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Importance Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. Objective To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 ca