Study of Intratumoral (IT) Ulevostinag (MK-1454) in Combination With Intravenous (IV) Pembrolizumab (MK-3475) Compared to IV Pembrolizumab Alone as the First Line Treatment of Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) (MK-1454-002)

Inclusion Criteria:

* Has histologically or cytologically confirmed diagnosis of metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC) that is considered incurable by local therapies
* Has not had prior systemic therapy administered in the recurrent or metastatic setting
* Has tumor PD-L1 expression of CPS ≥1. Tumor tissue must be provided for PD-L1 biomarker analysis
* Has measurable disease per RECIST 1.1, as assessed by BICR
* Has at least 1 measurable lesion which is amenable to injection
* Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Demonstrates adequate organ function within 7 days prior to treatment initiation
* Male participants of reproductive potential must agree to refrain from donating sperm and use a male condom plus partner use of an additional contraceptive method during sexual contact with females of childbearing potential during the intervention period with ulevostinag and for at least 120 days after the last dose of ulevostinag
* Female participants of childbearing potential who are not pregnant or breastfeeding must be willing to use a highly effective method of birth control or be surgically sterile or abstain from heterosexual activity during the intervention period and for at least 120 days after the last dose of study intervention, and agree not to donate eggs (ova, oocytes) to others or freeze/store for personal use
* Human immunodeficiency virus (HIV)-infected participants must meet these additional criteria:

  1. Has HIV-1 infection documented by using any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Day 1)
  2. Has well-controlled HIV on anti-retroviral therapy (ART)

Exclusion Criteria:

* Has disease that is suitable for local therapy administered with curative intent
* Has progressive disease (PD) within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
* Has had chemotherapy or biological cancer therapy in the recurrent or metastatic setting for the treatment of HNSCC
* Has had radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or participant has not fully recovered from adverse events (AEs) due to a previously administered treatment
* Is expected to require any other form of antineoplastic therapy while on study
* Has a history of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for at least 2 years
* Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years
* Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
* Has had an allogenic tissue/solid organ transplant
* Has a history of vasculitis
* Has a history of interstitial lung disease
* Has an active infection requiring systemic therapy
* Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
* Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
* Has had a severe hypersensitivity reaction to treatment a monoclonal antibody/components of the study treatment
* Has known Hepatitis B virus or Hepatitis C virus infections
* Has received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti-PD-L2) agent or if the participant has previously participated in Merck Sharp \& Dohme (MSD) MK-3475 clinical trials
* HIV infected participant who has had an HIV-related opportunistic infection within 6 months
* HIV infected participants who have a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Has not fully recovered from any effects of major surgery without significant detectable infection
* Has a history of re-irradiation for HNSCC at the projected injection site in the head and neck
* Has received a live-virus vaccine within 30 days of planned study treatment start
* Has been treated with a stimulator of interferon genes (STING) agonist (e.g. ulevostinag, ADU-S100)
* Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy, or used an investigational device, any of which occurred within 4 weeks of the first dose of study treatment