Background: Globally, GC/GEJ/EAC are one of the leading causes of cancer-related mortality. Systemic chemotherapy is the standard of care for advanced or metastatic GC/GEJC/EAC, but the prognosis is poor. In the CM 649 trial, nivolumab plus chemotherapy (Nivo+Chemo) demonstrated superior overall survival (OS) in patients with advanced GC/GEJC/EAC versus chemotherapy (Chemo) alone. The objective of this study is to estimate the NNTs comparing Nivo+Chemo versus Chemo for OS, progression free survival (PFS), and objective response rate (ORR) among patients in CM 649. Methods: Individual patient-level data from CM 649 were used for this analysis. The trial population included adult patients with previously untreated, unresectable, advanced or metastatic GC/GEJC/EAC who received Nivo+Chemo or Chemo alone as their 1L treatment. The analysis was performed in all randomized patients who received at least one dose of the study drug and a subgroup of patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 5. Chemo included either FOLFOX (fluorouracil, oxaliplatin, and leucovorin) or XELOX (capecitabine and oxaliplatin). NNTs were equal to the reciprocal of the absolute risk reduction and were calculated for OS and PFS over the 1-year period and objective response rate (ORR) over the entire trial period. Results: 1,549 patients who received treatment in the CM 649 trial (782 treated with Nivo+Chemo and 767 treated with Chemo) were included in this analysis. Among these 1,549 patients, 933 patients had PD-L1 CPS ≥ 5 (468 treated with Nivo+Chemo and 465 treated with Chemo). Among all treated patients, the NNTs (95% confidence interval (CI)) of Nivo+Chemo when compared to chemotherapy were 14.08 (8.31–45.97) and 9.70 (6.59–18.36) for OS and PFS over the 1-year period, and 8.95 (5.95–18.10) for ORR over the entire trial period. Among patients with PD-L1 CPS ≥ 5, the NNTs (95% CI) were 9.06 (5.76–21.20) for OS, 6.91 (4.85–12.03) for PFS, and 7.14 (4.75–14.37) for ORR. This analysis shows that for every 100 patients with GC/GEJC/EAC receiving Nivo+Chemo instead of Chemo, there were 7 additional overall survivors (100/NNT of OS) and 10 additional progression-free survivors (100/NNT of PFS) in the 1-year period, and 11 additional patients achieving objective response (100/NNT of ORR) during the entire trial period. Among patients with PD-L1 CPS ≥ 5, there were 11 additional overall survivors and 14 additional progression-free survivors in the 1-year period, and 14 additional patients achieving objective response during the entire trial period. Conclusions: NNT analyses showed consistent and meaningful benefits of Nivo+Chemo over Chemo in terms of OS, PFS, and ORR. Nivo+Chemo represents a promising 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116.