title: Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements.
abstract: OBJECTIVE
  A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC).
  
  
  METHODS
  Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed.
  
  
  RESULTS
  Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug.
  
  
  CONCLUSIONS
  Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.
authors.affiliation: University of North Carolina Lineberger Comprehensive Cancer Center, School of Medicine, Baltimore, Maryland, USA.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Hayes
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lucas
authors.forename: Tawee
authors.initials: T
authors.lastname: Tanvetyanon
authors.forename: Monika K
authors.initials: MK
authors.lastname: Krzyzanowska
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Murphy
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.forename: Dominic T
authors.initials: DT
authors.lastname: Moore
authors.forename: Arif
authors.initials: A
authors.lastname: Sheikh
authors.forename: Janelle
authors.initials: J
authors.lastname: Hoskins
authors.forename: Michele C
authors.initials: MC
authors.lastname: Hayward
authors.forename: Ni
authors.initials: N
authors.lastname: Zhao
authors.forename: Wendi
authors.initials: W
authors.lastname: O'Connor
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weck
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D002277:Carcinoma; D002291:Carcinoma, Papillary; D003967:Diarrhea / Q000139:chemically induced; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005838:Genotype; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010597:Pharmacogenetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D007457:Iodine Radioisotopes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins