Duration of Dual BRAF-MEK Inhibition in Melanoma

Transcript:Keith Flaherty, MD: Jason commented that the best strategy may not be all drugs all the time. We’re seeing some early clinical trial results that are exploring that from a safety perspective and early efficacy focus. I would suggest, as the trials continue to mature, a novel strategy of actually on-and-off-again targeted therapy, maybe even as little as one week on, three weeks off, but really backing it out and not pushing to drive resistance to the targeted therapy.

I would suggest trying to leverage the positive immunologic effects without grinding and forcing the tumor to adapt in an immunosuppressive fashion. There is this interesting strategy that’s emerged, Jason, in a Cooperative Group trial, that might be of interest to viewers. We’re actually exploring an interrupted schedule of BRAF/MEK targeted therapy. Maybe you could explain the basis for that because this is a Cooperative Group trial that’s readily available to community investigators.

Jason Luke, MD, FACP: The SWOG trial.

Keith Flaherty, MD: Yeah, exactly.

Jason Luke, MD, FACP: Alain Algazi from UCSF is running a trial looking at the dabrafenib/trametinib, BRAF/MEK combination, with an interrupted schedule, with the idea that you would hit the MAP kinase pathway, suppress it, kill tumor cells, but then not keep it on indefinitely. The idea is that perhaps the response rate is going to end up being lower there, but maybe the therapy will have a longer duration of benefit. I think it’s open basically to anybody who is doing Cooperative Group Research, and so I absolutely recommend putting patients in that trial.

Jeffrey Weber, MD, PhD: I would think that could be a tough pitch for patients though. You’re a patient and you’re responding to the drug and then someone says, ‘Well, we’re going to give you this terrifically effective drug and then we’re going to stop it.’ And what’s the duration? Is it a month or eight weeks?

Jason Luke, MD, FACP: Off the top of my head, I don’t know. I’d had to check.

Jeffrey Weber, MD, PhD: I think it’s about a month.

Keith Flaherty, MD: Five weeks on, three weeks off was the final schedule versus continuous, which is the standard. It’s interesting. I think we’d all agree that five weeks of therapy is enough to have an anti-tumor effect. I guess the issue is, is three weeks of therapy enough to lose some of that effect?

Jeffrey Weber, MD, PhD: Right.

Jason Luke, MD, FACP: I would actually push back on your pushback to say that I am really surprised by the number of patients that come to me who are scared to death the day they start taking BRAF-inhibitor therapy that they’re going to progress. So we’ve lost sight. The idea that you might develop resistance eventually has become so pervasive that patients, many that I come in contact with, just have a disproportionate worry. And I’m like, ‘No, you’re on this great treatment.’ A third of the patients will be on it for two years.

Jeffrey Weber, MD, PhD: But they want to go on immunotherapy. You see, they’ve done their reading and they’ve decided they want to take advantage of the tail of the curve.

Jason Luke, MD, FACP: But I think, in the context of some of this data that we’re getting now, a sizable fraction of patients do very, very well for a long time on targeted therapy. I think we need to push back on that message that everyone needs to get on anti-PD-1 therapy. There are other drugs that are very effective.

Keith Flaherty, MD: The other thing about the interrupted schedule is the presence of a re-treatment effect. It’s been seen with other oncogene-targeted therapies in other cancers, EGFR and ALK inhibitors in lung cancer, imatinib in GIST. It’s known to be the case that if patients are off, away from their targeted therapy for a period of time, they can re-sensitize. And it does make you think that it’s probably not absolutely necessary to press all the time on these targets. But it’s a research question that needs to be addressed.

Jeffrey Weber, MD, PhD: But that’s an interesting question. I’d love to hear my colleagues’ views. In those who have been on a targeted therapy, presumably went to immunotherapy, and then progressed after a six-month interval, yes, I’ve been able to go back on BRAF/MEK and I’ve seen transient responses. Do you all feel that these tend to be transient re-responses or do you see long-term remissions that are meaningful?

Jason Luke, MD, FACP: Transient.

Keith Flaherty, MD: Celeste Lebbe from France just published a small series of patient cases like this. If you look at the individual patients’ treatment period number 1 versus treatment period number 2, the depth of response and duration of response is less and shorter each time. And that’s a consistent point, especially if you treated them until resistance the first time, gave them a period of time off, you tried another therapy, and then came back. The resistance biology is unfortunately probably not completely gone by the time you get there.

Rene, let’s just touch on one point. Imagine you have a patient in front of you with a BRAF mutation. You’ve gone through immunotherapy first-line, maybe first and second, depending on how you packaged the available treatments. Now they’re on BRAF-inhibitor therapy, maintaining disease control for a time but starting to break through, solitary brain metastases or a lesion or two that are larger now than they were at their nadir but still smaller than they were at the beginning.

What’s your approach in terms of this concept of treating beyond progression? Is that something you feel offers real benefit? Do you have patients who you think have actually derived sustained benefit from that?

Rene Gonzalez, MD: I think yes. I really don’t have any data, especially with the brain metastases, as you mentioned. The efficacy of these drugs in the brain is there, but it’s less than what it is systemically with both BRAF inhibitors. So I have no problems at all about treating a patient with brain metastasis with gamma knife surgery and continuing treatment. Systemically, it’s less because there you know that the drug is getting in there. But still, I think if it is easy to treat a solitary site, or two, or three of progression, I’m happy to do that. But I start looking for what else is out there.

Transcript Edited for Clarity