Jeffrey S. Weber, MD, PhD: It even gets into triple therapies. Mike, let’s finish: tell me about the BRAF, MEK, and CDK4/6 inhibitor combination. Now you’re into a triple-drug combination, which sounds interesting, but I just don’t know much about it. What can you tell us?

Michael A. Davies, MD, PhD: The genetic studies that we’ve done for melanoma have confirmed that almost all cutaneous melanomas have oncogenic events that activate the RAS/RAF/MAP kinase signaling pathway, which is the basis for the development of the BRAF and MEK inhibitors. It’s pretty clear that the second, almost universal event in cutaneous melanomas are aberrations in cell-cycle regulators, which really feed into the P16-CDK4 axis. And it really seems that in order for melanoma to develop and progress, it’s essential to lose control of cell-cycle progression. There’s a potential therapeutic opportunity, therefore, of targeting that pathway, so we actually have new agents that target CDK4, which have been approved in breast cancer and are showing activity in other cancers as a viable therapeutic strategy. And so, we’ve actually done trials before with CDK4 inhibitors combined with MEK inhibitors, often targeting RAS-mutant patients, based on promising preclinical studies.

We heard at this ASCO about early results from a triple combination of the BRAF inhibitor, encorafenib; the MEK inhibitor, binimetinib; and the CDK4/6 inhibitor, ribociclib. Interestingly, the data actually suggested that this triple combination had a lower response rate and progression-free survival than what had been reported previously with the encorafenib/binimetinib combination.

Now, that being said, the dose of encorafenib used in this triplet was actually lower than what was used in the encorafenib/binimetinib combination, and they also noted that there was a significant number of patients who had dose delays and interruptions due to toxicity with the triplet combination. I think one of the challenges we have is that we were very fortunate when we combined BRAF and MEK inhibitors together. That combination was tolerated better than either single agent alone. The question with adding a third drug to that is whether or not that will be the case again or whether or not we’re going to have to come up with new dosing strategies and regimens to overcome problems with toxicity.

Jeffrey S. Weber, MD, PhD: One of the more encouraging triplets I heard about—and we didn’t hear much about it at this meeting, but we’ve heard about it in ASCO 2016—was the use of BRAF/MEK plus PD-1 inhibitors. I had a conversation with Antoni Ribas, who’s certainly a leader in that field, and he told me that he thought there was really modest increase in toxicity and, in his extended experience, very, very good responses—although BRAF/MEK will have a great response rate. So, Jason, do we see hope for PD-1 blockade or PD-L1 blockade plus BRAF/MEK?

Jason J. Luke, MD: Well, whether we have hope or not, we’re definitely going to find out. There are a whole bunch of these trials that have already been launched, and I think it’s an open question. I think we can make a scientific rationale for why it’s a good idea. But just as we were talking about reading out what happens, I think you could also make a case for sequential therapy and how we’re going to know it’s really better. One way or the other, it’s going to be an open question. We’ll have to see how these data sets evolve.

Michael A. Davies, MD, PhD: Jason, one thing I would postulate—and this comes back to something that Georgina and I worked on together—is that we know there are certain populations of patients who’re doing really well with our current therapies, but there are also groups where the outcomes have not been impacted nearly as much. And so, as we talked about looking at the predictors of outcomes with BRAF/MEK combination therapy, we know the patients with very high LDH are not doing as well, and that holds true for immunotherapy as well. So, the patients with large, bulky tumors.

I wonder, in terms of this question, when can you get a readout on whether or not a new agent is adding something? Is there a particular strategy for taking those groups of patients where the outcomes still remain poor and using that as your place to try and figure out, initially, whether you do get an additional benefit or not? It doesn’t exclude the possibility that you could do even better in patients with lower-risk disease, but do we need to think about designing trials specifically for patients who actually have the worst outcomes? And that was reflected in the ASCO presentation today of focusing on patients with brain metastases, where we know we need to be more aggressive and take more risks to improve outcomes. I would argue that even without brain metastases, those patients with very high LDH and a high tumor burden are groups of patients where there is still an unmet need for effective therapies.

Jeffrey S. Weber, MD, PhD: Well, you’re raising the bar, Mike. That’s a pretty difficult bar.

Georgina Long, MD, PhD: You are, I was going to say that.

Transcript Edited for Clarity