Beyond BRAF: Emerging Agents Aim at Other Melanoma Targets

Jason J. Luke, MD, FACP

Targeted therapy for melanoma is much more than just BRAF inhibition.

While more than half of cutaneous melanoma tumors are BRAF-positive, agents that target the other 3 subtypes—RAS mutant, NF1 mutant, and triple wild-type—identified by the Cancer Genome Atlas (TCGA) in 2015 now have the increasing potential to improve survival for non-BRAF patients, says Jason Luke, MD, an assistant professor of Medicine at the University of Chicago Medicine.

“When we talk about targeted therapy for melanoma, most people think of it as BRAF targeted therapy,” says Luke. “While other approaches are not as far along in clinical investigation, they will, over time, become part of the armamentarium of the treatment of melanoma.”

There are several therapeutic options for targeting non-BRAF mutations and beyond.

According to the TCGA, RAS- and NF1-mutant melanomas have deregulated MEK signaling and may be responsive to MEK inhibitors. Tumors that are of the triple wild-type subtype often contain mutations in receptor tyrosine kinases that may be responsive to receptor tyrosine kinase inhibitors.

In addition, RAS, NF1, and triple wild-type cancers all demonstrate overexpression of AKT3, a protein kinase that affects MEK and mTOR signaling pathways, suggesting that MEK and PI3K/AKT/mTOR pathway inhibitors could target this molecular alteration.

OncLive: What are the options for targeted therapy in melanoma?

In an interview with OncLive, Luke discusses how molecular subtyping has expanded targeted therapy approaches beyond BRAF inhibition, current trials investigating emerging targeted agents, and what can be expected in this space going forward.Luke: We can think about targeted therapy in multiple layers. The first might be to consider combination therapies to address BRAF-inhibitor resistance. Approximately 20% of patients with melanoma have activation of the PI3 signaling pathway. Therefore, adding an AKT inhibitor to BRAF/MEK might be helpful for BRAF-inhibitor resistance. There is already an ongoing clinical trial investigating this.

In the NRAS space, the use of MEK inhibitors has already proceeded to phase III studies. The NEMO trial, which looked at the MEK inhibitor binimetinib, met its primary endpoint of improving progression-free survival versus dacarbazine in patients with metastatic NRAS-mutant cutaneous melanoma. It is very likely that the standard of care for NRAS melanoma will be a MEK inhibitor within the coming year.

NF1 melanoma was not as understood prior to the TCG publication, but we’ve already launched into clinical trials. As part of the NCI-MATCH program, I am actually leading the NF1 arm, where if patients are found to to have NF1 mutations they can be treated with trametinib (Mekinist), a MEK inhibitor.

How will this approach change the treatment paradigm?

The triple wild-type population includes a host of variations. It includes KIT mutations, where we already have imatinib (Gleevec) available as the standard of care for KIT exon 11 and exon 13 mutations. It also includes GNAQ or GNA11 mutations that we find in uveal melanoma. Those are a little more difficult to treat, but MEK inhibitors have some activity and we are also looking at MET inhibitors.Here, we are discussing a personalized approach to each patient. If you do molecular sequencing and there is no BRAF mutation, we used to call that BRAF wild-type. We’ve known for a while now that BRAF wild-type is made up of a host of different molecular abnormalities.

Is there a specific non—BRAF-targeted agent that you are most excited about right now?

With these non—BRAF-targeted agents, what toxicities are expected?

Before if a patient’s tumor sample was BRAF-negative/BRAF wild-type, they were out of luck; they didn’t have a treatment option. Now, we know there is a host of other things we can test for and, eventually, apply drug approaches. Therefore, we can apply targeted therapies across the board.I am excited about all of them but, in the NRAS population, I think within 1 year we will have approved drugs. That is very exciting because it will be a new approach for melanoma. More importantly, there will be clinical trials that will selectively try to go after subsets of genomics in melanoma such as NF1 or GNA11. We will apply this to individual patients.With non-BRAF targeting, a lot of the work has really been focused around MEK inhibitors. There is an approved MEK inhibitor, which is trametinib.

The other agents in this field, cobimetinib (Cotellic) and binimetinib, are both MEK inhibitors, and toxicities are going to be similar to trametinib. That means patients may experience rash, edema, and, in rare cases, elevations of CPK, myelocytosis, or eye changes. Everything we already know about MEK inhibitors will apply across these agents, so oncologists should not be hesitant to use them for toxicity reasons.