Treatment of Unresectable or Metastatic Extrahepatic Cholangiocarcinoma with a Targetable Molecular Alteration

This protocol applies to patients with unresectable or metastatic extrahepatic cholangiocarcinoma (eCCA) in whom molecular profiling has identified an actionable molecular alteration.

Clinical Scenario

Molecular profiling of unresectable or metastatic eCCA is strongly recommended and may reveal a range of actionable alterations — including FGFR2 fusion/rearrangement, IDH1 R132 mutation, BRAF^V600E mutation, HER2/ERBB2 positivity, NTRK gene fusion, or RET fusion. Identification of any such alteration defines a distinct precision-oncology treatment opportunity in this setting.

Treatment Approach (partial overview)

When molecular profiling confirms a targetable alteration, precision oncology — using a regulatory-approved targeted agent matched to that specific molecular finding — is the established approach. Multiple distinct approvals are in place across the different alteration types encountered in this population; the complete agent-selection algorithm is in the full protocol.

Instant Access to Structured Evidence-Based Regimens

References

DOI: 10.1016/j.jhep.2025.03.007

Gemcitabine and cisplatin in combination with either durvalumab or pembrolizumab should be considered standard of care for the first-line systemic treatment of patients with unresectable or metastatic eCCA (LoE 2, strong recommendation, consensus).
Patients with unresectable or metastatic eCCA should receive molecular profiling to identify and therapeutically address actionable alterations and to support inclusion into clinical trials (LoE 2, strong recommendation, strong consensus).
Currently, FDA and EMA approvals exist for futibatinib and pemigatinib in patients with FGFR2 fusion/rearrangements, and, based on phase III data, for ivosidenib in IDH1 R132 mutant biliary tract cancer.
A tumour-agnostic FDA approval exists for the combination of dabrafenib and trametinib in patients with solid tumours harbouring a BRAF^V600E mutation, and who have progressed following prior treatment.
For HER2 positive (IHC 3+) biliary cancers, the bispecific antibody zanidatamab has received FDA approval for patients with previously treated, unresectable or metastatic disease.
Further, the antibody-drug conjugate trastuzumab-deruxtecan was granted tumour-agnostic FDA approval in adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment.
Entity-independent EMA and FDA approvals exist for NTRK-fusion positive tumours (entrectinib and larotrectinib).
Repotrectinib has been approved by the FDA and EMA for tyrosine kinase inhibitor-naïve and -pretreated solid tumours harbouring NTRK gene fusions, and a positive CHMP opinion (EMA) was issued in November 2024 for this indication.
In patients with advanced RET fusion-positive solid tumours, selpercatinib was approved by the FDA and EMA.

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