This randomized phase 2 open-label study will evaluate the safety and efficacy of zimberelimab (AB122) monotherapy, domvanalimab (AB154) in combination with zimberelimab, and domvanalimab in combination with zimberelimab and etrumadenant (AB928) in front-line, PD-L1 positive, metastatic non-small cell lung cancer.

Inclusion Criteria:

• Male or female participants; age ≥ 18 years
• Histologically confirmed, treatment naive, metastatic squamous or non-squamous NSCLC with documented high PD-L1 expression, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Must have at least 1 measurable lesion per RECIST v1.1
• Adequate organ and marrow function

Exclusion Criteria:

• Use of any live vaccines against infectious diseases within 28 days of first dose of investigational medicinal products (IMPs)
• Any gastrointestinal condition that would preclude the use of oral medications (eg, difficulty swallowing, nausea, vomiting, or malabsorption)
• History of trauma or major surgery within 28 days prior to the first dose of IMP
• Concurrent medical condition requiring the use of supra-physiologic doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive medications
• Positive test results for Hepatitis B surface antigen, Hepatitis C virus antibody with presence of Hepatitis C qualitative RNA or human immunodeficiency virus (HIV-1 and/or HIV-2) antibody at screening
• Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy.
• Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer

Arcus will provide access to individual de-identified participant data and related study documents (e.g., protocol, Statistical Analysis Plan [SAP], Clinical Study Report [CSR]) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions.

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