title: Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.
abstract: BACKGROUND
  Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity.
  
  
  METHODS
  A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity).
  
  
  RESULTS
  Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low.
  
  
  CONCLUSIONS
  The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence.
authors.affiliation: Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. Electronic address: pasqualisandro@hotmail.com.
authors.forename: Sandro
authors.initials: S
authors.lastname: Pasquali
authors.affiliation: Melanoma and Esophageal Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: vanna.chiarion@ioveneto.it.
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion-Sileni
authors.affiliation: Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: carlor.rossi@unipd.it.
authors.forename: Carlo Riccardo
authors.initials: CR
authors.lastname: Rossi
authors.affiliation: Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy; Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy. Electronic address: simone.mocellin@unipd.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D058990:Molecular Targeted Therapy / Q000379:methods; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases
keywords: Immune checkpoint inhibitor; Melanoma; Metastatic; Network meta-analysis; Targeted therapy