Biological therapies reviewed

This article reviewed the development and use of biological therapies in the treatment of advanced melanoma, including possible future directions.

Targeted molecular therapies and immunotherapies are two commonly used therapeutic approaches for the treatment of advanced melanoma.

Targeted molecular therapies interfere with specific biological processes or pathways that are important in the development, growth, and spread of a particular cancer. A common molecular target is the MAPK pathway (mitogen-activated protein kinase pathway). A genetic mutation in the BRAF gene is often responsible for the development of melanoma by over-activating the MAPK pathway.

Immunotherapies stimulate the immune system to act against cancer cells. Ipilimumab (Yervoy) is an example of a successful immunotherapy commonly used in the treatment of advanced melanoma. Multiple trials regarding the use of Interleukin-2 (IL-2) (a substance normally produced in the body to stimulate an immune response) in melanoma patients have also been performed in recent years.

Several studies have demonstrated that high-dose IL-2 is associated with prolonged survival of advanced melanoma patients. However, these studies also reported a high rate of adverse effects and only a relatively low response rate among patients. New research is currently being conducted into adoptive immunotherapy, in which specific immune cells are harvested from the tumor, and then re-given to the patient after chemotherapy treatments together with high-dose IL-2. Some small studies have shown complete response to treatment in up to 40% of patients.

Vemurafenib (Zelboraf) was the first targeted therapy approved for the treatment of melanoma patients with BRAF mutations after proven to prolong survival in multiple clinical trials. Trametinib (mekinist) is another MAPK-pathway targeting drug that has recently been approved for use in the treatment of wide spread (metastatic) melanoma. A recent trial has shown that trametinib is associated with significantly increased survival rates compared to chemotherapy, with 22% of patients responding to treatment. Dabrafenib (Tafinlar) and MEK162 are both new MAPK-pathway targeting drugs currently being investigated. Both have shown similar response rates in early, small trials. New research regarding MAPK inhibition is currently focused on combination therapy. Early trials have demonstrated that combinations of MAPK-pathway based drugs, such as dabrafenib and trametinib given together, are safe for use and show improved response rates. Studies evaluating the combination of more than two drugs are also currently underway.

An exciting prospect in the future treatment of melanoma is the combination of MAPK-pathway targeted therapy with an immunotherapeutic drug. A recent early phase study investigating the combination of vemurafenib and ipilimumab has shown high rates of toxic side effects and was terminated. However, several new combination trials are expected to commence shortly.