Background: In the pivotal CheckMate-649 trial, nivolumab in combination with chemotherapy (nivo + chemo), compared with chemotherapy alone (chemo), demonstrated superior efficacy in patients with previously untreated, advanced gastric, gastro-esophageal junction, or esophageal adenocarcinoma (collectively: gastroesophageal adenocarcinoma). This study aimed to describe the real-world patterns of use and effectiveness of nivo + chemo for first-line (1L) treatment of advanced gastroesophageal adenocarcinoma. Methods: Patients aged ≥18 years, newly diagnosed with unresectable, advanced or metastatic, HER2-negative gastroesophageal adenocarcinoma, who received nivo + chemo or chemo only between 4/1/2021 and 5/31/2022 were identified from the Flatiron Health database. Chemo regimens included FOLFOX or CAPEOX. Patients were followed from index date (start of 1L therapy) until death, loss of data availability, or end of data abstraction (05/31/2022), whichever occurred first. Results: 352 patients with advanced or metastatic gastroesophageal adenocarcinoma were eligible for the analysis (N=158 in the nivo + chemo group and N=194 in the chemo group). Baseline demographic and clinical characteristics were balanced between groups. Median follow-up was 3.6 (interquartile range [IRQ]: 1.5–8.1) months for nivo + chemo and 4.4 (IQR: 1.9–7.6) months for chemo. 44.3% of patients in the nivo + chemo group and 36.1% in the chemo group had <3 months of follow-up available. Median overall survival (OS) from index date was not reached (95% confidence interval [CI]: 9.0 months, –) in the nivo + chemo group and was 10.0 (95% CI: 8.5, 11.6) months in the chemo group. 43 patients (27.2%) in the nivo + chemo group died during the study period compared with 64 patients (33.0%) in the chemo group. Median progression-free survival (PFS) from index date in patients who received nivo + chemo was 6.9 (95% CI: 5.6, 8.2) months compared to 5.5 (95% CI: 4.8, 7.4) months in patients who received chemo. Similar trends were observed in the subgroup of patients with a PD L1 combined positive score (CPS) ≥1, while data on the CPS ≥5 subgroup were not mature enough for meaningful analyses. Conclusions: The addition of nivolumab to chemotherapy for 1L treatment of advanced or metastatic gastroesophageal adenocarcinoma showed a trend towards survival benefit in the real-world setting. The study is ongoing. Subsequent analyses will capture a larger patient sample and longer follow-up, and describe PD L1 CPS-based subgroups.