Immunotherapy in managing metastatic melanoma: which treatment when?

Expert Opin Biol Ther. 2017 Dec;17(12):1523-1538. doi: 10.1080/14712598.2017.1378640. Epub 2017 Sep 17.


Ten to fifteen percent of melanoma patients develop distant or unresectable metastasis requiring systemic treatment. Around 45% of the patients diagnosed with metastatic cutaneous melanoma harbor a BRAFV600 mutation and derive benefit from combined targeted therapy with MAPK pathway inhibitors. These offer a rapid response that translates into improvement of symptoms and increased quality of life. However, resistance often develops with subsequent progressive disease. Immunotherapy with checkpoint inhibitors may be offered to BRAF-mutated and wild-type patients and is associated with longer and durable responses that can continue over years. Areas covered: In this review, the authors discuss the late evidence for targeted and immunotherapy in melanoma patients, as well as therapy sequencing. Immunotherapy in special populations is also addressed. Expert opinion: Effective treatments are currently available. However, there are still unanswered questions of the best therapy sequence, the clear superiority of combined immunotherapy versus monotherapy in all patients, and therapy duration. Since different promising treatments will become available, clinical trials comparing the diverse options in terms of safety, efficacy and cost- effectiveness are required to make the right decisions. Consequently, patients should be encouraged to participate in clinical trials, whenever possible.

Keywords: BRAF inhibition; CTLA-4 blockade; MEK inhibition; Metastatic melanoma; PD-1/PD-L1/2 inhibition; biomarkers; combination therapy; immune checkpoint blockade; immunotherapy; targeted therapy.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Brain Neoplasms / secondary
  • Brain Neoplasms / therapy
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism
  • Drug Therapy, Combination
  • Humans
  • Imidazoles / therapeutic use
  • Immunotherapy*
  • Ipilimumab / therapeutic use
  • MAP Kinase Kinase Kinases / immunology
  • MAP Kinase Kinase Kinases / metabolism
  • Melanoma / immunology
  • Melanoma / pathology
  • Melanoma / therapy*
  • Nivolumab
  • Oximes / therapeutic use
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / immunology
  • Proto-Oncogene Proteins B-raf / metabolism
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Skin Neoplasms / therapy*


  • Antibodies, Monoclonal
  • CTLA-4 Antigen
  • Imidazoles
  • Ipilimumab
  • Oximes
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase Kinases
  • dabrafenib

Supplementary concepts

  • Melanoma, Cutaneous Malignant