Expert Discusses Role of Mutation Status in Treatment Decisions for Melanoma

Ryan J. Sullivan, MD

Ryan J. Sullivan, MD

Although there are several single- and dual-agent treatment options available for patients diagnosed with melanoma who harbor aBRAFmutation, therapeutic options for patients with non-BRAFmelanoma are still limited.

There are potential combination strategies, including MEK and ERK inhibitors, under investigation for ptients withNRAS-mutant tumors, which make up about 20% to 25% of the melanoma patient population, says Ryan J. Sullivan, MD. However, the activity that has been seen with these options is only in the 15% to 20% range, compared with the above 50% response rates seen in early trials of BRAF inhibitors.

In an interview withTargeted Oncology, Sullivan, assistant professor, medicine, Harvard Medical School, and assistant professor, Hematology/Oncology, Massachusetts General Hospital, discussed the available therapies for patients withBRAF-mutant and non-BRAF-mutant melanoma, as well as the current role of mutation status in treatment decision making.

TARGETED ONCOLOGY:What therapies are available to melanoma patients who do not have aBRAFmutation?

Sullivan:Approximately 40% to 50% of melanoma patients have aBRAFmutation. There are a series of therapies that have been developed and are FDA approved for patients who haveBRAFmutations. These include dabrafenib [Tafinlar] trametinib [Mekinist], and vemurafenib [Zelboraf], and then the combinations of dabrafenib and trametinib, and vemurafenib and cobimetinib [Cotellic]. As of yet, there are no targeted therapies approved for patients who do not have aBRAFmutation.

TARGETED ONCOLOGY:Are there any therapies in the pipeline for patients with non-BRAFmelanoma?

Sullivan:There was a large phase III trial of the MET inhibitor binimetinib for patients withNRAS-mutant melanoma. Depending on which series you look at, 15% to 25% of patients with melanoma will have anNRASmutation in their tumor. That tends to activate the same pathway thatBRAFactivates. The types of potential therapies we could see being effective would be MEK inhibitors, which is downstream of anNRASmutation in their tumor, and then ERK inhibitors. There is activity with both of those. We see responses when we give MEK inhibitors and ERK inhibitors, but it's 15% to 20% of the time, not 50% to 60%, like we saw with the early trials ofBRAFinhibitors.

A randomized, phase III trial was done, randomizing patients to either dacarbazine or binimetinib, which is a MEK inhibitor. The results of that study showed that patients' tumors progressed a little less rapidly when they got binimetinib compared to chemotherapy, but, unfortunately, they didn't live any longer. It wasn't clear that there was a role for that drug as an approved agent. The FDA did not approve that drug for the treatment ofNRAS-mutant melanoma. It is actually effective in the combination with another BRAF inhibitor called encorafenib, so it could still get FDA approved, but not forNRAS-mutant melanoma. That was the largest trial to date and the best shot that a drug has had to be approved for a non-BRAFand molecular subclass of patients.

There are trials looking at MEK inhibitors plus other drugs. There should be trials of ERK inhibitors plus other drugs. I think we will find the right combination at some point. The challenge is, when we give MEK inhibitors, they have a fair number of side effects, and almost every other drug that blocks something in a pathway causes diarrhea and rash. It becomes hard to give drugs at full dose at the same time, and that is a problem because to be effective, you probably need the dose at the correct exposure level in your blood system so the tumor dies and stops growing. It's hard to do that. We got lucky with BRAF/MEK combinations. It's not quite going to be the same thing with MEK inhibitors plus other types of drugs.

TARGETED ONCOLOGY:How are patients with melanoma currently being treated? How does mutation status factor into treatment decisions?

Sullivan:We treat patients with immunotherapies. The standard-of-care immunotherapies are the anti—PD-1 antibodies or combinations with PD-1 antibodies plus ipilimumab [Yervoy]. Once we have a patient who has been tried on the standard-of-care immunotherapies, we generally see if they have a mutation, and then we look to find a clinical trial, potentially of either 1 drug or a combination of drugs that could work. Unfortunately, nothing has panned out that has led to FDA approval and changed the standard of care.

TARGETED ONCOLOGY:Do you typically have all patients tested for mutations at the time of diagnosis?

Sullivan:I'm a very strong proponent of getting as much information as possible as early in the game as possible. We tend to doBRAFmutation testing in stage III and IV patients, but now that the price of testing has come down and most patients are having next-generation sequencing studies performed, there is no reason not to have a panel of common mutations in melanoma performed on the tumor at the time of diagnosis to better understand what potential options are available. But to date, anybody who has high-risk stage III or IV melanoma should have [sequencing] of their tumor.

TARGETED ONCOLOGY:How big of a part does toxicity play when deciding on treatment?

Sullivan:It's critical to consider what you are getting for whatever degree of toxicity there is. I think where we are going is we are going to have better tolerated immunotherapy combinations that will be available to our patients. Those will likely be preferred, as long as you're not losing anything or losing much in terms of efficacy. As soon as you start reducing the effectiveness of a therapy, then there is a real balance. The conversation with a patient is always: these are the side effects with this drug, these are the side effects with this other drug, these are the side effects when you put them together, and this is what you get for those degrees of side effects.

TARGETED ONCOLOGY:What kind of advice would you give to a community oncologist regarding treatment decisions?

Sullivan:The general rule as a community oncologist or as an academic oncologist is that if you have a patient in front of you and you don't have a standard treatment, assess whether that patient is appropriate for and interested in a clinical trial. In the absence of a clinical trial, outside of immunotherapy, the only options are cytotoxic chemotherapies, like dacarbazine or temozolomide, or a combination of carboplatin plus paclitaxel. There can be responses with those therapies, and some patients do benefit. If a patient is otherwise well, can't make it to drive or fly in to the location of a potential trial, or is not a candidate for a clinical trial, it's perfectly reasonable to offer second- or third- or fourth-line chemotherapy, depending on where that patient is and what types of therapies they have had.

Reference:

Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol.2017;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8.