title: DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma.
abstract: BACKGROUND
  Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma.
  
  
  METHODS
  In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes.
  
  
  RESULTS
  Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone.
  
  
  CONCLUSIONS
  The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy.
  
  
  BACKGROUND
  DOC-MEK (EudraCT no: 2009-018153-23).
authors.affiliation: Department of Oncology, Oxford University Hospitals NHS Trust, Oxford.
authors.forename: A
authors.initials: A
authors.lastname: Gupta
authors.forename: S
authors.initials: S
authors.lastname: Love
authors.forename: A
authors.initials: A
authors.lastname: Schuh
authors.forename: M
authors.initials: M
authors.lastname: Shanyinde
authors.forename: J M
authors.initials: JM
authors.lastname: Larkin
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.forename: P D
authors.initials: PD
authors.lastname: Nathan
authors.forename: S
authors.initials: S
authors.lastname: Danson
authors.forename: C H
authors.initials: CH
authors.lastname: Ottensmeier
authors.forename: P
authors.initials: P
authors.lastname: Lorigan
authors.forename: L
authors.initials: L
authors.lastname: Collins
authors.forename: A
authors.initials: A
authors.lastname: Wise
authors.forename: R
authors.initials: R
authors.lastname: Asher
authors.forename: R
authors.initials: R
authors.lastname: Lisle
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D008565:Membrane Proteins; D043823:Taxoids; D000077143:Docetaxel; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF; MEK; melanoma; phase II; selumetinib; trial