Background: Efficacy of 2^nd line chemotherapy in advanced gastric/gastro-oesphageal junction (GEJ) adenocarcinoma remains limited. No study up until now has evaluated the efficacy of immune checkpoint inhibitors combined with chemotherapy as 2^ndline treatment of advanced gastric/GEJ adenocarcinoma. Methods: DURIGAST PRODIGE 59 is a randomized, multicenter, phase II study designed to assess the efficacy and safety of the combination of FOLFIRI plus durvalumab (anti-PD-L1 until progression) (FD) versus FOLFIRI plus durvalumab and tremelimumab (anti-CTLA-4 for 4 cycles) (FDT). Key eligibility criteria included advanced gastric/GEJ adenocarcinoma, platinum-based first-line chemotherapy and ECOG performance status (PS) 0 or 1. Patients were randomized in a 1:1 ratio to FD versus FDT. The primary endpoint is progression-free survival (PFS) at 4 months, which was expected to be 70% (H₀:50%). With an α risk of 5%, a power of 85% and 5% of non-evaluable patients, 47 evaluable patients are needed by arm. Secondary endpoints included safety, overall survival (OS) and quality of life. Results: Between August 2020 and June 2021, 96 patients were randomized, 48 in each arm. The median age was 59.7 years, 30.4% were women and 66.3% ECOG PS 1. All in all, 22.8% had HER2+ tumors and 4.3% dMMR/MSI tumors. The 4-month PFS were 44.7% [90%CI: 32.3–57.7] and 57.8% [90%CI: 44.5–70.3] in the FD and FDT arms, respectively. Primary endpoint was not met. Median PFS were 3.8 and 5.9 months, disease control rates 68.9% and 73.8% and median OS not reached and 10.1 months in FD and FDT arms, respectively. Eight patients in FDT arm had tremelimumab re-introduction at progression. Twenty-one patients, 8 in FD arm and 13 in FDT arm, are still being treated with a median duration of treatment of 7.8 and 10.9 months. All in all, 50.0% and 47.8% of patients experienced at least one grade 3-4 adverse events related to the treatment (neutropenia: 13.0 vs 21.7%, anemia: 10.9 vs 6.5%, diarrhea: 2.2 vs 8.7% and vomiting: 6.5 vs 10.9%), in FD and FDT arms, respectively. In both arms there was no clinically significant deterioration of quality of life superior to 10 points according to EORTC QLQ-C30 global health status. Conclusions: The DURIGAST PRODIGE 59 trial demonstrates an acceptable safety profile of immune checkpoint inhibitors plus FOLFIRI in 2^nd line treatment for advanced gastric/GEJ adenocarcinoma. FDT combination demonstrates a clinically relevant efficacy never before achieved with a median PFS of 6 months and should be evaluated in a phase III trial. Updated results including PFS according to centralized review and PD-L1 status will be presented during ASCO meeting. Clinical trial information: NCT03959293.