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Background The global Phase 3 study RATIONALE 302 (NCT03430843) evaluated the efficacy and safety of second-line tislelizumab, an anti-PD-1 antibody, in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC). Here, we report data from the overall and Europe/North America (EU/NA) populations. Methods Eligible adult patients had disease progression during or after first-line systemic therapy, ≥1 evaluable lesion per RECIST v1.1 and an Eastern Cooperative Oncology Group performance score (ECOG PS) of ≤1. Patients were randomized (1:1) to receive tislelizumab 200 mg intravenously Q3W or investigator-chosen chemotherapy (paclitaxel, docetaxel, or irinotecan) and treated until disease progression, intolerable toxicity, or withdrawal. Stratification factors included chemotherapy option, region, and ECOG PS. The primary endpoint was overall survival (OS) in all patients (ITT population). The key secondary endpoint was OS in PD-L1 positive (vCPS ≥10%) patients; other secondary endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), health-related quality of life and safety. Results 512 patients (overall population) were randomized to tislelizumab (n=256) or chemotherapy (n=256), of which 108 (21%) patients were enrolled into EU/NA subgroup (n=55 tislelizumab, n=53 chemotherapy). On 1 December 2020 (data cut-off), median follow-up was 6.9 and 6.8 months in the overall population and EU/NA subgroup, respectively. Tislelizumab improved OS vs chemotherapy in the overall population (median OS 8.6 vs 6.3 months; HR 0.70, 95% CI 0.57–0.85; p=0.0001); survival benefit was consistently observed in the EU/NA subgroup (median OS 11.2 vs 6.3 months; HR 0.55; 95% CI 0.35–0.87). Treatment with tislelizumab was associated with improved ORR (20.3% [95% CI 15.6%–25.8%] vs 9.8% [95% CI 6.4%–14.1%]) and median DoR (7.1 vs 4.0 months; HR 0.42, 95% CI 0.23–0.75) vs chemotherapy in the overall population. Improvement in