Update on Immunotherapeutics in the Management of Metastatic Melanoma

David Bulir, MD, PhD; Steven Liang, BHSc, PhD (Candidate); Maureen O'Malley, MD, FRCPC; Elaine McWhirter, MD, MSc


Skin Therapy Letter. 2019;24(1) 

In This Article

Dual Inhibition of MEK and BRAF

Approximately 50% of all melanomas are positive for BRAF mutations. BRAF encodes the B-Raf proto-oncogene; when mutated, it leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and unregulated cell growth.[4,5] Specific inhibitors of BRAFV600 mutations were first approved for use by Health Canada in 2012.[4,5] Confirmation of BRAF mutational status from testing either primary tumor samples or metastatic lesions is required before initiating therapy.[4] Monotherapy with the BRAF inhibitors dabrafenib and vemurafenib have shown significant clinical benefit compared to standard chemotherapy.[6–8] Acquired resistance and paradoxical activation of the MAPK pathway in response to BRAF inhibition has been addressed through combination therapy of BRAF and MEK inhibitors.[4] Combination MEK/BRAF inhibition has been shown to provide a greater overall survival, response rate, and progression-free survival compared to monotherapy with BRAF inhibitors alone.[9–11] Recently, a phase II trial comparing dabrafenib to dabrafenib plus trametinib, a MEK inhibitor, demonstrated durable long-term overall survival. Patients receiving dabrafenib were allowed to cross over to the combination therapy group if disease progression occurred. In patients who received combination therapy from the start, or crossed over from monotherapy, the 4 year and 5 year overall survival rates were 30% and 28%, respectively. Overall survival rates were noted to be higher at 45% and 51% in patients with normal baseline serum lactate dehydrogenase (LDH) levels or with normal LDH with fewer than three metastases, respectively, in patients receiving both dabrafenib and trametinib.[12]