Biliary Tract Cancer Clinical Trial Timeline: In-depth Report

Coverage: 39 landmark trials cited by NCCN Biliary Tract Cancers V1.2026 (37 published with full PMID traceability + 2 ongoing with only NCT / design paper) + mixed three-subtype enrollment (GBC / ICC / ECC) + eight biomarker-matched pathways

Curated by Dual Brain Lab (csilab.net)

1. One-sentence definition

This report maps the evolution logic and current decision landscape of systemic therapy for biliary tract cancer (BTC; including gallbladder cancer / GBC, intrahepatic cholangiocarcinoma / ICC, extrahepatic cholangiocarcinoma / ECC) over the past 16 years (2010-2026) as reflected in the landmark clinical trials cited by NCCN Biliary Tract Cancers V1.2026, providing frontline clinicians a traceable panoramic map for “who, what, and why” decisions in 2026.

Iron rule: every data point of every trial is traceable to PubMed (PMID) or ClinicalTrials.gov (NCT id) — each [PMID xxxxxxxx] in the text can be opened directly in PubMed for source verification.

2. Vertical: timeline of five treatment paradigms

BTC systemic therapy has gone through five paradigm shifts in the past 16 years: adjuvant chemo upgraded from observation to capecitabine, then expanded to S-1 as a parallel three-way option → advanced 1L GemCis (gemcitabine + cisplatin) dominated uniformly for 12 years → IO (immune checkpoint inhibitor) + GemCis double hit forming a class effect rewrote the 1L backbone → 8 biomarker-matched precision pathways (FGFR2 / IDH1 / HER2 / BRAF V600E / NTRK / MSI-H / NRG1 / KRAS G12C) rolled out in parallel → advanced 2L layered marginal benefit from FOLFOX with an East-West divide on nal-IRI.

Each shift was smaller than in NSCLC but larger than in pancreatic cancer — reflecting BTC’s distinct molecular architecture: ICC is enriched for FGFR2 / IDH1 (10-20%), GBC is enriched for HER2 (15-20%), and all three subtypes share MSI-H / BRAF / NTRK / NRG1 / KRAS G12C tumor-agnostic basket pathways. This “subtype × biomarker dual heterogeneity” makes BTC’s precision-therapy density second only to NSCLC, far exceeding HCC and pancreatic cancer.

2.1 Adjuvant chemo evolution (2015-2024): from GEMOX/gemcitabine failure → capecitabine tacit ascent → S-1 / GemCis-CRT East-West divergence

Story: before BILCAP, adjuvant BTC was observation + some-centers chemo. PRODIGE-12 and BCAT, two European / Japanese phase III trials, both rendered GEMOX and gemcitabine monotherapy adjuvant negative. BILCAP was tacitly accepted globally on a borderline-ITT / significant per-protocol basis; ASCOT delivered a clean ITT-positive result in a Japanese population with S-1; OSTWAL 2024 delivered the first positive DFS for GemCis + CRT in high-risk Indian GBC. An arc from “all fail → marginal win → clean win → subtype-specific.”

• PRODIGE-12 [PMID 30707660] (Edeline 2019 J Clin Oncol, N=194): R0/R1 mixed BTC adjuvant GEMOX (gemcitabine + oxaliplatin) vs observation. RFS HR 0.88 (95% CI 0.62-1.25, p=0.48) negative, OS likewise negative. Proved not every adjuvant doublet works — what wins in advanced doesn’t always win in adjuvant.
• BCAT [PMID 29405274] (Ebata 2018 Br J Surg, N=225, Japan): ECC-only R0 adjuvant gemcitabine monotherapy vs observation. OS HR 1.01 (95% CI 0.70-1.45, p=0.97) zero difference. The cleanest negative in a subtype-specific adjuvant trial — gemcitabine monotherapy fully exits the adjuvant recommendation. The BCAT + PRODIGE-12 IPD meta-analysis [PMID 35182925] reaffirmed “gemcitabine-based adjuvant doublets do not benefit BTC.”
• BILCAP [PMID 30922733] (Primrose 2019 Lancet Oncol, N=447, UK): R0/R1 mixed BTC adjuvant capecitabine × 8 cycles vs observation. ITT mOS 51.1 vs 36.4 months, HR 0.81 (95% CI 0.63-1.04, p=0.097) just missed; per-protocol HR 0.75 (95% CI 0.58-0.97, p=0.028) significant. ESMO/NCCN/CSCO all adopted it as adjuvant standard — rationale: per-protocol significant + real-world dose reduction unavoidable + no better data. This is BTC’s first tacitly-ascendant adjuvant standard in 30 years.
• ACTICCA-1 [PMID 26228433] (Stein 2015 BMC Cancer design paper / NCT02170090): European multicenter N≈783 resected mixed BTC, adjuvant GemCis × 8 cycles vs amended capecitabine (control arm amended post-BILCAP). The first direct head-to-head comparison of GemCis doublet vs capecitabine monotherapy as adjuvant; still ongoing as of 2026-04, primary results not yet published. The most anticipated BTC adjuvant phase III.
• ASCOT / JCOG1202 [PMID 36681415] (Nakachi 2023 Lancet, N=440, Japan): R0 mixed BTC adjuvant S-1 × 4 cycles vs observation. mOS 62.4 vs 51.1 months, HR 0.69 (95% CI 0.55-0.86, p=0.001) significant. The cleanest ITT-positive adjuvant phase III in BTC to date. Japanese guidelines accordingly list S-1 as adjuvant SoC. In the Asian setting with DPYD polymorphism and S-1 tolerability, this “Eastern-specific” path stands alongside BILCAP.
• SWOG-S0809 [PMID 25964250] (Ben-Josef 2015 J Clin Oncol, N=79, single-arm phase II): ECC + GBC only (T2-T4 or node-positive) adjuvant GemCap × 4 cycles → CRT (concurrent capecitabine, 54 Gy). 2-year OS 65% (met pre-specified ≥60% threshold), similar across R0/R1 subgroups. The main evidence basis for NCCN recommending adjuvant CRT in ECC/GBC R1-margin / N+ patients.
• OSTWAL-2024-GEMCIS-CRT-GBC [PMID 38958997] (Ostwal 2024 JAMA Oncol, N=80, India Tata Memorial): high-risk GBC only (T3-T4 / N+ / R1) adjuvant GemCis × 4 cycles + CRT vs observation. DFS HR 0.62 (95% CI 0.43-0.89, p=0.009) significant, mDFS 28.0 vs 14.0 months. The first RCT to show positive DFS for adjuvant chemo + CRT in a single GBC subtype, filling the GBC-underrepresentation gap in mixed-subtype trials.

Takeaway: in 2026 adjuvant BTC — capecitabine monotherapy (BILCAP) is the Western default; S-1 × 4 cycles (ASCOT) is the Asian preferred; high-risk ECC/GBC (R1 / N+) adds CRT (SWOG-S0809 / OSTWAL) as intensification; GEMOX and gemcitabine monotherapy no longer used in adjuvant; ACTICCA-1 (GemCis vs capecitabine) readout will definitively rewrite the decision tree.

2.2 Advanced 1L (2010-2025): GemCis dominates 12 years → three triplet challenges all fail → IO double-hit forms class effect

Story: after ABC-02 enshrined GemCis as 1L in 2010, no one dethroned it for 12 full years. Three triplet challenges in different directions (add nab-paclitaxel / switch to mFOLFIRINOX / add S-1) all failed. Not until 2022-2023 did TOPAZ-1 + KEYNOTE-966 — using durvalumab and pembrolizumab, two fully independent PD-(L)1 inhibitors — converge on HR 0.80-0.83, formally establishing IO + GemCis as a class effect.

• ABC-02 [PMID 20375404] (Valle 2010 NEJM, N=410, UK): treatment-naive advanced BTC (ICC 39% / GBC 38% / ECC 20% / ampullary 3%) GemCis vs gemcitabine monotherapy. mOS 11.7 vs 8.1 months, HR 0.64 (95% CI 0.52-0.76, p<0.001). The control base for all BTC 1L trials over 12 years; the “backbone drug” status of GemCis underlying every IO + GemCis class-effect trial was established here.
• AMEBICA / PRODIGE-38 [PMID 34662180] (Phelip 2022 J Clin Oncol, N=191, France phase II RCT): mFOLFIRINOX vs GemCis 1L. 6-month PFS 44.5% vs 47.3%, PFS HR 0.93, OS HR 0.97 all negative, with markedly higher toxicity (G3-4 AEs ~72% vs ~60%). Regimens that win in pancreatic cancer don’t carry over to BTC.
• KHBO1401-MITSUBA [PMID 35900311] (Ioka 2023 J Hepatobiliary Pancreat Sci, N=246, Japan): GCS triplet (GemCis + S-1) vs GemCis. mOS 13.5 vs 12.6 months, ITT HR 0.79 (95% CI 0.60-1.04, p=0.094) just missed; per-protocol HR 0.73 (p=0.046). Occasionally used in Japanese daily practice, not adopted globally as SoC.
• TOPAZ-1 [PMID 38319896] (Oh 2022 NEJM Evid, N=685, global, Asia 54% / Europe 30% / Americas 16%): durvalumab (PD-L1) + GemCis vs placebo + GemCis. OS HR 0.80 (95% CI 0.66-0.97, p=0.021), mOS 12.8 vs 11.5 months (delta only 1.3 months); 24-month landmark OS 24.9% vs 10.4% (delta 15 percentage points). Median OS gap is small but the long-tail survivor proportion doubles — IO benefit is not uniformly distributed but enriched in durable responders. FDA approved 2022-09.
• KEYNOTE-966 [PMID 37075781] (Kelley 2023 Lancet, N=1069, global): pembrolizumab (PD-1) + GemCis vs placebo + GemCis. OS HR 0.83 (95% CI 0.72-0.95, p=0.0034), mOS 12.7 vs 10.9 months. 55% larger than TOPAZ-1, with HR nearly overlapping TOPAZ-1 (0.80 vs 0.83). Two fully independent teams, two different drugs (PD-L1 vs PD-1), two different regimens (durvalumab maintenance vs pembrolizumab monotherapy maintenance), HR converging on 0.80-0.83 — a textbook class effect. FDA approved 2023-10.
• SWOG-1815 [PMID 39671534] (Shroff 2025 J Clin Oncol, N=441, US): GemCis + nab-paclitaxel triplet vs GemCis doublet 1L. mOS 11.8 vs 11.4 months, HR 0.93 (95% CI 0.75-1.16, p=0.52) negative. Phase II single-arm data had raised expectations; the phase III closed the “add-taxane” path.

Takeaway: 2026 advanced BTC 1L SoC = IO + GemCis (durvalumab or pembrolizumab, HR 0.80-0.83 class effect). Three triplet concepts (add taxane / switch to FOLFIRINOX / add S-1) all failed. The core branchpoint in daily clinical practice is “which IO fits this patient” rather than “add IO or not” — see §3.2.

2.3 Advanced 2L (2019-2024): FOLFOX marginal + nal-IRI East-West divergence + IO/regorafenib monotherapy historical value

Story: 2L BTC has hovered near the “6-month OS floor” for 16 years. ABC-06 delivered a marginal win with FOLFOX and became standard; NIFTY and NALIRICC used the same drug (nal-IRI + 5FU/LV) in Korea vs Germany and reached opposite conclusions; IO monotherapy (nivolumab) and regorafenib produced modest results in unselected populations, but established the early signal that “IO has enrichment in the MMR-deficient subgroup of refractory BTC.”

• ABC-06 [PMID 33798493] (Lamarca 2021 Lancet Oncol, N=162, UK): after gemcitabine-class failure, mFOLFOX + active symptom control (ASC) vs ASC alone. mOS 6.2 vs 5.3 months, HR 0.69 (95% CI 0.50-0.97, p=0.031); 12-month OS 25.9% vs 11.4%. BTC’s first positive 2L RCT, establishing mFOLFOX as 2L standard. Delta only 0.9 months — low ceiling.
• NIFTY [PMID 36951834] (Hyung 2023 JAMA Oncol, N=174, Korea): after gemcitabine-class failure, liposomal irinotecan (nal-IRI) + 5FU/LV vs 5FU/LV alone. PFS HR 0.56 (95% CI 0.39-0.81, p=0.002), mPFS 7.1 vs 1.4 months. OS HR 0.82 (p=0.27) negative, but the PFS signal is the strongest in BTC 2L history.
• NALIRICC [PMID 38870977] (Vogel 2024 Lancet Gastroenterol Hepatol, N=100, Germany AIO): same nal-IRI + 5FU/LV vs 5FU/LV, OS HR 0.68 (95% CI 0.44-1.04, p=0.074) borderline non-significant, mOS 8.2 vs 6.9 months. Same drug, same 2L setting, same control — Korean PFS+ but German OS negative — East-West population PK / molecular background (HBV / liver fluke vs sporadic) / ICC-to-ECC ratio differences could all plausibly explain it.
• KIM-2020-NIVO-BTC [PMID 32352498] (Kim 2020 JAMA Oncol, N=54, US phase II single-arm): gemcitabine-class refractory BTC nivolumab monotherapy. ORR 22% (12/54), mPFS 3.7 months, mOS 14.2 months. The 22% ORR in an unselected population is well above the historical 5-10% chemo-refractory ORR — but responses enriched in the MMR-deficient subgroup, providing proof-of-concept for IO moving into 1L via TOPAZ-1 / KN-966.
• SUN-2019-REGO-BTC [PMID 30561756] (Sun 2019 Cancer, N=43, US phase II single-arm): after gemcitabine-class failure, regorafenib 160 mg. DCR 56%, ORR 11%, mPFS 2.0 months, mOS 7.4 months. Multikinase TKI shows only marginal activity in BTC; no phase III followed. In 2026 still occasionally used as “palliative when no better option exists,” not SoC.

Takeaway: in 2026 advanced BTC 2L and beyond — mFOLFOX + ASC (ABC-06) is the global default; nal-IRI + 5FU/LV is used in Korea / parts of Asia-Pacific based on NIFTY PFS data, while the West is cautious after NALIRICC OS negative; IO monotherapy is recommended only for MSI-H / TMB-H selective populations; regorafenib used occasionally when all other options are exhausted. The ceiling of these 2L chemo paths will be rewritten by the biomarker-matched strategies in §2.4.

2.4 Biomarker-matched precision therapy (2018-2026): eight pathways + 2/3 ICC three-subtype reshaping

Story: in 2018, NAVIGATE (larotrectinib for NTRK fusion) opened the door with the FDA’s first tumor-agnostic approval. In 2020, four landmark trials published the same year — FIGHT-202 (pemigatinib for FGFR2 fusion) + ClarIDHy (ivosidenib for IDH1 mutation) + ROAR (dabrafenib + trametinib for BRAF V600E) + KEYNOTE-158 (pembrolizumab for MSI-H) — densely opened the ICC precision-therapy door. From 2021-2024, four HER2 pathways with different mechanisms (MyPathway → HERIZON-BTC-01 → SGNTUC-019 → DESTINY-PanTumor02) rolled out in the GBC-enriched population. In 2025 zenocutuzumab (NRG1 fusion) and in 2026 TRIDENT-1 (repotrectinib, next-gen TRK for NTRK fusion) completed the final two pieces. 8 biomarker-matched pathways collectively cover ~30-40% of BTC patients, making BTC’s precision-therapy density the highest solid-tumor map outside NSCLC.

2.4.1 FGFR2 pathway (ICC-exclusive, 10-15% of ICC patients)

• FIGHT-202 [PMID 32203698] (Abou-Alfa 2020 Lancet Oncol, N=146, single-arm phase II): FGFR2 fusion / rearrangement+ CCA (>95% ICC) 2L pemigatinib. Cohort A (FGFR2 fusion, n=107) ORR 35.5% (95% CI 26.5-45.4), mDoR 7.5 months, mPFS 6.9 months, mOS 21.1 months; Cohort B (other FGFR alteration) ORR 0%; Cohort C (no FGFR alteration) ORR 0%. Fusion is the true driver, not all FGFR alterations are equivalent. FDA accelerated approval 2020-04 — BTC’s first precision drug.
• FOENIX-CCA2 [PMID 36652354] (Goyal 2023 NEJM, N=103, single-arm phase II): 100% ICC, FGFR2 rearrangement+ 2L futibatinib (covalent / irreversible FGFR1-4 inhibitor). ORR 41.7% (95% CI 32.1-51.9), mDoR 9.7 months, mPFS 8.9 months, mOS 20.0 months. Covalent binding may overcome some resistance mutations to reversible inhibitors. FDA accelerated approval 2022-09.
• RAGNAR [PMID 37541273] (Pant 2023 Lancet Oncol, N=217 across ≥15 tumor types / BTC n=27): FGFR1-4 alteration tumor-agnostic erdafitinib. Overall ORR 30%; BTC subgroup ORR ~26%. FDA accelerated approval 2024-09 for tumor-agnostic FGFR-altered solid tumors — providing a third path for BTC patients with FGFR1/3/4 alterations (not the mainstream FGFR2 fusion).
• FIGHT-302 [PMID 32677452] (Bekaii-Saab 2020 Future Oncol design paper / NCT03656536): 1L FGFR2 rearrangement+ ICC pemigatinib vs GemCis head-to-head phase III. ESMO 2024 oral reported positive PFS; full manuscript still unpublished as of 2026-04. If formally published as positive, it would switch FGFR2+ ICC 1L SoC from IO + GemCis to pemigatinib — the first example of “molecular-selected 1L replacing IO + GemCis.”

2.4.2 IDH1 pathway (ICC-enriched, 10-20% of ICC patients)

• ClarIDHy [PMID 32416072] (Abou-Alfa 2020 Lancet Oncol, N=185; OS update [PMID 34554208] Zhu 2021 JAMA Oncol): IDH1 mutation+ (R132 hotspot) CCA (90% ICC) ≥1 prior line ivosidenib vs placebo (2:1 randomization, crossover allowed). mPFS 2.7 vs 1.4 months, HR 0.37 (95% CI 0.25-0.54, p<0.001); ITT OS 10.3 vs 7.5 months, HR 0.79 (p=0.093) — diluted by 70% crossover; crossover-adjusted OS HR 0.49. BTC’s first truly phase III biomarker trial (FIGHT-202 / FOENIX were both single-arm phase II). FDA approved 2021-08.

2.4.3 HER2 pathway (GBC-enriched, 15-20% of GBC patients; lower in ICC/ECC)

Four different mechanisms in parallel — in solid tumors this level of target richness is matched only by HER2+ breast cancer.

• MyPathway-BTC [PMID 34339623] (Javle 2021 Lancet Oncol, N=39 BTC cohort single-arm): HER2+ (IHC 3+ or IHC 2+/FISH+) BTC pertuzumab + trastuzumab. ORR 23.1% (95% CI 10.7-39.9), mPFS 4.0 months, mOS 10.9 months. First prospective HER2-doublet data in BTC; IHC 2+/FISH+ enrollment dilutes the signal but establishes proof-of-concept.
• HERIZON-BTC-01 [PMID 37276871] (Harding 2023 Lancet Oncol, N=87 single-arm phase IIb): HER2 amplification (IHC 3+ or IHC 2+/ISH+) BTC (GBC 40% / ICC 35% / ECC 25%) 2L+ zanidatamab (HER2 bispecific antibody, simultaneously binding domain 2 + 4). ORR 41.3% (95% CI 30.7-52.5), mDoR 12.9 months, mPFS 5.5 months, mOS 15.5 months. FDA accelerated approval 2024-08 — BTC’s third biomarker-targeted approval (after FGFR2 / IDH1).
• SGNTUC-019 [PMID 37751561] (Nakamura 2023 J Clin Oncol, N=30 BTC cohort single-arm basket): HER2+ BTC tucatinib (HER2-selective small-molecule TKI) + trastuzumab. ORR 46.7% (95% CI 28.3-65.7), mPFS 5.5 months, mOS 13.5 months — the highest BTC HER2-doublet numbers historically (small N, interpret cautiously).
• DESTINY-PanTumor02 [PMID 37870536] (Meric-Bernstam 2024 J Clin Oncol, N=41 BTC cohort single-arm): HER2-expressing (IHC 3+ or 2+) solid tumors 7-cohort trastuzumab deruxtecan (T-DXd ADC). BTC ORR 36.6% (IHC 3+ 56.3% / IHC 2+ 20.0%), mPFS 7.0 months, mOS 9.9 months. FDA tumor-agnostic accelerated approval 2024-04 for HER2 IHC 3+ solid tumors — expanding the BTC HER2-eligible population from “amplification” to “overexpression.” ILD risk requires monitoring.

2.4.4 BRAF V600E pathway (ICC-enriched, 3-5% of ICC)

• ROAR-BTC [PMID 32818466] (Subbiah 2020 Lancet Oncol, N=43 BTC cohort single-arm basket): BRAF V600E+ BTC (85% ICC) 2L dabrafenib + trametinib. ORR 51% (95% CI 36-67), mPFS 9.0 months, mOS 11.7 months — historically the highest ORR for any BTC biomarker cohort. FDA tumor-agnostic accelerated approval 2022.
• NCI-MATCH-H [PMID 32758030] (Salama 2020 J Clin Oncol, N=35 pan-tumor / BTC subgroup n=7-8): BRAF V600E+ non-melanoma non-NSCLC solid tumors dabrafenib + trametinib independent NCI validation. Overall ORR 38%, mPFS 11.4 months. BTC subgroup results consistent with ROAR — providing an independent replication beyond ROAR and strengthening the BRAF V600E + dab/tram evidence package.

2.4.5 NTRK fusion pathway (cross-subtype, <1% of BTC)

Three NTRK inhibitors in parallel + next-gen for resistance mutations.

• NAVIGATE-LAROTRECTINIB [PMID 29466156] (Drilon 2018 NEJM, N=55 pan-tumor / BTC n=2-3): TRK fusion+ solid tumors larotrectinib. Overall ORR 75% (95% CI 61-85). FDA’s first tumor-agnostic biomarker approval 2018-11 — a regulatory milestone. BTC patient numbers very small but responses consistent.
• STARTRK-ENTRECTINIB [PMID 31838007] (Doebele 2020 Lancet Oncol, N=54): NTRK fusion+ solid tumors entrectinib (pan-TRK/ROS1/ALK, good CNS penetration). Overall ORR 57.4% (95% CI 43.2-70.8), mDoR 10.4 months. BTC subgroup not reported separately due to small N. FDA tumor-agnostic approval 2019-08.
• TRIDENT-1 [PMID 41639379] (Besse 2026 Nat Med): NTRK fusion+ solid tumors repotrectinib (next-gen TRK, active against NTRK G595R / G667C / F589L resistance mutations). TRK-naïve cohort ORR 58% (95% CI 37-77), TRK-pretreated cohort ORR 50% (95% CI 28-72). FDA approved 2023-11 — providing a sequential precision option for BTC patients resistant to larotrectinib / entrectinib.

2.4.6 MSI-H / dMMR / TMB-H pathway (cross-subtype, BTC MSI-H ~2-3%)

• KEYNOTE-158-MSIH [PMID 31682550] (Marabelle 2020 J Clin Oncol, N=233 pan-tumor / BTC cohort K n=22; long-term [PMID 35680043] Maio 2022 Ann Oncol): MSI-H / dMMR non-CRC solid tumors pembrolizumab. Overall non-CRC MSI-H ORR 34.3%; BTC subgroup ORR 40.9% (95% CI 20.7-63.6). BTC-specific data supporting the FDA tumor-agnostic approval of 2017.
• ANDRE-2023-DOSTARLIMAB [PMID 37917058] (André 2023 JAMA Netw Open): dMMR solid tumors dostarlimab. Overall dMMR ORR 38.7% (95% CI 31.6-46.2), 24-month DoR rate 69.0%. BTC subgroup consistent with overall cohort. Provides an anti-PD-1 equivalent option to pembrolizumab for MSI-H / dMMR BTC.
• CHECKMATE-848 [PMID 39107131] (Schenker 2024 J Immunother Cancer, N≈200 TMB-H pan-tumor): TMB-H (≥10 mut/Mb) solid tumors nivolumab + ipilimumab vs nivolumab monotherapy. ORR 43.3% vs 26.0%, PFS HR 0.72 (95% CI 0.60-0.88). BTC-specific data not separately published, but establishes randomized evidence that “TMB-H is an optional biomarker for IO combinations (overlapping ~40-50% with MSI-H).”

2.4.7 NRG1 fusion pathway (cross-subtype, <1% of BTC)

• ENRGY [PMID 39908431] (Schram 2025 NEJM, N=64 pan-tumor / BTC subgroup n=3-5): NRG1 fusion+ solid tumors zenocutuzumab (HER2×HER3 bispecific, competitively blocking NRG1-HER3 signaling). Overall ORR 34% (95% CI 22-47), mDoR 11.1 months, mPFS 6.8 months. BTC subgroup consistent with the overall cohort. FDA accelerated approval 2024-08 for NRG1 fusion+ NSCLC and pancreatic cancer — tumor-agnostic data supports BTC use.

2.4.8 KRAS G12C pathway (cross-subtype, ~1-2% of BTC)

• KRYSTAL-1-BTC [PMID 37099736] (Bekaii-Saab 2023 J Clin Oncol, N=12 BTC subgroup single-arm basket): KRAS G12C+ BTC adagrasib 600 mg BID. BTC ORR 33.3% (95% CI 9.9-65.1), DCR 83.3%. BTC is the first GI tumor beyond NSCLC / CRC to demonstrate KRAS G12C inhibitor activity — adding an eighth biomarker-matched pathway.

2.4.9 RET fusion pathway (cross-subtype, <1% of BTC)

• LIBRETTO-001-BTC [PMID 36108661] (Subbiah 2022 Lancet Oncol, N=45 non-lung non-thyroid / BTC n=7): RET fusion+ solid tumors selpercatinib. ORR 43.9% (95% CI 29.5-59.3), mDoR 24.5 months. BTC subgroup ORR consistent with overall cohort. FDA tumor-agnostic approval 2022.
• ARROW-BTC [PMID 35962206] (Subbiah 2022 Nat Med, N=29 non-lung non-thyroid): RET fusion+ solid tumors pralsetinib. ORR 57% (95% CI 37-76), 12-month DoR rate 81%. BTC data sparse but equivalent to selpercatinib. FDA tumor-agnostic accelerated approval 2022-08.

Takeaway: in 2026, a newly diagnosed advanced BTC patient must have comprehensive molecular profiling (NCCN V1.2026 strongly recommended) covering FGFR2 / IDH1 / HER2 / BRAF V600E / NTRK / MSI-H / dMMR / TMB-H / NRG1 / KRAS G12C / RET. 8 biomarker-matched pathways collectively cover 30-40% of patients — the biggest difference from HCC (0 biomarker-matched) and pancreatic cancer (POLO + 5%). If FIGHT-302 publishes as 1L positive, it will be the first precedent of “molecular-selected 1L replacing IO + GemCis.”

2.5 Ongoing phase III and pending readouts (key 2026-2028 inflection points)

Story: BTC’s key 2026-2028 readouts concentrate on two fronts: adjuvant setting (ACTICCA-1 GemCis vs capecitabine) and 1L FGFR2-selective setting (FIGHT-302 pemigatinib vs GemCis). Either outcome will directly rewrite the decision tree.

• FIGHT-302 [PMID 32677452] (Bekaii-Saab 2020 Future Oncol design / NCT03656536): 1L FGFR2+ ICC pemigatinib vs GemCis. ESMO 2024 reported positive PFS readout; full manuscript still pending as of 2026-04.
• ACTICCA-1 [PMID 26228433] (Stein 2015 BMC Cancer design / NCT02170090): adjuvant GemCis × 8 cycles vs amended capecitabine (control arm amended after BILCAP). Designed as the only direct head-to-head comparison of GemCis doublet vs capecitabine monotherapy in adjuvant. Primary completion expected 2026-2027.
• GEMSTONE-202 (China CStone Pharmaceuticals sugemalimab + GemCis 1L phase III, positive readout reported at ASCO GI 2024/2025): as of 2026-04, the primary manuscript and public NCT ID are both unregistered — this knowledge base strictly follows the “PMID / NCT traceable” principle, not currently included in the main database. Will add as a v2 supplement once the primary publication appears.

Takeaway: the key variables of BTC decision-tree in 2026-2028 = (a) whether adjuvant GemCis beats capecitabine (ACTICCA-1) + (b) whether 1L FGFR2+ switches to pemigatinib monotherapy (FIGHT-302) + (c) whether the Chinese domestic IO + GemCis data GEMSTONE-202 is published. Each will recalibrate §3’s horizontal decision landscape.

3. Horizontal: 2026 current decision landscape (six dimensions)

Projecting the vertical evolution onto the 2026 clinical decision tree, the following are six key branchpoints and the evidence basis for each.

3.1 Newly diagnosed BTC: immediate comprehensive molecular profiling

NCCN V1.2026 explicitly recommends comprehensive molecular testing (tissue or ctDNA) for all newly diagnosed advanced BTC, covering: FGFR2 fusion / rearrangement + IDH1 R132 mutation + HER2 amplification / overexpression + BRAF V600E + MSI-H / dMMR + TMB-H + NRG1 fusion + NTRK fusion + RET fusion + KRAS G12C. Molecular testing results directly affect:

• 2L targeted accessibility (FGFR2 → pemigatinib / futibatinib / erdafitinib; IDH1 → ivosidenib; HER2 → zanidatamab / T-DXd / tucatinib + trastuzumab; BRAF V600E → dabrafenib + trametinib; NTRK → larotrectinib / entrectinib / repotrectinib; MSI-H → pembrolizumab / dostarlimab; NRG1 → zenocutuzumab; G12C → adagrasib; RET → selpercatinib / pralsetinib)
• 1L regimen selection (if the FIGHT-302 manuscript is positive, FGFR2+ ICC 1L may switch to pemigatinib monotherapy replacing IO + GemCis)
• Clinical trial enrollment (FIGHT-302 / ACTICCA-1 / GEMSTONE-202 and other domestic / global recruitment)

Missing any biomarker = missing an ORR 30-50% high-yield responder population — in BTC, a tumor with 8-9 parallel biomarker pathways, the cost of non-testing is far higher than in NSCLC.

3.2 Advanced 1L: the two PD-(L)1 choices in the IO + GemCis class effect for fit patients

2026 mainstream: treatment-naive advanced BTC (regardless of PD-L1 status) preferred option = IO + GemCis × 8 cycles → IO maintenance — two independent phase III datasets with HR converging on 0.80-0.83.

Contraindicated / not recommended in 2026:

• Triplet GemCis + nab-paclitaxel (SWOG-1815 PMID 39671534 negative)
• Triplet mFOLFIRINOX replacing GemCis (AMEBICA PMID 34662180 negative)
• Triplet GCS (GemCis + S-1, KHBO1401-MITSUBA PMID 35900311 ITT negative)

NCCN 2026: durvalumab + GemCis and pembrolizumab + GemCis are co-listed as Category 1 preferred (treatment-naive advanced BTC, regardless of subtype / PD-L1).

3.3 Adjuvant regimen: capecitabine vs S-1 vs GemCis-CRT three paths

2026 mainstream:

• Western / international default: capecitabine × 8 cycles (BILCAP per-protocol significant / ITT borderline, PMID 30922733) — globally adopted by guidelines
• Asian / Japanese preferred: S-1 × 4 cycles (ASCOT ITT positive HR 0.69, PMID 36681415) — the “Eastern-specific” path standing alongside BILCAP, well-tolerated given DPYD polymorphism background
• R1-margin / N+ ECC / GBC: adjuvant chemo → CRT (SWOG-S0809 PMID 25964250 / OSTWAL 2024 PMID 38958997, the latter being the first GBC-only DFS-positive RCT)
• Not recommended as adjuvant: GEMOX (PRODIGE-12 PMID 30707660 negative) + gemcitabine monotherapy (BCAT PMID 29405274 negative, IPD meta PMID 35182925 reaffirmed)

Key unresolved question: GemCis doublet vs capecitabine monotherapy in adjuvant — only ACTICCA-1 (PMID 26228433 design paper, NCT02170090) can answer directly; still ongoing as of 2026-04. Before ACTICCA-1 readout, 2026 clinical practice still uses capecitabine (West) / S-1 (Japan) as baseline.

NCCN V1.2026: capecitabine = Category 1 adjuvant standard for resected BTC. S-1 = Category 2A (based on ASCOT, not restricted to Asia but Western data lacking). CRT retained as Category 2B option in R1 / N+ settings.

3.4 Precision therapy eight pathways: which biomarker → which drug

Clinical decision implication: 2026 BTC precision therapy = “test without fail for 2L, test as early as possible for 1L.” The 2L decision window requires NGS report in hand within 4-6 weeks; FGFR2 fusion + IDH1 mutation + HER2 amp + BRAF V600E are the four ICC/GBC-enriched high-yield must-tests.

3.5 Advanced 2L+: FOLFOX + East-West nal-IRI divergence + IO/regorafenib fallback

2026 mainstream:

• Global default: mFOLFOX + ASC (ABC-06 PMID 33798493, HR 0.69 marginal win)
• Asia / Korea: nal-IRI + 5FU/LV based on NIFTY PFS data (PMID 36951834 PFS HR 0.56 positive) — note OS negative
• West: nal-IRI + 5FU/LV used cautiously — NALIRICC (PMID 38870977) OS negative / borderline
• MSI-H / dMMR / TMB-H selective: anti-PD-1 monotherapy (pembrolizumab / dostarlimab) or nivo + ipi (CHECKMATE-848 data)
• Biomarker-negative + multiline exhausted: regorafenib (SUN-2019-REGO-BTC PMID 30561756, DCR 56% / ORR 11% palliative only)

Clinical implication of the East-West nal-IRI divergence: do not extrapolate NIFTY Korean data to Western BTC, or vice versa. BTC’s cross-population heterogeneity is larger than typically assumed — possible PK / molecular background differences (HBV / liver fluke vs sporadic) / ICC-to-ECC ratio differences need to be considered separately.

3.6 Three-subtype differences (GBC / ICC / ECC): biomarker enrichment and decision triage

Although most registration trials enrolled mixed three subtypes (TOPAZ-1 ICC 56%, KEYNOTE-966 GBC 30%, BILCAP mixed three-subtype, etc.), biomarker enrichment differences determine subtype-specific triage for precision therapy:

4. Research Gaps: the ten unresolved clinical questions

This report identifies the following gaps, all concretely defined questions (not the cliché of “more research needed”):

1. GemCis doublet vs capecitabine monotherapy in adjuvant head-to-head: post-BILCAP all guidelines adopted capecitabine but on a borderline ITT; ACTICCA-1 (NCT02170090) answers directly, still no readout as of 2026-04, key 2026-2027 inflection point.
2. FGFR2+ ICC 1L pemigatinib vs IO + GemCis: FIGHT-302 (NCT03656536) reported positive PFS at ESMO 2024, full manuscript and OS data still unpublished as of 2026-04; if published positive, it would be BTC’s first precedent of “molecular-selected 1L replacing class-effect IO + chemo.”
3. East-West nal-IRI 2L divergence: NIFTY (Korea PFS positive PMID 36951834) vs NALIRICC (Germany OS negative borderline PMID 38870977) — same drug, same 2L, different results — which of PK / molecular background / ICC-vs-ECC ratio / trial design is the dominant explanation? No matched prospective analysis exists.
4. IO benefit biomarker enrichment in TOPAZ-1 and KEYNOTE-966: neither phase III used PD-L1 selection but the 24-month landmark shows long-tail enrichment — who are the “long-tail responders”? Need pre-specified PD-L1 / TMB / dMMR / IFN-γ signature retrospective analysis and prospective validation.
5. HER2 IHC 3+ vs 2+ differentiated decisions: DESTINY-PanTumor02 BTC cohort IHC 3+ ORR 56% vs IHC 2+ 20% (PMID 37870536) — suggesting IHC score should be a stratification variable for treatment intensity, but a unified algorithm integrating IHC + ISH + NGS is missing.
6. MSI-H in BTC only 2-3%: KEYNOTE-158 BTC ORR 40.9% (PMID 31682550) is significant but N=22 too small; does BTC need a microsatellite + TMB + dMMR IHC tripartite panel to improve detection?
7. High-risk GBC adjuvant CRT with GemCis vs capecitabine choice: OSTWAL 2024 (PMID 38958997, India, GemCis + CRT positive) vs SWOG-S0809 (PMID 25964250, US, GemCap + CRT single-arm) — head-to-head between the two different chemo backbones is missing.
8. GEMSTONE-202 absent: China sugemalimab + GemCis 1L phase III data reported positive at ASCO GI 2024-2025 but manuscript and NCT registration both untraceable as of 2026-04; Chinese IO + GemCis practice evidence lacks a rigid 1L benchmark.
9. NRG1 / KRAS G12C / RET fusion in BTC cohorts too small: ENRGY BTC subgroup n=3-5, KRYSTAL-1-BTC n=12, LIBRETTO-001 BTC n=7 — all tumor-agnostic basket subsets, lacking BTC-only confirmatory data.
10. Late-line (3L+) BTC data nearly blank: all phase III concentrated on 1L/2L; beyond 3L there is no standard regimen, no large RCT, no ctDNA-guided treatment rotation protocol.

5. 2024-2026 latest developments

5.1 FDA / NMPA new approvals (ten key entries)

(This section shows 10 key approvals; the complete BTC-related approval record also includes dabrafenib + trametinib tumor-agnostic 2022 / pembrolizumab MSI-H 2017 / dostarlimab dMMR 2021 / larotrectinib 2018 / entrectinib 2019 / selpercatinib + pralsetinib RET tumor-agnostic 2022 / adagrasib NSCLC KRAS G12C 2022 and other tumor-agnostic pathways)

5.2 Key conference readouts (2024-2026, lower-weighted tagging)

The following entries are candidate-pool only before formal peer review, not in the main database. Those with PMIDs have been promoted to the main database.

• FIGHT-302 ESMO 2024 oral (Bekaii-Saab et al.): 1L FGFR2+ ICC pemigatinib vs GemCis PFS-positive readout; full OS / ORR / safety manuscript still not published in a peer-reviewed journal as of 2026-04 — will rewrite the §3.2 decision tree once published.
• GEMSTONE-202 ASCO GI 2024-2025 (CStone Pharmaceuticals): China sugemalimab + GemCis 1L phase III positive readout — manuscript and NCT ID both untraceable as of 2026-04.
• TRIDENT-1 long-term follow-up (TRK-naive BTC subgroup data): awaiting 2026 H2 update.
• ACTICCA-1 interim safety (reported 2024-2025): no primary readout yet, awaiting 2026-2027 H1.
• HERIZON-BTC-302 phase III (zanidatamab 1L in HER2+ BTC): ongoing, readout awaited 2027+.

5.3 Ongoing phase III (2025-2028 readout highlights)

• FIGHT-302 (NCT03656536, pemigatinib 1L vs GemCis in FGFR2+ ICC) — 2026 H2 full manuscript expected
• ACTICCA-1 (NCT02170090, GemCis vs capecitabine adjuvant head-to-head) — 2026-2027 primary completion
• HERIZON-BTC-302 (zanidatamab 1L combination phase III in HER2+ BTC) — 2027+
• GEMSTONE-202 (China sugemalimab + GemCis 1L) — manuscript pending publication
• Multiple IDH1 / FGFR2 / HER2 / NRG1 / KRAS G12C confirmatory phase III / single-arm registrational trials ongoing for 2026-2028

6. Convergent insights and judgments

6.1 Vertical × Horizontal: the 2026 BTC landscape is shaped by three “resonances”

Overlaying vertical paradigm evolution and horizontal current decision landscape, the 2026 BTC landscape is a superposition of three resonances:

1. GemCis dominates 12 years → IO double-hit class effect (HR 0.80-0.83 narrow-band convergence): the GemCis uniform standard starting from ABC-02 in 2010 persisted for 12 years, rewritten simultaneously by TOPAZ-1 + KEYNOTE-966 using two independent PD-(L)1 inhibitors — HR converging at 0.80-0.83 this narrow band is the textbook definition of class effect. Homologous to the pembro + chemo / atezo + chemo multi-IO class effect in NSCLC.
2. 8 biomarker-matched pathways in parallel + three-subtype biomarker enrichment differences: FGFR2 / IDH1 enriched in ICC 10-20%, HER2 enriched in GBC 15-20%, BRAF / NTRK / MSI-H / NRG1 / KRAS G12C / RET shared cross-subtype. Collectively covering 30-40% of patients — this density is second only to NSCLC (10+ biomarkers covering 50%+), far exceeding HCC (0 biomarkers) and pancreatic cancer (POLO + 5%). BTC is the second GI tumor after NSCLC to truly enter the “molecular-selected first” era.
3. Three-path adjuvant parallelism + East-West divergence: capecitabine (BILCAP, West), S-1 (ASCOT, Asia), GemCis-CRT (SWOG-S0809 / OSTWAL 2024, R1/N+ ECC/GBC) three paths + ACTICCA-1 head-to-head pending. East-West BTC is not only epidemiologically different (Asia GBC-heavy / West ICC-heavy / India high-risk GBC), but treatment selection itself diverges East-West.

These three resonances together explain one clinical phenomenon: the 1L decision tree for a newly diagnosed advanced BTC patient in 2026 has 4 more decision layers than in 2018 (subtype classification → full-panel molecular testing → IO + GemCis vs FGFR2-selective 1L → Chinese / Western IO selection + clinical trial enrollment).

6.2 Clinical decision takeaways (for junior-mid oncologists)

1. “Panel first, then decide” is already SoC: in 2026, starting IO + GemCis for a newly diagnosed advanced BTC without comprehensive molecular profiling is wrong — missing any of FGFR2 / IDH1 / HER2 / BRAF / MSI-H / NRG1 / KRAS G12C / RET equals missing an ORR 30-50% response path.
2. Advanced 1L defaults to IO + GemCis class effect: durvalumab + GemCis (TOPAZ-1) and pembrolizumab + GemCis (KEYNOTE-966), choose one, HR converging 0.80-0.83. Do not use GemCis monotherapy as 1L SoC anymore.
3. Triplet 1L rejected by three independent phase III: SWOG-1815 (add nab-pac) / AMEBICA (switch to mFFX) / KHBO1401-MITSUBA (add S-1) all failed — do not try triplet combinations replacing the GemCis backbone again.
4. 2026 adjuvant default capecitabine (West) / S-1 (Asia): GEMOX and gemcitabine monotherapy adjuvant exit the recommendation (PRODIGE-12 / BCAT negative, IPD meta reaffirmed). Reassess whether to switch to GemCis only after ACTICCA-1 readout.
5. R1 / N+ ECC/GBC add CRT: SWOG-S0809 (ECC + GBC) and OSTWAL 2024 (GBC only) supporting data — not universal adjuvant, but high-risk subgroup intensification.
6. ICC patients: focus on FGFR2 + IDH1 + BRAF V600E triad: ICC is the most precision-therapy-dense subtype; any one positive in the triad opens a phase III-level targeted path.
7. GBC patients: HER2 IHC + ISH must-test: GBC is BTC’s second-largest precision niche; HER2+ GBC has 4 mechanistically distinct targeted options (zanidatamab / T-DXd / tucatinib + trastuzumab / pertuzumab + trastuzumab) to choose from.
8. 2L FOLFOX is default + note East-West nal-IRI divergence: mFOLFOX + ASC (ABC-06) is global default. Do not extrapolate NIFTY Korean PFS-positive to the West — NALIRICC was OS-negative borderline in Germany.
9. Late-line IO monotherapy recommended only for MSI-H / dMMR / TMB-H: in unselected populations IO monotherapy ORR 22% looks useful but PFS is short (KIM-2020-NIVO-BTC); use only after biomarker selection.
10. The 9 BTC drug classes to know in 2026: durvalumab + pembrolizumab + GemCis (1L backbone) / mFOLFOX (2L) / pemigatinib + futibatinib + erdafitinib (FGFR2) / ivosidenib (IDH1) / zanidatamab + T-DXd + tucatinib + trastuzumab + pertuzumab + trastuzumab (HER2) / dabrafenib + trametinib (BRAF V600E) / pembrolizumab + dostarlimab (MSI-H) / zenocutuzumab (NRG1) / adagrasib (KRAS G12C) / selpercatinib + pralsetinib (RET) / larotrectinib + entrectinib + repotrectinib (NTRK) — 16 years ago BTC had only the GemCis one-size-fits-all option; 2026 is already a complex decision map of 16+ drugs and 8 parallel precision pathways.

7. Information sources

The metadata of the 39 trials in this report was independently verified via PubMed and ClinicalTrials.gov. Each [PMID xxxxxxxx] in the text can be directly verified on PubMed.

• Published trials: 37, covering 2010-2026 (all PMID-verifiable)
• Ongoing / design papers: 2 (FIGHT-302 PMID 32677452 design paper + ACTICCA-1 PMID 26228433 design paper, primary-result manuscripts pending)
• NCCN guideline citations: 39/39 directly hit NCCN Biliary Tract Cancers V1.2026 reference section or extended evidence base
• 2017-2024 FDA new approvals: 10+ (durvalumab / pembrolizumab + GemCis / pemigatinib / futibatinib / erdafitinib / ivosidenib / zanidatamab / T-DXd / zenocutuzumab / repotrectinib / dabrafenib + trametinib / larotrectinib / entrectinib / selpercatinib / pralsetinib / pembrolizumab + dostarlimab MSI-H / dMMR / nivo + ipi TMB-H and other tumor-agnostic pathways)
• 2024-2026 key conference readouts: 3 (FIGHT-302 ESMO 2024 / GEMSTONE-202 ASCO GI 2024-2025 / TRIDENT-1 long-term follow-up) — awaiting manuscript upgrade
• Supporting PMIDs (cited in text but not in main trial table): 3 (ClarIDHy OS update PMID 34554208 / KEYNOTE-158 long-term follow-up PMID 35680043 / BCAT + PRODIGE-12 IPD meta PMID 35182925)
• Research gaps: 10

7.1 Report-body citation list (sorted by PMID)

The table below lists the PMIDs bracket-cited in the report body, each clickable for PubMed URL verification.

7.2 Verification conventions

• Each PMID is directly accessible for verification via https://pubmed.ncbi.nlm.nih.gov/{PMID}/
• Each NCT id is accessible via https://clinicaltrials.gov/study/{NCT_id}/
• Conference abstracts (ASCO GI / ESMO / EORTC) are searched via official conference systems; all conference citations in this report are lower-weight tagged — not peer-reviewed, final data defers to journal publication
• FIGHT-302 / ACTICCA-1 are cited via “design-paper PMID + ESMO/ASCO oral readout” before manuscript publication; the PMID will be updated once the formal manuscript is published
• If you find a trial name / year / conclusion in this report inconsistent with PubMed for any PMID, corrections are welcome

The trial timeline lives here

Chinese: /trials/btc/ English: /en/trials/btc/

Each trial has an independent detail page, including:

• Full intervention / comparator regimens
• Primary endpoint values + 95% CI
• Key findings + clinical significance
• Clickable links to PMID / NCT original sources

39 trials · 4 chapters · 2010 to 2026 · synced with NCCN Biliary Tract Cancers V1.2026.

Closing

BTC has undergone a unique evolution in oncology over the past 16 years — from 2010’s ABC-02 enshrining GemCis as 1L unchallenged for 12 years, to 2022-2023’s TOPAZ-1 + KEYNOTE-966 writing IO into the 1L backbone with a narrow-band HR 0.80-0.83 class effect, to 2018-2026’s dense rollout of eight-to-nine biomarker-matched pathways (FGFR2 / IDH1 / HER2 / BRAF / NTRK / MSI-H / NRG1 / KRAS G12C / RET) covering 30-40% of patients.

BTC’s precision-therapy density is second only to NSCLC, far exceeding HCC (0 biomarker-matched approvals) and pancreatic cancer (POLO + 5%). What drives this difference is not incidence (BTC global incidence <3/100,000, well below gastric / liver cancers), but the uniqueness of molecular architecture — ICC enriched for FGFR2 fusion + IDH1 mutation, GBC enriched for HER2 amp, three subtypes sharing the MSI-H / BRAF / NTRK / NRG1 / KRAS G12C / RET tumor-agnostic basket pathways. This “subtype × biomarker dual heterogeneity” makes BTC a “PMID-traceable + mandatory-panel + multi-pathway-parallel” highly-precise tumor type.

The value of this report lies not in “exhaustively listing all trials” (PubMed can), but in compressing 16 years of evolution + current decisions + unresolved gaps into the cognitive bandwidth of a single read. Next time you face a newly diagnosed BTC patient, every branch of the decision tree will have this map to consult, trace, and question.

Clinician × AI = Research Superpower + Clinical Decision Amplifier

—— Dual Brain Lab · 2026-04-21