BRAF/MEK Combo Approved for Melanoma

The FDA recently approved Array BioPharma's BRAF/MEK inhibitor combination encorafenib (Braftovi)/binimetinib (Mektovi) for patients with metastatic or inoperable melanoma with a BRAF V600E or V600K mutation. The approval was based on the results of the phase III COLUMBUS trial. The agency concurrently approved the THxID BRAF Kit (bioMérieux) as a companion diagnostic to test for the mutations.

The encorafenib/binimetinib combination is the third one approved for the disease; the others are Novartis's dabrafenib (Tafinlar)/trametinib (Mekinist), and vemurafenib (Zelboraf; Genentech)/cobimetinib (Cotellic; Genentech/Exelixis).

“From a conceptual standpoint, this is nothing dramatically novel,” says Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, NY. However, “I think that there is a patient population that is going to certainly benefit from these drugs, and I think the question our clinical practice is trying to understand, when it comes time for giving a patient a BRAF/MEK inhibitor combination, now which one do we choose?”

Ryan Sullivan of Dana-Farber/Harvard Cancer Center in Boston, MA, points out that although it's difficult to draw conclusions across trials, the encorafenib/binimetinib combination seems more effective than the others: Patients treated with the new regimen had a median progression-free survival (PFS) of 14.9 months, compared with a median PFS of 7.3 months in the control group that received vemurafenib, the first FDA-approved BRAF inhibitor for melanoma. Median PFS was 11.9 months for patients in the dabrafenib/trametinib COMBI-v trial and 9.9 months for those in the vemurafenib/cobimetinib coBRIM trial.

Additionally, in the COLUMBUS trial, patients who received encorafenib alone had longer PFS than patients who received vemurafenib alone (9.6 months vs. 7.3 months), which Postow and Sullivan think could indicate that encorafenib is a more potent BRAF inhibitor.

Sullivan adds that many patients treated with dabrafenib/trametinib or vemurafenib/cobimetinib experience serious adverse events: The former can cause fevers and chills, whereas the latter can be associated with severe photosensitivity, side effects that may require skipping or reducing doses. “Neither of those toxicities are seen to a great degree with encorafenib and binimetinib,” he says, adding that he has switched some patients to the new combination, which may become the preferred option. In comparison, encorafenib/binimetinib was most commonly associated with fatigue, nausea, and diarrhea.

Regardless, Sullivan and Postow agree that the new combination is unlikely to affect whether clinicians prescribe checkpoint inhibitors, such as nivolumab or pembrolizumab, or BRAF/MEK inhibitor combinations as a first-line treatment.

“Our default is to give immunotherapy first, particularly in the stage 4 setting,” Sullivan says, but “that's definitely an unsettled question, and one that we are hoping will be answered through the course of a couple of [ongoing] clinical trials.”

For example, a phase III ECOG-ACRIN trial is exploring whether patients should get dabrafenib/trametinib followed by Bristol-Myers Squibb's CTLA4 inhibitor ipilimumab (Yervoy) and PD-1 inhibitor nivolumab (Opdivo), or vice versa. The phase II SECOMBIT trial is comparing encorafenib/binimetinib followed by ipilimumab/nivolumab with the inverse. Additional trials are testing various combinations of BRAF/MEK inhibitors and immune checkpoint inhibitors.

Sullivan hopes that future studies will delve into other potential uses for encorafenib/binimetinib—as an adjuvant therapy, for example, or to treat brain metastases. “What this approval provides is another option for our patients, and because it's approved, it will be easier to work with in clinical trials, and we can begin to ask more specific questions.” –Catherine Caruso