Afatinib is an oral, irreversible EGFR/ErbB family receptor inhibitor with clinical activity in recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Previously, EGFR-inhibition with cetuximab in combination with docetaxel and postoperative radiation therapy (PORT) was shown in RTOG 0234 to be well tolerated with higher rates of disease-free survival compared to historical results with cisplatin and PORT. We therefore aimed to assess the tolerability of afatinib in combination with docetaxel and PORT in a cohort of patients with high-risk pathologic features after definitive surgery. This was an open label, non-randomized, phase 1, 3+3 dose-escalation study. Eligible patients had resected stage III-IV SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx with high-risk features of either positive margins (tumor at ink), extracapsular nodal extension, N3 nodal stage, or T4 tumor with bone invasion. Patients received afatinib at an initial dose of 30 mg daily for 1 week prior to PORT and then daily during PORT. Docetaxel 15 mg/m2 was given weekly during PORT. The maximum PORT dose was 66 Gy, 2 Gy/fraction. Toxicities were scored using CTCAE v4.0. Eleven patients (6 women) were enrolled with a median age of 61 years (44-66 yrs), AJCC stage of III (n = 2) or IV (n = 9) and oral cavity (n = 10) and larynx (n = 1) primary tumors. Seven patients received the starting 30 mg dose including 2 patients that withdrew consent after starting treatment, and 2 that experienced hypersensitivity reactions due to docetaxel and were taken off-study. There were 2 dose-limiting toxicity (DLT) events of grade 3 diarrhea and mucositis at the initial 30 mg dose. Four patients receive the de-escalated 20 mg dose. There were 2 DLT’s (grade 3 mucositis). There were no grade 4 or 5 events. The most common toxicity was diarrhea occurring in 9 of 11 patients (grade 3 in 2 patients), and mucositis occurring in 8 of 11 patients (grade 3 in 4 patients). The combination of afatinib with both PORT and docetaxel for mucosal SCCHN was shown to be difficult to tolerate with a high rate of grade 3 toxicity, mostly mucositis, in this cohort of patients requiring postoperative chemoradiation to the oral cavity. Afatinib may be better tolerated with PORT alone and this is currently being tested in a prospective phase 1 trial in an intermediate-risk cohort. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc.