Originally published as JCO Early Release 10.1200/JCO.2008.17.5984 on February 9 2009

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Randomized Phase II Trial of Erlotinib Versus Temozolomide or Carmustine in Recurrent Glioblastoma: EORTC Brain Tumor Group Study 26034

From the Daniel den Hoed Cancer Center, Rotterdam; and Medisch Centrum Haaglanden, the Hague, the Netherlands; Medical Oncology Department, Bellaria-Maggiore Hospital, Bologna, Italy; Beatson Oncology Centre, Glasgow, United Kingdom; Hopital de la Salpêtrière, Paris; Centre Antoine Lacassagne, Nice; Centre Rene Gauducheau, Nantes, St. Herblain; and Institute Gustave Roussy, Villejuif Cedex, France; Medical Oncology, University Hospital Gasthuisberg, Leuven; Cliniques Universitaires St. Luc, Brussels; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; and F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Corresponding author: M.J. van den Bent, MD, Neuro-Oncology Unit, Daniel den Hoed Cancer Center, PO Box 5201, 3008AE Rotterdam, the Netherlands; e-mail: m.vandenbent{at}erasmusmc.nl.

Purpose 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.

Patients and 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.

Conclusion Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.

Supported in part by Hoffman-la Roche Ltd, Basel, Switzerland; by Grants No. 5U10 CA11488-34 through 2U10 CA11488-36 and 5U10 CA11488-38 from the National Cancer Institute; the European Organisation for Treatment of Cancer headquarters is supported by Fonds Cancer.

The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00086879 [ClinicalTrials.gov] .

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