Systemic Therapy of Metastatic Melanoma: On the Road to Cure

SIMPLE SUMMARY: Malignant melanoma is more dangerous than most other skin cancers due to its ability to spread early and aggressively. Until the development of new therapeutic strategies, the median survival of patients with metastatic melanoma was just a few months. Immunotherapy, the first regimen, leading to significant improvement, blocks immune checkpoints, which normally dampen immune responses, enabling our defense cells to recognize and destroy cancer cells again. Immunotherapy achieves long-term survival in about 50% of metastatic melanoma patients. Besides, targeted therapy has also significantly improved the survival of melanoma patients, blocking cell-signaling proteins, which are altered in about 50% of melanomas and lead to uncontrolled tumor cell growth. In addition to the approved regimens, there are numerous new treatment strategies, ranging from modified viruses to personalized immune cells that attack and destroy tumor cells. This review shall give an insight into both already approved regimens and upcoming developments. ABSTRACT: This decade has brought significant survival improvement in patients with metastatic melanoma with targeted therapies and immunotherapies. As our understanding of the mechanisms of action of these therapeutics evolves, even more impressive therapeutic success is being achieved through various combination strategies, including combinations of different immunotherapies as well as with other modalities. This review summarizes prospectively and retrospectively generated clinical evidence on modern melanoma therapy, focusing on immunotherapy and targeted therapy with BRAF kinase inhibitors and MEK kinase inhibitors (BRAF/MEK inhibitors), including recent data presented at major conference meetings. The combination of the anti-PD-1 directed monoclonal antibody nivolumab and of the CTLA-4 antagonist ipilimumab achieves unprecedented 5-year overall survival (OS) rates above 50%; however, toxicity is high. For PD-1 monotherapy (nivolumab or pembrolizumab), toxicities are in general well manageable. Today, novel combinations of such immune checkpoint inhibitors (ICIs) are under investigation, for example with cytokines and oncolytic viruses (i.e., pegylated interleukin-2, talimogene laherparepvec). Furthermore, current studies investigate the combined or sequential use of ICIs plus BRAF/MEK inhibitors. Several studies focus particularly on poor prognosis patients, as e.g., on anti-PD-1 refractory melanoma, patients with brain metastases, or uveal melanoma. It is hoped, on the road to cure, that these new approaches further improve long term survival in patients with advanced or metastatic melanoma.