Jeffrey S. Weber, MD, PhD: The other sort of important issue that’s come up over the last couple of years is 1 that’s dear to the heart of almost all of us here, and that is how do you manage brain metastases. And it used to be, the urban legend is that as soon as you had brain metastases, that meant you had a 3-month, 4-month median survival and you were going to die. It didn’t matter what treatment you had. But to some people’s surprise, that is not the case. Jason, tell us about current management. For example, the idea in the old days was that you’d give whole-brain radiation, and then you’d follow-up with subsequent therapy. But I gather most of us—including, I’m sure, you—were pretty cynical about the utility of whole brain. Has that been put to rest yet?

Jason J. Luke, MD, FACP: In medicine we never try to say never, but I would actually have to say yes. I think we have gotten to a point in the field that everyone here and everyone you speak with would say, “Please just do not do whole-brain radiation on patients with metastatic melanoma.” And the details of that are really that we now have these systemic agents that can be quite effective. Whole-brain radiation really had never been...to have efficacy in melanoma specifically. And we’re aware from previous studies now that BRAF inhibitors can induce responses, albeit it with potentially attenuated PFS [progression-free survival]. But it’s the immunotherapies that are really changing the game in that setting.

And so combination immunotherapy, shown by the Australian group, as well as a group led by Dr Tawbi, really should be the standard of care at this point—ipilimumab and nivolumab in patients who can get immunotherapy, but again, not all patients with brain metastases are good candidates for that, but I really think that is the standard of care. We need to try to get patients to immunotherapy as fast as we can. Because the initial results are 50% disease control in the brain, and there’s really no other therapy that has the potential to do that. And going back to what you said, 3-month PFS, and now we’re talking about people who are out years with brain metastases who are doing just fine. I just think we can’t emphasize that enough. Doing whole-brain radiation first messes up the potential to do that, to get that immunotherapy, and we really need to try to make sure people aren’t doing that anymore.

Jeffrey S. Weber, MD, PhD: Hussein, can you delve into the details? I guess you’ve led the so-called CheckMate 204 study, which for me was a practice-changing trial. But can you tell us some of the details?

Hussein A. Tawbi, MD, PhD: To back up just a second, I would say to Jason’s point, whole-brain radiation has not only limited efficacy but also neurocognitive decline, which I think is really relevant. Radiation in general, with now more stereotactic radiosurgery, can be really effective. It can be highly useful. Most of the decision making that we do is really a joint decision with the radiation oncologists, and we try to bring them into the discussion as early as possible. But again, with the fact that we have systemic therapies that have the ability to control the brain for a long period of time, I think that’s really relevant.

In our study of ipilimumab and nivolumab—which, by the way, was used at the high dose of ipilimumab, 3 mg/kg, and the nivolumab was 1 mg/kg—we gave 4 doses of induction and maintenance as the standard regimen. We had reported the data on 94 patients, and now at this ASCO [American Society of Clinical Oncology Annual Meeting] we report an extended number of patients, up to 101, which is the full accrual. We report with a median follow-up of now 20 months in a population that only 8 years ago had an overall survival of only 4½ months. Now we have followed these patients for a long period of time.

And we proved 2 key things. I think 1 is actually that this combination is safe in the brain. So even though you have established brain metastases, you can give combination immunotherapy without being too concerned about increasing brain edema, or causing seizures, or any of that. In fact, when we did the study, we actually saw that all our patients improved instead of having again adverse effects that were brain-specific. They still had adverse effects that ipilimumab-nivolumab gives everyone else—immune-related hepatitis, colitis, and so on. The other thing that was really critical is that we have complete response rates that we will update to be 29% complete response and a partial response rate of about 26%, 27%, for an overall response rate of 55%. And 63% of patients got to 6 months without progression. And that’s where actually a plateau formed, where there was very little progression after that in the brain. And that was also reflected in an overall survival at 1 year of 82%. However, our study in that population was patients who were asymptomatic that had stopped steroids at least 10 days before initiating ipilimumab and nivolumab.

At this ASCO, we also presented a cohort of 18 patients who we selected to be symptomatic on steroids, or on steroids who were treated with the same combination. And we had responses, but there were only 4 responses out of 18, so 22% as compared with 55%. And it was interesting to see that most of the patients who responded were not on steroids at the time of initiation of therapy. I think that study had very small numbers, making it hard to really make a definitive conclusion. But I would say that it’s clearer, as we all knew for a long time, that steroids are not a good idea when you want to treat with immunotherapy. I think we need to kind of develop new approaches for those patients and maybe perhaps incorporate radiation.

Jeffrey S. Weber, MD, PhD: Ryan, we’ve heard about immunotherapy for brain metastases. What’s the role for targeted therapy? Is there a role for targeted therapy?

Ryan J. Sullivan, MD: There’s definitely a role for targeted therapy. I think if you had a choice, as Jason mentioned, between targeted therapy and combined immunotherapy—and there’s no reason you shouldn’t give combined immunotherapy, meaning there isn’t an absolute contraindication—you should give combined immunotherapy. The data that Dr Tawbi has just described are remarkable. They overwhelm anything else we’ve ever seen in patients with metastatic brain metastases with melanoma.

Targeted therapy is effective. Many patients respond. The response rate is probably not quite as high as it is in patients who have extracranial disease, but it approaches that. It approaches 45% to 65% response rates in the various cohorts of the COMBI-MB study. The challenge of that, as Dr Luke also alluded to, is that the progression-free survival looks like a staircase that begins at day 0 and ends at day 365. By a year, almost everybody had progressed, and it was pretty steady, about half of patients at 6 months. You don’t see that plateau that Hussein is describing with combined ipilimumab-nivolumab.

I think there are certain scenarios in which it’s a must. A patient who’s on a ton of steroids, who is BRAF mutant and has enumerable brain metastases, you need to cytoreduce that patient and get them off steroids, and then potentially maybe switch them to ipilimumab-nivolumab. That’s a potential use of targeted therapy, or the scenario that you use it in. It’s really to get people out of trouble with their brain metastases and hope that you can get them to combined immune checkpoint inhibitor therapy.

Transcript Edited for Clarity