Title: Erbitux® (Cetuximab) Plus Temozolomide as Radiochemotherapy for Primary Glioblastoma (GERT): Interim Results of a Phase I/II Study
Abstract: The targeting of the epidermal growth factor receptor (EGFR) using cetuximab has proven to be a successful. Glioblastomas (GB) are known to express high levels of EGFR. This prospective, single-armed phase I/II trial of chemoradiation with TMZ and cetuximab in patients with primary GB analyzes feasibility and toxicity. Patients with primary GB are included into this protocol. Radiotherapy is delivered with a median of 60 Gy in 5x2Gy/week. TMZ is prescribed concomitantly at a dose of 75mg/m2, followed by 6 cycles of adjuvant TMZ. Cetuximab is applied as weekly infusions (loading dose 400 mg/m2 day 1, and concomitant with radiation weekly at 250 mg/m2). Seventeen patients were included into this interim-analysis according to the protocol. Fourteen patients were male (82%) and 3 patients were female (18%). Median age at diagnosis was 48 years (range 27-59 years). Neurosurgical resections had been performed in all patients, which were complete in 7 patients (41%), subtotal in 7 patients (41%), and a biopsy only was conducted in 3 patients (18%). Pathology evaluation revealed a glioblastoma in all patients. O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation was investigated in the tumor tissue: 33% of the patients had an unmethylated, and 66% a methylated MGMT-gene promotor. EGFR-analysis is currently being conducted with immunohistochemistry as well as in-situ hybridization. Treatment was initiated after a median of 15 days after primary diagnosis. Median follow-up time was 13 months. Radioimmunotherapy with cetuximab is safe and well tolerated. Minor side effects from treatment included focal alopecia, local skin erythema and nausea/vomiting; cetuximab-related side effects included acneiform rash in all patients. In one patient cetuximab infusions were discontinued after occurrence of bilateral pulmonary embolism in treatment week 7. One patient died in treatment week 4 after tumor progression and massive brain edema, which was not controlled by medication including high-dose steroids. In all other patients the scheduled 7 cycles of cetuximab was applied. The overall survival (OS) rate was 87% at 12 months. Common prognostic factors such as age and extent of neurosurgical resection did not influence OS significantly. Methylated MGMT was not associated with longer OS (log-rank p = 0.22). Progression-free survival (PFS) rate was 81% at 6 months (PFS6) and 37% at 12 months (PFS12). Methylated MGMT was not associated with longer PFS (log-rank p = 0.59). Early data from trimodal therapy in glioblastoma patients with radiotherapy, temozolomide and cetuximab indicate feasibility without an increased toxicity profile. The local response as well as OS appear to be very promising.