Teaching pack: Biliary tract cancer (cholangiocarcinoma)

Biliary tract cancers comprise intrahepatic cholangiocarcinoma (iCCA, rising in incidence), perihilar and distal extrahepatic cholangiocarcinoma, and gallbladder cancer. They share late presentation (jaundice, weight loss) and dependence on surgical resection as the only cure, achievable in a minority, which keeps five-year survival under 20%. Risk factors differ by region: liver flukes and hepatolithiasis in East Asia, primary sclerosing cholangitis in the West, gallstones and chronic inflammation for gallbladder cancer. Biliary drainage is usually a prerequisite for any treatment.

The systemic landscape was gemcitabine-cisplatin alone from ABC-02 (2010) until TOPAZ-1 (durvalumab, 2022) and KEYNOTE-966 (pembrolizumab, 2023) added PD-(L)1 blockade with a modest median benefit but a doubling of two-year survival. Adjuvant capecitabine (BILCAP) is standard after resection. What sets biliary cancer apart is its genomic actionability: roughly 40% of intrahepatic tumours carry FGFR2 fusions (pemigatinib, futibatinib), IDH1 mutations (ivosidenib), HER2 amplification or overexpression (zanidatamab, trastuzumab deruxtecan), NRG1 fusions (zenocutuzumab, approved 2026), BRAF V600E, or MSI-high status, so molecular profiling at diagnosis is guideline-mandated.

• Genotype-directed therapy in ~40% of patients.
• Chemo-immunotherapy first line with a doubling of two-year survival (TOPAZ-1, KEYNOTE-966).
• Four biomarker-directed drug classes approved (FGFR2, IDH1, HER2, NRG1), plus tumour-agnostic BRAF, MSI-H and NTRK options: ~40% of intrahepatic tumours have an actionable alteration.
• Next-generation FGFR inhibitors targeting resistance mutations are in phase 3 (FIRST-308).
• Zanidatamab moving into first line for HER2-positive disease (HERIZON-BTC-302).
• Liver transplantation protocols extend curative options to selected unresectable perihilar tumours.

1. 1965Klatskin describes perihilar cholangiocarcinoma
2. 1993Mayo Clinic begins neoadjuvant chemoradiation and transplant for perihilar cholangiocarcinoma
3. 2010ABC-02: gemcitabine-cisplatin becomes standard
4. 2013FGFR2 fusions and IDH1 mutations characterised as drivers of intrahepatic cholangiocarcinoma
5. 2017BILCAP: adjuvant capecitabine adopted
6. 2020Pemigatinib: first FGFR2 inhibitor
7. 2020Pemigatinib: first targeted approval in biliary cancer
8. 2021Ivosidenib approved (ClarIDHy); infigratinib approved then withdrawn (2022)
9. 2022TOPAZ-1: immunotherapy first line
10. 2022TOPAZ-1: first immunotherapy approval; futibatinib approved

• Zenocutuzumab (treatment)
• SHR-8068 (treatment)
• TQB2102 (treatment)
• D07001 (treatment)
• TQB3454 (treatment)
• HMPL-453 (treatment)
• Tovecimig (treatment)
• XNW27011 (treatment)
• AZD4360 (treatment)
• CGT4859 (treatment)
• Spevatamig (treatment)
• VB15010 (treatment)

• KEYNOTE-966 (phase 3, n=1,069): Overall survival: 12.7 months vs 10.9 months, HR 0.83
• TOPAZ-1 (phase 3, n=685): Overall survival (updated): 12.9 months vs 11.3 months, HR 0.76
• ABC-02 (phase 3, n=410): Overall survival: 11.7 months vs 8.1 months, HR 0.64
• ASCOT (JCOG1202) (phase 3, n=440): 3-year overall survival: 77.1% vs 67.6%, HR 0.69
• ABC-06 (phase 3, n=162): Overall survival: 6.2 months vs 5.3 months, HR 0.69
• ClarIDHy (phase 3, n=187): Progression-free survival: 2.7 months vs 1.4 months, HR 0.37

• FGFR inhibitor resistance.
• Late diagnosis.
• Median survival in advanced disease is still barely a year; the immunotherapy benefit is a small tail with no predictive biomarker.
• FGFR inhibitor resistance (polyclonal kinase-domain mutations) limits benefit to ~7-9 months; sequencing next-generation agents is unproven.
• Second-line chemotherapy is weak (FOLFOX) and evidence for liposomal irinotecan is contradictory.
• Gallbladder cancer is under-represented in trials despite distinct biology and high HER2 prevalence.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. Why does trastuzumab deruxtecan work in 'HER2-low' breast cancers that older HER2 drugs ignored?
   Answer

   Its cleavable linker releases a membrane-permeable topoisomerase-I payload (DXd) at high DAR, so a small amount of HER2 is enough to deliver drug and the payload diffuses to kill neighbouring cells (bystander effect); HER2-low is a delivery address, not a driver. DESTINY-Breast04 and -06 proved it.
3. In what setting did T-DXd move into early-stage HER2-positive breast cancer in 2026?
   Answer

   Neoadjuvant (DESTINY-Breast11, T-DXd followed by THP, pCR 67.3% vs 56.3%) and post-neoadjuvant residual disease (DESTINY-Breast05, beating T-DM1), both approved Q2 2026.
4. What did the dostarlimab rectal cancer study show?
   Answer

   In mismatch-repair-deficient locally advanced rectal cancer, dostarlimab alone produced a complete clinical response in 100% of patients, sustained in more than 40 patients by 2025, allowing surgery and radiation to be avoided.
5. Which new target has an approved antibody, an approved CAR-T in China, and ADCs in phase 3 for gastric cancer?
   Answer

   Claudin 18.2: zolbetuximab (Vyloy), satricabtagene autoleucel (satri-cel, CARsgen, China), and ADCs such as CMG901/AZD0901.
6. What does a FAPI PET scan see that an FDG scan often misses?
   Answer

   The activated fibroblasts (FAP) in tumour stroma, present in more than 90% of epithelial cancers, giving high contrast in pancreatic, gastric, HCC, and peritoneal disease where FDG is weak; it is not yet approved.

• Wikipedia: https://en.wikipedia.org/wiki/Cholangiocarcinoma
• Wikipedia: https://en.wikipedia.org/wiki/Cholangiocarcinoma
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517