Geoffrey Thomas Gibney, MD: In patients with BRAF-mutated melanoma, as well as melanoma in general that is advanced and unresectable, we’ve made major progress in the treatment strategies. However, there still are major hurdles, major unmet needs. Currently, we do not know how to select patients very precisely for the therapy that we offer. The BRAF genotyping is very important for selecting patients who would benefit from BRAF-targeted therapy. But even within that population of patients, there are patients with BRAF mutations that respond very well or less well. And we really need to be able to sort out those patients better ahead of time, so we can have better discussions with patients and maybe even develop the therapeutic approach better. Or if we know that they have a BRAF mutation but are predicted to have a poor response to BRAF-targeted therapy, that may be a patient that you would offer immunotherapy first, and vice versa, the same would be true.

We have been able to identify resistance mechanisms for BRAF-targeted therapy as well as immunotherapies. There has been some investigation into looking at these as markers to predict who would have a better response or predictive model. It’s still very early and has not been very successful to the point where we can use it in routine clinical practice. What we’re lacking are prospective studies with a biomarker that is used to select patients to guide a treatment, and hopefully we will get there soon. And this will really make a major improvement in the way we treat patients and their outcomes.

Ryan J. Sullivan, MD: What’s clear about the field with targeted therapy, particularly BRAF-targeted therapy in melanoma, is we’re not there yet in terms of having therapies that work for the great majority of our patients. They work for the great majority of our patients, but they only work for a relatively short period of time for most of those patients. And so what we’d really like to be able to do is develop more robust strategies that target the MAP [mitogen-activated protein] kinase pathway but potentially other targets in cancer cells that might lead to more prolonged and deeper responses in our patients just with targeted therapy.

Now, there are a number of different combination studies that are being looked at. We’re looking at targeting apoptosis, the idea being if we can create more tumor cell death at the beginning of therapy, that that may actually translate into a longer and deeper response for those patients. People are looking at combining or targeting other things in tumor cells. There’s something called autophagy, which is in response to targeted therapy, cancer cells essentially use this protective mechanism to get around and survive the initial insult of the BRAF-targeted therapy. So targeting that with BRAF-targeted therapy is being looked at. There’s a lot of really amazing high impact profile papers looking at targeting autophagy in the setting of BRAF and MEK inhibitor therapy in melanoma. And there’s now clinical data that are being generated in patients in a number of trials, that either have been done or are being done looking at that.

There are other alternative pathways that get activated in the setting of BRAF-targeted therapy that could be potential targets for combination with BRAF-targeted therapy. There’s a pathway called the PI3 kinase pathway, which often gets activated in the setting of BRAF inhibitor or BRAF/MEK inhibitor resistance. So it makes sense to block the pathway in combination with BRAF/MEK inhibitor therapy. The challenge with all of those therapies, all those strategies is toxicity. We got lucky with the combination of BRAF/MEK inhibitor therapy in that some of the adverse effects that are dominant with those 2 types of therapies are mitigated when we give them together because BRAF inhibitors activate the pathway in normal cells. MEK inhibitors block the pathway in normal cells, and so there can be a canceling out of adverse effects.

But that’s not true with lots of other types of drugs, particularly small molecule inhibitors. So giving BRAF/MEK inhibitor plus an inhibitor of apoptosis, we may not be able to get away with the same doses of all 3 drugs. There’s a target called CDK4/6 [cyclin-dependent kinases 4 and 6]. It’s an important protein for regulating the cell cycle. You can imagine that cancer cells need to undergo cell cycle. It’s one of the ways that they’re defined as a cancer cell, so blocking that can be important. And inhibitors of CDK4/6 have been FDA approved for breast cancer.

We’ve actually looked at inhibiting BRAF and MEK with CDK4/6 therapy, and a trial showed that the response rate of encorafenib/binimetinib and a CDK4/6 inhibitor called ribociclib was actually less effective. It was a lower response rate than encorafenib/binimetinib by itself. And how can that be? Well, the reason that probably was is you couldn’t get away with giving the drugs at the right doses. And so just giving all 3 drugs and seeing what’s the tolerable dose and moving forward with that regimen led to suboptimal response rates. So that’s the challenge now, and it may be that we have to pivot to a different type of drug development strategy. Typically what we do in phase I trials, if it’s 1 drug we give the drug until it’s no longer tolerable, then we back off, we find the right dose, and we say that’s the dose we’re going to move forward with.

In combinations, same thing. Oftentimes, in combinations you pick the drug you think is the most important and you just bring up the dose of the other one until you think it’s tolerable or until it’s not tolerable, and you do the same thing and you come back down, and you settle on your dose. With 3 drugs it’s even more complicated, and with 4 drugs…the complexity begins to build. Now, one of the things that we might be able to get away with is giving intermittent therapy with BRAF/MEK inhibitor therapy and then coming in with a second or third or fourth inhibitor to block a different pathway, and then doing some sort of therapy where somebody is always on something but it’s not always the same thing.

And we might be able to get away with that more readily with encorafenib and binimetinib, only because they have short half-lives. And so that may actually be the best use of that regimen, in building combination therapies, multi-drug targeted combination therapies where you then add in a different drug, ideally with a short half-life and then we go back to other drug. And so I think we’re going to have to rethink how we do phase I clinical trials, taking advantage of the fact that we think intermittent therapy isn’t necessarily bad, it may be good. And then also taking advantage of short half-lives of these drugs, so that we can give drugs at an effective dose but that is tolerable to give when we’re giving other drugs, just maybe not at the same time but within the same week or the same month.

Geoffrey Thomas Gibney, MD: In BRAF-targeted therapy, the emerging data have been very exciting, both in the adjuvant setting as well as treating patients with widespread active disease. We now have seen a shift in a lot of the treatments that we’ve been using toward the adjuvant setting. So what I would expect to see is that in larger numbers patients with BRAF-mutated melanoma will actually be receiving it in the adjuvant setting to prevent recurrence. This hopefully will be a more effective strategy because we have seen, in retrospective studies, that patients with more widespread disease, more aggressive disease, the durability of benefit and the response rate is lower with BRAF-targeted therapy. So perhaps in the adjuvant setting, this would be a much more effective strategy.

There has also been publication of the data from the COMBI-AD study showing what we think are cures, patients that would have relapsed that now haven’t relapsed and potentially cured with adjuvant BRAF-targeted therapy. We also do know there is activity in the brain. However, the control, the time that it is durable, appears to be limited. But this is another avenue that we’ve seen open up where BRAF-targeted therapy can be used to treat patients with active brain metastases.

Going forward, there are a number of studies trying to improve upon that. One of the areas that research has evolved into is combining the immunotherapy agents with the BRAF-targeted therapies. There have been several large trials that have been conducted and are ongoing with a BRAF/MEK inhibitor combined with an anti—PD-1 [anti–programmed cell death protein 1] or PD-L1 [programmed death-ligand 1] drug. We’ve seen some of the data come out, in particular with dabrafenib plus trametinib plus pembrolizumab. And the adverse effect profile does seem to be higher, the severe adverse effect rate. We do see very good activity with the triple combination, but what we haven’t seen is a clear improvement in the outcome of patients by using the 3 drugs compared to BRAF/MEK inhibitor combination alone.

The other trials with BRAF/MEK inhibitor combinations plus a PD-1 or PD-L1 drug, these were very large randomized phase III trials that we’re still waiting to see the data. The early data that were presented from the phase I exploratory studies did show some promising results. So these studies, if positive, could actually change the way we approach a BRAF-mutated melanoma patient. That in the future, we may be offering BRAF-targeted therapy plus an I/O [immuno-oncology] agent at the same time.

Transcript Edited for Clarity