Looking to the Future of Melanoma

Transcript:Jeffrey Weber, MD, PhD: Let’s shift a little bit since we’re talking about looking to the future. There are an awful lot of trials in the melanoma space.

Dirk Schadendorf, MD: Which is good news.

Jeffrey Weber, MD, PhD: Which is great news. Although, we’re almost victims of our own success. We were just talking about that a lot of doctors in the community, now that we have successful treatment, they’re keeping the patients. Reinhard wants all of them to come to the academic centers. But we’re victims to our success because they’re not always coming to the centers; they’re treated in the community because we have real drugs. But what about the NRAS population? We know we have lots of options for the BRAF-mutated patients; 20% are NRAS-mutated. Is there anything, Reinhard, for these patients?

Reinhard Dummer, MD: Well, first, I would say that this population is typically a little bit of advanced age and often has a high mutational burden. So, these patients are good candidates for immunotherapy. And if immunotherapy failed, there was not a good treatment option out there. Based on in vitro and in vivo investigations, we know that in those situations—and with an activating NRAS mutation—we have upregulation of the pathway that is very sensitive for a MEK inhibitor. And this has been shown, in a phase II clinical trial, that we have increased progression-free survival, and this was now investigated in a protective randomized trial with a clear result. There was obviously an improvement of progression-free survival in the overall patient population, and this seems to be especially promising in patients pretreated with immunotherapy. This can be an argument to say this is a reasonable option. Unfortunately, the overall outcome concerning overall survival was disappointing. We have to find out, first, what is the reason for this? And second, it’s clear that the MEK inhibitor alone is not the end of the story. So, it can be a backbone, and we have to find out which are the next molecules that should be combined with this backbone.

Jeffrey Weber, MD, PhD: Yes, I think we all agree that combinations are the future here. Pembrolizumab and nivolumab are wonderful drugs, but they’re the backbones on which all these combinations will be based. So, Caroline, what about BRAF or BRAF/MEK inhibitors plus pembrolizumab or plus nivolumab? Does that look reasonable to you?

Caroline Robert, MD, PhD: Yes, sure. I think we have a lot of trials that evaluate this combination, either in the simultaneously given drugs or sequential. And also, I would like that we could initiate, in an easier way, some trials, like phase II trials, that could evaluate these sequences, because I’m a little bit afraid that we get engaged in big phase III trials and we realize that’s all, that it’s not the best setting. But there are some trials, like, for example, the Italian trial. SECOMBIT is going to be initiated, which is a sequencing trial. And 1 arm is only 2 months of the targeted agent combined and then ipilimumab/nivolumab—that will be interesting. Roche and Novartis, they both are going to launch big trials, where the backbone there is a BRAF/MEK inhibitor combination, plus 1 anti-PD-1 or anti-PD-L1 inhibitor. So, that will be interesting. The thing is that right now, it’s not so easy to know what the best design is.

Jeffrey Weber, MD, PhD: Interestingly, if the resistance mechanisms are the same, I suppose, or have some commonality, I guess you could argue they would be logical candidates to combine or you could go the other way. But again, the best data I’ve seen are on the pembrolizumab/dabrafenib/trametinib combination. Tony presented the initial data, that was KEYNOTE-022. That looked pretty darn good. I think, essentially, everybody responded.

Caroline Robert, MD, PhD: The other thing is that these drugs are very effective. Dabrafenib has 70% responses. We’ll see in how it goes.

Jeffrey Weber, MD, PhD: I was surprised, though, to hear about the pembrolizumab. So, you can combine everything with pembrolizumab or with nivolumab. It’s really amazing

Transcript Edited for Clarity