In locally advanced squamous cell carcinoma of the head and neck (HNSCC), positivity for human papillornavirus (HPV) confers a favorable prognosis especially for patients with tumors located in the oropharynx (OPSCC) (1, 2). Standard treatment of locally advanced disease is cisplatin-based chemoradiation, either in the primary setting or as adjuvant treatment after surgery. The combination of high cure rates but often dramatic toxicity under these regimes has resulted in the development of various clinical trials testing de-intensification approaches, and some early phase trials have reported promising results (3—7). Two phase 3 trials, however, which together recruited more than 1,000 patients, concordantly reported inferiority of the rather cautious deintensification concept of exchanging cisplatin for the also approved anti-EGFR antibody cetuximab under maintenance of the full radiation dose (8, 9). In line with these negative clinical results, we had previously shown that cetuximab completely fails to radiosensitize HPV-positive HNSCC cells in vitro (10). This clearly urges caution and speaks in favor of careful predinical evaluation of novel agents and concepts.