The general aim of the study is to evaluate the anti-tumour activity and the tolerance profile of Pembrolizumab + RT in comparison to cetuximab + RT in patients with locally advanced HNSCC and to explore potential correlations between treatment outcome and the immune landscape.

A majority of HNSCC are locally advanced and commonly treated with concomitant chemo-radiotherapy (CT-RT). However, a large proportion of patients with locally advanced stage are not suitable for receiving cisplatinum-based chemotherapy (CT) concomitant with radiotherapy (RT) either due to age, general and/or medical condition(s).

An alternative standard treatment has been established, combining RT and cetuximab.

However, both CT-RT and cetuximab-RT which are considered as standard approaches in locally advanced non operated HNSCC are associated with poor outcome in patients with the most advanced T stage (T4) and/or N stage (>=N2) and/or HPV negative tumours. A new and promising approach could target immune response.

Pembrolizumab is a high-affinity monoclonal anti-PD1 antibody which showed antitumor activity in melanoma and NSCLC. In the KEYNOTE-012 (multi-center, nonrandomized Phase Ib HNSCC), Pembrolizumab was well tolerated and safe with no serious drug related AEs reported. About 51% (26/51) of patients had decreased tumor burden which was seen both in HPV (-) and HPV(+) HNSCC.

This observation led to the hypothesis generated in the current study that Pembrolizumab is potentially a very active drug in HNSCC and that the combination of Pembrolizumab with radiotherapy will be well tolerated, given the very good toxicity profile of the drug and will improve the outcome of patients with locally advanced HNSCC non suitable for CT-RT, as compared to the treatment of reference combining cetuximab and RT.

Inclusion Criteria:

1. Written informed consent
2. Age ≥18 ≤ 80 years.
3. Performance Status ECOG 0-1
4. Histologically confirmed diagnosis of previously untreated locally advanced HNSCC (Stage III, IVa and IVb according to the American Joint Committee on Cancer Staging System) of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx
5. Availability of pre-treatment tumour tissue (for biomarker analysis, PD -L1, TILs and immune-monitoring)
6. p16 expression from tumor sample (immunohistochemistry)
7. Recording of the smoking history
8. No viral infection (HIV, Hepatitis B/C)
9. No autoimmune disease
10. No immunodeficiency or immunosuppressive therapy
11. No active CNS disease
12. No interstitial lung disease
13. No active infection
14. Women of child-bearing potential: negative serum pregnancy test at screening and use of appropriate contraception methods from study entry
15. Patients not proposed cisplatin-based chemotherapy because of age, general condition, if medically unfit or patient refusal.
16. Adequate organ laboratory values
17. Health insurance coverage

Exclusion Criteria:

1. Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers;
2. Squamous cell cancer involving cervical neck nodes with unknown primary site;
3. Metastatic disease;
4. 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, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent;
5. Weight loss of >10% during the last 3 weeks prior the screening visit;
6. Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol;
7. Concomitant treatment with any drug on the prohibited medication list such as live vaccines (for details, see the protocol);
8. History of another malignancy within the last 3 years (exception of in situ carcinoma and skin carcinomas);
9. If female, pregnant or lactating;
10. 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.
11. Known hypersensitivity reaction to study medication;
12. Any social, personal, medical and/or psychologic 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.