title: Clinical responses to selumetinib (AZD6244; ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.
abstract: BACKGROUND
  The high prevalence of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma v-ras oncogene homolog (NRAS) mutations in melanoma provides a strong rationale to test the clinical efficacy of mitogen-activated protein kinase kinase (MEK) inhibition in this disease. The authors hypothesized that the presence of BRAF or NRAS mutations would correlate with clinical benefit among patients who received treatment with combination regimens that included the MEK inhibitor selumetinib.
  
  
  METHODS
  BRAF and NRAS mutation status was determined retrospectively in available tissue specimens from patients with melanoma who were enrolled in a phase 1 trial of selumetinib in combination with 1 of 4 drugs (dacarbazine, docetaxel, temsirolimus, or erlotinib). The clinical response rate and the time to progression (TTP) were assessed as a function of BRAF and NRAS mutation status.
  
  
  RESULTS
  Among 18 patients analyzed, 9 patients (50%) harbored a BRAF mutation (8 had a valine-to-glutamic acid substitution at residue 600 [V600E]; 1 had an arginine nonsense mutation at residue 603 [R603]), 4 patients (22%) harbored an NRAS mutation (2 had a glutamine-to-arginine substitution at residue 61 [Q61R], 1 had a glutamine-to-lysine substitution at residue 61 [Q61K], and 1 had a glycine-to-lysine substitution at residue 12 [G12S]), and 5 patient (28%) had the wild type of both genes. These mutations were mutually exclusive. Among the 9 patients who had BRAF mutations, 5 patients (56%) achieved a partial response, and 4 patients (44%) achieved stable disease for at least 6 weeks. No patient with the wild-type BRAF gene achieved a clinical response (P = .01 vs patients with BRAF mutations). The presence of an NRAS mutation did not correlate with the clinical response rate. The presence of a BRAF mutation was correlated significantly with the TTP in a multivariate model (hazard ratio, 0.22; P = .02 vs wild-type BRAF).
  
  
  CONCLUSIONS
  Higher response rates and longer TTP were observed with selumetinib-containing regimens in patients who had tumors that harbored a BRAF mutation compared with patients who had wild-type BRAF.
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sapna P
authors.initials: SP
authors.lastname: Patel
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Papadopoulos
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Glass
authors.forename: Carol S
authors.initials: CS
authors.lastname: Vaughn
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)