Advanced cholangiocarcinoma in 2025: Therapeutic sequencing and global implementation

Area of Science:

• Oncology
• Genomics
• Clinical Trials

Background:

• Cholangiocarcinoma (CCA) is an aggressive biliary tract cancer with poor prognosis.
• Standard first-line chemotherapy (gemcitabine plus cisplatin) offers limited survival benefits.
• Actionable genomic alterations are common in intrahepatic CCA, supporting genotype-directed therapies.

Purpose of the Study:

• To review contemporary evidence for first-line treatment of advanced cholangiocarcinoma.
• To evaluate the efficacy of chemotherapy, targeted therapy, and immunotherapy.
• To synthesize findings from randomized trials, large cohorts, and phase 2 studies.

Main Methods:

• Systematic literature search of PubMed, Embase, Cochrane, and ClinicalTrials.gov (2010-2025).
• Inclusion of randomized trials, large prospective cohorts, and pivotal phase 2 studies.
• Qualitative evidence synthesis using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

Main Results:

• Gemcitabine plus cisplatin with durvalumab improved overall survival (12.9 vs. 11.3 months) without increased toxicity.
• Fibroblast growth factor receptor inhibitors showed response rates of 35%-42% in biomarker-selected populations.
• Ivosidenib improved progression-free survival in IDH1-mutant CCA (2.7 vs. 1.4 months).
• Other targeted therapies and immunotherapies demonstrated clinically meaningful activity.
• Network meta-analysis indicated genotype-matched therapy reduced progression risk (HR, 0.44).

Conclusions:

• Chemoimmunotherapy is the reference first-line regimen for advanced cholangiocarcinoma.
• Early comprehensive genomic profiling is essential for timely, matched targeted therapy.
• Genomic profiling maximizes population-level benefit in cholangiocarcinoma treatment.