Background: Overall survival of patients with advanced and refractory esophageal squamous cell carcinoma (ESCC) is poor. Most patients are 65 years or older, present with advanced and metastatic disease and suffer from extensive co-morbidity and decreased functionality. While approved therapies beyond first-line therapy have not been available for decades, just recently treatment with PD-1 antibodies has shown to improve progression-free and overall survival in this patient cohort. Thus, we assessed the combination of nivolumab and ipilimumab in this vulnerable and older patient population. Methods: In this multi-center, open-label phase II trial older patients with ESCC with progression or recurrence of disease following first-line therapy were treated with nivolumab and ipilimumab. Patients had to pass a brief geriatric assessment using the G8 screening tool in combination with the Deficit Accumulation Frailty Index (DAFI). A safety run–in phase was initiated with nivolumab (240mg fixed dose Q2W). Following a safety assessment, patients then went on to receive the combination therapy of nivolumab/ipilimumab (nivolumab 240 mg fixed dose Q2W; ipilimumab 1 mg/kg Q6W), in case safety was critical patients were allowed to continue with nivolumab monotherapy. The primary outcome was overall survival. Progression-free survival, quality of life and adverse events were also assessed. Results: In total 66 evaluable patients (16 female, 50 male) with ESCC were enrolled in this trial after successful geriatric assessment, median age was 70.5 years (range 55-84 years). 44 patients were treated with the combination therapy of nivolumab and ipilimumab, 22 patients with nivolumab only. The primary endpoint was met with a median OS of 7.2 months (95% CI, 5.7 to 12.4 months) (p < 0.006; versus historical control treated with standard chemotherapy). Median PFS was 2.7 months (95% CI, 2.5 to 2.9 months). ORR was 18.2% (95% CI, 9.8 to 29.6), all cases were partial responses. Grade 3 or more treatment related adverse events were observed in ̃25% of patients. Conclusions: The combination therapy of nivolumab and ipilimumab demonstrates improved overall survival and sustained confirmed responses in the second line therapy of older European patients with ESCC. Geriatric assessment is feasible in the setting of a prospective immune therapy trial. Overall, the RAMONA trial confirmed efficacy and safety of combination checkpoint inhibitor therapy in G8 prescreened older patients with ESCC in Europe beyond first line therapy. Clinical trial information: NCT03416244.