Mutations of Clinical Significance in Melanoma

Transcript:Keith T. Flaherty, MD: Now that’s a nice reminder that there’s increasing need to be thinking about molecular testing, gene expression profiling still being in the validation mode. But there are a few tests that we need to consider, particularly in the advanced disease population. So, Georgina, maybe just a quick check on mutations that are important to assay and then maybe a little even more detail on them, like in the BRAF context specifically. What do you think of as being the really key features that you need to know about a patient to help guide treatment?

Georgina Long, BSc, MBBS: Okay. So, now going back to the patient interface, away from the research and what’s critical when you’ve got someone sitting in front of you and you need to make decisions about currently available treatments, or even clinical trials, which are still very important. Number one, you need to know whether the tumor has a BRAF mutation, particularly a V600 BRAF mutation. There are several different types of V600 mutations, such as V600E and V600K. V600E tends to be associated with younger aged, truncal primaries, whereas V600K on the other hand is associated with chronic sun damage, and probably a high mutational load—although we haven’t looked at that data specifically as of yet. But it’s there. So, V600K is associated with scalp, head, and neck primaries, all the things associated with chronic sun damage. And then you’ve got V600R, V600M, and these rarer V600 mutations. That’s number one. We have to know whether they’ve got the BRAF mutation.

Routinely we do tests in RAS mutation . . . that’s because we do trials, although that would not be required for your standard available treatments. I think increasingly we’ll be looking at NF1. C-KIT is not used as much because there are no available drugs that target KIT. There are some, but really our other treatments tend to be much more tolerable and better and more efficacious. And to be frank, no KIT inhibitors are actually approved for melanoma. But that’s the panel we do. If I had to treat, the one that’s critical is the BRAF. You just to need to know whether it’s BRAF mutant or BRAF wild type. However, in the next 2 years, I’d say that we’re going to have to test for some of these other mutations in the matter. And most centers around the world will do a whole panel of mutations as a matter of course.

Keith T. Flaherty, MD: Right. And certainly for research purposes that’s important. But, Jason, maybe a couple of comments on the issue of melanoma subtypes and what clinicians’ expectations can be. When they have a patient in front of them with advanced metastatic melanoma, typical cutaneous, mucosal, acral, and uveal, how are you thinking about this genetic testing model and the likelihood of finding something that you can jump on?

Jason J. Luke, MD: Absolutely, yes. So, one thing I would explain to patients is that melanoma is not necessarily skin cancer, and that most of melanoma is cutaneous melanoma, which is where we see the mutations that were predominantly just described—BRAF, NRAS, NF1. There are melanocytic melanomas that can rise in other parts of the body, including acral lentiginous melanomas or mucosal melanomas, as well as uveal melanomas. And we see a different mutational spectrum in those types of tumors. So, for a practicing clinician, it’s important to have a sense of that because in those less common mutations the incidence of BRAF mutation is much lower. It’s not that it’s inappropriate to test for it, but you really should not have an expectation you’re going to find it in those types. And that’s where mutation testing for some of these other tumor types really comes into play, because there’s an enrichment then for RAS mutation, but maybe most importantly for KIT mutation, in some of these other tumors.

And it’s worth noting that there’s a fair amount of data—three phase II studies now—for KIT inhibitors, and maybe there’s a slight difference between Australia and the United States where our NCCN Compendium do list KIT inhibitors as a reasonable consideration. Now, the efficacy is there to be considered. But I will point out that if you look in the KIT inhibitor space, you can see many different mutations in KIT as compared with BRAF, and that actually makes a big difference. So, which exons of KIT are mutated makes a huge difference in responsiveness to KIT inhibitors. And if you find the appropriate exon mutation, they can actually be almost as effective as monotherapy BRAF. But it’s worth noting that just any KIT mutation doesn’t necessarily mean you’ll respond to a KIT inhibitor.

Keith T. Flaherty, MD: And this year’s ASCO is going to introduce the concept that moving outside of the BRAF-mutant realm might have targeted therapies perhaps for the NRAS-mutant population. But how do you think about the rest of melanoma in terms of a foothold for targeted therapies and F1-mutant melanoma, or the uveal melanomas with their very common gene AQ, gene A11 mutations?

Jason J. Luke, MD: Well, I think it’s an evolving role. Based on what we’ve learned from cutaneous melanoma, this is something we really need to drill down on. And it does point out that we haven’t cured melanoma and that there’s a lot of work still to be done, especially in some of these molecular subsets. Because they’re not rare, but we have some patients who have good responses to, say, an MEK inhibitor in the context of an uveal melanoma with a gene AQ, but it’s not uniform.

And so what’s the rest of that underlying biology and what combination approaches could we think about? I think MEK inhibitors are reasonable as a consideration for NF1 and for gene AQ, gene A11, but they’re not the be-all and end-all. And that points out that we really still need to focus on those clinical trials to investigate that population.

Keith T. Flaherty, MD: I totally agree.

Georgina Long, BSc, MBBS: I want to emphasize that we all thought that MEK inhibition would help with some of these, particularly gene AQ, gene A11, and really we’re not doing anything. We’re not getting the right pathway, we’re not hitting it hard enough, and we’re just not making any impact in uveal melanoma. So, we’ve got a lot of work to do both on the immunotherapy front, but also just on the pathways, activating and revealing how best to target them. It’s an unmet need.

Transcript Edited for Clarity