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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

Bone Tumor Clinical Trial Timeline: A 40-Year Dual-Track Map

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

Bone Tumor Clinical Trial Timeline: In-Depth Report

Coverage: 35 landmark trials cited by NCCN Bone Cancer V2.2026 (34 published, all PMIDs traceable + 1 rEECur phase 3 primary manuscript pending) + 5 subtypes (osteosarcoma / Ewing sarcoma / chondrosarcoma / chordoma / GCTB)

Curated by Dual Brain Lab (csilab.net)

1. One-Sentence Definition

This report traces the evolution and current decision landscape of systemic therapy for bone sarcomas (osteosarcoma + Ewing sarcoma + chondrosarcoma + chordoma + GCTB — five subtypes combined) over the past 40 years (1986-2026), focusing on landmark clinical trials cited in NCCN Bone Cancer V2.2026, to provide frontline clinicians with a traceable panoramic map for 2026 decisions on “who, what, and why.”

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

2. Vertical: Timeline of Four Treatment Paradigms

Bone tumor systemic therapy has evolved over 40 years along a logic completely different from NSCLC or BTC — the mainstream major subtypes (osteosarcoma + Ewing sarcoma) have held a 40-year chemo backbone (MAP / VDC-IE) undefeated; the rare subtypes (chondrosarcoma + GCTB + chordoma) instead achieved precision-targeted breakthroughs first after 2010; and IO has failed across virtually all subtypes. These three forces together shape the “dual-track reality” of the 2026 bone tumor decision landscape: mainstream stagnation + rare-subtype precision breakthroughs + IO failure.

The scale of each paradigm shift is far smaller than the five leaps seen in NSCLC — the reason lies in the unique biology of bone tumors: low TMB (tumor mutational burden) + cold tumor immune-desert + osteosarcoma / Ewing lacking a unified driver gene + rare subtypes conversely having clear druggable drivers (IDH1 / RANKL / PDGFR).

2.1 Osteosarcoma MAP 40-Year Backbone Era (1986-2026): From Foundation to All Intensification Failures + Marginal TKI Gains in Relapse

Story: MIOS 1986 moved adjuvant chemotherapy from “optional” to “mandatory,” pushing 2-year RFS (relapse-free survival) from 17% to 66%. Over the following 40 years all intensification strategies — adding ifosfamide, adding interferon, adding MTP-PE, switching to neoadjuvant sequencing, switching to targeted agents — failed to further improve OS. Relapsed osteosarcoma entered the multi-TKI (tyrosine kinase inhibitor) era, where sorafenib / regorafenib / cabozantinib / pazopanib — all VEGFR-axis drugs — delivered “4-6 month PFS marginal wins” without anyone changing OS.

MIOS [PMID 3520317] (Link 1986 NEJM, N=113): non-metastatic high-grade extremity osteosarcoma, postoperative adjuvant multi-drug chemotherapy (high-dose methotrexate + doxorubicin + BCD + cisplatin) vs surgery alone with observation. 2-year RFS 66% vs 17%, OS similarly significantly improved. Established the foundation that “osteosarcoma adjuvant chemo is mandatory”; all subsequent trials used this as baseline, and the 60-70% EFS (event-free survival) ceiling has been fixed here ever since.
POG-8651 [PMID 12697883] (Goorin 2003 JCO, N=106): neoadjuvant chemotherapy + surgery + adjuvant chemotherapy vs upfront surgery + adjuvant chemotherapy. 5-year EFS 61% vs 69%, OS no difference. A rarely cited “inconvenient truth” — the “neoadjuvant is standard” narrative has no RCT support on survival data; it became standard because neoadjuvant enables limb-sparing surgery + makes histologic response stratification a prognostic tool.
COSS-86 [PMID 9789613] (Fuchs 1998 Ann Oncol, N=171): high-risk osteosarcoma MAP backbone plus ifosfamide. vs historical control COSS-82, 10-year EFS/OS no significant improvement. Europe’s earliest intensification-failure signal, foreshadowing EURAMOS-1.
INT-0133 [PMID 18235123] (Meyers 2008 JCO, N=662): MAP ± ifosfamide ± MTP-PE (mifamurtide, muramyl tripeptide phosphatidylethanolamine), 2×2 factorial design. MTP-PE arm 6-year OS 78% vs 70% (p=0.03); ifosfamide addition failed (EFS p=0.39). The only “possible” frontline OS-positive signal in 40 years, but factorial interaction left interpretation contested: FDA refused approval of mifamurtide, EMA approved. Ifosfamide failed for the first time here.
EURAMOS-1 Good Responders [PMID 26033801] (Bielack 2015 JCO, N=716): patients with good histologic response after neoadjuvant MAP (<10% viable tumor cells), adjuvant MAP + pegylated interferon alfa-2b maintenance vs MAP alone. 3-year EFS 77% vs 74%, HR 0.83 (p=0.21) negative. IFN toxicity caused about 40% of patients not to complete planned treatment.
EURAMOS-1 Poor Responders [PMID 27569442] (Marina 2016 Lancet Oncol, N=618): patients with poor histologic response after neoadjuvant MAP (≥10% viable tumor cells), postoperative MAPIE (MAP + ifosfamide + etoposide) vs continued MAP. EFS HR 0.98 (95% CI 0.78-1.23, p=0.86) completely negative. Risk of secondary AML (acute myeloid leukemia) rose notably. The largest frontline RCT in osteosarcoma history (two-arm total N=1334), both arms negative — the 2000s strategy of “intensify for poor responders” was definitively shut down here.
SORAFENIB-ISG [PMID 21527590] (Grignani 2012 Ann Oncol, N=35): sorafenib monotherapy in relapsed / unresectable osteosarcoma. 4-month PFS 46%, mPFS 4 months, mOS 7 months, ORR 8%. The first positive TKI signal in osteosarcoma, benefit short but reproducible; paved the way for subsequent VEGFR TKIs.
SORAFENIB-EVEROLIMUS [PMID 25498219] (Grignani 2015 Lancet Oncol, N=38): sorafenib + everolimus (mTOR inhibitor) combination in relapsed osteosarcoma. 6-month PFS 45%, failed to meet prespecified 50% threshold; notable toxicity. Adding mTOR didn’t help — the osteosarcoma TKI story is mainly about the VEGFR angiogenesis axis.
SARC024 [PMID 31013172] (Davis 2019 JCO, N=42 randomised): regorafenib vs placebo (crossover allowed) in adult relapsed / metastatic osteosarcoma. mPFS 3.6 vs 1.7 months (HR 0.42, p=0.017), 8-week progression-free rate ~65% vs 0%, no RECIST response. The first positive PFS signal in modern relapsed osteosarcoma.
REGOBONE [PMID 30477937] (Duffaud 2019 Lancet Oncol, N=38): independent European validation of SARC024, also regorafenib vs placebo. 8-week progression-free rate 17/26 vs 0/12, mPFS 16.4 vs 4.1 weeks. Cross-continental replication is rare in sarcoma — SARC024 + REGOBONE together pinned regorafenib as a 2L option in relapsed osteosarcoma.
CABONE [PMID 32078813] (Italiano 2020 Lancet Oncol, dual cohorts N=45 each): cabozantinib (60 mg/d) monotherapy in relapsed osteosarcoma + relapsed Ewing sarcoma. Osteosarcoma 6-month PFR 33%, ORR 12%; Ewing sarcoma 6-month PFR 26%, ORR 26% (one of the highest ORRs ever recorded in relapsed Ewing). The only relapsed-osteosarcoma TKI producing real RECIST tumor shrinkage.
PAZO-OSTEO [PMID 35075361] (Frankel 2022 J Oncol, N=12, slow accrual and early termination): pazopanib 800 mg/d in relapsed osteosarcoma with lung metastases. PFS numbers in the same band as sorafenib / regorafenib / cabozantinib, confirming VEGFR TKI class effect.
AOST1321 [PMID 41159913] (Janeway 2026 Clin Cancer Res, N=40): denosumab (RANKL inhibitor) monotherapy in relapsed / refractory pediatric + AYA osteosarcoma, two cohorts. Failed to meet prespecified efficacy threshold, both cohorts negative. The “hijacking osteoclast biology” hypothesis was refuted in osteosarcoma — sharp contrast with the near-universal response of GCTB to denosumab: the same drug is landscape-changing in one bone tumor and inactive in another, a textbook example of bone tumor heterogeneity.

Takeaway: in 2026, frontline osteosarcoma SoC (standard of care) = the MIOS 1986 MAP chemotherapy framework continued. All intensification failed (EURAMOS-1 both arms / COSS-86 / MTP-PE contested). Relapsed osteosarcoma = VEGFR TKI marginal PFS (regorafenib the archetype, double-validated by SARC024 + REGOBONE; cabozantinib produces real shrinkage). Denosumab has no antitumor activity in osteosarcoma itself — retained only for skeletal-related-event prevention.

2.2 Ewing Sarcoma: Interval Compression Marginal Wins + High-Risk Transplant + First-Ever Relapse RCT rEECur (2003-2024)

Story: after INT-0091 established the Ewing sarcoma VDC-IE backbone (vincristine / doxorubicin / cyclophosphamide / ifosfamide / etoposide) in 2003, subsequent progress came not from new drugs but from trial-design optimization: AEWS0031 compressed dosing interval from every 3 weeks to every 2 weeks (“timing matters more than new drugs”) to grab 8 percentage points of EFS; EURO-EWING-99-R2 added busulfan-melphalan (BuMel) + autologous HSCT in high-risk localized disease to grab 14 percentage points. rEECur 2024 used Bayesian adaptive design to give relapsed Ewing sarcoma its first RCT-level answer.

INT-0091 [PMID 12594313] (Grier 2003 NEJM, N=518): newly diagnosed localized or metastatic Ewing family tumors (<30 years), alternating VDC/IE vs VDC alone. Localized 5-year EFS 69% vs 54% (p=0.005), 5-year OS 72% vs 61%; no benefit in metastatic subgroup. Established VDC-IE as the North American Ewing sarcoma standard and for the first time displayed the biological watershed between localized and metastatic disease.
AEWS0031 [PMID 23091096] (Womer 2012 JCO, N=587): newly diagnosed localized Ewing, VDC/IE every 2 weeks vs every 3 weeks (interval compression with G-CSF support). 5-year EFS 73% vs 65% (p=0.048), no additional toxicity. “Same chemo, more frequent” = 8 percentage points of EFS. Dose-dense VDC/IE q2w became the North American SoC. This is the only clear frontline improvement in Ewing sarcoma — not a new drug, but a trial-design win.
EURO-EWING-99-R1 [PMID 24982464] (Le Deley 2014 JCO, N=856): standard-risk localized Ewing, VAC (vincristine+actinomycin+cyclophosphamide) vs VAI (vincristine+actinomycin+ifosfamide) consolidation after VIDE induction. 3-year EFS 75.4% vs 78.2%, HR 1.12 (CI 0.89-1.41) non-inferiority achieved. Cyclophosphamide consolidation is non-inferior to ifosfamide with less renal toxicity — the de-escalation answer for standard-risk disease.
EURO-EWING-99-R2 [PMID 30188789] (Whelan 2018 JCO, N=240): high-risk localized Ewing (poor response after induction or large axial tumor), BuMel + autologous HSCT vs conventional VAI consolidation. 3-year EFS 67.1% vs 52.9%, HR 0.64 (CI 0.43-0.95, p=0.026); OS improved similarly. One of the few positive results in modern osteosarcoma / Ewing intensification trials — the trick was “use high intensity only in the high-risk subgroup.”
VIT-WAGNER [PMID 16317751] (Wagner 2007 Pediatr Blood Cancer, N=14 pediatric): irinotecan + temozolomide (no vincristine in original version) in progressive pediatric Ewing family tumors. ORR 63%, median response duration 8.3 months. Subsequently MSK / CHOP / Warsaw / Virginia groups added vincristine to evolve into the VIT three-drug regimen — the historical seed of the entire VIT narrative.
VIT-RACIBORSKA [PMID 23776128] (Raciborska 2013 Pediatr Blood Cancer, N=22, Poland): VIT (vincristine + irinotecan + temozolomide) three-drug regimen in relapsed / refractory Ewing. ORR ~68%, mOS ~20 months. VIT consistently produced ~60-70% ORR across multiple countries and cohorts yet never entered an RCT — a textbook case of an “evidence-weak regimen becoming practical standard by pragmatic convergence.”
rEECur [NCT03416517] (McCabe 2024 Lancet Oncol manuscript pending): the first Bayesian adaptive multi-arm multi-stage RCT in relapsed Ewing (N=451 cumulative). Four arms vs historical topotecan+cyclophosphamide (TC) reference: gemcitabine+docetaxel (GD) eliminated at 2020 interim; irinotecan+temozolomide (IT) eliminated at 2022 interim; high-dose ifosfamide won in the phase 3 stage and became the new reference standard for relapsed Ewing. PMID not yet indexed in PubMed at the time of this report (2026-04-21); cited by NCT ID + conference readout.

Takeaway: in 2026 Ewing sarcoma frontline = North American AEWS0031 dose-dense VDC/IE q2w + high-risk localized disease goes to EURO-EWING-99-R2 BuMel HSCT; relapsed 2L = rEECur winner high-dose ifosfamide (replacing the pragmatic-standard VIT of many years), VIT retained in NCCN guidelines but demoted; cabozantinib (CABONE Ewing arm ORR 26%) has genuine tumor-shrinking activity as an off-label monotherapy.

2.3 Rare-Subtype Precision Therapy: IDH1 / RANKL / PDGFR — First Three Driver Lines Reaching Targeted Therapy (2010-2025)

Story: osteosarcoma + Ewing sarcoma have no clear druggable driver genes; but the rare subtypes each have an independent driver — chondrosarcoma IDH1/2 mutation ~50% central type, GCTB RANKL signaling axis, chordoma brachyury + PDGFR pathway. “Where there’s a driver, there’s a way” also holds true in bone tumors — the stage just moves to the rare subtypes.

Naming pitfall warning: ivosidenib (Tibsovo / AG-120, Agios/Servier) = selective IDH1 inhibitor for chondrosarcoma + AML + BTC; vorasidenib (Voranigo / AG-881, Agios/Servier) = dual IDH1/2 inhibitor for glioma. These are most easily confused in 2024-2025 literature — chondrosarcoma uses ivosidenib, not vorasidenib.

Chondrosarcoma IDH1 + BRCAness (synthetic lethality) Path

IVOSIDENIB-CHONDRO-P1 [PMID 32208957] (Tap 2020 JCO, N=21 single-arm phase 1): advanced IDH1 R132-mutant conventional chondrosarcoma, ivosidenib 500 mg QD. RECIST ORR 0/21, DCR (disease control rate) 52%, mPFS 5.6 months, 39% of patients with PFS > 6 months; plasma 2-HG (2-hydroxyglutarate, the IDH1-mutant metabolite) suppressed > 93%. No RECIST PR (partial response) but PFS + biomarker dual evidence shows “on-target effect.” The first “precision therapy works” signal in bone tumors.
IVOSIDENIB-CHONDRO-LT [PMID 40100120] (Tap 2025 Clin Cancer Res, N=21 long-term follow-up): same cohort with long-term follow-up. Updated mPFS ~7.4 months; subgroup on treatment > 2 years; safety benign (manageable QTc prolongation, fatigue). The mature readout anchored IDH1 inhibition as the first real precision-therapy win in bone sarcoma, directly supporting NCCN listing of ivosidenib for IDH1+ chondrosarcoma.
OLAPARIB-IDH-SARC [PMID 34994649] (Eder 2021 JCO Precis Oncol, N=15): olaparib (PARP inhibitor) monotherapy in IDH1/2-mutant advanced mesenchymal sarcomas (mostly chondrosarcoma). CBR (clinical benefit rate) 11/15 (73%), no RECIST PR, mPFS ~8 months. Mechanistic basis: IDH mutation → 2-HG accumulation → inhibits α-KG-dependent DNA demethylation / HR repair → BRCAness (BRCA-deficient-like) phenotype → PARP-inhibitor sensitivity. The “second shot” of the IDH narrative — synthetic lethality rather than direct enzyme inhibition.
SARC-PAZO-CHONDRO [PMID 31509242] (Chow 2020 Cancer, N=47 single-arm phase 2): pazopanib 800 mg QD in unresectable / metastatic chondrosarcoma. 16-week DCR 43%, ORR ~5%, mPFS 7.9 months, conventional-type mOS ~27 months. Dedifferentiated type has worse prognosis. Disease-stabilization signal for anti-angiogenic TKI in chondrosarcoma — a non-IDH option.
REGOBONE-CHONDRO [PMID 33895682] (Duffaud 2021 Eur J Cancer, N=46 randomised placebo-controlled): regorafenib vs placebo in metastatic / locally advanced chondrosarcoma. 12-week non-progression rate 44% vs 24%, mPFS 19.8 vs 8.0 weeks, no RECIST PR. Running a placebo-controlled RCT in a rare subtype is difficult — another anti-angiogenic TKI disease-stabilization piece of evidence.

GCTB (Giant Cell Tumor of Bone) RANKL Path

DENOSUMAB-GCTB-P2 [PMID 20149736] (Thomas 2010 Lancet Oncol, N=37): denosumab 120 mg SC (days 1, 8, 15, 29 + Q4W) in relapsed / unresectable GCTB. Histologic response rate 86% (30/35, defined as >90% giant-cell elimination or no radiographic progression), symptoms markedly relieved. RANKL validated as central driver in GCTB — a concept-breakthrough phase 2.
DENOSUMAB-GCTB-INTERIM [PMID 23867211] (Chawla 2013 Lancet Oncol, N=282): three-parallel-cohort (unresectable / high-morbidity surgery / phase 2 rollover) expansion. Unresectable cohort 6-month progression-free 96%, high-morbidity-surgery cohort 48% avoided planned surgery or underwent downsized surgery, ONJ (osteonecrosis of the jaw) ~1%. FDA-approval basis dataset; established the “surgical de-escalation” role.
DENOSUMAB-GCTB-LT [PMID 31704134] (Chawla 2019 Lancet Oncol, N=532 long-term follow-up): the largest GCTB denosumab dataset, followed up to ~5 years. Unresectable cohort annual progression rate still < 5%; cumulative ONJ ~5%, atypical femur fracture rare. Mature readout locking denosumab as modern GCTB SoC + establishing the “use-and-pause” intermittent dosing paradigm. GCTB evolved from “unresectable = fatal” to “medical therapy → limb-sparing surgery” — the clinical pathway was completely rewritten.

Chordoma brachyury / PDGFR Path

IMATINIB-CHORDOMA-P2 [PMID 22331945] (Stacchiotti 2012 JCO, N=50): imatinib 800 mg QD in PDGFRB-positive advanced chordoma. RECIST ORR 2%, DCR 64%, mPFS 9 months; Choi-criteria response rate higher than RECIST (density change). PDGFRB-pathway inhibition = the first systemic therapy in the smallest bone-tumor histology; Choi provided an alternative yardstick for chordoma assessment.
IMATINIB-EVEROL-CHORDOMA [PMID 30216418] (Stacchiotti 2018 Cancer, N=43): imatinib + everolimus combination after imatinib failure. ORR 2/43 (5%), Choi response 20/43, mPFS 11.5 months. Combination yielded limited increment over monotherapy.
GI6301-CHORDOMA [PMID 33594772] (DeMaria 2021 Oncologist, N=34 randomised): brachyury vaccine (GI-6301, inactivated yeast expressing brachyury) + standard radiotherapy vs placebo + radiotherapy in locally advanced unresectable chordoma. 6-month ORR 35% vs 18% (not significant, small sample); brachyury-specific immune response detected in most vaccinated patients. The only randomised brachyury-directed study in chordoma — not formally statistically significant but keeps the brachyury-targeting program alive.

Takeaway: in 2026 rare-subtype bone tumors have entered the “where there’s a driver, there’s a way” precision era: (a) chondrosarcoma IDH1+ → ivosidenib (NCCN-listed, based on two CHONDRO-P1 + LT readouts) + PARP as the BRCAness second shot (OLAPARIB-IDH-SARC); (b) GCTB → denosumab rewriting surgical pathway (Thomas 2010 → Chawla 2013 / 2019 three phase 2 mature datasets); (c) chordoma → imatinib as backbone (Stacchiotti 2012), with combinations + brachyury vaccine providing modest increments.

2.4 Cross-Subtype Immunotherapy (2014-2024): SARC028 All-Failed + Alliance A091401 Soft-Tissue Door Left Ajar + Chordoma Exception

Story: IO (immune checkpoint inhibitor) posts 40%+ ORR in MSI-H colorectal cancer, 33% in melanoma, and rewrote the 1L backbone in NSCLC. In bone tumors it has failed almost completely — the reason is biology: low TMB + immune-desert + low PD-L1 expression. But SARC028 saw 20% response in dedifferentiated chondrosarcoma + Alliance A091401 combination-IO data + Migliorini chordoma exceptional case series left three narrow windows open for the “IO in bone” story.

SARC028 [PMID 28988646] (Tawbi 2017 Lancet Oncol, bone subgroup n=40): pembrolizumab 200 mg Q3W monotherapy phase 2 in advanced osteosarcoma / Ewing / chondrosarcoma / dedifferentiated chondrosarcoma. Osteosarcoma ORR 5% (1/22), Ewing 5% (1/13), chondrosarcoma 0% (0/5), dedifferentiated chondrosarcoma 20% (1/5). The landmark trial for “IO across-the-board rout in bone tumors” — not a trial-design problem, but a biologically determined one. The 20% in dedifferentiated chondrosarcoma is the only signal worth chasing.
ALLIANCE-A091401 [PMID 29370992] (D’Angelo 2018 Lancet Oncol, N=96 across bone + STS): nivolumab monotherapy vs nivolumab + ipilimumab combination, randomised non-comparative (no head-to-head p value). ORR 5% vs 16%; responses concentrated in soft tissue sarcomas (UPS, leiomyosarcoma, myxofibrosarcoma, angiosarcoma), with osteosarcoma contributing little. Combination IO tripled monotherapy response in soft tissue — leaving a narrow IO-combination door open.
ALLIANCE-A091401-EXPANSION [PMID 39343511] (Seligson 2024 J Immunother Cancer, expansion N=89): histology-enriched expansion cohorts (UPS, dedifferentiated liposarcoma, dedifferentiated chondrosarcoma). Nivo monotherapy ORR ~10%, nivo+ipi ~21% in selected histologies; osteosarcoma cohort failed to meet prespecified activity threshold. Dedifferentiated chondrosarcoma is the bone subtype most likely to respond to IO — still not at practice-changing magnitude.
CHORDOMA-IO-MIGLIORINI [PMID 28919999] (Migliorini 2017 Oncoimmunology, N=3 compassionate case series): anti-PD-1 compassionate use in recurrent chordoma after prior surgery / RT / imatinib failure. All 3/3 patients had clinical + radiographic response (SD to PR lasting several months); correlative analysis showed PD-L1 expression and immune infiltration in chordoma tissue. The first report of chordoma response to IO — despite small N, hypothesis-generating value is high: chordoma is the only potential exception to the IO-all-failed rule in bone, worth large-sample validation.

Takeaway: in 2026 IO use in bone tumors is restricted to the following three categories only: (a) dedifferentiated chondrosarcoma (SARC028 + Alliance expansion signal); (b) chordoma compassionate use (Migliorini + subsequent prospective pending); (c) tumor-agnostic MSI-H / dMMR / TMB-H subgroups (rare). IO monotherapy not recommended for osteosarcoma + Ewing sarcoma + classic chondrosarcoma — off-label use offers extremely low clinical benefit plus unexpected toxicity plus insurance-denial risk.

3. Horizontal: The 2026 Decision Landscape (Six Dimensions)

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

3.1 Newly Diagnosed Osteosarcoma / Ewing: NGS Panel Mandatory + 5-Subtype Classification

Subtype classification determines everything downstream in bone tumors. Every newly diagnosed bone tumor requires: (a) central pathology review to confirm histology (osteosarcoma / Ewing / chondrosarcoma / chordoma / GCTB); (b) molecular testing with a comprehensive NGS panel covering at minimum IDH1/2 R132 hotspot (chondrosarcoma), H3F3A G34W/V (GCTB adjunct), EWSR1-FLI1 / EWSR1-ERG fusion (Ewing confirmation), BRCA1/2 + SDH + PDGFR + MSI status (cross-subtype actionable targets). Missing IDH1 = missing the ivosidenib path; missing MSI-H = missing tumor-agnostic IO.

3.2 Osteosarcoma Local + Adjuvant: MAP Remains SoC / No Gain from Intensification

2026 mainstream: resectable non-metastatic high-grade osteosarcoma = neoadjuvant MAP (high-dose methotrexate + doxorubicin + cisplatin) → limb-sparing surgery → adjuvant MAP, maintaining the framework established by MIOS 1986. POG-8651 [PMID 12697883] showed no survival difference, yet neoadjuvant remains SoC because of surgical feasibility for limb-sparing + histologic-response stratification (not a survival advantage).

Key branchpoints:

Subgroup	Recommendation
Resectable non-metastatic, high-grade, pediatric / AYA	Neoadjuvant MAP → surgery → adjuvant MAP (MIOS framework)
Poor histologic response (≥10% viable tumor cells)	Maintain MAP, do not add ifosfamide / etoposide (EURAMOS-1-PR [PMID 27569442] HR 0.98 negative + secondary AML risk)
Good histologic response (<10% viable tumor cells)	Maintain MAP, do not add pegylated interferon (EURAMOS-1-GR [PMID 26033801] HR 0.83 negative)
Adult osteosarcoma	Use MAP framework (with adjustments — doxorubicin dose adjustment + methotrexate caution)
INT-0133 [PMID 18235123] MTP-PE	Available in EMA regions only; FDA not approved; not a global SoC

Not recommended: adding ifosfamide or mTOR or any “intensification” strategy on top of the MAP backbone; neoadjuvant SBRT / proton-boosted regimens have no phase 3 positive evidence in frontline osteosarcoma.

3.3 Ewing Sarcoma: Interval Compression vs High-Dose Alkylator + rEECur New Standard

2026 mainstream:

Subgroup	Recommendation
Newly diagnosed localized Ewing (North American path)	AEWS0031 [PMID 23091096] dose-dense VDC/IE q2w (5y EFS 73%)
Newly diagnosed localized Ewing (European path)	VIDE induction → risk-stratified consolidation: standard risk = EURO-EWING-99-R1 [PMID 24982464] VAC or VAI; high risk (poor response / large axial) = EURO-EWING-99-R2 [PMID 30188789] BuMel + autologous HSCT (3y EFS 67%)
Newly diagnosed metastatic Ewing	VDC-IE framework + multidisciplinary + consider BuMel consolidation; INT-0091 [PMID 12594313] metastatic subgroup no benefit suggests simply adding drugs is useless
First relapse / refractory (age 4-50)	rEECur [NCT03416517] high-dose ifosfamide (new reference standard, superior to VIT and TC)
Relapse (high-dose ifos intolerant / renal impairment)	VIT (VIT-RACIBORSKA [PMID 23776128] + VIT-WAGNER [PMID 16317751] multi-cohort convergent evidence, ~60-70% ORR)
Relapse + TKI-naive	cabozantinib (CABONE [PMID 32078813] Ewing arm ORR 26%) off-label

Key controversy: North American dose-dense and European VIDE + BuMel have no head-to-head RCT; in practice, choose by patient location / center experience.

3.4 Rare-Subtype Target Matching: IDH1 Chondrosarcoma / RANKL GCTB / PDGFR Chordoma — Three Paths

2026 mainstream:

Subtype	Biomarker / Driver	First-Line Therapy	Key Trial
Conventional chondrosarcoma	IDH1 R132 mutation (~50% central type)	ivosidenib 500 mg QD	IVOSIDENIB-CHONDRO-P1 [PMID 32208957] + LT [PMID 40100120]
Conventional chondrosarcoma IDH1+ and ivosidenib failure	IDH mutation-driven BRCAness	olaparib (PARP inhibitor)	OLAPARIB-IDH-SARC [PMID 34994649]
Conventional / dedifferentiated chondrosarcoma IDH-negative or untested	Angiogenesis axis	pazopanib or regorafenib	SARC-PAZO-CHONDRO [PMID 31509242] / REGOBONE-CHONDRO [PMID 33895682]
GCTB unresectable / high-morbidity surgery	RANKL signaling	denosumab 120 mg SC Q4W (with use-and-pause intermittent dosing)	DENOSUMAB-GCTB-P2 [PMID 20149736] + INTERIM [PMID 23867211] + LT [PMID 31704134]
Chordoma local therapy exhausted	PDGFRB pathway	imatinib 800 mg QD	IMATINIB-CHORDOMA-P2 [PMID 22331945]
Chordoma progression after imatinib	mTOR combination	imatinib + everolimus	IMATINIB-EVEROL-CHORDOMA [PMID 30216418]
Chordoma locally advanced unresectable + radiotherapy	brachyury	GI-6301 vaccine + standard radiotherapy (clinical trial / compassionate only)	GI6301-CHORDOMA [PMID 33594772]

3.5 IO Use Restrictions: IO Monotherapy Not Recommended in Osteosarcoma + Ewing + Classic Chondrosarcoma

2026 mainstream:

Osteosarcoma + Ewing sarcoma + classic chondrosarcoma → Not recommended any IO monotherapy (SARC028 [PMID 28988646] three subtypes ORR 0-5%)
Dedifferentiated chondrosarcoma → SARC028 + Alliance A091401 expansion [PMID 39343511] signal supports consideration of nivolumab + ipilimumab; still not practice-changing
Chordoma → Migliorini [PMID 28919999] 3-case positive signal; compassionate use or prospective trial; not casual off-label use
Tumor-agnostic MSI-H / dMMR / TMB-H (rare in bone tumors, < 1-2%) → pembrolizumab / nivolumab based on cross-tumor basket data
Alliance A091401 [PMID 29370992] supports nivo + ipi combination > monotherapy in soft tissue, but did not deliver significant improvement in the osteosarcoma subgroup

Key principle: the low-TMB + immune-desert biology of bone tumors means IO is not a “haven’t-found-the-right-drug problem” but a “biology doesn’t support it” problem. Off-label use requires careful assessment of insurance coverage + toxicity + futility risk.

3.6 Relapse Setting: All Existing Regimens Are Marginal + Clinical Trial Priority

2026 mainstream:

Subtype	Relapse 2L+ First Choice	Alternatives	Notes
Osteosarcoma	regorafenib (SARC024 [PMID 31013172] + REGOBONE [PMID 30477937])	cabozantinib (CABONE [PMID 32078813] osteosarcoma arm PFR 33% + ORR 12%) / pazopanib (PAZO-OSTEO [PMID 35075361]) / sorafenib monotherapy	All VEGFR TKIs in the same PFS band, none have changed OS
Ewing sarcoma	high-dose ifosfamide (rEECur)	VIT triplet / cabozantinib (CABONE Ewing arm ORR 26%) / high-dose alkylator + HSCT	rEECur first RCT-level 2L answer
Chondrosarcoma	IDH1+ goes to ivosidenib / PARP; IDH- goes to pazopanib or regorafenib	Clinical trial	Rare subtype, phase 3 lacking
GCTB	Long-term denosumab (Chawla LT)	Surgery / radiotherapy local salvage	Global SoC
Chordoma	imatinib ± everolimus	IO compassionate (Migliorini) / proton re-irradiation / brachyury vaccine	Small histology, multidisciplinary-led

Universal principle: all existing regimens for relapsed bone tumors deliver marginal PFS benefit — none cure. Every newly diagnosed relapsed osteosarcoma / Ewing / chondrosarcoma patient should be evaluated first for clinical trial enrollment — ADC (antibody-drug conjugate, e.g., TROP-2), adoptive cell therapy (TIL / CAR-T), novel targets (anti-TIGIT / anti-LAG3) are the main directions.

4. Research Gaps: Ten Unresolved Clinical Questions

This report identifies the following gaps, all definable specific questions (not “more research needed” boilerplate):

Biological explanation for 40-year MAP / VDC-IE unsurpassability in osteosarcoma + Ewing: after EURAMOS-1 both arms + COSS-86 + INT-0091, every intensification strategy has failed — is MAP / VDC-IE already at the “chemo ceiling,” or do osteosarcoma / Ewing have unidentified resistance pathways? The molecular basis of intrinsic chemoresistance has not been systematically characterized.
Biomarkers for IO failure (TMB / PD-L1 / MHC): in SARC028 [PMID 28988646] bone subgroup ORR 5% — is this uniformly low or does it hide responders? TMB / PD-L1 / HLA loss / neoantigen prediction models lack prospective validation; the mechanism of the 20% responder rate in dedifferentiated chondrosarcoma is unclear.
IDH1-selective inhibition vs pan-inhibitor in chondrosarcoma: ivosidenib (IDH1-only, AG-120) in CHONDRO-P1 + LT — ORR 0% + DCR 52%; vorasidenib (IDH1/2 dual inhibitor, AG-881, glioma indication) has no prospective chondrosarcoma data — do selective vs dual-inhibition strategies have different activity in bone tumors?
GCTB denosumab post-discontinuation relapse risk: denosumab-GCTB-LT [PMID 31704134] confirmed long-term control, but the rebound risk after discontinuation and the biology of relapse (RANKL-signaling restoration vs de novo osteoclast generation) is not systematically characterized; the optimal use-and-pause intermittent rhythm has no RCT.
Chordoma PDGFR monotherapy vs combination + integration with proton radiotherapy: imatinib [PMID 22331945] → imatinib + everolimus [PMID 30216418] combination delivers limited increment; optimal sequencing / concurrent use with proton / heavy-ion radiotherapy has no prospective data.
Role of neoadjuvant SBRT / proton in rare subtypes: proton / carbon-ion therapy is standard for local control in chondrosarcoma / chordoma, but its integration with systemic therapy (ivosidenib / denosumab / imatinib) — concurrent / sandwich / sequential — lacks RCTs.
Pediatric vs adult osteosarcoma biology differences: pediatric / AYA osteosarcoma MAP cure rate ~60%, while adult (> 40 years) cure rate is significantly lower — is this “cannot tolerate full-dose MAP” or “adult osteosarcoma is a different subtype”? Genomic classification has yet to answer.
Genomic / transcriptomic subtype stratification: osteosarcoma is highly heterogeneous (MYC / CDK4 amplification, TP53 complex rearrangements, gene-signature subtypes), yet classification has not yet driven treatment selection; STAG2 / TP53 / CDKN2A co-mutation subtypes in Ewing have not entered stratification.
High-dose ifosfamide cardiotoxicity / renal-toxicity sequelae in relapsed Ewing: rEECur established high-dose ifosfamide, but long-term safety of high cumulative ifosfamide dosing in pediatric / AYA — long-term renal / cardiac function / secondary tumor risk — requires registry-based long-term follow-up.
Early phase 1 signals of ADC / CAR-T / TIL in bone tumors: TROP-2 ADC, B7-H3 CAR-T, GD2 CAR-T, TIL — all have anecdotal early activity in osteosarcoma / Ewing phase 1; but due to rare-case + pediatric-trial complexity, phase 2 confirmatory progress is slow.

5. 2024-2026 Latest Developments

5.1 FDA / NMPA New Approvals / Guideline Expansion

ivosidenib bone tumor extension: FDA first approved ivosidenib in 2021 for IDH1+ AML and BTC; NCCN Bone V2.2026 formally lists ivosidenib as a recommended option for IDH1+ conventional chondrosarcoma — based on CHONDRO-P1 [PMID 32208957] + CHONDRO-LT [PMID 40100120] two readouts. The chondrosarcoma indication is not a standalone indication on the FDA label, but NCCN-guideline-level recommendation is in place.
denosumab GCTB update: FDA approved denosumab for GCTB in 2013 (based on Chawla INTERIM [PMID 23867211]); after 2019 LT [PMID 31704134] data, prescribing information was updated for long-term safety (ONJ ~5%, atypical femur fracture monitoring).
No new osteosarcoma approvals: no osteosarcoma / Ewing systemic therapy received new FDA approval in 2024-2026. Denosumab’s AOST1321 [PMID 41159913] 2026 negative readout in osteosarcoma explicitly refuted extending denosumab to osteosarcoma as antitumor therapy.
China NMPA: domestic TKI (anlotinib) is outside NCCN but used in Chinese practice off-label for relapsed soft tissue sarcoma + osteosarcoma; no large-scale phase 3 osteosarcoma data.

5.2 Key Conference Readouts (2024-2025, Weighted Lower)

The following entries serve as candidate pool only before formal peer review; they do not enter the main library. Those with a PMID have been promoted to the main library.

rEECur phase 3 winner (McCabe 2024 ESMO / 2024 Lancet Oncol manuscript pending): high-dose ifosfamide won as the new reference standard for relapsed Ewing sarcoma; full manuscript still not indexed on PubMed as of 2026-04. Cited by NCT03416517 + conference readout.
AOST1321 2026 readout: [PMID 41159913] fresh publication (Janeway 2026 Clin Cancer Res); denosumab as antitumor therapy in osteosarcoma negative in both cohorts — explicitly refutes the “hijacking osteoclast biology” hypothesis in osteosarcoma.
IVOSIDENIB-CHONDRO-LT 2025 readout: [PMID 40100120] long-term follow-up confirming durability of CHONDRO-P1 PFS + biomarker signal; included as NCCN Bone V2.2026 reference.
Alliance A091401 Expansion 2024: [PMID 39343511] histology-enriched expansion cohorts reconfirming dedifferentiated chondrosarcoma as the bone subtype most likely to respond to IO, with osteosarcoma still inactive.

5.3 Ongoing Phase III / Early Signals (Selected)

Adoptive cell therapy (TIL / CAR-T) in osteosarcoma: B7-H3 CAR-T, GD2 CAR-T have anecdotal response signals in pediatric / AYA osteosarcoma / Ewing phase 1; Stanford / MSK / COG multicenter phase 2 accrual ongoing.
TROP-2 ADC (sacituzumab govitecan / datopotamab deruxtecan) early signals in osteosarcoma / Ewing basket trials; no phase 3 yet.
SARC032 (pembrolizumab + radiotherapy) primarily designed for soft tissue sarcoma — bone-related subgroup data to watch.
Anti-TIGIT / anti-LAG3 combination IO has no positive signals in bone tumors to date.

6. Synthesis and Judgment

6.1 Vertical × Horizontal: The 2026 Bone Tumor Landscape Is Shaped by Three “Dual-Track Resonances”

Overlaying vertical paradigm evolution on the horizontal current decision landscape reveals that the 2026 bone tumor landscape exhibits “dual-track resonances” completely different from NSCLC / BTC:

Mainstream major subtypes (osteosarcoma + Ewing) 40-year stagnation vs rare subtypes (chondrosarcoma + GCTB + chordoma) precision breakthroughs in parallel: osteosarcoma MIOS 1986 MAP backbone unchanged for 40 years, all intensification failed (EURAMOS-1 both arms / COSS-86 / MTP-PE contested / all relapse TKIs marginal); meanwhile in the same period, chondrosarcoma IDH1 → ivosidenib, GCTB → denosumab, chordoma → imatinib all delivered phase 2-level positive signals. “Biology determines outcomes” — mainstream major subtypes lack clear druggable drivers, while rare subtypes each have an independent driver. This is the “anti-scale phenomenon” unique to bone tumors (the commonest histologies have the most resources yet are hardest to break through).
IO cross-subtype all-failure + three narrow windows left open: SARC028 osteosarcoma / Ewing / classic chondrosarcoma ORR 0-5% confirms IO is not a cure-all; but dedifferentiated chondrosarcoma (SARC028 + Alliance expansion) + chordoma (Migliorini + PD-L1 expression evidence) + MSI-H (rare but tumor-agnostic effective) three narrow windows remain. “Biology gate-keeps” rather than “haven’t tried the right drug” — low TMB + immune-desert keep the IO monotherapy ceiling very low in osteosarcoma / Ewing.
Trial-design innovation vs new-drug approvals ratio inversion: in bone tumors, the most valuable frontline improvements in the past 25 years came from trial design, not new drugs — AEWS0031 compressed VDC/IE q3w to q2w grabbing 8 percentage points of EFS; EURO-EWING-99-R2 used high-risk-stratified BuMel HSCT to grab 14 percentage points; rEECur used Bayesian adaptive design to give relapsed Ewing its first RCT answer. This “design beats new drug” phenomenon is almost unseen in NSCLC (driver era) / BTC (biomarker era).

These three resonances together explain a clinical phenomenon: for a newly diagnosed bone tumor patient in 2026, the core branchpoint in the decision tree is not “which newest drug to pick” but “first confirm the subtype + driver diagnosis → follow mainstream chemo backbone or rare-subtype precision → IO mostly hands-off”.

6.2 Clinical Decision Takeaways (for Junior-Mid Oncologists)

“Confirm subtype first, then decide” is an iron rule: five bone tumor subtypes (osteosarcoma / Ewing / chondrosarcoma / chordoma / GCTB) have completely different treatments. Any non-specialist center receiving a case should immediately arrange central pathology review + an NGS panel covering at minimum IDH1/2 / EWSR1 fusion / H3F3A / SDH / PDGFR / MSI. Missing IDH1 = missing the chondrosarcoma ivosidenib path; missing H3F3A = missing GCTB confirmation.
Do not add drugs to the osteosarcoma MAP backbone casually: the MIOS [PMID 3520317] 1986 framework has been undefeated for 40 years. EURAMOS-1 both arms (poor responder + good responder) negative [PMID 27569442 + 26033801] explicitly tell us: adding ifosfamide / interferon on top of MAP is useless — only more toxicity.
Dose-dense is a free win in Ewing: AEWS0031 [PMID 23091096] compressed q3w to q2w grabbing 8 percentage points of EFS — no new drug, no extra toxicity. This is the single most important frontline decision in Ewing sarcoma.
High-risk localized Ewing goes BuMel: EURO-EWING-99-R2 [PMID 30188789] high-risk subgroup BuMel + autologous HSCT delivers 3-year EFS 67% vs 53%, a rare positive modern osteosarcoma / Ewing intensification RCT — prerequisite is correctly identifying “high risk” (poor induction response or large axial tumor).
IDH1 testing mandatory in chondrosarcoma: IDH1+ chondrosarcoma goes to ivosidenib (IVOSIDENIB-CHONDRO-P1 + LT [PMID 32208957 + 40100120]), with olaparib BRCAness second shot [PMID 34994649] after failure. ivosidenib is not vorasidenib — chondrosarcoma uses AG-120, glioma uses AG-881 — do not confuse them when prescribing.
GCTB = denosumab is SoC: Thomas 2010 [PMID 20149736] + Chawla 2013 [PMID 23867211] + 2019 LT [PMID 31704134] three progressive phase 2 datasets lock it in — GCTB changed from “unresectable = fatal” to “medical therapy → limb-sparing surgery.” Note long-term ONJ ~5% + atypical femur fracture monitoring + use-and-pause intermittent dosing.
Chordoma = multidisciplinary + proton + imatinib: chordoma prefers proton / heavy-ion radiotherapy + surgery; when systemic therapy is exhausted, imatinib [PMID 22331945] serves as backbone, with everolimus combination [PMID 30216418] or brachyury vaccine clinical trial after failure.
IO is not a cure-all: osteosarcoma + Ewing + classic chondrosarcoma (non-dedifferentiated) — not recommended to empirically use IO monotherapy (SARC028 [PMID 28988646]). Off-label use combines triple negatives: extremely low clinical benefit + unexpected toxicity + insurance-denial risk.
Rational expectations for relapse 2L: relapsed osteosarcoma regorafenib / cabozantinib / pazopanib — all VEGFR TKIs — offer 4-6 month PFS marginal wins, none curative; relapsed Ewing high-dose ifosfamide was just established as the new standard by rEECur; relapsed chondrosarcoma goes by IDH classification or anti-angiogenic TKI. Clinical trial enrollment (ADC / CAR-T / TIL / novel targets) is the benefit-window opportunity.
Lesson from AOST1321 denosumab osteosarcoma negative: the same drug (denosumab) is landscape-changing in GCTB and inactive in osteosarcoma [PMID 41159913]. Five-subtype bone tumor heterogeneity is far greater than one imagines — do not casually extrapolate one subtype’s success to another.

7. Information Sources

Metadata for the 35 trials in this report was independently verified through PubMed and ClinicalTrials.gov. Every [PMID xxxxxxxx] in the text can be verified directly in PubMed.

Published trials: 34, covering 1986-2026 (PMIDs verifiable)
Ongoing / primary manuscript pending: 1 (rEECur phase 3 McCabe 2024 ESMO readout, NCT03416517, primary publication not yet PubMed-indexed)
NCCN guideline citations: 27/35 (77%) directly hit NCCN Bone Cancer V2.2026 reference section; the remaining 8 are expected misses within NCCN literature-scope limits (Alliance A091401 IO series, Migliorini chordoma compassionate 3 cases, AOST1321 just-published in 2026, MIOS 1986 historical, etc.)
Key 2024-2026 new data: 3 (AOST1321 [PMID 41159913], IVOSIDENIB-CHONDRO-LT [PMID 40100120], Alliance-A091401-Expansion [PMID 39343511])
Research gaps: 10

7.1 In-Text Citation List (by PMID Ascending)

The following table is the bracket-cited PMID list in this report text — each can be clicked through to PubMed URL for verification.

PMID	Trial / Paper	Year	Journal	Text Location
3520317	MIOS	1986	N Engl J Med	§2.1 osteosarcoma MAP / §6.2
9789613	COSS-86	1998	Ann Oncol	§2.1
12594313	INT-0091	2003	N Engl J Med	§2.2 Ewing / §3.3
12697883	POG-8651	2003	J Clin Oncol	§2.1 / §3.2
16317751	VIT-WAGNER	2007	Pediatr Blood Cancer	§2.2 / §3.3
18235123	INT-0133	2008	J Clin Oncol	§2.1 / §3.2
20149736	DENOSUMAB-GCTB-P2 (Thomas)	2010	Lancet Oncol	§2.3 GCTB / §3.4 / §6.2
21527590	SORAFENIB-ISG	2012	Ann Oncol	§2.1
22331945	IMATINIB-CHORDOMA-P2	2012	J Clin Oncol	§2.3 chordoma / §3.4 / §6.2
23091096	AEWS0031	2012	J Clin Oncol	§2.2 / §3.3 / §6.2
23776128	VIT-RACIBORSKA	2013	Pediatr Blood Cancer	§2.2 / §3.3
23867211	DENOSUMAB-GCTB-INTERIM (Chawla)	2013	Lancet Oncol	§2.3 / §3.4 / §6.2
24982464	EURO-EWING-99-R1	2014	J Clin Oncol	§2.2 / §3.3
25498219	SORAFENIB-EVEROLIMUS	2015	Lancet Oncol	§2.1
26033801	EURAMOS-1 Good Responders	2015	J Clin Oncol	§2.1 / §3.2 / §6.2
27569442	EURAMOS-1 Poor Responders	2016	Lancet Oncol	§2.1 / §3.2 / §6.2
28919999	CHORDOMA-IO-MIGLIORINI	2017	Oncoimmunology	§2.4 IO / §3.5
28988646	SARC028	2017	Lancet Oncol	§2.4 / §3.5 / §6.2
29370992	ALLIANCE-A091401	2018	Lancet Oncol	§2.4 / §3.5
30188789	EURO-EWING-99-R2	2018	J Clin Oncol	§2.2 / §3.3 / §6.2
30216418	IMATINIB-EVEROL-CHORDOMA	2018	Cancer	§2.3 / §3.4 / §6.2
30477937	REGOBONE	2019	Lancet Oncol	§2.1 / §3.6
31013172	SARC024	2019	J Clin Oncol	§2.1 / §3.6
31509242	SARC-PAZO-CHONDRO	2020	Cancer	§2.3 / §3.4
31704134	DENOSUMAB-GCTB-LT (Chawla)	2019	Lancet Oncol	§2.3 / §3.4 / §4 / §6.2
32078813	CABONE	2020	Lancet Oncol	§2.1 / §3.3 / §3.6
32208957	IVOSIDENIB-CHONDRO-P1 (Tap)	2020	J Clin Oncol	§2.3 / §3.4 / §4 / §6.2
33594772	GI6301-CHORDOMA	2021	Oncologist	§2.3 / §3.4
33895682	REGOBONE-CHONDRO	2021	Eur J Cancer	§2.3 / §3.4
34994649	OLAPARIB-IDH-SARC	2021	JCO Precis Oncol	§2.3 / §3.4 / §6.2
35075361	PAZO-OSTEO	2022	J Oncol	§2.1 / §3.6
39343511	ALLIANCE-A091401-EXPANSION	2024	J Immunother Cancer	§2.4 / §3.5 / §5.2
40100120	IVOSIDENIB-CHONDRO-LT (Tap)	2025	Clin Cancer Res	§2.3 / §3.4 / §5.2 / §6.2
41159913	AOST1321	2026	Clin Cancer Res	§2.1 / §5.1 / §5.2 / §6.2

(The rEECur phase 3 primary manuscript is cited by NCT03416517 + McCabe 2024 ESMO readout; PMID will be added to the table once indexed.)

7.2 Verification Conventions

Every PMID can be accessed directly via https://pubmed.ncbi.nlm.nih.gov/{PMID}/ for verification
Every NCT id can be accessed via https://clinicaltrials.gov/study/{NCT_id}/
Conference abstracts (ASCO / ESMO / CTOS) are searched through official conference systems; all conference citations in this report are “weighted lower” — not peer-reviewed, final data defers to journal publication
After rEECur manuscript publication, the corresponding PMID will be updated
If you find a discrepancy between a PMID’s trial name / year / conclusion in this report and PubMed, corrections are welcome

Clinical Trial Timeline Is Here

Chinese: /trials/bone/ English: /en/trials/bone/

Each trial has an independent detail page, including:

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

35 trials · 5 subtypes · 1986 to 2026 · synced with NCCN Bone Cancer V2.2026.

Closing

Bone tumors over the past 40 years are the oncology field with the strongest “dual-track reality” flavor — the mainstream major subtypes (osteosarcoma + Ewing) held the MAP / VDC-IE backbone undefeated for 40 years, with all intensification failed; in the same period, the rare subtypes (chondrosarcoma + GCTB + chordoma) each leveraged an independent driver gene to achieve precision-therapy breakthroughs; IO at the cross-subtype level failed almost completely, leaving three narrow windows (dedifferentiated chondrosarcoma, chordoma, rare MSI-H subgroups) open.

This landscape of “mainstream stagnation + rare breakthroughs + IO failure” forms a sharp contrast with NSCLC’s “5-paradigm leaps + 10 drivers all entering 1L + IO rewriting the backbone.” The driver behind it is not resource investment (osteosarcoma / Ewing have far more global decades of RCT resources than chordoma), but biology — mainstream major subtypes lack clear druggable drivers, while rare subtypes each have independent drivers; low TMB + immune-desert in bone tumors keep the IO ceiling low. This is a domain where “biology determines the treatment ceiling,” not a “haven’t-found-the-drug yet” problem.

For a newly diagnosed bone tumor patient in 2026, the core branchpoints in the decision tree are not “which newest drug to pick” but “confirm subtype first → follow mainstream chemo backbone or rare-subtype precision → IO mostly hands-off → relapse prioritizes clinical trial.”

The value of this report lies not in “exhaustively listing all trials” (PubMed can do that), but in compressing 40 years of evolution + current decisions + unresolved gaps into a single reading bandwidth. Next time you face a newly diagnosed bone tumor patient, every branchpoint in the decision tree has this map to consult — checkable, traceable, debatable.

Clinician × AI = Research Superpower + Clinical Decision Amplifier

—— Dual Brain Lab · 2026-04-21