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), a poor prognosis (five-year survival under 20%), and dependence on surgical resection as the only cure, achievable in a minority. 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8. 2021Ivosidenib approved (ClarIDHy); infigratinib approved then withdrawn (2022)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 (product)
• HERIZON-BTC-302 (trial)
• FIRST-308 (trial)
• Tinengotinib (product)
• Zanidatamab (product)
• Trastuzumab deruxtecan (product)
• ctDNA-guided switching among FGFR inhibitors (idea)
• Liquid biopsy (ctDNA) (technology)
• Liver transplantation for cancer (Milan criteria and beyond) (technology)
• Radioembolisation (TARE / SIRT, yttrium-90) (technology)
• FAPI PET (technology)
• Sonesitatug vedotin (product)

• 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
• ClarIDHy (phase 3, n=187): Progression-free survival: 2.7 months vs 1.4 months, HR 0.37
• BILCAP (phase 3, n=447): Overall survival (ITT): 51.1 months vs 36.4 months, HR 0.81
• FIGHT-202 (phase 2, n=147): Objective response rate: 35.5%

• 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
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1517