title: Therapeutic efficacy of combined BRAF and MEK inhibition in metastatic melanoma: a comprehensive network meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Several recent randomized clinical trials have preliminarily demonstrated that initial targeted therapy with combined BRAF and MEK inhibition is more effective in metastatic melanoma (MM) than single agent. To guide therapeutic decisions, we did a comprehensive network meta-analysis to identify evidence to robustly support whether combined BRAF and MEK inhibition is the best initial targeted therapeutic strategy for patients with MM.
  
  
  METHODS
  The databases of PubMed and trial registries were researched for randomized clinical trials of targeted therapy. Data of outcome were extracted on progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Network meta-analysis using a Bayesian statistical model was performed to evaluate relative hazard ratio (HR) for PFS and OS, odds ratio (OR) for ORR.
  
  
  RESULTS
  Finally, 16 eligible trials comprising 5976 participants were included in this meta-analysis. PFS were significantly prolonged in patients who received combined BRAF-MEK inhibition compared with those who received BRAF inhibition (HR: 0.58, 95%CI: 0.51-0.67, P < 0.0001) or MEK inhibition alone (HR: 0.29, 95%CI: 0.22-0.37, P < 0.0001). Combined BRAF-MEK inhibition also improved the OS over BRAF inhibition (HR: 0.67, 95%CI: 0.56-0.81, P < 0.0001) or MEK inhibition alone (HR: 0.48, 95%CI: 0.36-0.65, P < 0.0001). The ORR was superior in combined BRAF and MEK inhibition comparing with BRAF inhibition (OR: 2.00, 95%CI: 1.66-2.44, P < 0.0001) or MEK inhibition alone (OR: 20.66, 95%CI: 12.22-35.47, P < 0.0001).
  
  
  CONCLUSIONS
  This study indicates that concurrent inhibition of BRAF and MEK improved the most effective therapeutic modality as compared as single BRAF or MEK inhibition for patients with MM.
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Ruiqin
authors.initials: R
authors.lastname: Mai
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Songxia
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Weixiang
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Siming
authors.initials: S
authors.lastname: Rong
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Cong
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yunxian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Huanming
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yabin
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuanshen
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China.|Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Guohong
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001499:Bayes Theorem; D018572:Disease-Free Survival; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: combing BRAF and MEK inhibition; melanoma; targeted therapy