Efficacy and safety of immune checkpoint inhibitors in patients with high microsatellite instability/mismatch repair-deficient advanced cholangiocarcinoma: A propensity score-matched study.

[BACKGROUND & AIMS] Microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cholangiocarcinoma (CCA) represents a rare molecular subtype with potential sensitivity to immune checkpoint inhibitors (ICIs). However, real-world evidence regarding the efficacy and safety of ICIs in MSI-H/dMMR CCA remains limited.

[METHODS] We conducted a single-center, retrospective real-world study of patients with advanced CCA treated with ICI-based regimens. MSI-H/dMMR status was determined by next-generation sequencing and/or immunohistochemistry. A contemporaneous microsatellite-stable (MSS) cohort was included as a control group. Propensity score matching (PSM) was performed to balance baseline characteristics. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate, disease control rate, and safety.

[RESULTS] Among 331 patients, 23 (6.9%) were identified as MSI-H/dMMR. After 1:3 PSM, 23 MSI-H/dMMR patients were matched with 69 MSS/preserved MMR (pMMR) patients, achieving well-balanced baseline characteristics. MSI-H/dMMR patients demonstrated significantly prolonged survival compared with MSS/pMMR patients. Median PFS was 64.1 months vs. 7.2 months, and median OS was 70.5 months vs. 14.0 months, respectively (both p <0.001). MSI-H/dMMR status remained the strongest independent prognostic factor for both OS and PFS in multivariable Cox analyses. Objective response rate and disease control rate were significantly higher in MSI-H patients than in matched MSS/pMMR patients. Subgroup analyses showed consistent survival benefits of MSI-H/dMMR across tumor subtype, PD-L1 expression, and CA19-9 strata. Genomic profiling revealed frequent alterations in ARID1A, PBRM1, and KMT2D among MSI-H/dMMR tumors. ICI-based therapy was generally well tolerated; grade 3-4 adverse events occurred predominantly in chemotherapy-containing regimens.

[CONCLUSIONS] In this real-world PSM study, MSI-H/dMMR CCA was associated with markedly improved survival and durable clinical benefit from ICI-based therapy, with a manageable safety profile. These findings support MSI-H/dMMR as a key actionable biomarker and underscore the importance of routine MSI testing in CCA.

[IMPACT AND IMPLICATIONS] This study addresses a critical knowledge gap regarding the clinical benefit of immune checkpoint inhibitors in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cholangiocarcinoma, a rare but biologically distinct subtype characterized by heightened immunogenicity. Our findings demonstrate that MSI-H/dMMR status is a strong and consistent predictor of durable survival across diverse clinical contexts, providing valuable evidence for clinicians, researchers, and stakeholders involved in the management of biliary tract cancers. These results support routine MSI-H/dMMR testing and personalized immunotherapy strategies in clinical practice, while also offering a framework for future translational research and policy decisions aimed at improving access to molecular profiling and precision oncology approaches.