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Background: While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. Methods: The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next‐generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. Results: Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109; 95% CI, 0∼Inf; P =.002). No significant correlations were found between clinical outcome and inflammation‐related indicators. NGS profiling of the available tumor tissues, revealed largely non‐overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06‐1.21; P =.067), ERBB2 (HR = 0.15; 95% CI, 0.02‐1.19; P =.04), or PKHD1 (HR < 0.01; 95% CI, 0‐Inf; P =.04) showed strong association with increased progression‐free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK‐RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02‐0.63; P =.003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P =.032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7‐88.5; P <.001; 9p Del; HR = 4.88 × 109; 95% CI, 0‐Inf; P <.001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05‐1.17; P =.057). Conclusion: Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification. [ABSTRACT FROM AUTHOR]