title: Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data.
abstract: BACKGROUND
  We executed a comparative systematic review and meta-analysis of the efficacy and toxicity of doublet BRAF/MEK inhibition versus single-agent BRAF inhibitor in the management of BRAF-mutant advanced melanoma.
  
  
  METHODS
  Eligible studies included prospective studies evaluating doublet regimens versus BRAF-inhibitor monotherapy for the management of BRAF-mutant advanced melanoma.
  
  
  RESULTS
  Our search strategy yielded 200 potentially relevant citations from searched databases. After preclusion of ineligible studies, four studies were included in the final analysis. Efficacy analyses demonstrate that BRAF/MEK inhibition strategy is associated with a significant improvement in ORR [OR 1.35; 95 % CI (1.16, 1.58); P = 0.0002], PFS [HR 0.56; 95 % CI (0.49, 0.64); P < 0.00001] and OS [HR 0.70; 95 % CI (0.58, 0.84); P = 0.0001]. Moreover, this combination is associated with a higher RR for diarrhea [1.30; 95 % CI (1.30, 1.49); P = 0.0002], decreased ejection fraction [4.63; 95 % CI (2.56, 8.37); P = <0.00001], acneiform dermatitis [1.61; 95 % CI (1.03, 2.53); P = 0.04] and pyrexia [1.98; 95 % CI (1.72, 2.27); P < 0.00001].
  
  
  CONCLUSIONS
  Our meta-analysis has demonstrated that combination of MEK/BRAF inhibitors is associated with higher ORR, PFS and OS. However, this comes at the expense of a higher risk of selected toxicities.
authors.affiliation: Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Lotfy Elsayed street, Cairo, 113331, Egypt. Omar.abdelrhman@med.asu.edu.eg.
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Rahman
authors.affiliation: Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Lotfy Elsayed street, Cairo, 113331, Egypt.
authors.forename: H
authors.initials: H
authors.lastname: ElHalawani
authors.affiliation: Clinical Oncology Department, Nasser Institute, Cairo, Egypt.
authors.forename: H
authors.initials: H
authors.lastname: Ahmed
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases
keywords: Dabrafenib; Melanoma; Trametinib; Vemurafenib