Study of GSK3359609 With Pembrolizumab and 5-fluorouracil (5-FU)-Platinum Chemotherapy in Participants With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Inclusion Criteria:

- Histological or cytological documentation of HNSCC that was diagnosed as recurrent or metastatic and considered incurable by local therapies.

- Primary tumor location of the oral cavity, oropharynx, hypopharynx or larynx.

- No prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally advanced disease and no disease progression/recurrence within 6 months of the completion of curatively intended systemic treatment).

- Measurable disease.

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.

- Adequate organ function.

- Life expectancy of at least 12 weeks.

- Female participants: must not be pregnant, not breastfeeding, and be either not a woman of childbearing potential (WOCBP); or be a WOCBP who agrees to use a highly effective method of birth control from 30 days prior to randomization and for at least 120 days after the last dose of study treatment.

- Male participants with female partners of child-bearing potential: must agree to use a highly effective contraception while receiving study treatment and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this periods.

- Provide tumor tissue from excisional or core biopsy (fine needle aspirates and bone biopsies are not acceptable) acquired within 2 years prior to randomization for PD-L1 immunohistochemistry (IHC) testing by central laboratory.

- Have PD-L1 IHC CPS status by central laboratory testing.

- Have results from testing of human papilloma virus (HPV) status for oropharyngeal cancer.

Exclusion Criteria:

- Prior therapy with an anti-PD-1/L1/L2, anti-Inducible T Cell Co-Stimulatory Receptor (ICOS ) directed agent.

- Systemic approved or investigational anticancer therapy within 30 days or 5 half lives of the drug, whichever is shorter.

- Has high risk of bleeding.

- Active tumor bleeding

- Grade 3 or Grade 4 hypercalcemia.

- Major surgery <=28 days prior to randomization.

- Toxicity from previous anticancer treatment that includes: a. Grade 3/Grade 4 toxicity related to prior immunotherapy and that led to treatment discontinuation and toxicity related to prior treatment that has not resolved to <=Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be <=Grade 2).

- Received transfusion of blood products or administration of colony stimulating factors within 14 days prior to randomization.

- Central nervous system (CNS) metastases, with the following exception: Participants with asymptomatic CNS metastases who are clinically stable and have no requirement for steroids for at least 14 days prior to randomization.

- Invasive malignancy or history of invasive malignancy other than disease under study within the last 3 years with the exception of any other invasive malignancy for which the participant was definitively treated, has been disease-free for <=3 years, curatively treated non-melanoma skin cancer or successfully treated in situ carcinoma and/or low-risk early stage prostate cancer.

- Autoimmune disease or syndrome that required systemic treatment within the past 2 years.

- Has a diagnosis of immunodeficiency or is receiving systemic steroids (>10 milligram (mg) oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to randomization.

- Receipt of any live vaccine within 30 days prior randomization.

- Prior allogeneic/autologous bone marrow or solid organ transplantation.

- Has current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents.

- Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions .

- Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.

- Recent history of allergen desensitization therapy within 4 weeks of randomization.

- History or evidence of cardiac abnormalities within the 6 months prior to randomization which include.

- Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.

- Active infection requiring systemic therapy.

- Known human immunodeficiency virus (HIV) infection, or positive test for hepatitis B active infection (presence of hepatitis B surface antigen), or hepatitis C active infection.

- History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies under investigation including any ingredient used in the formulation.

- Known history of active tuberculosis.

- Any serious and/or unstable pre-existing medical condition (aside from malignancy).

- Any psychiatric disorder, or other condition that could interfere with participant's safety, obtaining informed consent, or compliance to the study procedures in the opinion of the investigator.

- Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the date of randomization.