Background: GB is a malignant primary incurable CNS tumor with poor prognosis. RT + TMZ is standard treatment for newly diagnosed GB suitable for radical treatment. ErbB pathway dysregulation has a role in the pathogenesis of GB and EGFR activation contributes to RT resistance. The irreversible ErbB family blocker afatinib has a manageable safety profile and modest activity in recurrent GB. This Phase I study assessed the feasibility of first-line afatinib + RT ± TMZ in GB. Methods: This 3+3 dose-escalation study enrolled 36 pts with newly diagnosed GB. Treatment was stratified by MGMT promoter methylation status. Pts with promoter methylation received RT + TMZ + afatinib (20, 30, 40 mg/day) for 6 wks (RT period), then afatinib 40 mg/day + TMZ for up to 6 months before afatinib 40 mg/day until progression/undue AEs (maintenance period; Regimen M). As TMZ has limited benefit in pts with unmethylated MGMT, these pts received RT + afatinib then afatinib (Regimen U). Primary endpoint: MTD of afatinib + RT ± TMZ. Secondary endpoints: AEs, ORR, PK. Results: In regimen M, 20 pts (median [range] age: 52.5 [25?66] yrs) were treated for median [range] 151 [6?2340] days (20 mg n = 7; 30 mg n = 6; 40 mg n = 7); of those evaluable for MTD, 1/6, 0/6 and 2/5 had dose-limiting toxicities (DLTs) in the RT period (2 grade [G] 4 thrombocytopenia and 1 G3 vomiting). MTD of afatinib + RT + TMZ was 30 mg/day. In regimen U, 16 pts (53.5 [34?68] yrs) were treated for median [range] 168 [1?397] days (20 mg n = 3; 40 mg n = 13); of those evaluable for MTD, 0/3 and 1/6 had DLTs (1 G3 diarrhea) in the RT period. MTD of afatinib + RT was 40 mg/day. Common treatment-related AEs (TRAEs) are shown in the Table. ORRs were 25% and 6% in regimens M and U, respectively. PK evaluation indicated that combination of afatinib with RT + TMZ had no influence on afatinib exposure. Conclusions: The MTD of afatinib + RT was 30 mg/day with TMZ and 40 mg/day without TMZ. The safety profile of afatinib + RT ± TMZ was as expected, based on the known profiles of the individual agents. Common TRAEsClinical trial information: NCT00977431