initiate a response at one place that would after be more diffuse. And we have these TLR agonist results that have been presented at ASCO. It was last year, and it was quite interesting, although very preliminary. So, let’s not shut ourselves out of anything that could help us.

Axel Hauschild, MD, PhD: And PV-10, the Provectus drug, is going to phase III, or it was. I think the first patient is already in, so there are at least 6 injectable agents which are going to phase II and III now. There is a lot of room for this. The problem is that maybe not every medical oncologist is willing to invest so much time for the technical equipment, because you need to inject it under ultrasound guidance into lymph nodes and subcutaneous metastases. So, that’s a question of logistics. And not everybody who is a conservative physician, which means they’re not operating every day, is treating patients intralesionally. It’s for the surgical oncologists. In the United States, that’s an issue, but we don’t have these sorts of surgical oncologists in Germany, so it’s done by us as dermato-oncologists. So, it’s a logistics question for intralesional agents.

Reinhard G. Dummer, MD: What really convinced me is that you see clear systemic effects of the local injection, and this is also in the phase Ib trial with the T-VEC/pembrolizumab combination. There is a phase where you just use T-VEC and see an activation in peripheral blood. You also see that noninjected lesions are more infiltrated, this is documented, and have a dominant interferon-gamma signal. And this shows that intralesional therapy is different with systemic therapy.

Jeffrey S. Weber, MD, PhD: You can make a cold tumor into a hot tumor, it sounds like, even at a distance, which is why I assume people are pursuing these strategies. But, lastly, in thinking about trials, there have been data presented with a novel targeted combination. So, Reinhard, can you tell us about the COLUMBUS study?

Reinhard G. Dummer, MD: This is an investigation, a clinical trial, that is focusing on encorafenib/binimetinib. These are 2 new targeted agents. Encorafenib is a BRAF inhibitor. I would really call it second generation, because it is a very sticky molecule and has a long dissociation time. This means it combines to the catalytic domain of BRAF and stays there for 20 hours. So, this is 5 to 10 times longer than conventional BRAF inhibitors.

You get a very profound inhibition of BRAF, and this is combined with binimetinib, which is an allosteric inhibitor of MEK1/2. Actually, with this combination, you can dose encorafenib quite high, 450 mg, together with binimetinib. This was compared to a conventional BRAF inhibitor, vemurafenib, encorafenib monotherapy, and a lower dose of the BRAF inhibitor and the MEK inhibitor. So, 300 mg of encorafenib instead of 450. And we saw, in summary, in this very complex clinical trial, that we can say there is an increase in PFS with vemurafenib at 7 months, whereas it was 9 months with encorafenib, 12 months with encorafenib low-dose plus binimetinib, and 14.9 months for the highest combination. This is very interesting, because it shows that the harder you hit the pathway, the better the results, and this is demonstrated in PFS but also in response duration. So, I think this gives new insight to the potential of BRAF/MEK strategies.

Jeffrey S. Weber, MD, PhD: I think a lot of us thought that, exactly what you said: that if you would only be able to increase the dose, do a better job of blocking the catalytic domain, and then have a slower off-rate, you’d probably have a better drug. So, this combination may now give us a third option for treating BRAF-mutated patients.

Transcript Edited for Clarity 
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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
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