What is the role of immunotherapy in treating advanced cholangiocarcinoma?

Immunotherapy in Advanced Cholangiocarcinoma

Gemcitabine and cisplatin combined with either durvalumab or pembrolizumab should be the standard first-line treatment for patients with unresectable or metastatic cholangiocarcinoma who have good performance status (ECOG 0-1). 1

First-Line Treatment Algorithm

Standard Regimen for All Subtypes

• Add durvalumab to cisplatin-gemcitabine as the preferred immunotherapy combination, based on the TOPAZ-1 trial demonstrating superior overall survival (12.9 vs 11.3 months, HR 0.76) with FDA and EMA approval 1
• For extrahepatic cholangiocarcinoma specifically, durvalumab shows particularly strong benefit with HR 0.61 (95% CI 0.41-0.91) 1
• Pembrolizumab plus cisplatin-gemcitabine is an acceptable alternative based on KEYNOTE-966 trial (HR 0.83 for overall survival), also FDA/EMA approved 1, 2

Critical Distinction by Anatomic Subtype

• Intrahepatic cholangiocarcinoma: Pembrolizumab combination shows stronger benefit (HR 0.76) 1
• Extrahepatic cholangiocarcinoma: Durvalumab combination demonstrates superior efficacy (HR 0.61), whereas pembrolizumab showed no clear benefit (HR 0.99) in subgroup analysis 1

When Cisplatin-Gemcitabine is Contraindicated

• Use CAPOX (capecitabine-oxaliplatin) or GEMOX (gemcitabine-oxaliplatin) regimens 1
• Gemcitabine monotherapy for ECOG 2 patients 1
• Do not add immunotherapy to these alternative backbones as efficacy data only supports cisplatin-gemcitabine combinations 1

Second-Line Immunotherapy Considerations

Molecular Testing is Mandatory

• Prioritize targeted therapies over immunotherapy for actionable alterations (FGFR2 fusions, IDH1 mutations, HER2 amplification, BRAF V600E, NTRK fusions) 1
• FOLFOX remains the standard second-line chemotherapy in absence of targetable alterations 1

Specific Immunotherapy Indications in Second-Line

• Immune checkpoint blockade for dMMR/MSI-H tumors who have not received durvalumab in first-line 1
• MSI-high cholangiocarcinoma responds to anti-PD-1 antibodies 1
• Sequential dual-agent immunotherapy (ipilimumab plus nivolumab) can produce durable responses after progression on single-agent pembrolizumab, even without MSI-H or high tumor mutation burden 3

Critical Pitfalls to Avoid

Bevacizumab Safety Requirements

• Mandatory esophagogastroduodenoscopy before initiating bevacizumab to screen for esophageal varices 1
• Contraindicated in grade 2 or higher varices until treated, due to bleeding risk 1
• This applies to any anti-VEGF therapy combinations being considered 1

Performance Status Thresholds

• ECOG 0-1 required for immunotherapy-chemotherapy combinations 1
• ECOG 2 patients should receive gemcitabine monotherapy only 1
• ECOG 3-4 patients receive supportive care only 1

Hepatic Function Requirements

• Child-Pugh A liver function required for immunotherapy combinations 2
• Patients with hepatic encephalopathy, clinically apparent ascites, or recent variceal bleeding are ineligible 2
• Hepatitis B patients must have controlled disease (viral load <2000 IU/mL) 2

Autoimmune Disease Exclusions

• Patients with autoimmune disease requiring systemic therapy within 2 years are ineligible for checkpoint inhibitors 2
• Medical conditions requiring immunosuppression are contraindications 2

Treatment Duration and Monitoring

Immunotherapy Duration

• Continue pembrolizumab for maximum 35 cycles (approximately 24 months) 2
• Durvalumab treatment continues until disease progression or unacceptable toxicity 1
• Chemotherapy backbone: Gemcitabine can continue beyond 8 cycles, but cisplatin maximum 8 cycles 2

Assessment Schedule

• Tumor status assessment every 6 weeks through 54 weeks, then every 12 weeks thereafter 2
• Treatment may continue beyond RECIST-defined progression if clinically stable and deriving benefit 2

Emerging Evidence and Future Directions

Combination Strategies Under Investigation

• SBRT combined with immunotherapy demonstrates acceptable safety profiles and may enhance systemic response 4
• Consider adding SBRT to oligometastatic sites during first-line immunotherapy-chemotherapy for limited disease burden 4
• Immunotherapy combined with locoregional therapies (TACE, TARE) shows promise but remains investigational 5

Limitations of Current Immunotherapy

• Immunotherapy monotherapy is less effective in cholangiocarcinoma compared to other solid tumors due to the immunosuppressive and desmoplastic tumor microenvironment 6, 7
• The inflammatory microenvironment and exuberant desmoplastic reaction contribute to treatment resistance 6
• This explains why combination approaches (immunotherapy plus chemotherapy) outperform monotherapy 1