Treatment of Metastatic Melanoma—Evolution from Monotherapy to Combination Therapies

The most prevalent genetic alteration identified in melanoma is a mutation in the BRAF gene that increases the activity of the BRAF protein. As many as 50% of melanoma tumors express a BRAF mutation; the most common is the V600E mutation, found in 80% to 90% of BRAF-mutant patients. The first targeted therapy developed for melanoma, vemurafenib, directly inhibits the BRAF protein. In August 2011, the Food and Drug Administration (FDA) approved vemurafenib for treatment of metastatic melanoma with the BRAF V600E mutation. Now, a second BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, have been filed with the FDA for treatment of metastatic melanoma and several late-stage dabrafenib plus trametinib combination trials are underway.

Results from the phase III vemurafenib BRIM-3 trial showed that those patients who were treated with vemurafenib had a 63% reduced risk of death compared to those in the control chemotherapy arm. In a longer-term follow-up in 2012, the median overall survival rate was 13.2 months with vemurafenib compared to 9.6 months in the chemotherapy arm.

“Vemurafenib appears to have had a substantial impact in our practice,” says Keith Flaherty, MD, of Harvard Medical School and director of Developmental Therapeutics at Massachusetts General Hospital (MGH) Cancer Center. Flaherty played a significant role in the development of vemurafenib in both early- and late-stage clinical trials.

Metastatic melanoma patients harboring a BRAF mutation now experience substantially prolonged survival compared to our recent historical comparison prior to 2009, says Flaherty. “Some of this is surely related to the direct effects of vemurafenib, and some of it may well be related to the fact that these patients are now also able to go on to receive other therapies that they would not have previously,” he says. Some of these other therapies include ipilimumab, an immunotherapy antibody also approved by the FDA in 2011, as well as other agents currently being evaluated in clinical trials.

In August 2012, the BRAF inhibitor dabrafenib was filed for approval in the U.S. and Europe based on a clinical trial comparing it to chemotherapy in metastatic melanoma. Trametinib, a drug that inhibits the MEK protein, was filed in parallel.

While each drug is an independently effective treatment (monotherapy), the real excitement is in the BRAF–MEK inhibitor combination. Interim results from a phase II trial have been reported. “The combination of trametinib and dabrafenib seems to markedly enhance not only initial tumor response, but the durability of those responses,” Flaherty says. “The current evidence regarding the dabrafenib–trametinib combination is quite compelling, and suggests that a MEK inhibitor will play an absolutely critical role in the management of BRAF mutant melanoma once that combination is widely available to patients.”

Two global phase III trials are now underway comparing dabrafenib plus trametinib to either dabrafenib or vemurafenib alone. According to Flaherty, the BRAF–MEK inhibitor combination therapy will likely become the new standard of care for BRAF-mutated metastatic melanoma patients. Both efficacy data as well as an improvement in tolerability of the combination compared to monotherapy support this assertion.

The treatment paradigm continues to evolve in the BRAF-mutant population with other interventions likely to be added to the BRAF–MEK inhibitor combination family—triplet combinations. For those patients with an NRAS or NF1 mutation, “we are launching combination targeted therapy trials based on MEK inhibition as a backbone,” Flaherty says. “All of these have compelling preclinical data already in the published literature.”

The development of BRAF inhibitors has been an entryway for other novel targeted therapies. “Looking back at the current pace of translational research, it’s hard not to be optimistic about how the clinical picture will look 3 to 4 years from now,” Flaherty says.