Metastatic Melanoma: Insights into the Evolution of the Treatments and Future Challenges

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin‐2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B‐Raf and MEK inhibitors and allow the treatment of patients with B‐Raf mutated melanoma. Second, there are the immunotherapies, with anti‐CTLA‐4 and anti‐PD‐1 antibodies that are used for patients harboring a B‐Raf wild‐type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.