Randomized Trial of Avelumab-cetuximab-radiotherapy Versus SOCs in LA SCCHN (REACH)

Inclusion Criteria: 1. Age ≤ 80 years 2. Performance Status ECOG 0-1 3. Squamous cell carcinoma, previously untreated 4. Stage III, stage IVa (i.e. operable, but not operated) or IVb (non resectable) 5. Oral cavity, oropharynx, hypopharynx or larynx 6. Availability of pre-treatment tumour tissue sample (for p16 \& PD -L1 expression, TILs and immune landscape) 7. Recording of alcohol consumption and smoking history 8. Determination of the patient's ability to receive cisplatin 100 mg /m2 for 3 cycles (fit / unfit)\* 9. Written informed consent * Criteria for determining if a patient is fit for receiving high dose cisplatin: * Calculated creatinin clearance ≥ 60 mL/min as determined by the modified. method of Cockcroft and Gault or by the EDTA method * Absolute neutrophil count ≥1 500/μL, platelets ≥100 000/μL, hemoglobin ≥ 10 g/dL, aspartate (AST) and alanine transaminase (ALT) less than 2 times the upper limit of the normal range (ULN), total bilirubin ≤ 1.5 mg/dL, serum albumin \> 35 g/L * Peripheral neuropathy \< grade 2 * No clinical hearing loss (confirmed by audiogram) * Cardiac function compatible with hyperhydration; Left ventricular ejection fraction within the institutional normal ranges as measured by echocardiogram Exclusion Criteria: 1. Nasopharyngeal, paranasal sinuses, nasal cavity tumors or thyroid cancers 2. Squamous cell carcinoma involving cervical neck nodes with unknown primary site 3. Metastatic disease (stage IVc) 4. Viral infection (HIV, Hepatitis B/C) 5. Autoimmune disease 6. Immunodeficiency or immunosuppressive therapy 7. Active CNS disease 8. Interstitial lung disease 9. Active infection 10. Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, induction chemotherapy, prior surgical resection or RT, or use of any investigational agent 11. Weight loss of \> 10% during the last 4 weeks (except if renutrition with a feeding tube is planned before the onset of treatment or is ongoing) 12. Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol 13. Concomitant treatment with any drug on the prohibited medication list such as live vaccines 14. History of other malignancy within the last 3 years (exception of in situ carcinoma and skin carcinomas) 15. Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial 16. Known hypersensitivity reaction to study drugs 17. Any social, personal, medical and/or psychological factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent.