Encorafenib/Binimetinib Combo Shows Best-In-Class Efficacy in Melanoma

The combination of encorafenib (Braftovi) and binimetinib (Mektovi) demonstrated best-in-class overall survival (OS) and progression-free survival (PFS) in patients with BRAF-mutant metastatic melanoma, according to data presented at the 2018 ASCO Annual Meeting.

These encouraging results from the phase III COLUMBUS trial led to an FDA approval in June 2018 of the BRAF/MEK inhibitor combination for the treatment of this patient population.

At a median follow-up of 36.8 months, combining encorafenib at 450 mg daily and binimetinib at 45 mg twice daily (COMBO450) reduced the risk of death by 39% versus vemurafenib (Zelboraf) alone. The median OS for COMBO450 was 33.6 months (95% CI, 24.4-39.2) versus 16.9 months (95% CI, 14.0-24.5), respectively. Median PFS was 14.9 months for COMBO450 versus 7.3 months with single-agent vemurafenib (HR, 0.51; 95% CI, 0.39-0.67; P <.0001).

The survival benefit was maintained across all subgroups, according to Keith T. Flaherty, MD, coauthor of the study. He added that the combination appeared to be well tolerated.

Moreover, an interim analysis suggested an OS benefit for COMBO450 compared with single-agent encorafenib at 300 mg daily. The 33.6-month median OS for COMBO450 significantly surpassed that of 23.5 months for encorafenib monotherapy. Another analysis looked at the two BRAF inhibitors as single agents, and encorafenib showed superiority over vemurafenib.

In an interview with OncLive, Flaherty, director of the Termeer Center for Targeted Therapy at Massachusetts General Hospital, professor of Medicine, Harvard Medical School, discussed the clinical implications of the COLUMBUS trial of encorafenib plus binimetinib in patients with BRAF-mutated melanoma.

OncLive: Please provide some background to the COLUMBUS trial.

Flaherty: For several years now, we have known that BRAF mutations are a bonafide therapeutic target in melanoma, with about 45% of patients with advanced disease harboring these mutations. We had a first wave of advances around 2010 with vemurafenib and dabrafenib (Tafinlar) coming along and essentially proving that BRAF mutations are a good target. Those drugs ultimately became FDA approved just a couple years later. We began to understand that reactivation of the same pathway in which BRAF resides, the MEK pathway, was a very common theme. There were available MEK inhibitors, which target the downstream pathway from BRAF. It was immediately conceived that if we stitch these 2 drugs together, it would be useful.

That has been validated twice over, with dabrafenib/trametinib (Mekinist) and vemurafenib/cobimetinib (Cotellic) being FDA approved for the same population. Encorafenib was essentially the immediate next generation BRAF inhibitor to come along. It was developed in a laboratory to be a more potent and selective BRAF inhibitor than what we've seen before. It was [preclinically] tested head-to-head and shown to be superior. By the time encorafenib had entered clinical development, we knew that BRAF/MEK combination therapy was the emerging, new standard of care.