Gemcitabine-cisplatin plus durvalumab in advanced intrahepatic cholangiocarcinoma: effectiveness outcomes and characterization of the tumor microenvironment.

[BACKGROUND/AIMS] Most patients with intrahepatic cholangiocarcinoma (ICC) present with advanced, unresectable disease. Although gemcitabine-cisplatin (GC) plus durvalumab improves outcomes, its real-world potential for conversion to curative resection and the associated tumor microenvironment (TME) changes remain unclear.

[METHODS] In this prospective single-center study, 66 patients with advanced, initially unresectable ICC, were enrolled; 55 patients were evaluable. Patients received GC plus durvalumab. The primary endpoints were overall survival (OS), conversion success rate, and R0 resection rate. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Tumor response was assessed per RECIST v1.1. Landmark analyses evaluated OS by early objective response (CR/PR vs SD/PD at first assessment) and conversion surgery status. RNA sequencing and immunofluorescence were performed to explore molecular correlates of response.

[RESULTS] Among 66 enrolled patients, 46 (69.7%) had locally advanced and 20 (30.3%) had metastatic disease at baseline. Median OS was 13.0 months (95% CI, 9.97-15.8) and median PFS was 9.33 months (95% CI, 7.47-13.53). ORR and DCR were 27.3% and 65.2%, respectively. Ten patients (15.2%) achieved R0 resection after meeting predefined criteria for conversion surgery. Early CR/PR was associated with significantly longer OS, and, among the 18 patients who became eligible for surgery, those who underwent R0 resection had numerically longer OS than surgery-eligible patients who continued systemic therapy alone. Transcriptomics identified 135 DEGs between responders and non-responders, enriched in immune-regulatory and mesenchymal pathways. Immunofluorescence confirmed increased PD-L1 expression and CD8⁺ T-cell infiltration with reduced α-SMA after treatment.

[CONCLUSION] GC plus durvalumab showed encouraging efficacy with acceptable safety in advanced ICC and enabled R0 resection in a subset of patients. Immune activation and stromal remodeling may underlie treatment sensitivity, supporting TME-informed precision conversion strategies that warrant validation in larger multicenter cohorts.

[HIGHLIGHTS] This is the first prospective single-center study to evaluate gemcitabine-cisplatin (GC) plus durvalumab for conversion therapy in advanced intrahepatic cholangiocarcinoma (ICC), providing real-world evidence for resectability improvement. GC plus durvalumab achieved a median OS of 13.0 months and a 15.2% R0 resection rate, outperforming historical GC monotherapy and aligning with TOPAZ-1 outcomes in ICC-specific populations, while landmark analyses showed that early radiologic response and conversion surgery were both associated with superior overall survival. Transcriptomic and immunofluorescence analyses identified TME remodeling (↑CD8⁺T cells, ↓α-SMA) and γδT cell infiltration as potential mechanisms of response, offering novel biomarkers for precision conversion therapy. The regimen showed favorable safety with no treatment-related deaths, supporting its feasibility in advanced ICC patients eligible for curative-intent surgery.