What are the treatment options for HER2-negative stage 4 cholangiocarcinoma, including chemotherapy, immunotherapy, and targeted therapy?

Treatment of HER2-Negative Stage 4 Cholangiocarcinoma

For HER2-negative stage 4 cholangiocarcinoma, start cisplatin-gemcitabine plus durvalumab or pembrolizumab as first-line therapy, immediately obtain comprehensive molecular profiling for actionable mutations (FGFR2, IDH1, BRAF, NTRK, RET, KRAS), and use mutation-directed targeted therapy when available before proceeding to second-line FOLFOX. 1, 2

First-Line Treatment Algorithm

Standard Chemotherapy-Immunotherapy Backbone

• Initiate cisplatin-gemcitabine plus durvalumab or pembrolizumab for all patients with ECOG performance status 0-1, which extends median survival to 10-13 months compared to 3-4 months with best supportive care alone 1, 2
• This triplet regimen (chemotherapy plus immunotherapy) represents the current standard of care based on the most recent 2025 EASL guidelines 1
• For patients with contraindications to cisplatin (creatinine clearance <60 mL/min, cardiac disease), substitute with CAPOX (capecitabine-oxaliplatin) or GEMOX (gemcitabine-oxaliplatin) 2, 3

Critical Timing Consideration

• Start treatment early when patients are relatively stable rather than waiting for disease progression, as performance status at treatment initiation is the single most important prognostic factor 2, 3
• Optimize biliary drainage before chemotherapy initiation using metal stents for expected survival >6 months 2

Molecular Profiling Strategy

Immediate Testing Panel

• Order comprehensive molecular profiling immediately upon diagnosis to identify actionable mutations including: 1, 2
  • FGFR2 fusions/rearrangements
  • IDH1 R132 mutations
  • BRAFV600E mutations
  • HER2 amplification/overexpression (IHC 3+)
  • NTRK gene fusions
  • RET gene fusions
  • KRAS G12C mutations
  • MSI/MMR status

Important Caveat

• While these actionable mutations are relatively common in intrahepatic cholangiocarcinoma, FGFR2 fusions and IDH1 mutations occur only rarely in extrahepatic cholangiocarcinoma 1
• NTRK and RET fusions are generally infrequent across all cholangiocarcinoma subtypes 1

Targeted Therapy Options (When Mutations Present)

FDA-Approved Targeted Agents

• FGFR2 fusions/rearrangements: Pemigatinib or infigratinib 1
• IDH1 R132 mutations: Ivosidenib (based on phase III data) 1, 2
• BRAFV600E mutations: Dabrafenib plus trametinib (tumor-agnostic FDA approval for solid tumors with prior treatment) 1
• HER2 IHC 3+ positive: Zanidatamab (bispecific antibody, FDA-approved for previously treated disease) or trastuzumab-deruxtecan (antibody-drug conjugate, tumor-agnostic FDA approval) 1
• NTRK fusions: Entrectinib, larotrectinib, or repotrectinib 1
• RET fusions: Selpercatinib 1
• KRAS G12C mutations: Available through basket trials 1

Critical Decision Point

• Prioritize mutation-directed targeted therapy over standard second-line FOLFOX when actionable alterations are identified, as these agents show superior response rates in molecularly selected populations 2

Second-Line Treatment

Standard Approach

• FOLFOX (5-FU, leucovorin, oxaliplatin) is the established second-line standard for patients without actionable mutations or after progression on targeted therapy 1, 2
• Alternative second-line options include FOLFIRI or NalIRI+5FU 1
• Expected median survival benefit is less than 1 month with 5% response rate, but stable disease has value for quality of life 2

Treatment Duration and Monitoring

Chemotherapy Duration

• Continue chemotherapy for approximately 4-6 months or to maximal response, depending on toxicity and absence of progression 2
• When stopping chemotherapy, continue immunotherapy (durvalumab or pembrolizumab) until progression or unacceptable toxicity 1

Quality of Life Focus

Primary Treatment Goal

• Quality of life should be the primary treatment focus with survival as a secondary endpoint, as even stable disease translates to improved length and quality of life 2, 1
• This is particularly important given the difficulty in confirming objective radiological responses in perihilar disease 1, 2

Adjunctive Locoregional Therapies

Interventional Radiology Options

• Consider TACE (transarterial chemoembolization) or TARE (transarterial radioembolization) in combination with systemic treatment for intrahepatic disease 2
• These should complement, not replace, systemic therapy 2

What NOT to Do

Avoid These Approaches

• Do not use external beam radiotherapy for survival benefit in advanced disease—it has no proven survival benefit and significant toxicity; reserve only for palliative situations (painful metastases, bleeding) 1, 2
• Do not treat patients with ECOG performance status >2, as they show no survival benefit and increased toxicity 3
• Do not delay chemotherapy in eligible patients waiting for further disease progression 3, 4

Clinical Trial Participation

Strong Recommendation

• All patients with stage 4 cholangiocarcinoma should be actively encouraged to participate in clinical trials, as many promising newer agents and combinations (KRAS non-G12C alterations, FGFR2 amplifications, NRG1 fusions) are under investigation 1, 2, 1

Common Pitfalls to Avoid

• Do not proceed with chemotherapy before optimizing biliary drainage in jaundiced patients—this increases toxicity and reduces efficacy 2, 3
• Do not assume all cholangiocarcinomas have the same mutation profile—extrahepatic tumors have different molecular characteristics than intrahepatic tumors 1
• Do not wait for molecular profiling results before starting first-line chemotherapy-immunotherapy if the patient is symptomatic—start treatment and add targeted therapy later if actionable mutations are found 2
• Since this is HER2-negative disease, do not use HER2-targeted therapies (zanidatamab, trastuzumab-deruxtecan), but continue to screen for other actionable mutations 1