Cetuximab Plus Platinum and Taxane-based Chemotherapy, Followed by Avelumab and Cetuximab, as First-line Treatment for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Patients With a PD-L1 Combined Positive Score (CPS)≥1≤19.

1. Subjects able to sign the informed consent and ≥18 y-old.
2. Histologically or cytologically confirmed diagnosis of HNSCC.
3. Confirmed R/M HNSCC (i.e. oral cavity, oropharynx, larynx, hypopharynx) not suitable for curative loco-regional therapy.
4. PD-L1 CPS≥1≤19 (assessment allowed either on primary and/or recurrent/metastatic site of disease).
5. Measurable disease according to RECIST Criteria 1.1.6. Subjects should not have had prior systemic therapy administered in the R/M HNSCC setting.

7.Systemic therapy that was completed more than 6 months prior to signing consent, if given as a part of multimodal curative treatment for locally advanced disease, is allowed.

8.ECOG Performance Status (PS) 0-1. 9.Adequate bone marrow function: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL.

10.Adequate liver function: total bilirubin level \< 1.5 X Upper Limit of Normal (ULN) (except for known medical reason not interfering with liver function, such as Gilbert syndrome), AP, GGT \<3 x ULN and AST and ALT levels ≤ 2.5 × ULN.

11.Adequate renal function: calculated or analyzed creatinine clearance ≥ 30 mL/min.

12.Archival or fresh tissue of primary disease (i.e. T and/or N and/or M) OR recurrent/metastatic disease available at baseline (before starting TPE) (available as Formalin-Fixed Paraffin-Embedded - FFPE - or as unstained 10-20 slices).

13.Participants have to provide peripheral blood samples (at least 8-10 mL stored in EDTA) according the timing described in the translational part of the current protocol.

14.Palliative radiotherapy and/or surgery within 4 weeks before the study entry are allowed.

15.Symptomatic peripheral neuropathy NCI-CTC v5.0 grade ≥ 2 and / or ototoxicity grade ≥ 2, (except for cases in which ototoxicity is due to trauma or tumor-related mechanical impairment) or creatinine clearance \< 60 mL/min are acceptable and they must be approached with carboplatin (instead of cisplatin) since the trial start.

Exclusion criteria:

1. Nasopharyngeal, salivary gland, nasal sinus, and non-melanoma skin cancers are not allowed.
2. Life expectancy lower than 3 months according to the judgement of trial investigator is not allowed.
3. Previous chemotherapy, or biological therapy (i.e. Cetuximab), or immunotherapy administered for R/M setting of HNSCC is not allowed.
4. Diagnosis of immunodeficiency or subjects receiving systemic steroid therapy (> 10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy within 30 days prior to start of study treatment which cannot be interrupted.
5. Known allergic/hypersensitivity reaction to investigational products or any component in their formulations.
6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
7. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
8. Any diagnosed and/or treated additional malignancy within 5 years before the study entry with the exception of: curatively treated basal cell carcinoma of the skin, curatively treated squamous cell carcinoma of the skin, curatively treated prostate cancer, curatively resected in situ cervical cancer, and curatively resected in situ breast cancer.
9. Subjects with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subjects' participation for the full duration of the trial, or is not in the best interest of the subject to participate, according to the opinion of the treating investigator.
10. Significant neurologic or known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial.
11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (≤6 months prior to enrollment), myocardial infarction (≤6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
12. Prior organ transplantation including allogenic stem-cell transplantation.
13. Active uncontrolled infection requiring systemic therapy (i.e. I.V. antibiotics).
14. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
15. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening tests positive).
16. Live vaccination within 30 days of planned start of study treatment (inactivated vaccines are allowed).
17. Pregnancy (absence of pregnancy must be confirmed by negative serum or urine pregnancy test - ß-HCG - for women of childbearing potential) and/or breast-feeding are not allowed. Subjects of childbearing potential willing to use effective contraceptive method [Pearl Index \< 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilization, sexual abstinence] for the entire study duration and 30 days post-dosing.