BRAF/MEK Combinations Available in Advanced Melanoma



Hussein A. Tawbi, MD: The combination of BRAF and MEK inhibitors has been studied in actually 3 different combinations. So dabrafenib and trametinib was the first combination to go through phase II and phase III testing, and there’s a combination of vemurafenib and cobimetinib, and most recently we have encorafenib and binimetinib. And you know it’s really a good thing for our patients that we have 3 combinations, and the interesting part is that we know that each of them has a slightly different toxicity profile, as well as potentially a different efficacy profile. From a toxicity perspective we know that dabrafenib-trametinib, for instance, really causes a lot of fevers, and that tends to be the biggest kind of issue in how we manage that.

Vemurafenib and cobimentinib together seem to cause a lot of the skin toxicities and some GI [gastrointestinal] toxicities as well, in addition to occasionally causing fever, but they cause it to a lower degree than dabrafenib and trametinib. Encorafenib and binimetinib came along and really kind of improved in the toxicity profile of both combinations. And so we see less of the pyrexia, we see fewer of the GI adverse effects, and they definitely have a slightly different profile themselves.

Now the interesting part to me, as both a physician and a scientist, is actually that we do think that encorafenib and binimetinib work slightly differently from the dabrafenib-trametinib and vemurafenib-cobimentinib, mostly because of the pharmacokinetic properties. The 3 of them seem to kind of go after the same targets. So encorafenib goes after the BRAF-mutated protein, and binimetinib goes after MEK and causes MEK inhibition.

However, encorafenib, when it does go to the BRAF-mutated protein first, it seems to be able to inhibit almost equal degree. Whether it’s V600E or V600K or anything else, it seems to be a bit broader there. But the best part is that it actually kind of sticks to the target and stays there for much longer than other BRAF inhibitors, which in preclinical models we know that if you suppress the BRAF-mutated protein in the MAP kinase pathway, the longer you suppress it, the deeper you suppress it, the more likely you are to get a better response. So there seems to be that effect of the BRAF inhibitor.

And then the interesting part is the MEK inhibitors, which you know itself carries a bunch of the toxicity with the other 2 combinations. Traditionally those 2 other MEK inhibitors tend to actually last in the system very long, so they have a long half-life. They could take up to 2 to 3 weeks to wash about. Binimetinib, on the other hand, actually has a very short half-life in the matter of hours. And so that seems to help in terms of both having a lower toxicity profile and, again, managing the toxicity when you have to stop them.

Geoffrey Thomas Gibney, MD: So there are subtle differences in the pharmacodynamic properties and the biological properties of the BRAF and MEK inhibitors. We now have 3 agents within each class that have been approved by the FDA that are in clinical use. In particular, encorafenib has been studied in cell experiments and shown that the on-target effect with a single dose appears to last the longest compared with some of the other BRAF inhibitors that are currently approved. And that is reflected in the dosing that we use for patients where it’s once a day rather than twice a day.

In terms of the MEK inhibitors, those have various on-time with inhibition of the MEK protein kinase. Those agents are dosed relatively continuously in most patients. However, the duration that they’re present in the body, the half-life, can be short in some cases. For example, binimetinib is known to have a fairly short half-life and requires twice-daily dosing. This can have some advantages. For example, if there are adverse effects or toxicities that are related to the MEK inhibitor, if it has a shorter half-life and then you hold the drug, the drug will be out of the body quicker, and perhaps the adverse effects will be ameliorated quicker. And then the patient can work with the treating physician to decide how to redose at that point.

Transcript Edited for Clarity.

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