Biliary Cancers

Introduction

• Biliary tract cancers arise from epithelial cells of the bile ducts and are divided into 4 main categories by etiology, anatomy, and molecular biology:
  • Intrahepatic cholangiocarcinoma (IHCC): higher rate of mutation than EHCC and gallbladder ca. Most common alterations (IHCC): FGFR2 fusion (10 to 15%), IDH1 (15 to 25%), BRAF V600E (5%); MSI-H/dMMR uncommon (~1 to 3%).
  • Hilar cholangiocarcinoma (Klatskin tumor): aggressive, 5-yr OS <15%. Liver transplantation is a possible curative option for highly selected patients with LN-negative, primary tumor ≤3 cm, non-disseminated, locally advanced hilar tumors. Neoadjuvant chemoRT then liver transplantation is effective, and the combination of transplantation with neoadjuvant and/or adjuvant chemoRT gives higher PFS than potentially curative resection.
  • Distal (extrahepatic) cholangiocarcinoma: the non-hilar extrahepatic subtype; US extrahepatic bile duct ca a few thousand/yr (gallbladder plus other biliary ~12,000/yr, ACS).
  • Gallbladder cancer (GC): ~30 to 70% found incidentally at cholecystectomy; survival stage-dependent (T1a near 100% after simple cholecystectomy; 5-yr relative survival ~67% localized, ~20% all stages).
• Risk factors: metabolic syndrome, IBD, primary sclerosing cholangitis, hepatolithiasis, liver fluke, HCV > HBV (more common in Asia). Sex F>M, age >50 yrs, obesity. Gallstones causing chronic inflammation, gallbladder polyps (if ≥1 cm, cholecystectomy recommended; US primary imaging, cross-sectional staging only if invasive cancer suspected), porcelain gallbladder (hardened from calcium deposits), ethnicity (highest in Mexican, Latin American, and Native American), choledochal cysts (bile-filled sacs along the common bile duct).
• Histology: cholangiocarcinoma is >90% adenocarcinoma; remainder rare (adenosquamous, neuroendocrine, pure SqCC). IHC: positive for CK7 and CK19, negative for CK20 and ARG1 (argues against HCC).
• 3 main morphologies: Sclerosing (scirrhous), ↑ desmoplastic reaction and fibrosis, difficult to diagnose and resect. Nodular, constricting annular lesion, ↑ invasive, ↓ resectability, poor prognosis. Papillary, rare, bulky masses, ↑ biliary obstruction, ↑ resectability, better prognosis.

Staging

Localized cholangiocarcinoma

• Resection offers a chance of cure but recurrence is common (5-yr OS ~20 to 40%, better if N0/R0); ↓ OS with LN+ and R1 resection, so consider adjuvant treatment.
• For gallbladder ca ≥ T1b (muscle invasion): adjacent liver segment resection and lymphadenectomy must be performed.
• For T1a (lamina propria): simple cholecystectomy is sufficient (long-term OS ~100%, no need for liver or LN dissection).
• Centrally located tumors are often not resectable due to bilobar vascular and biliary invasion.
• Adjuvant capecitabine is established (BILCAP, category 1); the role of neoadjuvant therapy and adjuvant chemoRT is less well defined (few RCTs).
• Neoadjuvant chemotherapy: in select cases, 2 to 6 mo of treatment with reassessment every 2 to 3 mo is reasonable. No standard regimen defined; FOLFOX, Gem/Ox, Gem/Cape, Gem/Cis, and Durva/Gem/Cis can be used.
• Adjuvant chemotherapy: capecitabine (standard); GemOx is not standard (negative PRODIGE 12)
  • Adjuvant capecitabine (category 1). BILCAP study, completely resected cholangiocarcinoma or gallbladder carcinoma: capecitabine 1,250 mg/m² twice daily, days 1 to 14 q21d × 8 cycles vs observation. mOS 51 vs 36 mo (HR 0.81; P = .097, not significant per ITT); per-protocol mOS 53 vs 36 mo (HR 0.75; P = .028), significant; per-protocol mRFS 25.9 vs 17.4 mo.
  • Adjuvant GemOx: no difference in RFS (phase III PRODIGE 12-ACCORD 18, after curative-intent resection).
• Adjuvant RT: no substantial benefit of RT ± chemo.
• Adjuvant Gem/Cape × 4 then CapeRT: Intergroup S0809, single-arm Gem/Cape × 4 q21d then concurrent CapeRT. 2-yr OS 65% for all (67% R0, 60% R1); mOS 35 mo.
• Meta-analysis: best adjuvant benefit for LN+ (OR 0.49; P = .004) and R1 resection (OR 0.36; P = .002). Tumor depth and nodal involvement are the strongest recurrence predictors in distal bile duct cancer.
• No phase 3 adjuvant CRT trial exists (randomized phase 2 GECCOR-GB included a CRT arm); consensus supports RT for positive microscopic margins.

Advanced cholangiocarcinoma

First line

• GemCis + durvalumab (category 1), new SOC. TOPAZ-1 trial, untreated unresectable/recurrent/metastatic biliary tract ca: durvalumab 1,500 mg q3wk (or placebo) + gemcitabine 1,000 mg/m² and cisplatin 25 mg/m² on days 1 and 8 q3wk up to 8 cycles, then durvalumab 1,500 mg q4wk until progression.
  • mOS 12.8 vs 11.5 mo (HR 0.80; P = .021), primary endpoint; 24-mo OS 24.9% vs 10.4%; mPFS HR 0.75; ORR 26.7% vs 18.7%. Same TRAE.
  • TOPAZ-1 3-yr OS update (Oh, ESMO 2024): sustained benefit, 24-mo OS 24.9% vs 10.4%, 36-mo OS 14.6% vs 6.9%, confirming a durable long-term subset and supporting IO + chemo as new SOC.
• GemCis. ABC-02 (Advanced Biliary Ca), 410 patients: gemcitabine 1,000 + cisplatin 25 days 1 and 8 q3wk × 8 vs gemcitabine 1,000 mg/m² days 1, 8, 15 q4wk × 6. mPFS 8.0 vs 5.0 mo (P < .001); mOS 11.7 vs 8.1 mo (HR 0.64; P < .001). Same TRAE.
• GemOx: use if not a cisplatin candidate, but using GemOx in 1L generally discourages FOLFOX in 2L (repeat oxaliplatin); not absolute (ABC-06 tested FOLFOX after GemCis).
• Pembrolizumab + GemCis (KEYNOTE-966, Kelley Lancet 2023, PMID 37075781): 1L unresectable/metastatic biliary tract ca; mOS 12.7 vs 10.9 mo placebo + GemCis (HR 0.83). FDA Oct 31, 2023. Alternative to TOPAZ-1; choose by access/familiarity.
• ↑ tBili: do not use Gem/Cis if markedly elevated tBili; gemcitabine should start at a reduced dose of 800 mg/m² (about 20% reduction) if tBili >1.6. Use the modified de Gramont schedule instead (LV-modulated 5-FU bolus then 5-FU infusion).
• Pembrolizumab for unresectable/metastatic MSI-H or dMMR solid tumors, including biliary tract ca (KEYNOTE-158 pooled non-colorectal cohort: ORR 34.3%, mPFS 4.1 mo, mOS 23.5 mo; cholangiocarcinoma subgroup, n=22, ORR ~41%).

Second line

• Modified FOLFOX. ABC-06, 2L, primary endpoint OS: mOS 6.2 vs 5.3 mo (HR 0.69). Oxaliplatin can be difficult if the patient has ↑ neuropathy from prior GemCis.
• 5-FU/LV + liposomal irinotecan. NIFTY trial, metastatic biliary tract ca progressing during GemCis: mPFS 4.2 vs 1.7 mo (HR 0.61; P = .004, updated masked central review). SAEs higher with liposomal irinotecan (42% vs 24%); grade 3 to 4 neutropenia 24% vs 1%. New standard of care for patients without an actionable somatic mutation.
• Regorafenib.

• If progressed on GemOx: capecitabine + cisplatin, gemcitabine alone, or 5-FU/LV/irinotecan (FOLFIRI) with or without bevacizumab.

Targeted therapy

• IHCC has more mutations than EHCC and gallbladder ca. All biliary cancer patients should have NGS testing.
• IDH1 (~15 to 25%): ivosidenib (Tibsovo). ClarIDHy trial, 2L/3L, primary endpoint of ↑ PFS (QOL and OS secondary); trend toward ↑ OS 10.3 vs 7.5 mo (HR 0.79; crossover-adjusted HR 0.49). FDA 2021. Cost ~$1,000/day.
• BRAF V600E (~5%): dabrafenib and trametinib (FDA tissue-agnostic Jun 22, 2022). ROAR basket study, ORR 47% in 43 patients.
• FGFR2 fusion
  • Pemigatinib. FIGHT-202, anti-FGFR2, ORR 36%. TRAE ≥20%: hyperphosphatemia (!!!), alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, back pain, dry skin. Ocular toxicity and hyperphosphatemia are the most important.
  • Infigratinib. ORR 23% (1 CR, 24 PR), mDOR 5 mo in FGFR2-fusion IHCC (single-arm phase II); accelerated approval May 2021; US approval WITHDRAWN May 2024 (confirmatory trial could not enroll), no longer available.
  • Futibatinib (Lytgobi), irreversible FGFR1-4 TKI. FOENIX-CCA2 (Goyal NEJM 2023, PMID 36648936): ORR 42%, mDOR 9.7 mo in pretreated FGFR2-rearranged IHCC. FDA Sept 30, 2022 for previously treated unresectable/metastatic IHCC with FGFR2 fusions/rearrangements; active vs pemigatinib/infigratinib resistance mutations.
• HER2 (~5 to 20%, highest in gallbladder ca and EHCC)
  • Zanidatamab (Ziihera), bispecific HER2 mAb (2 distinct epitopes). HERIZON-BTC-01 (Harding Lancet Oncol 2023): ORR 52%, mDOR 14.9 mo in IHC 3+ HER2+ BTC after ≥1 prior gemcitabine-containing line. FDA Nov 20, 2024 for previously treated unresectable/metastatic HER2+ (IHC 3+) BTC. Confirmatory phase 3 HERIZON-BTC-302: 1L zanidatamab + CisGem with or without a PD-1 inhibitor.
  • Pertuzumab + trastuzumab (MyPathway): ORR 23% (9/39) in HER2-amplified/overexpressing BTC (responses enriched in RAS wild-type), mDOR 10.8 mo.
  • Trastuzumab deruxtecan (T-DXd), tissue-agnostic: DESTINY-PanTumor02 (Meric-Bernstam JCO 2024, PMID 37870536) biliary cohort (HER2 IHC 3+ or 2+): ORR 22% (~56% in IHC 3+), mDOR 8.6 mo, mPFS 4.6 mo. Basis for tissue-agnostic FDA approval (Apr 5, 2024) for HER2 IHC 3+ solid tumors after prior therapy, which includes biliary tract ca.
• RET (rare): selpercatinib. The LIBRETTO-001 basket trial included only one cholangiocarcinoma patient, who had a partial response.
• TMB-H ≥10 mut/Mb: pembrolizumab (tissue-agnostic) or ipi/nivo.
• MSI-H/dMMR: 1L pembrolizumab; 2L pembrolizumab or dostarlimab.
• NTRK gene fusion: entrectinib, larotrectinib.

Summary of biliary cancer treatment

• Resection, when feasible, is the mainstay of treatment for hepatobiliary tumors.
• Adjuvant capecitabine is SOC (BILCAP; OS benefit per-protocol, not significant in primary ITT analysis).
• Neoadjuvant treatment can be considered, especially in borderline resectable cases.
• Advanced 1L: Gem/Cis + durvalumab (TOPAZ-1) is SOC; can use GemOx if not a cisplatin candidate; pembrolizumab in 1L for MSI-H; pembrolizumab + GemCis (KEYNOTE-966) as an alternative.
• Advanced 2L: FOLFOX (only phase 3-validated 2L OS benefit, ABC-06), nal-IRI + 5-FU/LV (liposomal irinotecan, NIFTY regimen; not FOLFIRI), or Cape/Cis in patients without mutations.
• Ivosidenib for IDH1-mutated cholangiocarcinoma.
• Dabrafenib and trametinib for BRAF V600E-mutated tumors (ORR 47%).
• Pemigatinib and futibatinib for FGFR2 fusion (infigratinib US approval withdrawn 2024).
• Zanidatamab, pertuzumab + trastuzumab, and T-DXd for HER2.
• Pembrolizumab or dostarlimab for MSI-H; pembrolizumab or ipi/nivo for TMB-H.
• Entrectinib, larotrectinib for NTRK gene fusion.