Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)

This is a randomized, active-controlled, open-label study of pembrolizumab given prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or without cisplatin), as post-surgical therapy in treatment naïve participants with newly diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1 (PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab given before surgery and after surgery in combination with radiotherapy (with or without cisplatin) improves event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Inclusion Criteria: * Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries. * Is eligible for primary surgery based on investigator decision and per local practice * Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy. * Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy * Female participant that is not pregnant or breastfeeding * Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) * Has provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated * Has results from testing of HPV status for oropharyngeal cancer defined as p16 * Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of randomization Exclusion Criteria: * Has Stage T4B and/or N3 locoregionally advanced head and neck squamous cell carcinoma (LA HNSCC) and/or distant metastases * Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity. such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer (HNC) * Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin. * Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor * Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start * Has received a live vaccine within 30 days prior to randomization * 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 randomization * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy * Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis * Has Grade ≥2 audiometric hearing loss * Has Grade ≥2 neuropathy * Has Grade 3-4 bleeding due to the underlying malignancy * Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start * Has had previous allogeneic tissue/solid organ transplant * Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C (defined as Hepatitis C virus \[HCV\] ribonucleic acid is detected). * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study