Study on the Efficacy of Treatment by Radiotherapy and Pembrolizumab in Newly Diagnosed Metastatic Head & Neck Cancers

Inclusion Criteria:

1. Patient must have signed a written informed consent form prior to any study specificprocedures. When the patient is physically unable to give their written consent, atrusted person of their choice, independent from the investigator or the sponsor,can confirm in writing the patient's consent.

2. Histologically confirmed squamous cell carcinoma of head and neck (oral cavity,oropharynx, hypopharynx, and larynx) including unknown primary head and neck lymphnodes with distant metastases at presentation (T1-4 N0-3 M1). Histologicalconfirmation is required in case of a single metastatic lesion.

3. Eligible for treatment by pembrolizumab according to the European MarketingAuthorization

4. Patient ≥18 years old

5. Performance status: 0-1 (WHO)

6. Combined Positive Score (CPS) ≥1 for primary tumor (as determined per localpractice)

7. Subjects must have at least one measurable lesion as per RECIST v1.1 to assessefficacy

8. Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to randomization: a. If randomization is done before treatment start: i. Absolute neutrophil count ≥1.5 × 10⁹/L ii. Platelet ≥100 × 10⁹/L iii. Hemoglobin ≥90 g/L iv. Aspartateaminotransferase (AST) and alanine aminotransferase (ALT), ≤3 × upper limit ofnormal (ULN), (unless documented liver metastases where ≤5 x ULN is permitted) v.Bilirubin ≤1.5 × ULN. vi. Serum albumin ≥25 g/L vii. Creatinine clearance ≥30 mL/min (calculated per institutional guidelines or by Cockcroft-Gault or Modification ofDiet in Renal Disease (MDRD) formula) viii. Corrected serum calcium of ≤11.5 mg/dLor ≤2.6 mmol/L. b. If randomization if done after treatment start i. Absoluteneutrophil count ≥1.0 × 10⁹/L ii. Platelet ≥75 × 10⁹/L iii. Hemoglobin ≥85 g/L

9. Patient must agree to use adequate contraception methods for the duration of thestudy treatment and up to 4 months after the last dose of pembrolizumabadministration

10. Patients must be affiliated to a Social Security System (or equivalent)

11. No disease progression during systemic treatment if the randomization is done afterthe start of pembrolizumab for the current disease

Exclusion Criteria:

1. Symptomatic central nervous system (CNS) metastases and / or carcinomatousmeningitis

2. History of another malignancy within 2 years prior to study inclusion, with theexception of completely resected basal or squamous cell skin cancer, or successfullytreated in-situ carcinoma

3. Prior radiotherapy in the head and neck region

4. Any prior or current non-surgical treatment for invasive head and neck cancer. (except for pembrolizumab +/- chemotherapy for the current cancer for a maximum of 6cycles). This will include but is not limited to: prior tyrosine kinase inhibitors,any monoclonal antibody, chemotherapy, anti-PD-1/PD-L1 and CTLA-4, priorradiotherapy (RT), or use of any investigational agent. Loco-regional recurrent orsecond primary head and neck cancer after prior surgical treatment alone in the headand neck region could be eligible.

5. Known Acquired Immune Deficiency Syndrome (AIDS)

6. Known currently active infection including hepatitis B or hepatitis C

7. Patient having received live attenuated vaccine within 28 days prior to enrolment

8. Pregnant or breast feeding woman

9. Active autoimmune disease except vitiligo, type-1 diabetes, hypothyroid stabilizedwith hormonal substitution, or psoriasis which do not require systemic treatment

10. Active immunodeficiency or ongoing immunosuppressive therapy

11. Active symptomatic interstitial lung disease

12. Significant disease which, in the judgment of the investigator, as a result of themedical interview, physical examinations, or screening investigations would make thepatient inappropriate for entry into the trial

13. Any social, personal, medical, geographic and/or psychologic factor(s) that couldinterfere with the observance of the patient to the protocol and/or the follow-upand/or the signature of the informed consent

14. Prior organ transplantation including allogenic stem-cell transplantation

15. Other severe acute or chronic medical conditions including colitis, pneumonitis,pulmonary fibrosis or psychiatric conditions including active suicidal ideation; orlaboratory abnormalities that may increase the risk associated with studyparticipation and, in the judgment of the investigator, would make the patientinappropriate for entry into this study

16. Person deprived of their liberty or under protective custody or guardianship

17. Patient who have taken any investigational medicinal product or have used aninvestigational device within 30 days prior to study inclusion