Background: Perioperative FLOT chemotherapy has become a standard of care for locally advanced, resectable esophagogastric adenocarcinoma (EGA). However, patient outcomes are still unsatisfactory. Immune checkpoint inhibitors combined with chemotherapy have proven activity in advanced Her2 negative EGA with PD-L1 expression (KEYNOTE-590, Checkmate-649). Atezolizumab is a PD-L1 inhibitor with established efficacy and tolerability profiles and will be evaluated in this study in the perioperative treatment of potentially resectable EGA in combination with FLOT. As shown at ASCO 2022 for the phase II part of DANTE, adding atezolizumab to FLOT led to improved tumor downsizing and pCR (24% vs 15%). Of note, regression rates further improved with higher PD-L1 expression (33% vs 12% in tumors with CPS ≥10) or in MSI-high tumors (63% vs 27%). Prompted by these results, we decided to transition this trial from the initial phase II to a phase III design. Methods: This is a multinational, prospective, randomized, investigator-initiated, open label phase II/III trial. Patients (pts) with locally advanced, potentially resectable EGA (≥cT2 and/or N-positive) without distant metastases are enrolled. Based on the subgroup analyses of the phase II trial, we decided to limit the future enrollment to pts with high immune responsiveness, i.e. either of the following: MSI-high, PD-L1 CPS≥1, TMB ≥10/MB or EBV+. Eligibility status is centrally evaluated. Pts are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) plus 840 mg atezolizumab q2w followed by surgery and 4 additional cycles of FLOT/atezolizumab, followed by a total of 8 additional cycles of atezolizumab at 1200 mg every 3 weeks as monotherapy (arm A) or FLOT alone (arm B). Primary endpoint is event-free survival (EFS) as assessed by the Kaplan-Meier-Method. An estimated HR of 0.72 would correspond to a median EFS of 41.67 months for the experimental Arm A. This difference is considered clinically relevant. A total of 556 pts (318 events) will be randomized. As 177/295 pts with PD-L1 positive or MSI status were already enrolled into the phase II portion, additional 379 pts will be enrolled into phase III. Main secondary endpoints are rates of locally assessed pathological regression (complete and nearly complete pathological regression), OS, OS and EFS in the subgroup of pts with PD-L1 CPS ≥5 and ≥10 and pts with MSI, R0 resection, and safety. In addition, a prospective biomarker study including serial circulating tumor DNA analysis before and during treatment will be performed. Recruitment started 2018 and continues for phase III in 2023. Clinical trial information: NCT03421288.