Jeffrey S. Weber, MD, PhD: Let’s move on and talk about some of the combinations. Michael, talk to me about COLUMBUS. I don’t mean the explorer, I mean the clinical trial. That was encorafenib plus binimetinib; versus encorafenib, alone; versus vemurafenib, as the control arm. Those data were presented in an updated form at the 2018 ASCO annual meeting, and some of the data have recently been published in Lancet Oncology. Tell me about the data.

Michael A. Postow, MD: When we think about the BRAF-mutant space, we have traditionally had 2 BRAF/MEK combinations—dabrafenib and trametinib, and vemurafenib and cobimetinib. Now we have a third combination coming forward—encorafenib plus binimetinib.

The COLUMBUS study was a phase III study, as you mentioned, testing encorafenib and binimetinib versus encorafenib, alone, versus vemurafenib, alone. The control arm was vemurafenib, alone, which would be the historical standard BRAF inhibitor. To no surprise, the BRAF and MEK inhibitor combination was better than vemurafenib, alone, with better progression-free survival and better overall survival.

So, we now have solid, additional data for a new BRAF/MEK inhibitor combination—encorafenib and binimetinib. Here, it’s better than vemurafenib. I expect that it will be used. It’s a great combination. It has really impressive progression-free survival and overall survival results. The real question becomes, is it better, or are the side effects different than the existing BRAF and MEK inhibitor combinations?

Jeffrey S. Weber, MD, PhD: Michael, arithmetically, 33 is definitely better than 25. On a good day, 25 is the best median survival you’re going to see with any BRAF/MEK regimen in a metastatic, randomized trial.

Robert Andtbacka, MD, CM: We also have to remember that this study is done much later on. The subsequent lines of therapy that these patients have on this study are very different from the vemurafenib and cobimetinib study, as well as the dabrafenib and trametinib study.

Jeffrey S. Weber, MD, PhD: That’s an excellent point. It was also an international study. Some of these drugs were not available in Europe, Canada, or Australia, and some of them now are due to the more current COLUMBUS study.

Michael A. Postow, MD: So, the survival question—we know that it’s kind of heterogeneous. It is a difficult endpoint to put aside, and we’re going with cross-trial comparisons here. The progression-free survival is also very impressive. You could say, “Well, maybe this is a better selected group of patients,” but the vemurafenib control arm looks like vemurafenib from the COMBI-v study.

Jeffrey S. Weber, MD, PhD: Yes, 7.3 and 14.9 for encorafenib/binimetinib, and 14.3 is definitely different than 11.3.

Michael A. Postow, MD: So, it looks really good—encorafenib and binimetinib—in my opinion. Although that efficacy data is very impressive, the other thing that’s a real big issue is, what’s the side effect profile? And, as we think about making a choice between dabrafenib and trametinib, encorafenib and binimetinib, or vemurafenib and cobimetinib, what are the side effects? What kind of patient are we treating? What’s going to be important to that patient? How many pills do they need to take? These kinds of things are all going to be the intangibles that affect how we make our decisions for which BRAF/MEK combination regimen to go with for a patient.

Jeffrey S. Weber, MD, PhD: One thing that seems to determine the outcomes of a BRAF/MEK regimen is disease burden and LDH. I guess I’d want to know, in the COLUMBUS combination arm, what the LDH levels and the assessments of disease burden were. And, is that equivalent to any other trial? Obviously, that’s a back of a napkin calculation, but I think that would be very interesting.

Transcript Edited for Clarity