Metastatic Melanoma: New Targeted Therapies

By Isabella C. Martire, M.D.

The incidence of melanoma has been rising over the last twenty years. With chemotherapy the median survival was approximately nine months and the response rate was very low. With interlukin2 the response rate was ~10% with 5% of patients who had durable response, but the toxicity was so high that the majority of patients ended in the intensive care unit on pressors and ventilators.

The increase knowledge about the biology of melanoma lead to the development of new targeted therapies. The discovery of the mutations of the BRAF gene in 50% of melanoma translated in the development of vemurafenib and dabrafenib.

Vemurafenib is an oral medication given twice a day which is a powerful inhibitor of BRAF with a response rate of >50% and a complete response of 6% in stage IV melanoma patients translating in a median overall survival of ~ 16 months. The drug was FDA approved in 2011. Major side effects are skin reaction, joint pain, hair loss, fatigue and nausea.

Dabrafenib is also an oral drug taken twice a day that is a powerful BRAF inhibitor with a response rate of 60% and double the disease free survival compared to dacarbazine (chemotherapy originally used for melanoma). The most common side effects: hair loss, hand foot syndrome, rash, joint pain and H/A.

As far as immunotherapy ipilimumab, a human monoclonal antibody was also recently FDA approved. This antibody targets the cytotoxic T-lymphocyte antigen-4 (CTLA-4). This monoclonal antibody has a low response rate but it improved survival and 20% of patients were alive four years after receiving the therapy. This antibody is currently studied in combination therapy with other agents. Ipilimumab is intravenous over 90 minutes and particular attention needs to be paid to allergic reactions. Other possible reactions include: enterocolitis, hepatitis, rash, neuropathy and endocrine disorder.

Most recently the discovery that PD-1 (programmed death 1) is a receptor directly expressed by tumor cells has stirred the research toward the approval of nivolumab, a human PD-1 antibody with a 30% remission rate and less toxicity.

Hopefully combining different agents together will increase the efficacy and length of survival.