This study is designed to evaluate the efficacy and safety of tislelizumab and tislelizumab in combination with investigational agent(s) in first-line recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

This study will test whether tislelizumab alone and combined with other investigational agents can be used to improve treatment outcomes in participants with head and neck squamous cell carcinoma. The main goals of the study are to determine how many participants may no longer have evidence of cancer or have some improvement in the signs and symptoms of cancer after treatment and to determine what adverse events, or side effects, participants might experience.

Tislelizumab is used to block the programmed cell death protein-1 pathway so that immune system cells (T-cells) can better protect the body from infection and find tumor cells to attack. Tislelizumab may be used in combination with other therapies as a promising approach with potential therapeutic benefits to treat participants with cancer. The study will enroll approximately 160 participants. Participants will be randomly assigned (by chance, similar to flipping a coin) to one of the various treatment groups. Tislelizumab and investigational agents will be administered as an infusion through a vein at regularly scheduled intervals.

The study will take place at multiple centers worldwide. Treatments will continue until participants experience no benefits, too many side effects, or withdraw consent.

Inclusion Criteria:

• Participants with histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies

  1. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx
  2. Participants should not have had prior systemic therapy administered in the R/M setting; systemic therapy which was completed prior to randomization/enrollment if given as part of multimodal treatment for locally or locoregionally advanced disease is allowed

• Participants must have positive PD-L1 expression (Combined Positive Score [CPS] ≥ 1)

• Have at least 1 measurable lesion as defined per RECIST v1.1

• Eastern Cooperative Oncology Group Performance Status of 0 or 1

• Adequate hematologic and organ function as indicated by specific laboratory values within 7 days of first dose of study drug

• Willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug(s)

Exclusion Criteria:

• Recurrent or metastatic carcinoma of the nasopharynx (any histology), squamous cell carcinoma of unknown primary, squamous cell carcinoma that originated from the skin and salivary gland primary tumor or non-squamous histologies (eg, mucosal melanoma)
• Prior therapy with an anti-PD-1, anti-PD-L1, PD-L2, T-cell immunoglobulin and TIM-3, LAG-3, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
• Any active malignancy ≤ 2 years before randomization/enrollment except for the specific cancer under investigation in this study, those with a negligible risk of metastasis or death, and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, and carcinoma in situ of the cervix or breast)
• History of interstitial lung disease, noninfectious pneumonitis, or uncontrolled lung diseases including pulmonary fibrosis, and acute lung diseases
• A history of severe hypersensitivity reactions to other monoclonal antibodies or has experienced a severe immune-mediated adverse event (imAE), an imAE that led to treatment discontinuation, or a cardiac or ocular imAE of any grade with prior immunotherapy

Note: Other inclusion and exclusion criteria may apply