Overview of Biliary Tract Cancer Treatment
Biliary tract cancers include cholangiocarcinoma (intrahepatic and extrahepatic) and gallbladder cancer. These rare malignancies have poor prognosis, but recent advances in molecular profiling have identified actionable targets. FGFR2 fusions/rearrangements occur in 10-15% of intrahepatic cholangiocarcinoma, and IDH1 mutations in 10-20%. Gemcitabine plus cisplatin remains standard first-line chemotherapy, with targeted therapies and immunotherapy for biomarker-selected patients.
Treatment Approach by Molecular Profile
- FGFR2 Fusions/Rearrangements (10-15%): Pemigatinib, infigratinib, or futibatinib - highly effective targeted therapy
- IDH1 Mutations (10-20%): Ivosidenib - oral targeted therapy with durable responses
- MSI-H/dMMR (rare): Pembrolizumab - high response rates in this subgroup
- BRAF V600E Mutations (5%): Dabrafenib + trametinib combination
- Unselected/Wild-type: Gemcitabine + cisplatin first-line, FOLFOX or other chemotherapy second-line
Epidemiology & Impact
Biliary tract cancers (BTCs) encompass cholangiocarcinoma (intrahepatic and extrahepatic) and gallbladder carcinoma, collectively affecting approximately 12,000 people annually in the United States. While rare in Western countries, BTCs are much more common in Southeast Asia, where liver fluke infections (Opisthorchis viverrini and Clonorchis sinensis) are endemic risk factors. Incidence of intrahepatic cholangiocarcinoma has been rising steadily worldwide over the past three decades, increasing nearly 140% in the United States, while extrahepatic cholangiocarcinoma incidence has remained stable or declined. Risk factors vary by anatomic subtype but include primary sclerosing cholangitis, hepatolithiasis, Caroli disease, biliary cysts, chronic hepatitis B or C infection, cirrhosis, obesity, and diabetes. The prognosis remains poor, with overall 5-year survival rates of 5-15% for cholangiocarcinoma and 5-19% for gallbladder carcinoma, primarily because most patients present with unresectable or metastatic disease.
Molecular Biology & Biomarkers
BTC represents a molecularly diverse group of cancers with clinically actionable genomic alterations in approximately 40-50% of cases. Intrahepatic cholangiocarcinoma is particularly enriched for targetable alterations: FGFR2 fusions or rearrangements occur in 10-16% of cases and are the target of pemigatinib, futibatinib, and erdafitinib; IDH1 mutations are found in 10-20% and are targeted by ivosidenib; and HER2 amplification occurs in 5-15% of gallbladder carcinomas and extrahepatic cholangiocarcinomas. BRAF V600E mutations occur in approximately 5% of intrahepatic cholangiocarcinomas. Microsatellite instability (MSI-high) is found in 2-3% of BTCs and predicts response to checkpoint immunotherapy. The TOPAZ-1 trial established PD-L1 expression as a relevant biomarker, as the combination of durvalumab with gemcitabine-cisplatin improved survival across biomarker-unselected populations. Comprehensive genomic profiling is now recommended at diagnosis given the high frequency of actionable targets in this disease.
Evolving Treatment Landscape
Gemcitabine plus cisplatin has been the standard first-line chemotherapy for advanced BTC since the ABC-02 trial in 2010. The TOPAZ-1 trial marked a paradigm shift by demonstrating that adding durvalumab (an anti-PD-L1 antibody) to gemcitabine-cisplatin significantly improved overall survival, establishing this triplet as the new first-line standard of care. In the second-line setting, the FOENIX-CCA2 trial led to FDA approval of futibatinib for FGFR2 fusion-positive intrahepatic cholangiocarcinoma, joining pemigatinib as an approved targeted option. The ClarIDHy trial demonstrated that ivosidenib improves progression-free survival in IDH1-mutated cholangiocarcinoma versus placebo. For HER2-amplified tumors, zanidatamab and trastuzumab deruxtecan have shown promising activity. The rapidly expanding portfolio of targeted options has made molecular profiling at diagnosis essential for optimizing treatment sequencing in BTC.