Combination molecularly targeted drug therapy in metastatic melanoma: progress to date.

Previously characterized by a median overall survival of between 6 and 12 months, metastatic melanoma now has a number of novel and effective treatment options. The ability to target the mitogen-activated protein kinase (MAPK) pathway with BRAF (v-raf murine sarcoma viral oncogene homolog B1) or MEK (mitogen-activated protein kinase kinase) inhibitors can result in rapid clinical benefit, but is too often associated with limited durability of response. Resistance inevitably develops either via reactivation of the MAPK pathway or via bypass signalling pathways, such as the PI3K (phosphoinositide 3-kinase) pathway. Combination strategies are thus appealing with an aim to overcome potential resistance mechanisms. Already, the combination of the BRAF inhibitor, dabrafenib, along with the MEK inhibitor, trametinib, has shown promising results clinically and with an improved toxicity profile. Other combination strategies with agents that target the PI3K pathway, angiogenesis, and the immune system are in development or already underway, although potential overlapping toxicities require close monitoring. The currently available molecularly targeted agents that target the MAPK pathway and development of combination therapies for treatment of metastatic melanoma are discussed in further detail.