Background: Radiotherapy (RT) with concurrent EGFR inhibition (cetuximab) is standard of care in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) unfit for cisplatin treatment. This combination leads to both NK-cell mediated cytotoxicity and an increase in PD-L1 expression on tumor cells. By combining cetuximab-RT with a PD-L1 inhibitor (avelumab), we aim to develop a treatment regimen with at least similar efficacy as chemoradiation but less irreversible toxicity. Methods: Phase-IB trial (10 patients) to assess safety and toxicity of concurrent radiotherapy (5 times a week, total dose 35x2 Gy) with cetuximab (loading dose 400 mg/m² in week -1, 250 mg/m² week 1-7) and avelumab (10 mg/kg every 2 weeks concurrent with RT + 4 months maintenance). Results: At the time of analysis, 6 of 10 patients had started their treatment. One patient experienced a grade 3 cetuximab-related infusion reaction and withdrew from study before avelumab was administered. One 81 year old patient discontinued treatment after 2 avelumab cycles and 12x2 Gy RT. This patient experienced no toxicity except grade 2 dysphagia. The other 4 patients completed the prescribed treatment, 2 of them are still treated with maintenance therapy. Median follow-up after starting RT was 5.7 (3.7 – 7.4) months. One patient experienced an avelumab induced grade 3 pneumonitis 3 weeks post RT and discontinued avelumab after 4 cycles. The pneumonitis resolved after 4 days with 1mg/kg prednisone. All patients were in complete remission 2 weeks after completion of RT and 2 weeks after the completion of maintenance therapy (Ojiri 0), one patient had an Ojiri 1 response 2 weeks after maintenance therapy. Conclusions: These preliminary data suggest that avelumab can be safely administered with concurrent cetuximab-RT regimen to patients with locally advanced SCCHN, who are unfit for cisplatin treatment. Preliminary efficacy data in terms of treatment response and immune infiltrate will be further evaluated by ctDNA measurement and immunohistochemistry. Clinical trial information: NCT02938273