Precision Therapy on Dual Brain Lab

Biliary Tract Cancer Clinical Trial Timeline: A 16-Year Evolution Map

Tue, 21 Apr 2026 00:00:00 +0000

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.

Subgroup	Preferred	Alternative
All-comers PD-L1 unselected fit	durvalumab + GemCis [TOPAZ-1 PMID 38319896] or pembrolizumab + GemCis [KEYNOTE-966 PMID 37075781]	GemCis alone (when IO is not tolerated)
FGFR2 fusion+ ICC	(current) IO + GemCis; (once FIGHT-302 manuscript published) pemigatinib 1L replacement [FIGHT-302 PMID 32677452 ESMO 2024]	IO + GemCis fallback
Chinese / Asian patients	durvalumab / pembrolizumab + GemCis	Awaiting GEMSTONE-202 manuscript
ECOG 2 / IO-intolerant	GemCis alone [ABC-02 PMID 20375404]	Gemcitabine monotherapy (most frail)

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

Biomarker	BTC-enriched subtype	Prevalence (BTC overall / enriched subtype)	Preferred drug (FDA approval status)	Key trial
FGFR2 fusion / rearrangement	ICC	~10-15% ICC	pemigatinib (2020-04 FDA accelerated) / futibatinib (2022-09) / erdafitinib (2024-09 tumor-agnostic)	FIGHT-202 [PMID 32203698] / FOENIX-CCA2 [PMID 36652354] / RAGNAR [PMID 37541273]
IDH1 R132 mutation	ICC	~10-20% ICC	ivosidenib (2021-08 FDA approved)	ClarIDHy [PMID 32416072]
HER2 amp / overexp	GBC	~15-20% GBC	zanidatamab (2024-08 FDA accelerated) / T-DXd (2024-04 tumor-agnostic) / tucatinib + trastuzumab (off-label) / pertuzumab + trastuzumab	HERIZON-BTC-01 [PMID 37276871] / DESTINY-PanTumor02 [PMID 37870536] / SGNTUC-019 [PMID 37751561] / MyPathway-BTC [PMID 34339623]
BRAF V600E	ICC	~3-5% ICC	dabrafenib + trametinib (2022 tumor-agnostic)	ROAR-BTC [PMID 32818466] / NCI-MATCH-H [PMID 32758030]
NTRK fusion	cross-subtype	<1% BTC	larotrectinib / entrectinib / repotrectinib (next-gen)	NAVIGATE [PMID 29466156] / STARTRK [PMID 31838007] / TRIDENT-1 [PMID 41639379]
MSI-H / dMMR	cross-subtype	~2-3% BTC	pembrolizumab / dostarlimab	KEYNOTE-158 [PMID 31682550] / ANDRE-2023 [PMID 37917058]
TMB-H	cross-subtype	~3-5% BTC	nivolumab + ipilimumab	CHECKMATE-848 [PMID 39107131]
NRG1 fusion	cross-subtype (KRAS-WT enriched)	<1% BTC	zenocutuzumab (2024-08 FDA accelerated)	ENRGY [PMID 39908431]
KRAS G12C	cross-subtype	~1-2% BTC	adagrasib	KRYSTAL-1-BTC [PMID 37099736]
RET fusion	cross-subtype	<1% BTC	selpercatinib / pralsetinib (tumor-agnostic)	LIBRETTO-001 [PMID 36108661] / ARROW-BTC [PMID 35962206]

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:

Subtype	Enriched biomarker	Priority precision testing	Notes
ICC (intrahepatic cholangiocarcinoma)	FGFR2 fusion 10-15% / IDH1 mutation 10-20% / BRAF V600E 3-5%	FGFR2 + IDH1 + BRAF V600E triad	ICC is the most precision-therapy-dense BTC subtype
GBC (gallbladder cancer)	HER2 amp / overexp 15-20%	HER2 IHC + ISH must-test	GBC + HER2 = BTC’s second-largest precision niche; OSTWAL 2024 suggests GemCis-CRT intensification in high-risk GBC adjuvant
ECC (extrahepatic cholangiocarcinoma)	no single obvious enriched biomarker	comprehensive NGS looking for BRAF / NTRK / MSI-H / NRG1 / RET	ECC has the lowest precision hit rate; SWOG-S0809 CRT intensification in R1 / N+ setting
Three subtypes shared	MSI-H ~2-3% / NTRK <1% / NRG1 <1% / KRAS G12C ~1-2% / RET <1%	tumor-agnostic basket pathways	shared cross-subtype, not subtype-restricted

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”):

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.
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.”
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.
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.
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.
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?
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.
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.
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.
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)

Drug	Agency	Date	Indication / supporting trial
zanidatamab (Ziihera)	FDA	2024-08-29	2L+ HER2 amp BTC / HERIZON-BTC-01 [PMID 37276871]
pembrolizumab + GemCis	FDA	2023-10-31	1L advanced BTC (regardless of PD-L1) / KEYNOTE-966 [PMID 37075781]
durvalumab + GemCis	FDA	2022-09-02	1L advanced BTC (regardless of PD-L1) / TOPAZ-1 [PMID 38319896]
trastuzumab deruxtecan (Enhertu)	FDA	2024-04-05	tumor-agnostic HER2 IHC 3+ solid tumors (including BTC) / DESTINY-PanTumor02 [PMID 37870536]
futibatinib (Lytgobi)	FDA	2022-09-30	2L+ FGFR2 rearrangement+ ICC / FOENIX-CCA2 [PMID 36652354]
erdafitinib (Balversa)	FDA	2024-09-23	tumor-agnostic FGFR-altered solid tumors (including BTC) / RAGNAR [PMID 37541273]
zenocutuzumab (Bizengri)	FDA	2024-08-26	NRG1 fusion+ NSCLC and pancreatic cancer (tumor-agnostic data supports BTC) / ENRGY [PMID 39908431]
ivosidenib (Tibsovo)	FDA	2021-08-25	2L+ IDH1+ CCA / ClarIDHy [PMID 32416072]
pemigatinib (Pemazyre)	FDA	2020-04-17	2L+ FGFR2+ CCA / FIGHT-202 [PMID 32203698]
repotrectinib (Augtyro)	FDA	2023-11-15	tumor-agnostic NTRK fusion+ solid tumors (BTC applicable) / TRIDENT-1 [PMID 41639379]

(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:

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.
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.
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)

“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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

PMID	Trial / Paper	Year	Journal	Text location
20375404	ABC-02	2010	NEJM	§2.2 / §3.2
25964250	SWOG-S0809	2015	J Clin Oncol	§2.1 / §3.3
26228433	ACTICCA-1 (design paper)	2015	BMC Cancer	§2.1 / §2.5 / §3.3 / §4
29405274	BCAT	2018	Br J Surg	§2.1 / §3.3
29466156	NAVIGATE-LAROTRECTINIB	2018	NEJM	§2.4.5 / §3.4
30561756	SUN-2019-REGO-BTC	2019	Cancer	§2.3 / §3.5
30707660	PRODIGE-12	2019	J Clin Oncol	§2.1 / §3.3
30922733	BILCAP	2019	Lancet Oncol	§2.1 / §3.3
31682550	KEYNOTE-158-MSIH	2020	J Clin Oncol	§2.4.6 / §3.4 / §4
31838007	STARTRK-ENTRECTINIB	2020	Lancet Oncol	§2.4.5 / §3.4
32203698	FIGHT-202	2020	Lancet Oncol	§2.4.1 / §3.4 / §5.1
32352498	KIM-2020-NIVO-BTC	2020	JAMA Oncol	§2.3 / §6.2
32416072	ClarIDHy (primary)	2020	Lancet Oncol	§2.4.2 / §3.4 / §5.1
32677452	FIGHT-302 (design paper)	2020	Future Oncol	§2.4.1 / §2.5 / §3.2 / §4
32758030	NCI-MATCH-H	2020	J Clin Oncol	§2.4.4 / §3.4
32818466	ROAR-BTC	2020	Lancet Oncol	§2.4.4 / §3.4
33798493	ABC-06	2021	Lancet Oncol	§2.3 / §3.5
34339623	MyPathway-BTC	2021	Lancet Oncol	§2.4.3 / §3.4
34554208	ClarIDHy OS update	2021	JAMA Oncol	§2.4.2 (supporting)
34662180	AMEBICA / PRODIGE-38	2022	J Clin Oncol	§2.2 / §3.2
35182925	BCAT + PRODIGE-12 IPD meta	2022	Eur J Cancer	§2.1 (supporting) / §3.3
35680043	KEYNOTE-158 long-term follow-up	2022	Ann Oncol	§2.4.6 (supporting)
35900311	KHBO1401-MITSUBA	2023	J Hepatobiliary Pancreat Sci	§2.2 / §3.2
35962206	ARROW-BTC	2022	Nat Med	§2.4.9 / §3.4
36108661	LIBRETTO-001-BTC	2022	Lancet Oncol	§2.4.9 / §3.4
36652354	FOENIX-CCA2	2023	NEJM	§2.4.1 / §3.4 / §5.1
36681415	ASCOT / JCOG1202	2023	Lancet	§2.1 / §3.3
36951834	NIFTY	2023	JAMA Oncol	§2.3 / §3.5 / §4
37075781	KEYNOTE-966	2023	Lancet	§2.2 / §3.2 / §5.1
37099736	KRYSTAL-1-BTC	2023	J Clin Oncol	§2.4.8 / §3.4
37276871	HERIZON-BTC-01	2023	Lancet Oncol	§2.4.3 / §3.4 / §5.1
37541273	RAGNAR	2023	Lancet Oncol	§2.4.1 / §3.4 / §5.1
37751561	SGNTUC-019	2023	J Clin Oncol	§2.4.3 / §3.4
37870536	DESTINY-PanTumor02	2024	J Clin Oncol	§2.4.3 / §3.4 / §4 / §5.1
37917058	ANDRE-2023-DOSTARLIMAB	2023	JAMA Netw Open	§2.4.6 / §3.4
38319896	TOPAZ-1	2022	NEJM Evid	§2.2 / §3.2 / §5.1
38870977	NALIRICC	2024	Lancet Gastroenterol Hepatol	§2.3 / §3.5 / §4
38958997	OSTWAL-2024-GEMCIS-CRT-GBC	2024	JAMA Oncol	§2.1 / §3.3 / §4
39107131	CHECKMATE-848	2024	J Immunother Cancer	§2.4.6 / §3.4
39671534	SWOG-1815	2025	J Clin Oncol	§2.2 / §3.2 / §6.2
39908431	ENRGY	2025	NEJM	§2.4.7 / §3.4 / §5.1
41639379	TRIDENT-1	2026	Nat Med	§2.4.5 / §3.4 / §5.1

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

Pancreatic Cancer Clinical Trial Timeline: A 30-Year Evolution Map

Mon, 20 Apr 2026 00:00:00 +0000

Pancreatic Cancer Clinical Trial Timeline: An In-depth Report

Curated by Dual Brain Lab (csilab.net) Data cutoff: 2026-04 · Latest trial: RASolute-302 (ASCO GI 2026 topline)

1. One-sentence definition

This report maps the evolutionary logic and current decision landscape of landmark clinical trials in pancreatic ductal adenocarcinoma (PDAC) systemic therapy over the past 30 years (1994-2026), as cited in NCCN Pancreatic Adenocarcinoma V1.2026 (Principles of Systemic Therapy, PANC-G 13 pages, 52 references). The goal: give frontline clinicians a traceable panoramic map for “who, what, why” decisions at the 2026 time point.

Iron rule: every data point for every trial is traceable to PubMed (PMID) or ClinicalTrials.gov (NCT id) — each [PMID xxxxxxxx] in the text can be clicked to verify the PubMed original.

2. Longitudinal axis: six paradigm shifts over 30 years

PDAC systemic therapy has gone through six paradigm shifts in the past 30 years: adjuvant chemo upgraded from observation to gemcitabine, then to mFOLFIRINOX (mFFX, modified triplet), pushing OS from 18 to 54 months → advanced 1L formed the FOLFIRINOX / GnP chemo duopoly, rewritten a decade later by NAPOLI-3 → neoadjuvant / locally advanced three-path contention → advanced 2L from total failure to nal-IRI breakthrough → biomarker-matched sparse tiles (BRCA / MSI-H / NRG1 / NTRK) covering <10% of patients → KRAS three subtypes cracked open (G12C / G12D / pan-KRAS), with RASolute-302 in 2026 pushing 2L HR down to 0.40 for the first time.

Each shift rests on 1-3 phase III pivots. But compared to NSCLC’s five paradigm shifts, each PDAC shift is smaller in magnitude — the underlying biology differs: NSCLC runs on the “driver gene + immunotherapy” dual engine; PDAC faces a triple stranglehold of “90% KRAS trunk + stromal barrier + cold tumor”.

2.1 Adjuvant chemo evolution (1994-2023): observation → gemcitabine → mFOLFIRINOX

Story: before 1997 the PDAC post-op adjuvant standard was observation; CONKO-001 put gemcitabine on the standard shelf; ESPAC-4 won with combinations over monotherapy; PRODIGE-24 then used mFFX to push OS from 35 to 54.4 months — one real turnaround in 30 years. APACT delivered a lesson: what wins in the advanced setting (GnP) doesn’t necessarily win as adjuvant.

ESPAC-1 [PMID 15028824] (Neoptolemos 2004 NEJM, N=289, European 2×2 factorial): adjuvant chemotherapy (5-FU + leucovorin) significantly improved OS (mOS 20.1 vs 15.5 months, HR 0.71, p=0.009); adjuvant chemoradiation was potentially harmful (HR 1.28, p=0.05 adverse trend). This shifted European adjuvant practice from the GITSG-era chemoradiation preference to “chemo-first / radiation with caution.”
CONKO-001 [PMID 23982521] (Oettle 2013 JAMA long-term follow-up, N=368): gemcitabine vs observation. DFS median 13.4 vs 6.7 months (HR 0.55, p<0.001); 5-year OS 20.7% vs 10.4%, 10-year OS 12.2% vs 7.7%. First established adjuvant gemcitabine as the global standard, becoming the control for all subsequent adjuvant trials.
ESPAC-3 [PMID 20823433] (Neoptolemos 2010 JAMA, N=1088): gemcitabine vs 5-FU + leucovorin. mOS 23.6 vs 23.0 months (HR 0.94, p=0.39), OS equivalent but gemcitabine had fewer serious adverse events (7.5% vs 14%). Gemcitabine’s safety advantage locked it as the subsequent comparator.
ESPAC-4 [PMID 28129987] (Neoptolemos 2017 Lancet, N=732): gemcitabine + capecitabine vs gemcitabine monotherapy. mOS 28.0 vs 25.5 months (HR 0.82, p=0.032). Combination regimens beat monotherapy for the first time; from 2017 Europe widely adopted GemCap as adjuvant standard.
JASPAC-01 [PMID 27275872] (Uesaka 2016 Lancet, N=385): S-1 vs gemcitabine adjuvant, Japanese multicenter. mOS 46.5 vs 25.5 months (HR 0.57, p<0.0001) — S-1 a major win. Asian PDAC adjuvant standard diverged from Western practice (S-1-associated GI toxicity is better tolerated in Asian populations).
PRODIGE-24 / CCTG PA.6 [PMID 30575490] (Conroy 2018 NEJM, N=493): mFOLFIRINOX (oxaliplatin + irinotecan + leucovorin + 5-FU, modified doses) vs gemcitabine adjuvant. DFS 21.6 vs 12.8 months (HR 0.58, p<0.0001); mOS 54.4 vs 35.0 months (HR 0.64, p=0.003). This is the only time in 30 years of PDAC adjuvant trials that mOS was pushed past 4 years. From then on mFFX became the preferred adjuvant regimen for fit patients (ECOG 0-1).
APACT [PMID 36521097] (Reni 2023 JCO, N=866): nab-paclitaxel + gemcitabine vs gemcitabine adjuvant. Independently assessed DFS missed the primary endpoint (HR 0.88, p=0.18). OS (secondary endpoint) HR 0.82, p=0.045 showed statistical significance but FDA held firm on primary endpoint, denying the adjuvant indication. APACT’s lesson: what wins in the advanced setting (GnP in MPACT) doesn’t necessarily win as adjuvant — the adjuvant scenario demands a higher effect-size threshold.
PACT-15 [PMID 33301741] (Reni 2021 Lancet Gastro Hepatol, N=88, Italy): adjuvant PEXG (cisplatin+epirubicin+gemcitabine+capecitabine) vs gemcitabine. Phase IIb small-sample showed PEXG advantage, but did not enter global guidelines (insufficient sample size).

Takeaway: adjuvant PDAC evolved from “whether to treat” to “which combination.” In 2026 fit patients get mFFX (PRODIGE-24) as first choice; those who can’t tolerate or are older get GemCap (ESPAC-4) or gemcitabine monotherapy (CONKO-001); Asian populations may consider S-1 (JASPAC-01). Nab-paclitaxel + gemcitabine (APACT) is not recommended for adjuvant use.

2.2 Advanced 1L chemo duopoly (2011-2023): FOLFIRINOX / GnP coexist for a decade → NAPOLI-3 rewrites

Story: before 2011 advanced 1L PDAC had only gemcitabine monotherapy. PRODIGE-4 and MPACT, within two years, established two completely different toxicity-profile regimens (a triplet and a doublet), and no one dislodged them for a decade. Not until 2023, when NAPOLI-3 brought liposomal irinotecan (nal-IRI) into 1L, did the first challenger appear.

PRODIGE-4 / ACCORD-11 [PMID 21561347] (Conroy 2011 NEJM, N=342): FOLFIRINOX (oxaliplatin+irinotecan+leucovorin+5-FU) vs gemcitabine. mOS 11.1 vs 6.8 months (HR 0.57, p<0.001), ORR 31.6% vs 9.4%. Toxicity notable: grade 3/4 neutropenia 45.7%, diarrhea 12.7%. First choice for fit patients (ECOG 0-1), but not suitable for >75 years / elevated bilirubin / poor performance status.
MPACT [PMID 24131140] (Von Hoff 2013 NEJM, N=861): nab-paclitaxel + gemcitabine (GnP) vs gemcitabine. mOS 8.5 vs 6.7 months (HR 0.72, p<0.001), ORR 23% vs 7%. Relatively mild toxicity; patients with ECOG 2 or comorbidities may be considered. Became the other PDAC 1L pillar for a decade.
GEST [PMID 23547081] (Ueno 2013 JCO, N=834, Japan): gemcitabine vs S-1 vs GS (gemcitabine+S-1). S-1 monotherapy non-inferior to gemcitabine on OS (mOS 9.7 vs 8.8 months, HR 0.88, non-inferiority boundary met). Evidence base for Asian 1L monotherapy regimens.
CCTG PA.7 [PMID 36028483] (O’Callaghan 2022 Nature Communications, N=180): GnP ± durvalumab + tremelimumab. Primary endpoint OS negative (mOS 9.8 vs 8.8 months, HR 0.94, p=0.72). Reconfirmed that PDAC is a “cold tumor”; dual checkpoint blockade is ineffective in unselected populations.
NAPOLI-3 [PMID 37708904] (Wainberg / O’Reilly 2023 Lancet, N=770): NALIRIFOX (liposomal irinotecan + oxaliplatin + leucovorin + 5-FU) vs GnP as 1L. mOS 11.1 vs 9.2 months (HR 0.83, p=0.036), mPFS 7.4 vs 5.6 months. FDA approved as 1L standard in February 2024. First regimen in ten years proven better than GnP in 1L — though HR 0.83 is a marginal win.

Takeaway: 2026 advanced PDAC 1L decision tree — ECOG 0-1 choose FOLFIRINOX or NALIRIFOX (the latter just FDA-approved, real-world accessibility and reimbursement still rolling out); ECOG 2 or heavy comorbidity choose GnP; monotherapy only when very frail (gemcitabine or S-1). Dual checkpoint blockade in unselected populations is not recommended.

2.3 Neoadjuvant and locally advanced (2013-2024): three paths, still no verdict

Story: for resectable / borderline resectable / locally advanced PDAC, the optimal strategy for timing of surgery and integration of chemoradiation has been the most controversial area in PDAC for ten years. PREOPANC-1 established feasibility of neoadjuvant chemoradiation; Alliance A021501 showed SBRT doesn’t add value; PREOPANC-2 brought mFFX into neoadjuvant; NORPACT-1 issued a warning: neoadjuvant is not good for everyone.

LAP07 [PMID 27139057] (Hammel 2016 JAMA, N=449): locally advanced PDAC induction gemcitabine (± erlotinib) for 4 months, then stable/responders randomized to continued chemo vs capecitabine concurrent chemoradiation. Primary endpoint OS negative (mOS 16.5 vs 15.2 months, HR 1.03, p=0.83). Chemoradiation added to locally advanced PDAC showed no OS benefit, but LRPF (locoregional progression-free interval) extended by 7.6 months.
SCALOP [PMID 23474363] (Mukherjee 2013 Lancet Oncol, N=74): locally advanced PDAC induction gemcitabine + capecitabine for 12 weeks, then concurrent chemoradiation phase compared capecitabine vs gemcitabine as radiosensitizer. mOS 15.2 vs 13.4 months (adjusted HR 0.39, p=0.012) — capecitabine significantly better. From then on capecitabine became the preferred radiosensitizer in the locally advanced PDAC chemoradiation phase.
SCALOP-2 [PMID 34048677] (Mukherjee 2021 JCO, N=170): locally advanced PDAC post-induction ± nelfinavir (HIV protease inhibitor as radiosensitizer). Primary endpoint negative. The chemoradiation + sensitizer approach failed.
Alliance A021501 [PMID 35834226] (Katz / O’Reilly 2022 JAMA Oncology, N=126): resectable / borderline resectable PDAC neoadjuvant mFOLFIRINOX 8 cycles vs mFOLFIRINOX 7 cycles + SBRT. SBRT arm had worse 18-month OS (47.3% vs 66.7%). SBRT boost did not improve outcomes, and may even have harmed them. The borderline-resectable neoadjuvant SBRT concept was rejected.
PREOPANC-1 [PMID 35188492] (Versteijne 2022 JCO, N=246, long-term follow-up): borderline resectable / resectable PDAC neoadjuvant gemcitabine concurrent chemoradiation vs upfront surgery. 5-year OS 20.5% vs 6.5% (HR 0.73, p=0.025). Neoadjuvant chemoradiation showed OS benefit in long-term follow-up.
ESPAC-5F [PMID 37103886] (Ghaneh 2023 JAMA Oncology, N=90, pilot): borderline resectable PDAC neoadjuvant FOLFIRINOX / GemCap / chemoradiation vs upfront surgery. 1-year OS neoadjuvant chemo arm (any regimen) 77% vs upfront surgery 40%. Pilot sample small but direction clear — for borderline resectable, neoadjuvant chemo beats upfront surgery.
PREOPANC-2 [PMID 39500336] (Janssen 2024 Lancet, N=375): borderline resectable / resectable PDAC neoadjuvant mFOLFIRINOX 8 cycles vs neoadjuvant gemcitabine concurrent chemoradiation. Primary endpoint OS equivalent (HR 0.87, p=0.28). The two neoadjuvant paths are evenly matched; neither dominates.
NORPACT-1 [PMID 38237621] (Lassen 2024 Lancet Gastroenterology & Hepatology, N=140, Nordic): resectable pancreatic head cancer neoadjuvant FOLFIRINOX 4 cycles vs upfront surgery. Primary endpoint OS negative (mOS 25.1 vs 38.5 months, HR 1.52, p=0.0468 — direction “unfavorable”). For resectable (not borderline) PDAC, neoadjuvant FOLFIRINOX may delay surgery and harm outcomes. A warning that “neoadjuvant” is not suitable for all surgical candidates.
Alliance A021806 [PMID 39048905] (Katz 2024 design/update paper, ongoing): resectable PDAC perioperative mFOLFIRINOX vs adjuvant mFOLFIRINOX head-to-head. Primary not yet readout — this will be the first phase III to systematically answer “pre-op vs post-op chemo in resectable PDAC.”

Takeaway: 2026 neoadjuvant / locally advanced PDAC has no global consensus. Borderline resectable leans toward neoadjuvant chemo (PREOPANC-1/2 support, ESPAC-5F points the same way); for resectable pancreatic head cancer NORPACT-1 warns against casually giving neoadjuvant FFX; locally advanced chemoradiation serves locoregional control only (LAP07 OS neutral); SBRT boost neoadjuvant Alliance A021501 rejected; sensitizer approach SCALOP-2 rejected.

2.4 Advanced 2L and beyond (2014-2016): from total failure to nal-IRI breakthrough

Story: before 2016 advanced PDAC 2L had no standard regimen. CONKO-003 and NAPOLI-1 within two years moved 2L from “wait to die” to “have options.” PANCREOX, meanwhile, reminded us via FOLFOX’s failure in Western cohorts that “East and West results may differ.”

CONKO-003 [PMID 24982456] (Pelzer 2014 JCO, N=168, Germany): after gemcitabine failure, OFF (oxaliplatin + 5-FU + leucovorin) vs 5-FU + leucovorin. mOS 5.9 vs 3.3 months (HR 0.66, p=0.010). First positive 2L RCT in Europe.
NAPOLI-1 [PMID 26615328] (Wang-Gillam 2016 Lancet, N=417): after gemcitabine failure, liposomal irinotecan (nal-IRI) + 5-FU/LV vs 5-FU/LV vs nal-IRI monotherapy. nal-IRI+5FU/LV arm mOS 6.1 vs 4.2 months (HR 0.67, p=0.012). First 2L regimen globally approved by FDA; nal-IRI entered the PDAC essential arsenal from then on.
PANCREOX [PMID 27621395] (Gill 2016 JCO, N=108, Canada): after gemcitabine failure, mFOLFOX6 vs 5-FU/LV. mOS 6.1 vs 9.9 months (HR 1.78, p=0.02) — the FOLFOX arm was worse. Suggests CONKO-003’s OFF result could not be reproduced in Western cohorts; FOLFOX is not recommended in Western 2L.

Takeaway: 2026 advanced PDAC 2L — nal-IRI + 5FU/LV (NAPOLI-1) is the only globally approved regimen; OFF (CONKO-003) is an option in Europe; FOLFOX is not recommended in Western populations (PANCREOX). The 2L OS ceiling still sits at 6 months — this is the floor that the KRAS revolution aims to break through.

2.5 On the eve of precision therapy: four tiles don’t make a wall (2019-2025)

Story: before KRAS was cracked, PDAC had four “rare but actionable” biomarkers accessible via basket trials: BRCA (POLO), MSI-H (KEYNOTE-158), NRG1 (eNRGy), NTRK (NAVIGATE / STARTRK / TRIDENT-1). Each covers <2-5% of patients, totaling under 10%. “First tile” points the way but is far from a wall.

POLO [PMID 31157963 / 35834777] (Golan 2019 NEJM / Kindler 2022 JCO final OS, N=154): gBRCA1/2-mutant advanced PDAC (~6% of patients), ≥16 weeks of 1L platinum chemo without progression → olaparib maintenance vs placebo. mPFS 7.4 vs 3.8 months (HR 0.53, p=0.004), but mOS 19.0 vs 19.2 months (HR 0.83, p=0.35) negative. First FDA-approved biomarker-driven treatment in PDAC; but the PFS-OS mismatch (PFS significant / OS neutral) exposed the clinical-significance limits of maintenance therapy.
KEYNOTE-158 (PDAC cohort) [PMID 31682550] (Marabelle / Diaz 2020 JCO, PDAC n=22): MSI-H / dMMR advanced solid tumor basket, pembrolizumab monotherapy. PDAC subgroup ORR 18.2%. MSI-H PDAC is only 1-2% of patients; sample tiny but supports the tumor-agnostic approval.
eNRGy (PDAC cohort) [PMID 39908431] (Schram 2025 NEJM, PDAC n=36): NRG1-fusion advanced solid tumor basket, zenocutuzumab (HER2×HER3 bispecific antibody). PDAC subgroup ORR 42% (15/36), mDoR 11.1 months. NRG1 incidence in PDAC ~0.5-1.5% (enriched in KRAS wild-type PDAC). FDA 2024-12 accelerated approval — first non-chemo non-PARP biomarker-matched targeted approval in PDAC.
larotrectinib (NAVIGATE / pooled) [PMID 32105622] (Hong 2020 Lancet Oncology): NTRK-fusion tumor-agnostic, PDAC n=3, responses seen in small samples. NTRK in PDAC <0.5%.
entrectinib (STARTRK-2 integrated) [PMID 31838007] (Doebele 2020 Lancet Oncology): another NTRK-fusion tumor-agnostic path; PDAC subpopulation also has n=3-level small data.
TRIDENT-1 (PDAC cohort) (Drilon et al., ROS1/NTRK integrated analysis, 2025 ongoing manuscript): repotrectinib (next-gen NTRK/ROS1 TKI). NCT04094610. PDAC subgroup case count very small; awaiting full publication.

Takeaway: in 2026 all newly diagnosed PDAC should undergo comprehensive molecular profiling (covering at least KRAS subtype / BRCA1/2 / MSI / NRG1 / NTRK / HER2 / BRAF) — this is an explicit NCCN V1.2026 recommendation. But adding up the “four tiles,” only 5-10% of patients can enter biomarker-matched therapy. 90%+ of PDAC is still waiting for KRAS or another trunk breakthrough.

2.6 KRAS cracked open (2023-2026): G12C → G12D → pan-KRAS, three subtypes

Story: KRAS mutation occurs in 90%+ of PDAC; “undruggable” was clinical dogma for 30 years. Starting in 2021 G12C inhibitors won in lung cancer first (CodeBreaK 200 / KRYSTAL-1 NSCLC); in 2023 baskets extended to PDAC; in 2024 Revolution Medicines’ RMC-6236 (pan-KRAS G12X) phase 1 PDAC data shook ASCO GI / ESMO; in April 2026 RASolute-302 phase 3 topline pushed PDAC 2L HR down to 0.40 for the first time — an effect size unseen in 30 years.

KRYSTAL-1 (PDAC cohort) [PMID 37099736] (Bekaii-Saab 2023 JCO, PDAC n=21): KRAS G12C PDAC (~1-2% of PDAC patients), adagrasib 600 mg BID. ORR 33% (7/21), mPFS 5.4 months, mOS 8.0 months. First evidence that KRAS G12C inhibitors reproduce the lung-cancer response pattern in PDAC.
CodeBreaK 100 (PDAC cohort) [PMID 36546651] (Strickler 2023 NEJM, PDAC n=38): KRAS G12C PDAC, sotorasib 960 mg QD. ORR 21% (8/38), mPFS 4.0 months. The second drug in the G12C class, equivalent to KRYSTAL. Together they turned KRAS G12C PDAC from “untreatable” into a ~25% response 2L+ standard.
MRTX1133 phase I (NCT05737706): KRAS G12D-selective inhibitor (Mirati / BMS). 2023 dose-escalation started, but in 2024 due to PK issues and formulation constraints, clinical development terminated. The G12D story appeared interrupted.
RMC-9805 (zoldonrasib) phase I (NCT06040541): Revolution Medicines’ KRAS G12D-selective next-gen molecule. First public data at EORTC-NCI-AACR 2024 late-breaking abstract: PDAC G12D 2L+ ORR ~30% (safety and tolerability data better than MRTX1133). FDA Breakthrough Designation. G12D story continues with a handoff.
RMC-6236 (daraxonrasib) phase I/Ib (NCT05379985): Revolution Medicines’ pan-KRAS G12X “tri-complex RAS(ON) inhibitor”, simultaneously covering G12D/G12V/G12C/G13D (~85% of KRAS PDAC). 2024 ESMO and 2025 ASCO GI released the PDAC 2L cohort (n≈60-80): ORR ~36%, mPFS ~8.5 months, mOS ~14.5 months — versus historical PDAC 2L mOS of 6 months, an unprecedented effect size.
RASolute-302 (phase III, NCT06625320): RMC-6236 monotherapy vs investigator’s choice (FOLFIRINOX / GnP) in 2L+ KRAS G12X PDAC. April 2026 ASCO GI topline: mOS 13.2 vs 6.7 months, HR 0.40, p<0.001. This is an HR magnitude unseen in 30 years of PDAC 2L (previous largest 2L effect size was NAPOLI-1 HR 0.67). Full manuscript expected in 2026 H2.
AMPLIFY-201 (ELI-002 KRAS vaccine) [PMID 38195752] (Pant 2024 Nat Medicine, N=25 phase I): adjuvant-stage mKRAS mRNA lymph-node-targeted vaccine. 84% of patients produced mKRAS-specific T cells; among ctDNA-positive patients, 21/25 showed immune-response-related ctDNA decrease or clearance. Phase II AMPLIFY-7P ongoing. Opening move in KRAS vaccine adjuvant therapy.

Takeaway: in 2026 KRAS has shifted from PDAC’s “undruggable” barrier to three subtypes, three paths — G12C (adagrasib / sotorasib, 1-2% of patients, 2L+); G12D (RMC-9805, ~40% of patients, phase I); pan-KRAS G12X (RMC-6236 → RASolute-302, covering 85% of KRAS, phase III near approval). In the adjuvant setting, ELI-002 vaccine opens a second front. This is the first time in 30 years of PDAC that a driver-gene-level paradigm breakthrough has appeared.

3. Horizontal axis: the 2026 decision landscape (six dimensions)

Projecting the longitudinal evolution onto the 2026 clinical decision tree, here are six key branchpoints and the evidence base for each.

3.1 Newly diagnosed PDAC: do comprehensive molecular profiling immediately

NCCN V1.2026 explicitly recommends all newly diagnosed PDAC undergo comprehensive molecular testing (tissue or ctDNA), covering: KRAS mutation subtype (G12D / G12V / G12C / G12R / G13D / pan-KRAS status) + BRCA1/2 + PALB2 + MSI/dMMR + NRG1 / NTRK / HER2 / BRAF / ALK / ROS1. Molecular results directly influence: 1L regimen selection (BRCA-mutant patients can get olaparib maintenance after platinum chemo); 2L targeted accessibility (NRG1 → zenocutuzumab / NTRK → larotrectinib, entrectinib / G12C → adagrasib / G12X → RMC-6236 if RASolute approved); clinical trial enrollment (RASolute, AMPLIFY-7P and other KRAS-direction trials).

3.2 Advanced 1L: four-way decision by performance status

ECOG 0-1 and age <75: first choice FOLFIRINOX [PRODIGE-4 PMID 21561347] or NALIRIFOX [NAPOLI-3 PMID 37708904] (the latter FDA-approved 2024-02, accessibility and reimbursement still rolling out)
ECOG 2 or heavy comorbidity: GnP [MPACT PMID 24131140]
gBRCA1/2+: 1L platinum FOLFIRINOX/NALIRIFOX ≥16 weeks without progression → olaparib maintenance [POLO PMID 31157963]
Frail / ECOG 3 cannot tolerate combination: gemcitabine monotherapy or S-1 monotherapy [GEST PMID 23547081]

Note: dual checkpoint (durvalumab + tremelimumab) ineffective in unselected 1L (CCTG PA.7 PMID 36028483) — not a PDAC 1L consideration.

3.3 Adjuvant regimens: mFFX vs GnP vs S-1 vs GemCap vs gemcitabine

ECOG 0-1, age <75, triplet-tolerant: mFOLFIRINOX (PRODIGE-24 PMID 30575490, mOS 54.4 months, best 30-year data)
Western elderly or intermediate performance: GemCap (ESPAC-4 PMID 28129987, mOS 28.0 months)
Asian population (strongest Japanese evidence): S-1 (JASPAC-01 PMID 27275872, Asian-specific tolerability)
Combination-intolerant: gemcitabine monotherapy (CONKO-001 PMID 23982521)
Not recommended for adjuvant: nab-paclitaxel + gemcitabine (APACT primary endpoint negative, FDA did not approve the indication)

3.4 Borderline resectable / resectable: give neoadjuvant or not, give what

Decision prerequisites: surgical and imaging staging assessment (resectable / borderline resectable / locally advanced — three levels) + CA19-9 + ECOG status.

Resectable pancreatic head cancer: upfront surgery + post-op mFFX adjuvant is better than neoadjuvant FOLFIRINOX (NORPACT-1 PMID 38237621 warns neoadjuvant may harm resectable pancreatic head outcomes)
Borderline resectable: neoadjuvant chemo (FOLFIRINOX or GemCap) beats upfront surgery (ESPAC-5F / PREOPANC-1 / PREOPANC-2 consistently support); the two paths (neoadjuvant mFFX vs neoadjuvant gem-chemoRT) are equivalent (PREOPANC-2 PMID 39500336)
Locally advanced (unresectable): after 4-6 months of induction chemo, responders or stable patients choose chemoradiation (for locoregional control) or continued chemo (LAP07 PMID 27139057 shows no OS difference); SBRT boost neoadjuvant not recommended (Alliance A021501 PMID 35834226)
No neoadjuvant regimen recommends adding nelfinavir or other sensitizers (SCALOP-2 PMID 34048677)

3.5 Advanced 2L: three effective regimens, two East-West differences, KRAS stratification joins

Standard 2L: nal-IRI + 5FU/LV (NAPOLI-1 PMID 26615328) — only globally approved 2L regimen
Europe option: OFF regimen (CONKO-003 PMID 24982456, European evidence base)
West does not recommend FOLFOX: PANCREOX [PMID 27621395] shows FOLFOX 2L is worse in Western cohorts
KRAS G12C: adagrasib (KRYSTAL-1 PMID 37099736) or sotorasib (CodeBreaK 100 PMID 36546651), ORR 21-33%
KRAS G12X (including G12D) awaiting RASolute-302 approval: if approved, may become 2L first choice for KRAS-mutant PDAC (HR 0.40 effect size unprecedented)
BRCA1/2 PARP-naive: if no 1L maintenance was given, PARP can be considered in 2L
NRG1 fusion: zenocutuzumab (eNRGy PMID 39908431)
NTRK fusion: larotrectinib / entrectinib / repotrectinib
MSI-H/dMMR: pembrolizumab (KEYNOTE-158 PMID 31682550)

3.6 KRAS G12D subgroup (~40% of KRAS PDAC): the 2026 special waiting posture

PDAC KRAS mutation distribution is roughly: G12D 40% / G12V 30% / G12R 15% / G12C 1-2% / G13D 2-3% / other 10%. G12D is the largest subtype by number, but as of 2026-04:

MRTX1133 (Mirati/BMS G12D-selective) development terminated
RMC-9805 (zoldonrasib, Revolution Medicines G12D-selective) is only in phase I, with 2024 EORTC late-breaking-level data
RMC-6236 (pan-KRAS G12X) covers G12D; RASolute-302 phase III topline released but manuscript pending

G12D PDAC patient options in 2026: clinical trial enrollment (RASolute-302 / AMPLIFY-7P / RMC-9805 expansion cohorts) > standard chemo (FOLFIRINOX/GnP → NAPOLI-1). “Await RASolute approval + consider KRAS-directed trials” is the default posture for G12D PDAC in mid-to-late 2026.

4. Research Gaps: ten unresolved clinical questions

This report identifies the following gaps, all definable concrete questions (not the “need more research” cliché):

Resectable PDAC neoadjuvant vs adjuvant head-to-head: NORPACT-1 suggests neoadjuvant FFX may harm resectable pancreatic head cancer outcomes; Alliance A021806 is the first systematic head-to-head phase III; no verdict before its 2027-2028 readout.
RMC-6236 / RASolute-302 resistance mechanisms: after pan-KRAS inhibitor monotherapy mPFS of ~8 months, is resistance driven by secondary KRAS mutations / bypass activation / EMT phenotype / or mixed? Paired ctDNA resistance-typing studies are missing.
NALIRIFOX vs FOLFIRINOX 1L head-to-head: both contain oxaliplatin+5-FU+leucovorin; core difference is liposomal irinotecan vs standard irinotecan. Direct randomized comparison missing; clinical use relies on cross-trial inference.
Root cause of POLO’s negative OS: is the PFS HR 0.53 / OS HR 0.83 mismatch driven by control-arm crossover? Does BRCA+ PDAC PARP maintenance need finer biomarker stratification?
PDAC MSI-H subgroup (1-2%) checkpoint monotherapy vs combination: KEYNOTE-158 PDAC cohort ORR 18% is lower than other MSI tumor types; reasons (microenvironment / HLA loss / low TMB) not yet analyzed.
KRAS G12D-selective vs pan-KRAS long-term comparison: G12D-selective (RMC-9805) may have lower on-target toxicity, but pan-KRAS (RMC-6236) may handle subclonal KRAS heterogeneity better. Long-term follow-up comparison missing.
KRAS vaccine adjuvant vs ctDNA-guided extended chemo: AMPLIFY-201 phase I showed immune response, but the adjuvant comparator should not be only placebo (adjuvant PDAC already has mFFX) — the right phase III is mFFX + vaccine vs mFFX + placebo.
East-West results divergence — OFF Western vs FOLFOX Eastern: CONKO-003 OFF and PANCREOX FOLFOX gave opposite results with similar drug combinations; Euro-Asian population and dosing-detail differences not systematically explained.
Role of ctDNA in PDAC monitoring and treatment decisions: should ctDNA-positive adjuvant patients get intensified / extended chemo? Prospective ctDNA-guided randomized trials missing.
Revival path for stroma-targeting agents: PEGPH20 / simtuzumab and other stroma-targeting approaches have all failed in PDAC; but can KRAS inhibition + stromal remodeling combinations (e.g., RMC-6236 + AT9283 or similar FAK/CAF combos) break the stromal barrier? Not systematically studied.

5. 2024-2026 latest developments

5.1 New FDA / NMPA approvals (key selections)

2024-02 FDA: NALIRIFOX (liposomal irinotecan + oxaliplatin + leucovorin + 5-FU) approved for 1L metastatic PDAC (NAPOLI-3 [PMID 37708904])
2024-12 FDA accelerated approval: zenocutuzumab (NRG1-fusion advanced PDAC and NSCLC, eNRGy [PMID 39908431]) — first non-chemo non-PARP biomarker-matched targeted approval in PDAC
2024 FDA Breakthrough Designation: RMC-6236 (daraxonrasib, pan-KRAS G12X, Revolution Medicines) + RMC-9805 (zoldonrasib, KRAS G12D)
2023 FDA accelerated approval: repotrectinib (tumor-agnostic NTRK fusion, including PDAC; formally approved as NTRK-universal)

5.2 Key conference readouts (2024-2026, weighted down)

ASCO GI 2024 / ESMO 2024: RMC-6236 PDAC 2L phase I cohort data (Arbour / Ko et al. reports), ORR ~36%, mPFS ~8.5 months, mOS ~14.5 months
EORTC 2024 (late-breaking): RMC-9805 zoldonrasib KRAS G12D phase I, PDAC 2L+ cohort ORR ~30%
ASCO GI 2026: RASolute-302 phase III topline — RMC-6236 vs investigator’s choice in 2L+ KRAS G12X PDAC, mOS 13.2 vs 6.7 months, HR 0.40, p<0.001. Full manuscript expected NEJM/Lancet 2026 H2.
Nat Medicine 2024 (ELI-002): AMPLIFY-201 KRAS mRNA vaccine adjuvant phase I, 84% immune response [PMID 38195752]

5.3 Phase III in progress (2025-2028 readout selections)

RASolute-302 (NCT06625320): RMC-6236 vs SoC in KRAS G12X 2L+ PDAC — topline available, awaiting full manuscript
Alliance A021806 (NCT04340141): resectable PDAC neoadjuvant vs adjuvant mFOLFIRINOX head-to-head — primary completion expected 2027-2028
AMPLIFY-7P (NCT05726864, ELI-002 phase II adjuvant mKRAS vaccine) — readout expected 2027
PANOVA-3 (tumor treating fields + GnP vs GnP), PROOF 301 (olaratumab + FFX), NOVATE (ivonescimab series in PDAC) and several other ongoing trials, none mainstream breakthrough candidates

6. Intersectional insights and judgments

6.1 Longitudinal × horizontal: 2026 PDAC landscape shaped by two “resonances”

Stacking longitudinal paradigm evolution and horizontal current decision landscape, the 2026 PDAC landscape is two resonances superposed:

Chemo marginal optimization (2011-2024 decade) superposed with KRAS cracking (2023-2026): chemo went from PRODIGE-4 / MPACT’s mOS 8-11 months, to NAPOLI-3’s 11.1 months (marginal +2 months), then to RASolute-302 2L’s mOS 13.2 months (double the historical 2L 6 months). A two-stage evolution of chemo marginal + KRAS doubling shapes the 2026 landscape.
Biomarker-matched sparse hits (BRCA / MSI / NRG1 / NTRK totaling <10%) superposed with KRAS trunk (90%): the former are like “scattered lights”; the latter is like “turning on the main breaker.” KRAS’s importance is not “another biomarker,” but “finally can cover 90% of patients” — this is the NSCLC EGFR story arriving late in PDAC.

These two resonances together explain a clinical phenomenon: the 1L decision tree for a newly diagnosed stage IV PDAC patient in 2026 has 3 more decision layers than in 2016 (molecular profiling → KRAS subtype specificity → clinical trial enrollment priority → biomarker-matched accessibility).

6.2 Clinical decision takeaways (for junior-mid oncologists)

Routine molecular profiling: in 2026 all newly diagnosed PDAC should get comprehensive molecular profiling. Missing KRAS subtype means missing the G12X treatment path after RASolute approval; missing BRCA means missing POLO maintenance; missing NRG1 / NTRK means missing already-approved targeted options.
ECOG 0-1 and age <75: 1L first choice FOLFIRINOX or NALIRIFOX: don’t default to GnP out of “toxicity concern.”
Neoadjuvant is not universal: be cautious giving FOLFIRINOX neoadjuvant in resectable pancreatic head cancer (NORPACT-1 warning); borderline resectable is where to consider neoadjuvant.
Adjuvant first choice mFFX (PRODIGE-24): APACT lesson — what wins in the advanced setting doesn’t necessarily win as adjuvant. Nab-paclitaxel + gemcitabine not recommended for adjuvant.
2L nal-IRI + 5FU/LV is default: don’t use FOLFOX (PANCREOX warning in Western populations).
KRAS G12C 2L+ already has adagrasib / sotorasib: small subgroup but don’t miss it.
KRAS G12X (RMC-6236 / RASolute) will rewrite 2L+ standard in 2026-2027: watch the FDA approval timeline; simultaneously assess clinical trial enrollment feasibility (RASolute expansion / AMPLIFY-7P).
Don’t blindly push dual checkpoint blockade in PDAC: CCTG PA.7 rejected dual checkpoint + chemo in unselected populations. MSI-H PDAC is where pembrolizumab applies.
Locally advanced SBRT neoadjuvant adds nothing, sensitizers add nothing: Alliance A021501 / SCALOP-2, two lines of evidence pointing the same way.
nal-IRI, zenocutuzumab, KRAS G12C inhibitors, RMC-6236, ELI-002 — five drug classes clinicians must know: the 30-year PDAC drug-drought era is over; the 2024-2026 cluster of new approvals marks a new phase.

7. Information sources

All 37 trial metadata in this report were independently verified via PubMed and ClinicalTrials.gov. Each [PMID xxxxxxxx] in the text can be verified directly in PubMed.

Published trials: 33, covering 2004-2025 (PMID-verifiable)
Ongoing / not yet formally published: 4 (RMC-6236-001 / RMC-9805-001 phase I conference data only · TRIDENT-1-PANC manuscript pending · RASolute-302 phase III topline at ASCO GI 2026, full manuscript expected 2026 H2)
NCCN guideline citations: 30/37 (81%) directly hit the NCCN V1.2026 PANC-G reference section; the remaining 7 are expected 0-hit (phase I/III ongoing, or papers published after 2024 not yet incorporated into V1.2026)
2024-2026 FDA new approvals: 3 (NALIRIFOX / zenocutuzumab / two Breakthrough Designations)
2024-2026 key conference readouts: 4 (RMC-6236 ASCO GI/ESMO 2024 / RMC-9805 EORTC 2024 / RASolute-302 ASCO GI 2026 / AMPLIFY-201 Nat Med 2024)
Research gaps: 10

7.1 Citation index (sorted by PMID)

PMID	Trial / Paper	Year	Journal	Section
15028824	ESPAC-1	2004	NEJM	§2.1 Adjuvant chemo evolution
20823433	ESPAC-3	2010	JAMA	§2.1
21561347	PRODIGE-4 / ACCORD-11	2011	NEJM	§2.2 Advanced 1L / §3.2
23474363	SCALOP	2013	Lancet Oncology	§2.3 Neoadjuvant / locally advanced
23547081	GEST	2013	JCO	§2.2 / §3.2
23982521	CONKO-001	2013	JAMA	§2.1 / §3.3
24131140	MPACT	2013	NEJM	§2.2 / §3.2
24982456	CONKO-003	2014	JCO	§2.4 Advanced 2L / §3.5
26615328	NAPOLI-1	2016	Lancet	§2.4 / §3.5
27139057	LAP07	2016	JAMA	§2.3 / §3.4
27275872	JASPAC-01	2016	Lancet	§2.1 / §3.3
27621395	PANCREOX	2016	JCO	§2.4 / §3.5
28129987	ESPAC-4	2017	Lancet	§2.1 / §3.3
30575490	PRODIGE-24	2018	NEJM	§2.1 / §3.3
31157963	POLO initial	2019	NEJM	§2.5 / §3.5
31682550	KEYNOTE-158	2020	JCO	§2.5 / §3.5
31838007	entrectinib STARTRK	2020	Lancet Oncology	§2.5
32105622	larotrectinib pooled	2020	Lancet Oncology	§2.5
33301741	PACT-15	2021	Lancet Gastro Hepatol	§2.1
34048677	SCALOP-2	2021	JCO	§2.3
35188492	PREOPANC-1	2022	JCO	§2.3 / §3.4
35834226	Alliance A021501	2022	JAMA Oncology	§2.3 / §3.4
35834777	POLO final OS	2022	JCO	§2.5 / §3.5
36028483	CCTG PA.7	2022	Nat Communications	§2.2 / §3.2
36521097	APACT	2023	JCO	§2.1 / §3.3
36546651	CodeBreaK 100 PDAC	2023	NEJM	§2.6 / §3.5
37099736	KRYSTAL-1 PDAC	2023	JCO	§2.6 / §3.5
37103886	ESPAC-5F	2023	JAMA Oncology	§2.3
37708904	NAPOLI-3	2023	Lancet	§2.2 / §3.2 / §5.1
38195752	AMPLIFY-201 / ELI-002	2024	Nat Medicine	§2.6 / §5.2
38237621	NORPACT-1	2024	Lancet Gastro Hepatol	§2.3 / §3.4
39048905	Alliance A021806	2024	JCO (design)	§2.3 / §5.3
39500336	PREOPANC-2	2024	Lancet	§2.3 / §3.4
39908431	eNRGy / zenocutuzumab	2025	NEJM	§2.5 / §3.5 / §5.1

7.2 Verification conventions

PMIDs can be directly concatenated into PubMed URLs: https://pubmed.ncbi.nlm.nih.gov/<PMID>
NCT IDs can be directly concatenated into ClinicalTrials.gov URLs: https://clinicaltrials.gov/study/<NCT_ID>
Conference abstracts (ASCO GI / ESMO / EORTC) are retrievable via the official conference systems; all conference citations in this report are “weighted down” — not peer-reviewed, final data per journal publication
Phase I/III ongoing trials’ ORR / PFS / OS values are based on the latest public conference reports; minor adjustments possible upon manuscript publication

The clinical trial timeline is here

Chinese: /trials/pancreatic/ English: /en/trials/pancreatic/

Every trial has its own detail page with:

Full intervention / comparator regimen
Primary endpoint values + 95% CI
Key findings + clinical significance
Clickable jumps to PMID / NCT originals

37 trials · 4 chapters · 1994 to 2026 · 15+ country contributions · synced with NCCN V1.2026.

Closing

PDAC has been oncology’s “slowest-changing” field for 30 years — from the 1997 gemcitabine adjuvant foundation to mFFX’s DFS HR 0.58 in 2018, fit-patient adjuvant mOS only moved from 35 to 54 months. Advanced 1L went from PRODIGE-4’s 11 months to being marginally rewritten twelve years later by NAPOLI-3’s 11.1 months.

But 2023-2026, these three years, marked the first driver-gene-level paradigm breakthrough in 30 years: KRAS G12C → KRAS G12D → pan-KRAS G12X, three subtypes with three drug paths advancing; April 2026 RASolute-302 topline’s HR 0.40 is an effect size unseen in 30 years of PDAC 2L. Biomarker-matched sparse four tiles (BRCA / MSI-H / NRG1 / NTRK) + the KRAS trunk powering up, PDAC precision therapy is beginning to approach NSCLC’s 2012 landscape — still some distance from closing the “EGFR 10-year revolution” loop, but the door has been pushed open a crack.

This report’s value is not “exhaustively listing all trials” (PubMed can do that), but compressing 30 years of evolution + current decisions + unresolved gaps into one reading’s cognitive bandwidth. Next time you face a newly diagnosed PDAC patient, every branch in the decision tree has this map to consult, trace, and question.

Clinician × AI = Research Superpower + Clinical Decision Amplifier

—— Dual Brain Lab · 2026-04-20