• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of R/M HNSCC that is considered incurable by local therapies will be enrolled in this study:

‣ Subject may not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to signing consent if given as part of multimodal treatment for locally advanced disease is allowed.

⁃ The eligible primary tumour locations are oropharynx, oral cavity, hypopharynx, and larynx.

⁃ Subject may not have a primary tumour location site of nasopharynx (any histology).

• A male participant must agree to use a contraception as detailed in Appendix 3: Contraceptive Guidance and Pregnancy Testing of this protocol starting with the first dose of study treatment through the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period.

• A female participant is eligible to participate if she is not pregnant (see Appendix 3: Contraceptive Guidance and Pregnancy Testing), not breastfeeding, and at least one of the following conditions applies:

∙ Not a woman of childbearing potential (WOCBP) as defined in Appendix 3: Contraceptive Guidance and Pregnancy Testing OR

‣ A WOCBP who agrees to follow the contraceptive guidance in Appendix 3: Contraceptive Guidance and Pregnancy Testingduring the treatment period and for at least 180 days after the last dose of study treatment.

• The participant (or legally acceptable representative if applicable) willing and able to provides written informed consent for the trial. The participant may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.

• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• Archival or fresh tumor tissues must be available for evaluating relevant biomarkers. Newly obtained core needle or excisional biopsy of a tumor lesion not previously irradiated is preferred to archived tissue. If newly obtained samples cannot be obtained due to inaccessibility or patient safety concern, submission of paraffin block or formalin-fixed, paraffin embedded (FFPE) slides of up to 3 years prior to trial enrolment are acceptable (15 unstained slides of 5 microns in thickness). Refer to Section 6.1.5 for complete information on the tissue sample collection.

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

• Have adequate organ function as defined in the following table (Table 3). Specimens must be collected within 10 days prior to the start of study intervention.

‣ Absolute neutrophil count (ANC) ≥1500/µL

⁃ Platelets ≥100 000/µL

⁃ Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

⁃ Creatinine ≤1.5 × ULN

⁃ Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN

⁃ AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)

⁃ International normalized ratio (INR) OR prothrombin time (PT), Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants