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Background/Aims <p>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.</p> Methods <p>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.</p> Results <p>Among 66 enrolled patients, 46 (69.7%) had locally advanced and 20 (30.3%) had metastatic disease at baseline. Median OS was 13.0&#xa0;months (95% CI, 9.97–15.8) and median PFS was 9.33&#xa0;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.</p> Conclusion <p>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.</p> Graphical abstract Highlights <p>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.</p> <p>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.</p> <p>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.</p> <p>The regimen showed favorable safety with no treatment-related deaths, supporting its feasibility in advanced ICC patients eligible for curative-intent surgery.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Jiawei Xu,
  • Yifan Ji,
  • Min Feng,
  • Zhiheng Zhang,
  • Decai Yu

摘要

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.

Graphical abstract 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.