Originally published as JCO Early Release 10.1200/JCO.2008.18.0612 on October 27 2008

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Phase I/II Trial of Erlotinib and Temozolomide With Radiation Therapy in the Treatment of Newly Diagnosed Glioblastoma Multiforme: North Central Cancer Treatment Group Study N0177

Paul D. Brown, Sunil Krishnan, Jann N. Sarkaria, Wenting Wu, Kurt A. Jaeckle, Joon H. Uhm, Francois J. Geoffroy, Robert Arusell, Gaspar Kitange, Robert B. Jenkins, John W. Kugler, Roscoe F. Morton, Kendrith M. Rowland, Jr, Paul Mischel, William H. Yong, Bernd W. Scheithauer, David Schiff, Caterina Giannini, Jan C. Buckner

From the Mayo Clinic and Mayo Foundation, Rochester, MN; The University of Texas M. D. Anderson Cancer Center, Houston, TX; Mayo Clinic Jacksonville, Jacksonville, FL; Illinois Oncology Research Association Community Clinical Oncology Program (CCOP), Peoria; Carle Cancer Center CCOP, Urbana, IL; Meritcare Hospital CCOP, Fargo, ND; Iowa Oncology Research Association CCOP, Des Moines, IA; University of California, Los Angeles, Los Angeles, CA; and University of Virginia, Charlottesville, VA

Corresponding author: Paul Brown, MD, Department of Radiation Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: brown.paul{at}mayo.edu

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial.

Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m² daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m² daily for 5 days every 28 days). The primary end point was survival at 1 year.

Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival.

Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

published online ahead of print at www.jco.org on October 27, 2008.

Supported in part by Public Health Service Grants No. CA-25224, CA-37404, CA-35195, CA-35101, CA-37417, CA-63849, CA-35113, CA-35431, CA-60276, CA-35267, CA-35269, CA-35103, CA-108961, CA-114740, and CA-63848 from the National Cancer Institute, Department of Health and Human Services.

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: NCT00039494 [ClinicalTrials.gov] .

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