Background: Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers. Avelumab* is a fully human anti-PD-L1 IgG1 antibody that has shown promising efficacy and an acceptable safety profile in patients (pts) with adenocarcinoma of the stomach or gastroesophageal junction (AS/GEJ) treated in first-line (1L) and second-line settings. This open-label phase 3 study (NCT02625610) compares maintenance (Mn) treatment with single-agent avelumab vs continuation of 1L chemotherapy in pts with AS/GEJ. Methods: The primary objective of this global, multicenter trial is to demonstrate superiority of Mn therapy with avelumab vs continuation of 1L chemotherapy. Primary endpoint is overall survival or progression-free survival. Approximately 666 eligible pts will receive induction chemotherapy and upon completion, approximately 466 pts without disease progression will be randomized to receive treatment in the Mn phase. Main eligibility criteria include: histologically confirmed unresectable locally advanced or metastatic (LA/M) AS/GEJ, ECOG PS 0-1, no prior chemotherapy for LA/M disease, no prior therapy with any drug targeting T cell coregulatory proteins, and no concurrent anticancer treatment or immunosuppressive agents. Pts are not preselected for PD-L1 expression; HER2+ pts are excluded. During the induction phase, pts receive chemotherapy (oxaliplatin + 5-fluorouracil + leucovorin or oxaliplatin + capecitabine) for 12 wks. Pts entering the Mn phase are randomized to receive either avelumab 10 mg/kg as a 1h intravenous infusion Q2W or continuation of 1L chemotherapy. Treatment is given until disease progression, unacceptable toxicity, or consent withdrawal. Secondary endpoints include best overall response, quality of life (assessed via EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-STO22), safety as per NCI-CTCAE v4.03, and tumor biomarkers. Responses are evaluated according to RECIST 1.1 and adjudicated by a blinded independent review committee. Trial enrollment began in Dec 2015. *Proposed INN. Clinical trial information: NCT02625610