Dr Vernon Sondak on BRAF Mutations in Metastatic Melanoma

In this interview, Vernon Sondak, MD, explains the latest approach to treating patients with melanoma with BRAF mutations, including those whose disease has spread to the brain or other sites. Sondak is the chair of the Department of Cutaneous Oncology at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and holds the Richard M. Schulze Family Foundation Distinguished Endowed Chair in Cutaneous Oncology, and is also a professor in the Departments of Oncologic Sciences and Surgery at the University of South Florida Morsani College of Medicine.

Conversation has been lightly edited for clarity.

AJMC^®: It’s estimated that nearly 50% of patients diagnosed with melanoma have activating BRAF mutations. Could you please discuss the difference between BRAF mutations and BRAF wild type? And then do these mutations impact the severity or rate of progression of staging in melanoma?

Sondak: So the discovery of BRAF mutations in melanoma, which happened in 2002, really started the cataclysmic change we’ve seen in the management of melanoma. And was the first of many scientific breakthroughs that have now made it so much better for our melanoma patients and their chance of survival.

As you said, about half of all melanomas have this BRAF mutation. And it’s important to point out that the mutation is only in the melanoma. It’s not a mutation in the patient. This is something they often get confused about. It’s not a hereditary thing that they can give to their children.

We all have BRAF genes, normally. The melanoma mutates it in about half of the cases. And that one mutation drives the growth and spread of that melanoma. It allows it to proliferate. It allows it to grow. And it allows it, eventually, to spread.

And so melanomas that don’t have a BRAF mutation usually have a driver mutation in another part of the same pathway. For example, of the half that don’t have a BRAF mutation, many of them have an NRAS mutation. So that’s the second most common mutation.

But what’s different between NRAS and BRAF, and pretty much all the other known and less frequent mutations that seem to drive melanoma growth, is that we have drugs that can target that BRAF mutant protein and shut it down. And it’s a real testament to the value of science, and also the time frame of science.

As I said, it was found in 2002 that melanomas had this mutation in a high frequency. I remember when it came out. I didn’t even know what BRAF stood for. I didn’t know if the B was different, if there was an ARAF and a CRAF...what this all meant.

And very quickly, we learned about it. And by 2010, 8 years later, we were already seeing the clinical trials that proved it was making a huge difference in our patients’ outcome.

And by 2011, the first BRAF inhibitor was approved. Now we have 3 pairs of BRAF and MEK inhibitors; we use those drugs together. And even more effectively than either one alone, for our BRAF mutant melanoma cases.

AJMC^®: So the big difference between BRAF mutant melanoma and BRAF wild type is not in the severity, the progression, the prognosis, anything, except the BRAF mutation gives us another tool, another target?

So it doesn’t really matter if you didn’t treat the BRAF mutation—would it be worse or better? What matters is, if you don’t have the mutation, and other treatments don’t work, you just don’t have this in your back pocket.

And conversely, if you have the mutation, now the whole spectrum of targeted therapy drugs is available to you, in addition to the immune therapy drugs, and other drugs that we’ve used for melanoma over the years. So we don’t look at BRAF mutation status to predict what’s going to happen next. Will it show up here or there? We just look at it as, if we need to do treatment, what are our options?

And then, if they’re BRAF mutant, the obvious question is, does that mean we always target the BRAF mutation? Or do they still get the other treatments that we would give for someone who has no BRAF mutation, or BRAF wild type, or nontargetable mutation? And this is an area that has really evolved quite a bit in the last few years.

What do we know about targeting BRAF for treatment? In advanced disease, very widespread melanoma, even very symptomatic, right away, as soon as we started using this, the very first BRAF inhibitor, vemurafenib, in those first studies I was talking about, in the late 2000s and early, right in 2010. We were seeing what some people call the Lazarus effect. Somebody who seemed to be on the verge of death suddenly feeling much better, within days or weeks of starting treatment. The effect was that powerful.

But we also saw the effect wearing off after a few months, 6 months, 9 months. In the most advanced cases, the melanoma almost always figures out a way, eventually, to get around the drugs that we’ve used to block that protein.

So in the most advanced cases, BRAF-targeted therapy is extremely helpful. High response rates, great improvement in quality of life. But of a limited duration. Could be 6 months, 9 months, a year. That’s really important time. But it’s not likely to cure them at that advanced state.

So we next asked the question, “What if we used it before they got that bad? What if we used it to try to prevent the melanoma from coming back?” Well, there were concerns about that. Maybe we’d shoot the works, and it would delay it but then, when we needed it, when they were really feeling bad, it wouldn’t work?

To our surprise, when we used BRAF/MEK inhibitors in the adjuvant setting, to prevent stage III melanoma from coming back, it not only worked, it delayed the recurrence. But it delayed it, and it continues to delay it years after stopping the treatment. So that the melanomas didn’t seem to have as much ability to figure out a resistance mechanism, and escape the treatment, when we’d used it earlier on. And so, for some doctors, many are saying, “Wow, maybe that means we should use it right away, in these early-stage patients, to prevent the tumor from not only from coming back but developing resistance.”

But what about in between? The tumor has come back. It's not so advanced that they’re on the verge of dying right away, and where we know the effect of the BRAF mutation inhibitor will be limited. What if we just, as soon as they have a few lung metastases, something like that? Recently, just in the last few months, we’ve seen the results of a couple of randomized trials, that simply said, “Let’s flip a coin. Heads, you get the BRAF treatment first. Tails, you get immune therapy first, and get the BRAF treatment second, if the immune therapy didn’t work.”

Surprisingly, those studies both showed giving the immune therapy first was better. Presumably, the immune therapy was working better, a little bit earlier. The BRAF treatment was still working in those late stages. Where, if you left it the other way around, the immune therapy wasn’t nearly as good in the late stages as the BRAF drug was. So even though the tumor might eventually get resistant to the BRAF inhibitor, it was still better to use immune therapy first. Go for that immune-mediated cure. And if that didn’t work, you have the BRAF inhibitor.

So what does this mean for our patients if we use that strategy? What do we know? Well, the first big trial that looked at the most modern immune therapy that we’ve had years of experience with, the ipilimumab/nivolumab combination. We abbreviate it IPI/NIVO. If patients got IPI/NIVO first, as their first treatment for metastatic melanoma, and they had a BRAF mutation and then got the BRAF treatment second, 60% of those patients were still alive 5 years later. Some of them were still alive because the immune therapy worked, and they never needed the BRAF inhibitor. Probably about 40% of them. And the other 20% were still alive because coming in later with the BRAF drugs were carrying them further down, over the finish line, as it were.

Now, not all of those people are cured. But to have 60% of patients alive 5 years after their metastatic melanoma developed, when, prior to all these new drugs, including the new BRAF inhibitors, 20% of people would survive 1 year after diagnosis, this was just turned the whole world upside-down. It’s transformational.

So today, we think that BRAF-targeted therapy can be used in an adjuvant setting, after a known metastasis is treated surgically, but before distant diseases develop. Or after immunotherapy, in the case of metastatic disease. There’s still a lot that we don’t know. What if the person’s had one form of treatment in the adjuvant, and then come the new drugs, the new immune therapy drugs that are being developed, etc?

We’re still learning, but these recent clinical trials on the sequencing of immune vs targeted therapy have been very pivotal and, I think, give us some clarity and some real positive direction for what to tell our patients.

AJMC^®: How does treatment approach change for a patient whose disease has metastasized to the extent of distant metastases such as brain metastases and with a BRAF mutation? What factors are evaluated when determining how to sequence treatment?

[That's] the other area that we’re very interested in, of course, is in brain metastases. Melanomas, once they spread, they have a particular high propensity to spread to the brain. We don’t know why that is, what it is about those melanomas that cause that. But we know it’s very common, the further along things get, the more likely that the melanoma will appear in the brain.

We know that both immune treatments and BRAF-targeted treatments can shrink brain mets. But again, because of that eventual resistance phenomenon, most of the data suggest that, if we’re going to treat brain metastases with drugs, let’s start with immune therapy, that IPI/NIVO combination, and not start with the targeted therapy. Sometimes we radiate brain mets. Sometimes we remove them. We don’t always use drug treatment. But when we do, IPI/NIVO has become the standard, and we save the BRAF inhibitors if that doesn’t work. So a lot of change. And not just change, real progress, dramatic progress.

And now, in the last year, 6 months, additional drugs being approved, like a new immunotherapy combination involving a LAG-3 inhibitor that’s the combination of nivolumab, the standard anti-PD-1 drug, and relatlimab, the anti-LAG-3 drug, in a combination. We’re going to have to figure out where that fits in. It looks very promising, again, for both BRAF mutant and BRAF wild-type patients.

If there’s one take home message I would end with, it’s that you can’t use BRAF-targeted therapy if you don’t know the patient has a BRAF mutation. And you can’t know the patient has a BRAF mutation unless you test it. There’s nothing else, and nothing visible on the microscope or on the patient. There’s nothing we can say, “Oh, you must have that.” You’ve got to do the molecular testing, the genetic analysis of the cancer to find it out. It can be done by the pathologist with immunohistochemistry. That’s very useful if it’s positive, but it doesn’t cover all the possible mutations.

So the gold standard is to do full molecular testing, and there are several different ways to do that. And so we encourage surgeons, if they operate on somebody and they find positive nodes, to order the BRAF test. We encourage pathologists to get involved and suggest that the test should be done. Or do it with their immunochemical staining. And get that information as quickly as possible. It’s not necessary for the earliest melanomas, the thin ones that are cured in a high percentage just by surgery. But once it reaches stage III, we recommended BRAF testing, whenever it’s possible, in every case.

AJMC^®: How do mutations impact the risk of developing this metastatic melanoma, specifically to further locations in the body, like the liver or the brain mets that you mentioned?

Sondak: We don’t have a definite answer to that. We don’t really know. I don’t see much in the way of major differences in site of distant spread or rate, based on the BRAF status.

AJMC^®: What is the prognosis, typically, for a patient diagnosed with this advanced metastatic melanoma? Does the mutation impact that, or is it just, if you’re stage III or IV, it’s an overall timeline?

Sondak: The prognosis is impacted, as I was alluding to, by the ability to do additional treatment. So I said it was about a 60% 5-year survival in that study that had IPI/NIVO first and BRAF-targeted therapy for those who failed. For the same patients treated with the same drug to start with, but they were BRAF wild type, so there wasn’t anything that could be done afterward, their 5-year survival was about 10% lower. So the ability to treat increases the chance of a favorable outcome, because it’s just another—it’s like having a parachute if the plane is on fire.

AJMC^®: There are 3 most likely cancers to develop brain mets. As we mentioned, one was melanoma, and the others were lung cancer and breast cancer. And you mentioned we don’t exactly know why. Do we know any factors, and specifically in melanoma, that is likely to cause such growth of brain mets?

Sondak: There are probably homing factors in there. But right now, it’s not something that anybody can take a given patient and say, “You’re likely to get brain mets. We have to worry about it for you....It’s a complete mystery in any individual patient, why it happens or why it doesn’t happen.

AJMC^®: And in melanoma, what is the prevalence of brain mets, and what risk factors—which you just talked about in homing—are associated with developing brain mets? You don’t have to answer that second part again, since you just did it. But just the prevalence factor, if you don’t mind.

Sondak: About half of all patients who develop metastatic disease eventually get brain metastases. It’s not usually the first sign, but sometimes it is. But eventually, if our treatments don’t work when we first diagnose them with stage III or stage IV, about half of those patients eventually show up with brain mets.

AJMC^®: How does treatment approach change for a patient whose disease has metastasized to the extent of distant metastases, such as brain mets, and specifically with that BRAF mutation? And what factors do you personally evaluate when deciding how to sequence treatment?

Sondak: So the brain mets change everything about what we can do and what we can’t do. And it really is a ticket to go straight to IPI/NIVO combination immunotherapy if drug treatment is needed, if we’re not talking about just a tiny brain met that can be treated with radiation. Otherwise, if the patient doesn’t have a brain met, then we know that, right now, if the patient comes into stage IV disease totally untreated, immunotherapy first, targeted therapy later. What we still need to learn is, what if they’ve already had adjuvant immunotherapy? What if they had treatment with nivolumab or pembrolizumab after their first surgery, and now they’ve got lung mets? Does that change? And how do we integrate the new LAG-3 inhibitors? So that’s a whole other lecture.

AJMC^®: Do you have anything you want to add for closing thoughts on disease management or actionable mutations in melanoma that you want to share with your colleagues?

Sondak: Just that I think there’s no role for pessimism about melanoma, saying, “No, it’s awful. It’s untreatable. You can’t do anything.” These patients should be treated aggressively, at a center with a lot of experience in melanoma treatment. And if we do that, we get some amazing results at times.

Patients that I thought, and I have patients who, I will call them my ghost patients—they are alive because of taking these BRAF inhibitors or taking that immunotherapy. And I look at them, and I can’t even believe they’re still alive, with the kind of disease that they had.