There have been no head-to-head comparisons of encorafenib plus binimetinib and other BRAF+MEK inhibitor combinations across clinical trials, such as dabrafenib plus trametinib or vemurafenib plus cobimetinib, cautioned Dr Ben-Betzalel. Nevertheless, there does appear to be numerically better PFS in COLUMBUS than previous trials.

“An interesting part of this study, which I found fascinating, is that the investigators actually used a higher dose of encorafenib [450 mg] than is currently considered tolerable as a single agent,” Dr Khushalani said. “In other words, the addition of binimetinib appeared to allow them to raise the dose of encorafenib, to 450 mg daily.”

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The higher dose of BRAF inhibition might yield longer binding times or a mechanistic synergy between encorafenib and binimetinib, improving efficacy, and possibly explaining the long PFS outcomes reported for COLUMBUS, Dr Khushalani said.

“So, the question is, was it the higher dose of encorafenib that was utilized, or was it truly the combination [that was efficacious]?” he pondered.

A second part of the COLUMBUS trial, requested by the US Food and Drug Administration (FDA), will address that question; results addressing this question will be published in the future. (The FDA did not respond to a request to comment for this article.)

In the COLUMBUS trial, adverse events among patients administered the encorafenib plus binimetinib regimen included elevated gamma-glutamyl transpeptidase, increased blood creatine phosphokinase, and hypertension.1

“Interestingly, here, the main reason for drug discontinuation was nausea, which is something not frequently experienced with previous inhibitors,” Dr Ben-Betzalel noted. The one reported death “may or may not be related” to treatment, as the patient died by suicide, he said.

“We will have to wait until we gain clinical experience with this combination to see if the [toxicity profile] holds true in real-life,” he said.

Patients with lower disease burden and normal lactate dehydrogenase (LDH) levels did not see statistically significantly improved OS with encorafenib plus binimetinib, Dr Ben-Betzalel pointed out. “These patients probably responded well to immunotherapy as subsequent line and thus, probably there weren’t enough [OS] events to reach statistical significance [in COLUMBUS].”

Because BRAF plus MEK inhibition modulates the immune system, it might represent a salvage therapy opportunity after disease progression on immunotherapy, Dr Ben-Betzalel said.  “The future may lie in combinations of immunotherapy plus targeted therapy upfront. With numerous clinical trials underway, we should have those data soon.”

“I think the important thing here, with the newly reported findings from the COLUMBUS trial, is that it opens up another avenue of treatment,” Dr Khushalani said. “Patients and providers now have more choices and they will have to look closely at the patient’s situation to determine what combinations to use.”

“Another message is that just because a patient develops unique side effects with one [MEK+BRAF inhibitor] combination does not necessarily mean they will experience the same with other combinations,” Dr Khushalani added.

“If I have a patient develop high toxicity to encorafenib and binimetinib but that patient is still responding to treatment, then I would be very comfortable switching them to, say, dabrafenib plus trametinib,” Dr Khushalani  said. “It’s good to have that option available.”

Disclosure: The original study was funded by Array BioPharma and Novartis. For a full list of disclosures, please refer to the original study.


  1. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(10):1315-132.