Background: Blockade of the immune checkpoint receptor programmed death-1 (PD-1) has shown clinical benefit in multiple tumor types. Nivolumab (anti–PD-1) has demonstrated a survival advantage versus (vs) placebo in patients (pts) with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) (Kang YK et al. Lancet 2017;390:2461–71). Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates effector T-cell function and is a marker of T-cell exhaustion. Preliminary data in melanoma suggest that combining nivolumab with relatlimab (anti–LAG-3) could improve efficacy without substantially increasing toxicity vs nivolumab especially, but not exclusively, in LAG-3-expressing pts (Ascierto PA et al. Ann Oncol 2017;28(S5):LBA18). Furthermore, LAG-3 expression was as high as 33% in an analysis of solid tumors including GC (Edwards R et al. J Immunother Cancer 2017;5(S3):P510). Study CA224-060 will assess the clinical efficacy and safety of relatlimab and nivolumab with chemotherapy for first-line treatment of GC or GEJC. Methods: This is a randomized, open-label, multicenter, phase 2 study of relatlimab and nivolumab with oxaliplatin-based chemotherapy vs nivolumab with oxaliplatin-based chemotherapy. Approximately 250 adult pts with untreated, locally advanced, unresectable or metastatic GC or GEJC will be enrolled. To be randomized, pts must have tumor tissue for analysis of biomarkers, LAG-3 status, and PD-L1 combined positive score. Key exclusion criteria include HER2-positive status, untreated CNS metastases, or significant cardiovascular disease. The primary endpoint is objective response rate (ORR) using RECIST v.1.1 by blinded independent central review in LAG-3-expressing pts. Other endpoints include investigator-assessed ORR, ORR in LAG-3-negative pts, duration of response, overall survival, progression-free survival, and safety and tolerability. Efficacy signals in biomarker subgroups will be explored. Currently, 26 sites are activated with 15 randomized pts. Clinical trial information: NCT03662659