Keith T. Flaherty, MD
In metastatic melanoma, combinations aimed at the BRAF/MEK kinases have become the standard of care over targeted monotherapy for patients with actionable BRAF
mutations. In June 2018, the FDA approved a new dual targeted therapy regimen that combines encorafenib (Braftovi) with binimetinib (Mektovi) for patients with unresectable or metastatic melanoma with a BRAF
V600E or V600K mutation.
, Keith T. Flaherty, MD, who served as an investigator on the pivotal clinical trial, discussed the distinguishing features of this BRAF/MEK combination as well as some next steps, including the question of whether the regimen eventually could move to the adjuvant setting. Flaherty is director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center, and a professor of medicine at Harvard Medical School, both in Boston.
Please comment on the design of the COLUMBUS trial. Why was doublet therapy tested against a single agent that has since been displaced by dual targeted therapy?
The COLUMBUS trial was designed before we had definitive evidence of clinical efficacy for BRAF/MEK combination therapy compared with BRAF inhibitor monotherapy—meaning that we did not yet have evidence of an overall survival [OS] benefit. And preclinical data suggested that encorafenib was superior to previously developed BRAF inhibitors—vemurafenib [Zelboraf] and dabrafenib [Tafinlar]—in head-to-head comparison experiments.
So COLUMBUS was designed to test 2 questions: 1, is the addition of binimetinib to this novel BRAF inhibitor superior to encorafenib alone—as has been seen with vemurafenib and dabrafenib? and 2, is encorafenib truly a superior BRAF inhibitor to vemurafenib—which was chosen because it was 1 of the 2 prior BRAF inhibitors to demonstrate an OS benefit compared with previously standard therapy for melanoma?
How does this combination compare with the other approved BRAF/MEK combinations?
Since the encorafenib and binimetinib combination has not been compared directly with dabrafenib/trametinib [Mekinist] or vemurafenib/cobimetinib [Cotellic], the comparison statements can only be made with the significant caveat that cross-trial comparisons are fraught with confounders, the most notable of which can be unobvious differences in the enrolled patient populations.
Having said that, 1 thing that was demonstrated within COLUMBUS is that encorafenib is a superior BRAF inhibitor to vemurafenib. With that as the foundation for comparison, it is interesting to note that the median progression-free survival [PFS] is the longest seen with any of the BRAF/MEK combination regimens, and landmark PFS and OS data have consistently shown the same trend. The overall response rate is very similar to that observed with the other regimens, but the complete response rate appears higher when adjusted for maturity of data—complete rates have risen with each subsequent analysis for the other BRAF/MEK regimens.
What are the next steps for this combination?
As with the other BRAF/MEK regimens approved for use in melanoma, we wonder about the potential role of this regimen in the adjuvant setting. We know that dabrafenib/trametinib confers a greater benefit in terms of relapsefree survival than any other adjuvant therapy studied to date in melanoma. It’s possible that encorafenib and binimetinib could produce an even bigger protective effect.
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