Treatment Options for BRAF-Mutant Metastatic Melanoma

Jason Luke, MD, FACP:For a patient with newly diagnosedBRAF-mutant metastatic melanoma, there are many options that are reasonable treatment considerations. You could certainly consider a BRAF-directed therapy and in that realm, we have 2 approved combinations. Most commonly dabrafenib and trametinib, the BRAF and MEK inhibitors, are administered, but cobimetinib and vemurafenib are also available in that space. Even a third combination of encorafenib and binimetinib will be coming soon.

So, a BRAF-directed approach would be very reasonable. On the other side are the immunotherapies, and we know that the approved checkpoint immunotherapies in this space would be anti-PD-1 antibodies with pembrolizumab or nivolumab, as well as ipilimumab, and/or a combination with nivolumab and ipilimumab. There are many different options that could be considered and it’s hard to say that one is necessarily better than another given that we don’t have head-to-head randomized evidence.

On this question, it really would be a patient-level consideration of the pros and cons of each approach. Obviously, targeted therapy is attractive—it works quickly, it’s generally speaking pretty well tolerated. Now that being said, immunotherapy with anti-PD-1 monotherapy is quite effective—low toxicity—and the patients do have to come in to get the infusions every 3 weeks. Ipilimumab/nivolumab perhaps has the highest response rate in terms of immunotherapy and potential long-term benefit, but is associated with a higher degree of toxicity.

So, this is really a conversation with the patient about what their goals are and what their risk of benefit tolerance really is going to center on. I think any of them could be an appropriate option. In terms of choosing—in a patient like this who has a low volume of disease, a good performance status, low LDH—targeted therapy would certainly be very reasonable. But then, at the same time, those clinical factors are likely to suggest the patient will do well with other therapies as well, so monotherapy, PD-1 versus the combination, could also be considered.

One active question in the field is, should we be doing PD-L1 testing to help guide the choice of immunotherapy? Most melanoma oncologists think that that’s really not that valuable at the current time because most patients with melanoma end up being PD-L1-positive. And really, the consideration probably centers better on the patient’s ability to tolerate the increased toxicity of giving the ipilimumab/nivolumab combination. So, in my practice, I tend to give anti-PD-1 as a monotherapy first and sequentially administer ipilimumab if the patient progresses on anti-PD-1. I do that because I think the upside of response rate of 40% for PD-1 monotherapy is pretty good—low toxicity—and there are clinical trial data that suggest that sequential therapy may approximate combination therapy. But certainly, this is an area of argument amongst oncologists, and, again, it’s a patient-level decision.

In choosing a frontline therapy, if a patient has aBRAFmutation and chooses BRAF-targeted therapy, that can be very effective therapy over a long period of time. Certainly, in my practice, I have had patients who have gone on for years on that therapy. We even have some patients that were on the original clinical trials and they’re still going, doing very well. One wonders whether or not they really truly need to continue, but you can imagine for a patient with metastatic melanoma that they’re not in a hurry to stop the treatment that has given them 5 years of survival.

So, these therapies are, generally speaking, well tolerated. I describe them to patients as like antibiotics. They’re pills that you take, and they tend to work quickly to shrink the tumor. Usually, they’re quite well tolerated, although they can have some side effects. And so, this is where thinking about the different combinations can sometimes make a difference. I think probably most commonly people give dabrafenib and trametinib as the combination up front. Most people have the most familiarity with that combination.

The big toxicity that we worry about with that combination is really a pyrexia syndrome or fever syndrome. It can be somewhat occult, although sometimes it can be obvious—meaning patients usually start out with sensations of maybe fatigue, maybe some chills. By the time they start to get to fevers, it’s a little bit ‘cat’s out of the bag’ because we can start to see relapsing fevers to like 105 over and over and over, and that can be debilitating for patients. So, we really want to educate people up front to look for that toxicity. And as soon as they feel anything, they need to report it, stop the drugs, and just let them washout. For reasons we don’t really truly understand, usually when we take that approach of a washout, the toxicities tend to go away and when we restart the drugs, they don’t come back. It’s unclear why that happens. That’s really the big one we look for with dabrafenib/trametinib.

The other approved combination is vemurafenib and cobimetinib. It is also highly efficacious, very similar clinical data. Toxicity profile is slightly different, however, in that we see more cutaneous or skin toxicities, or a rash, a little more sun sensitivity with that combination, as well as a little bit more GI side effects. The cobimetinib can be a little more rough on the stomach. Which one is the correct one for an individual patient? Again, we’ll probably go back to their tolerance of the side effect profile. If we have an older individual who might do much more poorly if they get the fevers, you might consider vemurafenib/cobimetinib, but for a lot of patients, they start with dabrafenib/trametinib and take it from there.  

Transcript edited for clarity.

• A 46-year-old Caucasian female presented one year ago with deep ulcerated primary tumor and multiple involved lymph nodes.
• She was diagnosed with stage IIIC melanoma.
• Patient underwent wide local incision and compete lymph node dissection and appeared to be clear of disease.
• Patient decided not to pursue adjuvant therapy after surgery.
• Six months after surgery, she developed abdominal pain.
• Imaging showed multiple masses in the liver, > 1 cm, scattered pulmonary nodules and some enlarged lymph nodes.
• Tumor biopsy confirmed melanoma and mutational analysis showed BRAF V600E mutation.
• The patient is started on dabrafenib 150 mg bid and trametinib 2 mg qd.