Advances in the Treatment of Malignant Melanoma - Episode 12

Management of Brain Metastases in Melanoma

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Jeffrey S. Weber, MD, PhD: Let’s head back to Jason. The ipilimumab-nivolumab track record in brain metastases really did change my practice. Those are pretty recent data that have come out over the last year or 2. What can you tell us about your approach in treating melanoma patients who have brain metastases in frontline therapy? How do you decide ipilimumab-nivolumab, pembrolizumab, or nivolumab alone versus BRAF-MEK? What do the data lead us to?

Jason J. Luke, MD, FACP: This has been an evolving area that still remains the toughest spot in melanoma to deal with. What has really come forward is that there’s just no question anymore that the standard of care for patients with brain metastases that are asymptomatic or low-volume where you don’t have to intervene immediately is ipilimumab-nivolumab. I would even go farther to say nivolumab plus ipilimumab-3, although maybe you guys want to argue with that.

The reason for that is 2 trials. One was out of Australia and led by Georgina Long, the ABC-X trial, as well as the CheckMate204 study that Hussein Tawbi led. If you look at patients treated on these trials, this is a selection of patients with brain metastases. This isn’t the run-of-the-mill patient. The people who present with small-volume or asymptomatic lesions, the landmark 1-year survival is 80%. You think about dating back 5 to 10 years, the median survival for these patients was 6 months, and now we have 80% of them alive at a year. They’re durable. It’s response in the body. It’s response in the brain. It’s really quite impressive.

In my practice, that is enough that I don’t even radiate these patients. I give them ipilimumab-nivolumab, and then we watch and monitor. If we have to, we radiate later. These data really do change the game.

I mentioned that that isn’t every patient. In fact, it’s not even a majority by any means of patients with metastatic melanoma. Many patients present, they need steroids, they’ve got shift, and they’re sick. In those patients, it’s a barrier to think you’re going to give ipilimumab-nivolumab there because if they’re on steroids, it will blunt the effect, and/or they’re already too sick to think you’re going to stress them.

It’s really all hands on deck. That’s where BRAF mutational analysis is super important. Certainly, BRAF inhibitors are active and BRAF-MEK combination in CNS [central nervous system] metastases. Mike Davies presented the COMBI-MB study some years ago showing that you get responses as you would expect in the brain. The caveat is that they are not as durable as they would be otherwise in the body. Whereas the median PFS [progression-free survival] for BRAF and MEK in the body is on the order of about 11 months, in the brain it’s about 6 months. For patients who present with symptomatic brain metastases, I try to think about if there a way we can get them to ipilimumab-nivolumab, because the data for ipilimumab-nivolumab are so impressive.

It’s worth noting as a follow-on that Hussein Tawbi updated last year’s ASCO [American Society of Clinical Oncology Annual Meeting] with the symptomatic population, where they used ipilimumab and nivolumab and got not nearly the same kind of results. They had a response rate of about 20%, perhaps. Even those 20% were outliers who had weird stories and weren’t representative of the usual patient you would see if a patient is symptomatic with these high doses of steroids or has a shift or something like that.

The quick is that ipilimumab-nivolumab, if you can do it, is for sure the right answer. If not, use everything you can get, with the 1 caveat being not whole-brain radiation. At ASCO last year, there was a nice study looking at adjuvant whole-brain radiation after resection. The results were equivocal. There was no difference between the whole brain and not using whole brain.

If you looked at the numerical data, whole-brain was actually worse than doing nothing. All of us have treated patients and given whole-brain, and whole-brain is awful for patients, and in melanoma, it does not add anything. Please don’t use whole-brain radiation. We need to SRS [stereotactic radiosurgery] some lesions, we can use the BRAF-MEK, but try and get to ipilimumab-nivolumab. Do not use whole-brain radiation. Call everybody you know to try to get as much advice as you can because these are hard patients to manage.

Jeffrey S. Weber, MD, PhD: Su, will you forgo stereotactic radiosurgery in an asymptomatic patient who presents front line?

Sunandana Chandra, MD: That’s an excellent question. We usually always discuss these patients at our multidisciplinary melanoma tumor board. We have radiation oncology there, obviously medical oncology, surgical oncology, etc. If they’re asymptomatic and they are up to 3 cm or so, we usually wait. Three is probably pushing it in terms of sizes, but we try to forgo radiation therapy and give them some time on ipilimumab-nivolumab. We follow them very closely with respect to symptoms and radiographic imaging. We’ve had situations where their lesions have responded beautifully, and they haven’t required radiation. With SRS, although it’s fairly well tolerated, there can be adverse effects. We’ve seen radiation necrosis. It’s certainly not a benign modality.

Jeffrey S. Weber, MD, PhD: One last interesting thing is, in the trilogy or the IMspire150 trial, there were some data about the time to CNS metastases. This was presented prominently at AACR [American Association for Cancer Research] 1 month or so ago. Ryan, what can you tell us about that? You know that study pretty well.

Ryan J. Sullivan, MD: The study randomized patients to receive a triplet of vemurafenib, cobimetinib, a BRAF-MEK inhibitor, for 28 days, and then after 28 days, to fold in atezolizumab therapy. The comparator was vemurafenib, cobimetinib, and atezolizumab placebo. The data for the primary end point was progression-free survival. There was a progression-free survival advantage to giving triplet therapy versus doublet therapy.

It didn’t allow patients with active brain metastases, but there was a subset analysis looking at the time to develop brain metastases in patients who received doublet versus triplet therapy. It seemed to be a numerical difference, meaning the patients who got doublet therapy had a shorter time and were more likely to develop brain metastases than those who got the triplet therapy, though it didn’t meet statistical significance. It was a subgroup analysis. It wasn’t a ton of patients. I can’t really say that’s the way to go in terms of treating patients in frontline with brain metastases that are asymptomatic and overtreated. That’s a different experiment, so to speak.

There will be those types of trials. Already, there are a couple of trials, including a trial in SWOG that’s looking at triplet therapy.…That will be an important trial to understand whether targeted BRAF-MEK and combining that with PD-1 is as effective in patients with brain metastases than just nivolumab.

Transcript Edited for Clarity