Expanded Melanoma Subtypes Generate New Targeted Agents

Greg Kennelty

A recent publication from The Cancer Genome Atlas (TCGA) has opened the door wide for a slew of new, non-BRAF targeted agents in melanoma, according to Jason J. Luke, MD, FACP.

The publication cites four new types of melanoma, all of which previously fell under the umbrella term “BRAF wild type.” Luke, assistant professor of medicine, The University of Chicago, says in an interview with Targeted Oncology this expansion into several new non-BRAF subtypes will results in the formulation of several new targeted agents, as well as possibly combinations.

What are non-BRAF targeted agents?

When we talk about targeted therapy for melanoma, most people think of it as BRAF-targeted therapy. It's important to understand that BRAF only makes up about half of the driver mutations in melanoma. There was a publication of TCGA data set within the past year, which outlined that there are 4 major subsets of molecular melanoma. One of them is BRAF, another one is RAS mutations, predominantly the NRAS mutation, NF1 being a third population of mutational events, and the fourth was a hodgepodge — it's what they called a "triple wild type."

Beyond BRAF, there are BRAF/MEK combinations which is a standard of care, but how can we think about targeted therapies moving into the future? We can think about it in terms of multiple layers. The first might be to consider combination therapies to address BRAF-inhibitor resistance, and at least 20% of patients with melanoma have activation of PI3K signaling pathway. Therefore, adding an AKT inhibitor to BRAF/MEK inhibitors might be helpful for BRAF-inhibitor resistance. There is a clinical trial ongoing through the SWOG cooperative group to address that question.

In the NRAS space, the use of MEK inhibitors has already proceeded to phase III. In the NEMO trial of the MEK inhibitor binimetinib, that treatment met its primary endpoint of improving progression-free survival in patients with NRAS Q61 mutant melanoma. Within the coming year, it's very likely that a standard of care for NRAS mutant melanoma will be MEK inhibitors .

The third subset was NF1 mutant melanoma. This mutation was less well-understood before the TCGA publication. Again, we've already launched into clinical trials. As part of the NCI MATCH program, I am leading the NF1 arm in which if patients are found to have NF1 mutations, they can be treated with the MEK inhibitor trametinib.

Then there's the triple wild population, which can include a whole host of things. That includes KIT mutations in which we already have imatinib as the standard of care for EXON 11 and EXON 13 KIT mutations, which includes GNAQ and GNA11 mutations that we find in uveal melanomas. That population is more difficult to treat, but MEK inhibitors have had some activity.

We're also looking at other drugs such as MET inhibitors as well. Targeted therapies is much broader than just BRAF-targeted therapy, although these other approaches are not as far along in clinical investigation. Over time though, these treatments will become part of the armamentarium in melanoma.

Which of those subtypes is most exciting?

They're all exciting because I think what we're really getting at here is personalized approaches to each patient. If you do your molecular sequencing and there's not a BRAF mutation, we used to call that BRAF wild type. Now we know that BRAF wild type is made up of a host of other molecular abnormalities. If you're a patient and your tumor sample turns out to be BRAF wild type, or BRAF negative, then you were out of luck. You didn't have any treatment options. Now we know that there's a whole other host of things that we can test for, and apply to our approaches. We can now apply targeted therapies across the board.

In the NRAS population, I think we're going to have approved drugs for those patients. So I'd say that that's exciting because then we'll have a new drug approach for melanoma. More importantly there will be clinical trial options trying to selectively go after subsets of genomics in melanoma, such as NF1 and GNAQ. We'll be able to apply these to individual patients.

What about combining these upcoming targeted therapies with immunotherapies?

Combinations of targeted therapies and immunotherapies have been preliminarily investigated, as in a few phase I trials that have looked at the intersection of these agents. We've looked at both BRAF inhibitors with PD-L1, and that was presented at the Society for Melanoma Research meeting, where the combination of vemurafenib and atezolizumab showed a response rate of about 75%, which is interesting. It'll be important to look and see how that works over time.

There are also ongoing trials of BRAF/MEK plus PD-L1, and that data were presented at ASCO. Again, response rates looked about what we'd expect given the response rates of the individual drugs, so it's not really clear if adding them together really makes a difference. We will caution that pre-clinically, we do have some concerns that adding all of these drugs together may not be too helpful in the end. We need to be careful because we've been wrong about a lot of things in the lab before, so we don't know until we try in patients.

These combinations treatments are certainly not the standard of care in clinical practice now, and you really only see it in clinical trials. I would strongly advocate against that until we have data to support it, and we'll have to see how that goes over time.

What is expected in terms of toxicity from these non-BRAF targeted agents?

In the realm of non-BRAF targeting, a lot of the work has been focused on MEK inhibitors. There's a proven MEK inhibitor already, and that's trametinib. The other agents in this field, such as cobimetinib and binimetinib, they're still MEK inhibitors. So their toxicity profiles are going to be similar to trametinib.

It's going to be the same things you usually see. There are going to be rashes, you can see edema, you can see very rare side effects with elevations of CPK or myositis. All the things we knew about MEK inhibitors, they apply broadly across this class of agents. People shouldn't have reticence about using these agents as [patients] come into the clinics.