Background: The addition of immune checkpoint inhibitors to chemotherapy has improved outcomes in patients (pts) with metastatic esophagogastric adenocarcinoma (EGA), but treatment combinations and optimal pt selection need to be established. Objective: To investigate efficacy and tolerability of the programmed death-ligand 1 (PD-L1) inhibitor avelumab with ramucirumab and paclitaxel in the second line treatment of pts with metastatic EGA (NCT03966118). Methods: In this phase 2 multicenter single-arm clinical trial the reported results are based on a median follow-up of 27.4 months. Patients with previously treated metastatic EGA, adequate organ function, and eligibility for immunotherapy were included. Interventions: Pts with metastatic EGA after progression on platinum/ fluoropyrimidine based palliative first line treatment, checkpoint-inhibitor naive, received ramucirumab 8 mg/kg (d1,15), avelumab 10 mg/kg (d1,15) and paclitaxel 80 mg/m² (d1,8,15) q4w. Results: The pre-specified primary end point was overall survival rate at 6 months (mo) (H0≤50%, H1≥65%). A total of 60 patients (pts) were enrolled, 59 were evaluable (intention to treat, ITT). Participants had a median age of 64.0 yrs (range 18-81) and 80% were men. Baseline Eastern Cooperative Oncology Group performance status was 0 in 23 pts (39.0%) and 1 in 36 pts (61.0%); 29 pts (48.2%) had EGA localized in the esophagogastric junction and 30 in the stomach (51.8%). all pts had received prior platin/ 5-FU based chemotherapy, 40pts (67.8%) had prior taxanes. Central post-hoc biomarker analysis (56 pts) showed PD-1 ligand 1 (PD-L1) combined positive score of 5 or greater in 24 pts (42.9%). The observed overall survival (OS) rate at 6 mo was 71% (95% CI 61-84%) and at 12 mo 43% (95% CI 32-58%). The median OS (ITT) was 10.6 mo (95% CI 8.4-12.8); 9.4 mo (95% CI 7.2-11.7) in pts with PD-L1 CPS < 5 and 14.0 mo (95% CI 6.0-22.1; p = 0.25) in those with PD-L1 CPS≥5. Treatment was generally well tolerated without unexpected toxicities. Translational research identified subgroups with a longer survival possibly due to a higher treatment benefit. Pts with higher than median T cell repertoire (TRB) richness showed an elevated median OS of 20.4 mo compared to pts with lower than median TRB richness (med OS 8.3 mo; HR 0.43, 95% CI 0.23-0.81; p = 0.0079). Pts with lower than median cfDNA burden had a median OS of 19.2 mo compared to pts with higher than median cfDNA (med OS 7.3 mo; HR 0.30, 95% CI 0.16-0.59; p = 0.00022). Conclusions: In this multicenter clinical trial, ramucirumab and paclitaxel combined with avelumab showed favorable efficacy and tolerability in the second line treatment of pts with metastatic EGA. PD-L1 CPS≥ 5, cfDNA below the median or T cell richness above the median seem to predict for even better outcomes with median OS hardly seen before in the second line setting. Clinical trial information: NCT03966118.