New Targeted Therapy Duo Provides Advantages in BRAF-Mutant Melanoma

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.

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?

In an interview with OncologyLive^®, 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.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.

How does this combination compare with the other approved BRAF/MEK combinations?

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?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.

What are the next steps for this combination?

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.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.

How well do patients tolerate this combination?

Encorafenib and binimetinib are approved as distinct drugs. Is there any circumstance where either would be used as a monotherapy?

In the metastatic setting, we are deeply investigating targeted therapy/ immunotherapy combination regimens, and encorafenib and binimetinib could offer some advantages in that setting, as well. Lastly, we are working hard on overcoming melanoma cell-intrinsic mechanism of resistance to BRAF/MEK combination therapy and some of the combinations of greatest interest, such as CDK4/6 inhibitors.The tolerability of encorafenib and binimetinib is the most distinguishing feature of this regimen. We have known since the initial development of vemurafenib monotherapy that photosensitivity is uniquely observed with that agent and is a common problem. Dabrafenib monotherapy can be associated with mild fever, but, in combination with trametinib, that effect is amplified. Three-quarters of patients experience fever when receiving dabrafenib/trametinib, and in a subset of them, it is recurrent and truly problematic. Encorafenib and binimetinib posed no risk of photosensitivity and minimal risk, if any, of recurrent or complicated febrile syndromes.No, not presently. Binimetinib has been investigated as a single agent in a different subset of melanoma patients and did not demonstrate a sufficiently large benefit to garner FDA approval, and it is now clear that a BRAF inhibitor such as encorafenib—as with vemurafenib and dabrafenib—should never be given in the absence of a MEK inhibitor. This is reinforced by 2 elements of the trial data: efficacy and safety. The efficacy data are irrefutable: The addition of a MEK inhibitor to a BRAF inhibitor improves response rate and progression- free survival. In trials with sufficient statistical power and data maturity, OS is also improved. But toxicity is actually diminished by the addition of a MEK inhibitor to a BRAF inhibitor.

Those who have seen presentations of the trial data or read the published papers have difficulty appreciating the profundity of this effect because patients received BRAF/MEK combination therapy for far longer than BRAF inhibitor monotherapy in those trials and the aggregate toxicity data don’t account for this. On a per-month basis, there is far less toxicity and far less severe toxicity with BRAF/MEK combinations than BRAF inhibitor monotherapy. When considered with the efficacy data, I have yet to see a patient whose melanoma harbors a BRAF V600 mutation for whom I would consider BRAF or MEK inhibitor monotherapy.