Background: Identification of efficacy predictive biological biomarkers in HNSCC patients treated with anti-EGFR targeted therapy is still a challenge. In the recurrent/metastatic setting, sequential biopsies allowed correlating potential predictive and pharmacodynamic biomarkers with the outcome of patients treated with erlotinib (Agulnik M et al. J Clin Oncol. 2007;25:2184). Afatinib is an Erb-B family blocker that irreversibly blocks signaling from all relevant Erb-B family dimers and may overcome limitations of current EGFR-targeted treatment in HNSCC. We conduct a randomized phase II study with afatinib Methods: PREDICTOR is a UNICANCER sponsored multi-centre randomized phase II study of pre-operative afatinib aiming at identifying predictive and pharmacodynamic biomarkers of biological activity and efficacy in untreated non-metastatic HNSCC patients. Key eligibility criteria: confirmed non-metastatic HNSCC; T2-4N0-2 tumors (except T2N0 endolaryngeal tumors); planned date of surgery allowing the patient to receive 14 to 28 days of afatinib treatment; ECOG status 0-2. Target enrolment is 60 pts. Randomization is stratified on the site of primary tumor (oropharynx versus non-oropharynx). Pts are randomized 2:1 to receive afatinib (40mg/qd) OR no treatment (control arm). Dose adjustments are permitted according to the ocurrence of drug-related AEs (reduction to 30mg/qd). The primary endpoint is to identify predictive and pharmacodynamics biomarkers.Tumor samples are collected before treatment (biopsy) and after surgery (surgical specimen). Several molecules involved in the resistance to EGFR will be analyzed through different technics (Immunohistochemistry, High throughput protein analysis, FISH, PCR sequencing and qRT-PCR). Secondary endpoints include efficacy (tumor shrinkage), pathological response, metabolic response (FDG PET/CT scan assessment) and safety. Completion of pt recruitment and data analyses are awaited. Clinical trial information: NCT01415674.