What is the median survival for metastatic cholangiocarcinoma and what are the recommended first‑line (gemcitabine plus cisplatin with or without durvalumab) and subsequent treatment options, including targeted therapies for FGFR2 fusions or IDH1 mutations?

Survival of Metastatic Cholangiocarcinoma

For metastatic cholangiocarcinoma, median survival is approximately 12.9 months with first-line gemcitabine-cisplatin-durvalumab, compared to 3.9 months without treatment. 1, 2

Median Survival by Treatment Status

Untreated Disease

• Without any intervention, median survival is approximately 3.9 months 2, 3
• This represents the natural history of metastatic disease and underscores the aggressive biology of cholangiocarcinoma 2

First-Line Systemic Therapy

• Gemcitabine plus cisplatin plus durvalumab: 12.9 months median overall survival (HR 0.76,95% CI 0.64-0.91) 1
• Gemcitabine plus cisplatin plus pembrolizumab: HR 0.83 (95% CI 0.72-0.95) for overall survival, though benefit less pronounced in extrahepatic cholangiocarcinoma subgroup 1
• Historical gemcitabine plus cisplatin alone (without immunotherapy): 11.3 months median survival 1
• Gemcitabine monotherapy: 6-8 months median survival 1

The addition of immune checkpoint inhibitors (durvalumab or pembrolizumab) to gemcitabine-cisplatin is now standard of care and provides a statistically significant 1.6-month survival improvement. 1

Second-Line and Beyond

• With palliative chemotherapy after first-line progression: 6-11.7 months median survival 2, 3
• FOLFOX (5-FU/folinic acid-oxaliplatin) in second-line: modest survival benefit, validated by phase III data 1, 4
• Targeted therapies for specific mutations (see below) offer additional options for fit patients after first-line treatment 4, 5

First-Line Treatment Recommendations

Gemcitabine and cisplatin combined with either durvalumab or pembrolizumab should be administered as first-line therapy for all patients with metastatic cholangiocarcinoma who have ECOG performance status 0-2. 1, 2

Key Evidence

• The TOPAZ-1 trial demonstrated durvalumab added to gemcitabine-cisplatin improved median OS from 11.3 to 12.9 months 1
• This regimen is FDA and EMA approved for advanced biliary tract cancers 1
• The Keynote-966 trial showed similar benefit with pembrolizumab, though less pronounced in extrahepatic cholangiocarcinoma subgroups 1

Critical Pitfall

• Patients must have adequate performance status (ECOG 0-2) to tolerate this regimen 2
• Those with ECOG ≥2 despite adequate biliary drainage and treatment of sepsis should be considered for palliative care only 1

Subsequent Treatment Options After First-Line Progression

For Patients Without Targetable Alterations

FOLFOX (5-FU/folinic acid-oxaliplatin) should be offered as second-line therapy for patients with disease progression on first-line treatment. 1

• This is the only second-line regimen validated by phase III trial data 1, 4
• Alternative irinotecan-based options (5-FU with nanoliposomal-irinotecan) may be considered based on phase II data 1, 4

For Patients With Targetable Molecular Alterations

Systematic molecular profiling should be performed on all patients with advanced cholangiocarcinoma to identify actionable mutations, as targeted therapies provide superior outcomes compared to standard chemotherapy in molecularly selected populations. 4, 5, 6

FGFR2 Fusions or Rearrangements

• Pemigatinib, infigratinib, or futibatinib are FDA-approved FGFR2 inhibitors for previously treated locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements 5
• These agents have demonstrated objective response rates and progression-free survival benefits in this molecularly defined subset 5, 6

IDH1 Mutations

• Ivosidenib is FDA-approved for IDH1-mutant cholangiocarcinoma that has progressed on first-line chemotherapy 7, 5
• Provides median OS benefit with excellent tolerability profile 7
• Represents an excellent option given its favorable toxicity profile compared to cytotoxic chemotherapy 7

Other Targetable Alterations

• BRAF V600E mutations: BRAF inhibitors (with or without MEK inhibitors) 4, 5, 6
• HER2 (ERBB2) amplifications: HER2-directed therapies 4, 5, 6
• NTRK fusions: TRK inhibitors 5, 6
• Microsatellite instability-high (MSI-H) tumors: immune checkpoint inhibitors 4

Timing of Molecular Testing

• Molecular profiling should be performed at diagnosis or early in the disease course, not delayed until after first-line failure 4, 6
• This allows for treatment planning and ensures patients can access targeted therapies when appropriate 4
• Intrahepatic cholangiocarcinoma has the highest frequency of actionable alterations (FGFR2 fusions in 10-15%, IDH1 mutations in 10-20%) 4, 6

Critical Prognostic Factors Affecting Survival

Most Important Negative Predictors

• Lymph node involvement: Present in 50% at presentation, reduces 5-year survival to <20% 2, 3
• R1 resection status (positive margins): Associated with poor overall and recurrence-free survival 1
• Poor performance status: ECOG ≥2 predicts inability to tolerate systemic therapy 1, 2
• Peritoneal or distant metastases: Present in 10-20% at presentation 1, 3

Factors Affecting Treatment Tolerance

• Inadequate biliary drainage increases risk of sepsis and worsens outcomes 1, 3
• Recurrent cholangitis and liver failure are major causes of mortality 8
• Adequate drainage with metal stents improves survival compared to no drainage 3

Emerging Treatment Paradigms

The field is shifting toward combination strategies integrating immunotherapy, cytotoxic chemotherapy, and targeted therapies administered concomitantly to harness potential synergies. 6

• Multiple ongoing trials are evaluating targeted therapies in first-line settings combined with chemotherapy 7, 6
• Questions remain regarding optimal sequencing of targeted therapies and benefits of combining them with immunotherapy or locoregional therapies 7, 6
• The integration of these modalities represents a paradigm shift beyond sequential monotherapy approaches 6

Common Pitfalls to Avoid

• Do not delay molecular profiling until after first-line failure - test at diagnosis to enable treatment planning 4, 6
• Do not offer aggressive systemic therapy to patients with ECOG ≥2 without first optimizing biliary drainage and treating sepsis 1
• Do not assume all cholangiocarcinomas behave identically - intrahepatic disease has higher rates of actionable mutations than extrahepatic disease 4, 6
• Do not continue ineffective first-line therapy - transition to second-line FOLFOX or targeted therapy (if mutation present) at progression 1