BRAF/MEK Combinations Available in Advanced Melanoma

Source: The Conversation, June 2019


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.

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