Trametinib and Dabrafenib Combo Successful in Melanoma

treatment for BRAF-mutated metastatic melanoma

Jeffrey S. Weber, MD, PhD

Patients receiving a combination of MEK inhibitor trametinib (Mekinist) and BRAF inhibitor dabrafenib (Tafinlar) not only greatly improves long-term outcomes, but also lowers some adverse events (AEs) associated with either standalone agent for patients with BRAF-mutated metastatic melanoma, said 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, deputy director, 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."

Two phase III studies assessed the combination of trametinib and dabrafenib for patients with BRAF-positive melanoma in order to support a full approval for the combination. Results showed 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.

The FDA is currently evaluating data from these studies, with a decision expected in the next few weeks.

"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, 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). Longer follow-up showed 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."

Other BRAF/MEK combinations are under investigation based on these successes. In a phase III study, a combination of vemurafenib and MEK inhibitor cobimetinib was tested and the FDA is currently reviewing results from this study with an expected decision before the end of the year. 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&rsquo;re mutated, go with BRAF/MEK."

BRAF mutations were not only discovered in 2002, but found to be present in many malignancies. Following this discovery, BRAF inhibitors were 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."