Malignant Melanoma

MALIGNANT MELANOMA

Malignant melanoma is curable when it presents locally, with surgical resection being the main treatment approach. However, once spread to metastatic sites has been diagnosed, it is one of the most difficult cancers to treat because it is a relatively drug-resistant tumor. While dacarbazine, temozolomide, and cisplatin are the most active cytotoxic agents for this disease, the overall response rates to these agents remain low. Biologic agents, including interferon-α and interleukin-2 (IL-2), have greater activity than traditional cytotoxic agents, and treatment with high-dose IL-2 has led to cures, albeit in a relatively small subset of patients. Significant efforts have focused on utilizing biologic therapy with combination chemotherapy in what have been labeled biochemotherapy regi-mens. Although overall response rates as well as complete response rates appear to be much higher with biochemotherapy regimens compared with chemotherapy alone, treatment toxicity also seems to be increased. As such, this approach remains investigational.

The BRAFV600E mutation has been identified in the large majority of melanomas. This mutation results in constitutive acti-vation of BRAF kinase, which then leads to activation of down-stream signaling pathways involved in cell growth and proliferation. In August 2011, the FDA approved a novel, oral, and highly selec-tive small molecule inhibitor of BRAFV600E (vemurafenib) with highly promising activity in metastatic melanoma. Further studies are ongoing to confirm its activity as a single agent as well as in combination with other cytotoxic and biologic agents.