Immune checkpoint inhibitors in advanced cholangiocarcinoma: a systematic review of efficacy, safety, and emerging biomarkers.

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy often diagnosed at an advanced stage. For over a decade, gemcitabine-cisplatin (GemCis) remained the standard of care with limited survival benefit. The advent of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape, but variability in outcomes and a rapidly expanding evidence base require systematic synthesis. A systematic review was conducted following PRISMA 2020 guidelines. The review was not registered in PROSPERO or another prospective registry. PubMed/MEDLINE and Embase were searched from inception through 31 December 2024. Studies evaluating PD-1/PD-L1/CTLA-4 inhibitors alone or in combination for advanced CCA were included. Risk of bias was assessed using ROBINS-I for non-randomized studies and Cochrane RoB 2 for randomized controlled trials. A narrative synthesis was performed due to clinical and methodological heterogeneity. Fifty-one studies (≈ 4,800 patients) met inclusion criteria, including 8 randomized controlled trials and 43 non-randomized studies. First-line chemo-immunotherapy with durvalumab or pembrolizumab plus GemCis established new standards of care in TOPAZ-1 (mOS 12.9 vs. 11.3 months; HR 0.76) and KEYNOTE-966 (mOS 12.7 vs. 10.9 months; HR 0.83). Triplet regimens (chemotherapy + ICI + tyrosine kinase inhibitor [TKI]) demonstrated high activity (e.g., toripalimab + lenvatinib + GEMOX: ORR 80%, mOS 22.5 months). Second-line ICI monotherapy yielded modest ORRs (3-22%), while ICI + TKI combinations showed ORRs of 9-28%. Grade ≥ 3 treatment-related adverse events ranged from 10 to 17% (ICI monotherapy) to 70-75% (chemo-ICI). PD-L1 expression was not predictive in chemo-ICI; homologous recombination deficiency (HRD)/DNA damage response (DDR) mutations and circulating tumor DNA (ctDNA) clearance emerged as promising biomarkers. ICIs combined with chemotherapy have redefined first-line treatment for advanced CCA. Triplet and locoregional combinations show encouraging efficacy, warranting further validation. Biomarker-driven selection, particularly HRD/DDR status and ctDNA monitoring, will be critical to optimizing outcomes.