title: Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma.
abstract: OBJECTIVE
  To compare the efficacy and tolerability of the mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) 1/2 inhibitor selumetinib versus temozolomide in chemotherapy-naive patients with unresectable stage III/IV melanoma.
  
  
  METHODS
  This phase II, open-label, multicenter, randomized, parallel-group study examined the effect of 100 mg oral selumetinib twice daily in 28-day cycles versus oral temozolomide (200 mg/m(2)/d for 5 days, then 23 days off-treatment). The primary endpoint was progression-free survival.
  
  
  RESULTS
  Two hundred patients were randomized. Progression-free survival did not differ significantly between selumetinib and temozolomide (median time to event 78 and 80 days, respectively; hazard ratio, 1.07; 80% confidence interval, 0.86-1.32). Objective response was observed in six (5.8%) patients receiving selumetinib and nine (9.4%) patients in the temozolomide group. Among patients with BRAF mutations, objective responses were similar between selumetinib and temozolomide groups (11.1% and 10.7%, respectively). However, five of the six selumetinib partial responders were BRAF mutated. Frequently reported adverse events with selumetinib were dermatitis acneiform (papular pustular rash; 59.6%), diarrhea (56.6%), nausea (50.5%), and peripheral edema (40.4%), whereas nausea (64.2%), constipation (47.4%), and vomiting (44.2%) were reported with temozolomide.
  
  
  CONCLUSIONS
  No significant difference in progression-free survival was observed between patients with unresectable stage III/IV melanoma unselected for BRAF/NRAS mutations, who received therapy with selumetinib or temozolomide. Five of six patients with partial response to selumetinib had BRAF mutant tumors.
authors: Departments of Medicine and Dermatology, University of Pittsburgh, PA 15213, USA. KirkwoodJM@upmc.edu
authors: John M
authors: JM
authors: Kirkwood
authors: Lars
authors: L
authors: Bastholt
authors: Caroline
authors: C
authors: Robert
authors: Jeff
authors: J
authors: Sosman
authors: James
authors: J
authors: Larkin
authors: Peter
authors: P
authors: Hersey
authors: Mark
authors: M
authors: Middleton
authors: Mireille
authors: M
authors: Cantarini
authors: Victoria
authors: V
authors: Zazulina
authors: Karin
authors: K
authors: Kemsley
authors: Reinhard
authors: R
authors: Dummer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D057915:Drug Substitution; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C517975:AZD 6244; D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D003606:Dacarbazine; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000077204:Temozolomide