Panelists: Axel Hauschild, MD, University Hospital Schleswig-Holstein; Michael A. Davies, MD, PhD UT MD Anderson Cancer Center; Jason J. Luke, MD, FACP, University of Chicago; Caroline Robert, MD, PhD Gustave-Roussy; Merrick I. Ross, MD UT MD Anderson Cancer Center
Axel Hauschild, MD: There is exciting data on brain metastases. There is clearly a higher response rate for ipilimumab and nivolumab compared with a PD-1 [programmed cell death protein 1] antibody alone. But the most striking finding is, for me, the long duration of the responses. The quality of the response is much better. So for me the new standard of care is ipilimumab and nivolumab. But if you want to have a very fast response in a patient who is symptomatic, you also have the choice of giving a BRAF and MEK combination, at least in patients who have a BRAF mutation. Do you think that there is a new star on the horizon for using the BRAF and MEK combination of encorafenib and binimetinib? I haven’t seen data on brain metastases, but the data that have been presented on the COLUMBUS trial revealed an overall survival of 33 months. That looks pretty good. The 3-year survival data that have been presented look pretty good. Do you think that this is the way to go in the future—for the company to explore encorafenib, the BRAF inhibitor, and binimetinib, the MEK inhibitor, in brain metastases patients as well?
Jason J. Luke, MD, FACP: I think that’s absolutely an interesting place to go. A couple of other insightful things happened in that drug development paradigm. From the previous drug development of BRAF and MEK inhibitors, they learned that the addition of a MEK inhibitor actually facilitates a higher dose. So dose for dose, the encorafenib dose is actually higher than a dose of dabrafenib or vemurafenib. That may or may not be why we’re seeing an extended progression-free survival, and, perhaps, a longer overall survival. But to your point, that higher potency that may be higher in brain metastases would be very attractive, even for patients who failed a BRAF inhibitor previously. You may want to try this option later.
Caroline Robert, MD, PhD: Maybe it’s a situation where we could also explore a second trial, such as initiate with BRAF/MEK, and then, right after…this would be like what we are doing in several trials that are ongoing right now.
Jason J. Luke, MD, FACP: Yes.
Caroline Robert, MD, PhD: But not in the brain metastases space.
Axel Hauschild, MD: The switch of the regimen without having a progressive disease but having a nice response. And then you maintain the response, right? That’s the aim of it.
Merrick I. Ross, MD: Jason, it’s really interesting that you said that the MEK inhibitor makes the potency of the BRAF inhibitor greater. It’s interesting that it doesn’t translate into increased toxicity though, does it?
Jason J. Luke, MD, FACP: Well, it’s actually this paradoxical relationship around mitogen-activated protein [MAP] kinase signaling that we’ve discussed ad nauseam for 10 years. Giving that the MEK inhibitor allows for a decrease in toxicity, especially in this combination where encorafenib monotherapy wasn’t tolerable. So it can really only be given in combination. Blocking mitogen-activated protein kinase with a BRAF inhibitor alone gives substantial toxicity, but adding the MEK inhibitor actually reduces that a lot.
Axel Hauschild, MD: It’s not only this but it’s also the question of dose intensification. It was shown that 300 mg of encorafenib plus binimetinib given at a regular dose is less effective compared with the combination with 450 mg of encorafenib. Mike, is dose intensification an issue for the BRAF inhibitors?
Michael A. Davies, MD, PhD: Yes, absolutely. To put this into context, maybe we have to come back to where we stand with brain metastasis. So I led the COMBI-AD study of dabrafenib-trametinib in patients with BRAF-mutant disease with active or progressing brain metastases. The idea was, as we said, that the response rate in patients with brain metastases was about 60%. The disease-control rate was 80%. These were quite favorable results. What was quite striking was that the median progression-free survival was only 6 months, as compared with our previous studies in patients without brain metastases, in whom, essentially, the progression-free survival had been 12 months. And actually, 50% of patients in this trial progressed in the brain before they progressed extracranially.
And so, in terms of why it didn’t work as well in the brain as it did extracranially, certainly one of the questions is, was it because of insufficient blockade of the MAP kinase pathway? Clearly, we were getting blockade of the pathway to see that high rate of response as well as the disease control rate. But in the phase I trial of vemurafenib, we saw that the better you block the pathway, the better the response is. In the phase I, phase II development of dabrafenib-trametinib, we actually saw that going from 1 mg of trametinib to 2 mg of trametinib resulted in an increase in progression-free survival. And so, there is a consistent story that better blockade of the MAP kinase pathway does report in better clinical outcomes.
I think those are the questions that remain in the BRAF-targeted therapy field—how much can we block the pathway, and how much will that correlate with benefit? Again, with therapies like dabrafenib-trametinib, and you could argue with encorafenib-binimetinib and even with vemurafenib-cobimetinib, it’s not clear that we truly hit a dose-limiting toxicity. It’s not clear that we can’t go higher with these therapies. I think that’s one of the things we’ll explore.