Targeted Therapies Stage IV Melanoma
Until recently very few therapies were available for advanced melanoma, and the average survival was approximately nine months. The chemotherapeutic agent dacarbazine had approximately 15% response rate. Interleukin 2 had less than 10% response rate with 5% durable responses, but very high toxicities requiring ventilator and pressor support.
In recent years a better understanding of the biology of melanoma led to the development of new targeted agents with improved survival and an improved toxicity profile.
Approximately a decade ago researchers noted that approximately 50% of melanomas had a mutation of the serine/threonine kinase gene BRAF, which led to the development of the BRAF inhibitors vemurafenib and dabrafenib.
FDA approved in 2011, Vemurafenib had 80% response rate and increased the one year survival to 50% and two year survival to 40%. With vemurafenib, 6% of patients had complete response. The most common side effects are rash, joint pain, fatigue, nausea and hair loss.
Dabrafenib is another BRAF inhibitor with a response rate of approximately 60% and improvement in overall survival as well. DVT, cardiomyopathy, hyperglycemia are some of the side effects. Both BRAF inhibitors are oral drugs.
Approximately 10-20% of melanomas harbor the kit mutations. Imatinib is a multikinase inhibitor that has some efficacy in this type mutation with a response rate of approximately 30%.
Ipilimumab is a human monoclonal antibody that targets T-lymphocyte antigen 4 and by doing so continually activates T cells against the melanoma cells. The response rate to the monoclonal antibody is low approximately 15% but in 20% of cases durable up to 4 years. Ipilimumab is currently being tested in combination with other agents. Colitis, hepatitis, inflammation of the skin and nerves are potential side effects.
Currently nivolumab, a human PD-1 antibody, is also being investigated, as a new target to fight melanoma. Progress continues to be made to fight this very difficult to treat disease.