Insights From: Adil Daud, MD, University of California Medical Center
My personal approach to sequencing treatments in BRAF-mutant patients is to look at all the different factors that are involved. What we know today, based on an analysis that was published combining the COMBI-d and COMBI-v patient, is that if your LDH [lactate dehydrogenase] is normal and you have limited sites of disease, you can have extremely prolonged responses lasting up to 5 years. That’s 1 important factor to consider. The other factor to consider is that immune therapy can also work well for patients who are BRAF-mutant, just as it can work for patients who are not BRAF-mutant. It can work for either group of patients. The question is, what do you do first, and what do you do second?
There are some pros and cons to consider. I think with the BRAF inhibitors, and BRAF and MEK inhibitor combinations, you are talking about a simple oral treatment that you can take with you with limited need for physician visits. With immunotherapy, when you start immunotherapy, you have to consider the possibility of either combination or a single-agent immunotherapy, and in 1 to 2½% of cases they can be severe or life-threatening immune-related adverse events. And some of these include things like type 1 diabetes, neurological adverse effects, and cardiac adverse effects, which can be life-threatening and which are not reversible. I think that’s just a personal preference.
But on the advantage side, on the pro side for immunotherapy, once you’ve had a response, once you’ve had a complete response, you can stop treatment and then just follow patients. You’re not on an active treatment every single day, as you are with a BRAF inhibitor. So that could be an advantage. That’s something that immunotherapy offers us.
Now, we don’t have long-term data with immunotherapy today as we do with the combination of BRAF and MEK inhibitors. So we don’t know if immunotherapy responses can last, say, 5 years or 10 years. Many people suspect you can, but we don’t actually have that data.
On the other hand, with the BRAF and MEK inhibitors, even though the adverse-effect profile is generally more severe with the BRAF and MEK combination, there’s less of a likelihood of severe immune-related adverse events—things like multiple sclerosis, myasthenia gravis, heart failure, myocarditis, or type 1 diabetes, which are basically life-threatening adverse events—if you’re fit. I have a patient, for example, who’s 35 years old. And he had stage III melanoma, and he was interested. And he was BRAF-mutant, and we had a detailed discussion—this was a few years ago—and he opted to have immunotherapy. And so we started him on an immunotherapy single-agent PD-1 [programmed cell death protein 1], and about 6 months after starting treatment, he’s developed type 1 diabetes. And that basically means that every time he goes to the gym or every time he goes for dinner, he needs to figure out how much insulin he needs; he needs to inject it. So you know, he’s very much on top of his diabetes, but that’s a lifelong kind of thing, you know? It’s not something you could ever ignore. No matter what you’re doing, you have to think about the possibility of hypoglycemia and carry your insulin around. So that’s a major change in your lifestyle.
Now, with the BRAF and MEK inhibitors, if you have adverse effects, you can stop them. And the adverse effect resolves most of the time, and then you can restart your treatment or depending on the second size, you can dose reduce. With immune adverse effects, that’s not always possible. Many of them are long-lasting, permanent adverse effects. Again, that’s something to consider depending on the age and performance status and the LDH and what a person is looking for. Are you looking for a potential remission that doesn’t need treatment actively? Or are you looking for something that goes along with your lifestyle, that you could easily turn off and turn on? I think, in my experience, people have preferences, and I think if you listen to what they want, sometimes you can figure out what the right treatment option is.