BRAF/MEK Combination Highly Effective in Melanoma

Jeffrey S. Weber, MD, PhD

Adding the MEK inhibitor trametinib (Mekinist) to the BRAF inhibitor dabrafenib (Tafinlar) significantly improves long-term outcomes while lowering certain adverse events (AEs) associated with either agent alone for patients with BRAF-mutated metastatic melanoma, according to a talk by Jeffrey Weber, MD, PhD, at the 2015 Chemotherapy Foundation Symposium.

"The median survival for dabrafenib/trametinib is a very impressive 25 months, and you can't get much better than that in melanoma. One-year survival is 74%—very impressive," said Weber, from the NYU Langone Medical Center's Laura and Isaac Perlmutter Cancer Center. "This is one of the few times in oncology that adding a second drug to one drug actually decreases the side effects."

In 2002, BRAF mutations were discovered and found to be present in many malignancies. Following this discovery, BRAF inhibitors were quickly developed for patients with melanoma, with vemurafenib (Zelboraf) approved in 2011 followed in 2013 by dabrafenib and trametinib. Additionally, in January 2014, the combination of dabrafenib and trametinib received an accelerated approval for patients with BRAF-mutant metastatic melanoma.

"BRAF was felt to be a driver gene because tumor growth became dependent upon it if mutated, and if it were knocked out they would not grow and display all of the features of invasive cancer," Weber explained. "Much effort went into developing specific BRAF inhibitors as anticancer agents, and two have been FDA approved, as has a MEK inhibitor, so far."

Two phase III studies assessed the combination of dabrafenib and trametinib for patients with BRAF-positive melanoma, to support a full approval for the combination. The FDA is currently evaluating data from these studies, with a decision expected in the next few weeks.

In the first study, labeled COMBI-d, dabrafenib/trametinib was compared with dabrafenib alone in 423 treatment-naïve adults with BRAF-mutant metastatic melanoma. In the final analysis, median progression-free survival (PFS) was 11.0 months for dabrafenib plus trametinib versus 8.8 months for dabrafenib plus placebo (HR, 0.67; 95% CI, 0.53-0.84; P <.001).

The final results showed that overall survival (OS) was 25.1 months in the combination arm compared with 18.7 months with single-agent dabrafenib (HR, 0.71; 95% CI, 0.55-0.92; P = .011). The 1- and 2-year OS rates were 74% and 51%, respectively, with dabrafenib plus trametinib, and 68% and 42%, respectively, with dabrafenib alone.

"It kind of looks like there's a tail in the curve, and it's obvious the combo is better with a pretty respectable P value and hazard ratio versus a single BRAF inhibitor alone," Weber said.

In the second trial, known as COMBI-v, 704 patients were randomized to receive the combination of trametinib and dabrafenib or monotherapy with vemurafenib. The median PFS was 12.6 months with the combination versus 7.3 months for vemurafenib (HR, 0.61; 95% CI, 0.51-0.73; P <.001).

With longer follow-up, the median OS with dabrafenib/trametinib was 25.6 months compared with 18 months with vemurafenib (HR, 0.66; 95% CI, 0.53-0.81; P <.001). The estimated 2-year OS rate was 51% with the combination compared with 38% with vemurafenib monotherapy.

"There's a clear benefit that begins at the first follow-up at 2 months and extends all the way through," Weber said. "This absolutely confirms what was seen in the prior study. Together, in 1000 patients or more, there's a very reproducible overall survival—that's excellent for metastatic melanoma."

Based on this success, other BRAF/MEK combinations are under investigation. In a phase III study, vemurafenib was combined with the MEK inhibitor cobimetinib. The FDA is currently reviewing results from this study, with an expected decision regarding approval within the next few weeks. Additionally, the BRAF inhibitor encorafenib is being combined with the MEK inhibitor binimetinib for patients with BRAF-mutant melanoma, Weber noted.

With so many combinations currently being explored, AE profiles may start to be used to help guide treatment selection. For the combination of vemurafenib and cobimetinib, there is a similar reduction in skin-related toxicity versus single-agent BRAF inhibition; however, the rate of diarrhea was slightly higher.

"You decrease skin toxicity but increase some of the other toxicity with vemurafenib/cobimetinib," Weber said. "You're not going to see as much skin toxicity but, interestingly, you begin to get rashes, pyrexia, arthralgia that appear to be a little higher, and you actually see a little more diarrhea with that particular combination.”

In addition to targeted therapies, immune checkpoint inhibitors are also approved as treatments for metastatic melanoma. Moreover, data suggests these agents are effective in both BRAF-mutant and wild-type populations.

When deciding between upfront therapies, patient characteristics and disease burden should be considered. In patients with low burden BRAF-mutant indolent melanoma, immunotherapy may be an ideal frontline option, Weber noted. However, in rapidly growing, high disease burden BRAF-positive disease, the combination of a BRAF inhibitor and a MEK inhibitor should be used as first-line therapy.

"The challenge is who do you give targeted therapy to first and who do you give immunotherapy to first," said Weber. "Most of us agree that in a rapidly growing high disease burden patient, if they’re mutated, go with BRAF/MEK."

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