title: Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma.
abstract: OBJECTIVE
  Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated.
  
  
  METHODS
  We conducted a phase II trial in patients with melanoma whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg per os twice daily. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach.
  
  
  RESULTS
  The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (∼25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the five patients with melanoma accrued in the low pAKT cohort, there was one partial response (PR). Two other patients had near PRs before undergoing surgical resection of residual disease (one patient) or discontinuation of treatment due to toxicity (one patient). Among the two nonresponding, low pAKT patients with melanoma, co-mutations in MAP2K1, NF1, and/or EGFR were detected.
  
  
  CONCLUSIONS
  Tumor regression was seen in three of five patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort. These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors.
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors: Federica
authors: F
authors: Catalanotti
authors: David B
authors: DB
authors: Solit
authors: Melissa P
authors: MP
authors: Pulitzer
authors: Michael F
authors: MF
authors: Berger
authors: Sasinya N
authors: SN
authors: Scott
authors: Tunc
authors: T
authors: Iyriboz
authors: Mario E
authors: ME
authors: Lacouture
authors: Katherine S
authors: KS
authors: Panageas
authors: Jedd D
authors: JD
authors: Wolchok
authors: Richard D
authors: RD
authors: Carvajal
authors: Gary K
authors: GK
authors: Schwartz
authors: Neal
authors: N
authors: Rosen
authors: Paul B
authors: PB
authors: Chapman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases