title: Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034.
abstract: OBJECTIVE
  Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM.
  
  
  METHODS
  In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvIII mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. RESULTS; Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome.
  
  
  CONCLUSIONS
  Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.
authors.affiliation: Neuro-Oncology Unit, Daniel den Hoed Cancer Center, PO Box 5201, 3008AE Rotterdam, the Netherlands. m.vandenbent@erasmusmc.nl
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.forename: Roy
authors.initials: R
authors.lastname: Rampling
authors.forename: Mathilde C M
authors.initials: MC
authors.lastname: Kouwenhoven
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Antoine F
authors.initials: AF
authors.lastname: Carpentier
authors.forename: Paul M
authors.initials: PM
authors.lastname: Clement
authors.forename: Marc
authors.initials: M
authors.lastname: Frenay
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Baurain
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Armand
authors.forename: Martin J B
authors.initials: MJ
authors.lastname: Taphoorn
authors.forename: Alicia
authors.initials: A
authors.lastname: Tosoni
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Kletzl
authors.forename: Barbara
authors.initials: B
authors.lastname: Klughammer
authors.forename: Denis
authors.initials: D
authors.lastname: Lacombe
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000032:analysis; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D003606:Dacarbazine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D002330:Carmustine; D000077204:Temozolomide