Background: Advanced esophageal squamous cell cancer (ESCC) is frequently diagnosed in elderly patients (pts) with additional comorbidities. Limited treatment options are available. We report the safety interim analysis of a phase II clinical trial evaluating nivolumab and ipilimumab as second-line therapy for advanced ESCC in elderly pts. Methods: RAMONA is a multicenter open-label phase II trial assessing nivolumab/ipilimumab combination therapy in elderly pts (≥65 years). The geriatric status of the pts was assessed using the G8 screening tool and the Deficit Accumulation Frailty Index (DAFI). After a run-in phase of 3 cycles nivolumab (240mg Q2W), cohort assignment was based on a safety assessment. Pts with toxicities grade ≤2 were considered eligible for escalation to nivolumab (240mg Q2W)/ipilimumab (1mg/kg Q6W) combination therapy (cohort B). Other pts remained on nivolumab monotherapy (cohort A). Primary endpoint is overall survival (OS). Key secondary endpoint is time to Quality of Life deterioration defined as a loss of ≥ 10 points in the EORTC QLQ-C30 compared to baseline. Adverse events were assessed according to NCI-CTCAE version 4.03. Results: From February 2018 until February 2020, 69 pts entered the study. 61 pts were eligible for safety interim analysis. Median age of the pts was 71.9 yrs (± 5.4), median KPS score was 80% (50-100%). In 73.8% of the pts, metastases were detected at the time of study inclusion. Most pts received the IO therapy in ≥ 2^nd line (91.8%). The mean G8-score at screening was 11.9 points (46 pts ≤ 14 points, 75.4%) (mean DAFI: 0.19). Based on safety assessment, 42 pts were escalated to nivolumab/ipilimumab, while 9 pts remained on nivolumab monotherapy. 10 pts were not allocated at the time of analysis. Median numbers of cumulative doses were 3.0 [1.0 - 3.0] for the run-in phase (nivolumab), 6.0 [1.0 – 48.0] for nivolumab therapy (cohort A/B) and 2.5 [1.0 – 16.0] for ipilimumab (cohort B). Median treatment duration was 144.5 days (56-781 days) in cohort A and 231 days (85-484 days) in cohort B. Frailty indices remained stable after 3 cycles of nivolumab with limited toxicity at the time of the safety assessment. Drug-related treatment emergent adverse events (AEs) were observed in 42 pts (68.9%); 29/42 in cohort A, 8/9 in cohort B, and 5/10 pts not allocated at the time of analysis. Grade ≥3 AEs were detected in 9 pts of 42 in cohort A and 4 of 9 pts in cohort B. Drug-related treatment emergent serious adverse events (SAEs) were detected in 12 pts (19.7%); 8/42 in cohort A, 2/9 pts in cohort B, and 2/10 pts not yet allocated. Conclusions: Combined nivolumab/ipilimumab is a safe and feasible second-line therapy for elderly pts with advanced ESCC. Most pts could be escalated to nivolumab/ipilimumab. Treatment duration was exceptional long for a subset of pts. Clinical trial information: NCT03416244