Gastric Cancer Clinical Trial Timeline: 58 RCTs Across 25 Years Mapping a Subtyping Revolution

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

Gastric Cancer Clinical Trial Timeline — In-depth Report

Coverage: 58 landmark trials cited by NCCN Gastric + CSCO Gastric 2025 (all PMID / NCT traceable) + East–West perioperative / adjuvant branches + HER2 / CLDN18.2 / PD-L1 CPS / MSI four-layer subtyping + three subtyping revolutions

Curated by Dual Brain Lab (csilab.net)

1. One-sentence definition

This report traces the evolution logic and current decision landscape of gastric cancer (GC) and gastroesophageal junction cancer (GEJ) systemic therapy over the past 25 years (2001-2026), covering the landmark clinical trials cited by NCCN Gastric V2.2025 and CSCO Gastric 2025, providing frontline clinicians in 2026 a traceable panoramic map for “who, what, why” decisions.

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

Scope boundary: GC refers to adenocarcinoma arising from gastric mucosa; GEJ refers to cardia / esophagogastric junction adenocarcinoma. Of Siewert I-III, Siewert II-III belong to the gastric category (covered here), while Siewert I and esophageal adenocarcinoma (EAC) belong to the esophageal category (not covered). Globally ~970,000 new gastric cancers annually (5th most common malignancy) + ~660,000 deaths (5th leading cancer death), with China accounting for ~44%. HBV / H. pylori infection, chronic atrophic gastritis, and high-salt pickled diets are the main environmental factors; Lauren classification (intestinal vs diffuse) and molecular subtyping (TCGA: EBV / MSI / CIN / GS four types) are the main pathological and molecular axes.

While HCC uniquely walked a “0 predictive biomarker” path, gastric cancer went the opposite way — 25 years, three subtyping revolutions: anatomical subtyping (GEJ vs gastric body) from crude endoscopic split to the manifest HR differences in CheckMate-649 subgroups; East–West path divergence (FLOT4 German perioperative vs CLASSIC Korean adjuvant CAPOX vs INT-0116 US adjuvant chemoRT) with the same stage custom-fit across three continents; HER2 drug 10-year leap (ToGA 2010 trastuzumab + chemo → 2020 DESTINY T-DXd 2L → 2025 DESTINY-Gastric-04 T-DXd 2L standard + KEYNOTE-811 HER2 1L IO combo); biomarker subtyping refinement (HER2 / PD-L1 CPS / CLDN18.2 / MSI four-dimensional checkerboard). By 2026, treatment decisions have completely flipped from “which chemo regimen” to “first get the biomarker panel complete.”

2. Longitudinal: timeline of five treatment-paradigm shifts

Gastric cancer systemic therapy has gone through five paradigm shifts over 25 years: adjuvant / definitive chemoRT (2001 INT-0116) → birth of the perioperative chemo concept (2006 MAGIC → 2019 FLOT4) → HER2 targeted era (2010 ToGA → 2020-2025 T-DXd three-generation evidence) → IO + chemo 1L standard established (2021-2024 four phase IIIs concordantly positive) → CLDN18.2 new subtype + perioperative IO (2023-2025 SPOTLIGHT / GLOW / MATTERHORN).

Each shift had 2-4 phase IIIs pushing the old SoC to second-line. Compared to NSCLC’s “driver-gene × IO dual-engine” and HCC’s “0-biomarker / IO-backbone-alone,” gastric cancer is characterized by “biomarker subtyping started early (2010 HER2) but density grew slowly (CLDN18.2 joined 15 years later), with severe geographic branching (East Asia vs Europe/US vs China, each running its own adjuvant / perioperative playbook)” — which means the 2026 gastric decision tree neither unfolds 10+ drivers horizontally like NSCLC, nor “rides clinical parameters alone” like HCC, but is a “region × biomarker × line” three-dimensional checkerboard.

2.1 Chemotherapy backbone era (2001-2010): adjuvant chemoRT / perioperative chemo / HER2 — three starting points

Story: in 2001 INT-0116 first put adjuvant chemoRT on stage III postoperative gastric cancer standard (US default for 15 years); in 2006 MAGIC first proved the “perioperative chemo” concept in UK/Europe (5-year OS 36% vs 23%, HR 0.75), forming a transatlantic divergence with US adjuvant chemoRT; the same year V325’s DCF triplet pushed advanced chemo OS ceiling to 9.2 months, and REAL-2 (2008) used a 2×2 factorial to bring capecitabine / oxaliplatin into the advanced backbone; 2007-2008 Japan’s ACTS-GC / SPIRITS defined “S-1 as Asian default,” further diverging from Europe/US; in 2010 ToGA made HER2 gastric cancer’s first actionable biomarker — a targeted path that ran alone for 13 years.

INT-0116 [PMID 11547741] (Macdonald 2001 N Engl J Med, N=556): US postoperative 5-FU / LV + 45 Gy chemoradiation vs D0-D1 surgery alone. mOS 36 vs 27 months (HR 1.35, P=0.005, favoring treatment), 3-year OS 50% vs 41%. Established the NCCN “adjuvant chemoRT” branch as the US postoperative default for 15 years — but later ARTIST / ARTIST-2 showed RT adds nothing after adequate D2 dissection, phasing it out of Asian practice.
MAGIC [PMID 16822992] (Cunningham 2006 N Engl J Med, N=503, UK): perioperative ECF (epirubicin + cisplatin + 5-FU) 3 cycles preop + 3 postop vs surgery alone. 5-year OS 36% vs 23% (HR 0.75, P=0.009). The invention moment of the “perioperative chemo” concept — European standard for a decade-plus, until 2019 FLOT4 upgraded the backbone from ECF to FLOT.
V325 [PMID 17075117] (Van Cutsem 2006 J Clin Oncol, N=445): docetaxel + cisplatin + 5-FU (DCF) vs CF advanced 1L. mOS 9.2 vs 8.6 months (HR 0.77, P=0.02), ORR 37% vs 25%, G3-4 neutropenia 82%. First OS-positive triplet backbone, but toxicity too high for wide real-world uptake.
REAL-2 [PMID 18172173] (Cunningham 2008 N Engl J Med, N=1002): 2×2 factorial (epirubicin + platinum + fluoropyrimidine: ECF / ECX / EOF / EOX). Capecitabine non-inferior to 5-FU (HR 0.86), oxaliplatin non-inferior to cisplatin (HR 0.92), best arm EOX mOS 11.2 months. Brought capecitabine + oxaliplatin into the advanced backbone, laying the foundation for 20 years of CAPOX SoC status.
ACTS-GC [PMID 17978289] (Sakuramoto 2007 N Engl J Med, N=1059, Japan): D2 postoperative S-1 for 1 year vs surgery alone. 3-year OS 80.1% vs 70.1% (HR 0.68, P=0.003), 5-year OS 71.7% vs 61.1%. Definitive evidence for Japanese adjuvant S-1; the “Asia primarily adjuvant” tradition was set.
SPIRITS [PMID 18282805] (Koizumi 2008 Lancet Oncol, N=305, Japan): advanced S-1 + cisplatin (SP) vs S-1 monotherapy. mOS 13.0 vs 11.0 months (HR 0.77, P=0.04), ORR 54% vs 31%. SP became Japan’s advanced 1L default for 10+ years, yielding only in the ATTRACTION-4 / CheckMate-649 IO era.
ToGA [PMID 20728210] (Bang 2010 Lancet, N=584): trastuzumab + XP/FP chemotherapy vs chemo in HER2+ (IHC3+ or IHC2+/FISH+) advanced GC/GEJ. mOS 13.8 vs 11.1 months (HR 0.74, P=0.0046), IHC3+ / FISH+ subgroup mOS 16.0 vs 11.8 months (HR 0.65). First positive biomarker-targeted phase III in gastric cancer — HER2 defined the first molecular subtype of gastric cancer, a standard that ran for 13 years until KEYNOTE-811 layered pembrolizumab on top.

Takeaway: the 2001-2010 decade anchored the entire basic framework of modern gastric cancer — US adjuvant chemoRT (INT-0116) / European perioperative ECF (MAGIC) / Japanese adjuvant S-1 (ACTS-GC) / Japanese advanced SP (SPIRITS) / Euro-US advanced DCF + CAPOX (V325 + REAL-2) / global HER2+ trastuzumab (ToGA) — all six branches cemented in these 10 years. Every new drug in the following 15 years only “replaces, stacks, or refines” on these six branches.

2.2 East–West adjuvant / perioperative divergence takes shape (2010-2019): CLASSIC / FLOT4 / ARTIST / RESOLVE / PRODIGY

Story: in 2012 Korea’s CLASSIC took D2 postoperative CAPOX to 3-year DFS 74% vs 59% (HR 0.56), making “adjuvant doublet chemo” the Asian standard; the same year Europe’s CROSS used neoadjuvant CRT (carboplatin + paclitaxel + 41.4 Gy) to push GEJ/EAC OS from 24 to 49 months (HR 0.657) — global GEJ tri-modality SoC was established; 2015 / 2021 Korea’s ARTIST / ARTIST-2 proved RT adds nothing after adequate D2 dissection, closing the “Asian D2 postop RT debate”; 2018 Netherlands’ CRITICS likewise showed that adding postop CRT after preop chemo gives no extra benefit; in 2019 Germany’s FLOT4 used docetaxel + oxaliplatin + 5-FU + leucovorin (FLOT) triplet / quadruplet to push perioperative mOS from ECF’s 35 to 50 months (HR 0.77), establishing the new Euro-US perioperative backbone; 2021 Korea’s PRODIGY proved PFS HR 0.70 with neoadjuvant DOS + adjuvant S-1; the same year China’s RESOLVE established perioperative SOX as China’s perioperative standard.

CLASSIC [PMID 22226517] (Bang 2012 Lancet, N=1035, Korea / China / Taiwan): D2 postoperative CAPOX × 8 cycles (6 months) vs surgery alone. 3-year DFS 74% vs 59% (HR 0.56, P<0.0001), 5-year OS 78% vs 69% (HR 0.66). Asian adjuvant CAPOX 20-year SoC, still the first-choice doublet after D2 today.
CROSS [PMID 22646630] (van Hagen 2012 N Engl J Med, N=366, Netherlands): neoadjuvant carboplatin + paclitaxel + 41.4 Gy vs surgery alone. mOS 49.4 vs 24.0 months (HR 0.657, P=0.003), R0 92% vs 69%, pCR 29%. Global GEJ / EAC tri-modality SoC, still unsurpassed (Neo-AEGIS tried to show FLOT perioperative non-inferior to CROSS but was terminated early due to futility + COVID).
ARTIST [PMID 25559811] (Park 2015 J Clin Oncol, N=458, Korea): D2 postoperative XP ± RT vs XP alone. 3-year DFS 78.2% vs 74.2% (HR 0.740, P=0.0922, NS). Subgroups suggested benefit in node+ / intestinal Lauren, but overall ITT negative — challenged the applicability of US INT-0116 in the Asian adequate-D2 setting.
ARTIST-2 [PMID 33278599] (Park 2021 Ann Oncol, N=538, Korea): node+ gastric cancer D2 postoperative SOX 6 months vs SOX + RT (SOXRT) vs S-1 1 year. 3-year DFS 74.3% (SOX) vs 72.8% (SOXRT) vs 64.8% (S-1); SOX and SOXRT both superior to S-1, but no difference between them (HR 0.971). ARTIST-2 closed the “Asian D2 postop RT” debate — doublet chemo is sufficient, no RT needed.
FLOT4 [PMID 30982686] (Al-Batran 2019 Lancet, N=716, Germany): perioperative FLOT 4+4 cycles vs ECF/ECX 3+3 cycles. mOS 50 vs 35 months (HR 0.77, 95% CI 0.63-0.94), pCR 16% vs 6%. New Euro-US perioperative backbone, on top of which all subsequent perioperative IO layering (MATTERHORN / KEYNOTE-585 FLOT subgroup) is built.
JACCRO GC-07 [PMID 30925125] (Yoshida 2019 J Clin Oncol, N=915, Japan): stage III D2 postoperative S-1 + docetaxel vs S-1 monotherapy. 3-year RFS 66% vs 50% (HR 0.632, P<0.001). Definitive evidence for Japanese stage III adjuvant doublet; “add docetaxel for stage III” written into Japanese guidelines.
CRITICS [PMID 29650363] (Cats 2018 Lancet Oncol, N=788, Netherlands): preop chemo (ECC/EOC) + postop chemo vs postop CRT (45 Gy + capecitabine/cisplatin). mOS 43 vs 37 months (HR 1.01, P=0.90), negative. No benefit from adding postop CRT after preop chemo — same author team / same country as CROSS but opposite result (neoadjuvant CRT vs postadjuvant CRT), highlighting that RT timing is key.
ST03 [PMID 28163000] (Cunningham 2017 Lancet Oncol, N=1063, UK): perioperative ECX + bevacizumab vs ECX. 3-year OS 50.3% vs 48.1% (HR 1.08, P=0.36), negative; esophagogastric anastomotic leak 24% vs 10%. The attempt to “add bev to perioperative” failed completely + increased surgical complications.
PRODIGY [PMID 34133211] (Kang 2021 J Clin Oncol, N=530, Korea): neoadjuvant DOS (docetaxel + oxaliplatin + S-1) × 3 cycles + surgery + adjuvant S-1 vs surgery + adjuvant S-1. 3-year PFS 66.3% vs 60.2%, adjusted HR 0.70 (P=0.023). Definitive evidence for Korea’s “neoadjuvant DOS triplet” — a representative of Asian neoadjuvant-era regimen iteration.
RESOLVE [PMID 34252374] (Zhang 2021 Lancet Oncol, N=1094, China): locally advanced GC/GEJ D2 gastrectomy perioperative SOX vs adjuvant SOX vs adjuvant CAPOX. 3-year DFS 59.4% (perioperative SOX) vs 51.1% (adjuvant CAPOX), HR 0.77 (P=0.028); adjuvant SOX non-inferior to adjuvant CAPOX. Definitive Chinese evidence for perioperative SOX — “perioperative > pure adjuvant” confirmed by RCT in Chinese population.
G-SOX [PMID 25316259] (Yamada 2015 Ann Oncol, N=685, Japan): advanced 1L SOX (S-1 + oxaliplatin) vs CS (S-1 + cisplatin). mOS 14.1 vs 13.1 months, PFS HR 1.004 (non-inferior), SOX fewer G≥3 AEs (nephrotoxicity / neutropenia). SOX established as SP alternative in Japanese / Asian advanced 1L, providing the control-arm background for later ATTRACTION-4 / ORIENT-16.
TOPGEAR [PMID 39282905] (Leong 2024 N Engl J Med, N=574, international): perioperative chemo ± preop CRT. pCR 17% vs 8% (favoring CRT) but mOS 46 vs 49 months (HR 1.05, NS), mPFS 31 vs 32 months (NS). pCR improved but OS did not — textbook case of “pCR as surrogate endpoint is unstable in gastric cancer” (fundamentally different from the strong pCR-OS correlation in breast cancer).

Takeaway: 2026 adjuvant / perioperative SoC is geographically branched — Euro-US first-choice FLOT4 perioperative (4+4 cycles), China first-choice RESOLVE perioperative SOX, Japan stage III first-choice JACCRO GC-07 S-1 + docetaxel adjuvant, Korea first-choice CLASSIC adjuvant CAPOX or ARTIST-2 SOX 6 months, GEJ/EAC first-choice CROSS neoadjuvant CRT. US INT-0116 adjuvant chemoRT has exited Asian practice in the adequate-D2 era (ARTIST-2 closed the debate), preserved only for D0-D1 or inadequate-dissection scenarios. Three “no longer use” paths: bevacizumab perioperative (ST03 negative), postop CRT after preop chemo (CRITICS negative), and judging OS by pCR alone as surrogate (TOPGEAR lesson).

2.3 HER2 era’s 10-year leap (2010-2025): ToGA → T-DXd → KEYNOTE-811 / zanidatamab

Story: after 2010 ToGA made HER2 gastric cancer’s first biomarker pedestal, no second HER2 drug entered gastric cancer SoC for a full 10 years — LOGIC/TRIO-013 (lapatinib + CapeOx vs CapeOx) 2016 negative, TyTAN / GATSBY (T-DM1 vs paclitaxel) negative. Not until 2020 did DESTINY-Gastric-01 use trastuzumab deruxtecan (T-DXd, HER2-ADC) break the stalemate in 2L HER2+; in 2023 KEYNOTE-811 layered pembrolizumab onto trastuzumab + chemo as the new HER2+ 1L backbone; in 2025 DESTINY-Gastric-04 made T-DXd the 2L HER2+ standard (beating the 10-year RAINBOW ramucirumab + paclitaxel); in 2025 HERIZON-GEA-01 topline used zanidatamab (HER2 bispecific antibody, simultaneously binding domains 2 + 4) to challenge the trastuzumab 1L backbone.

LOGIC/TRIO-013 [PMID 26628478] (Hecht 2016 J Clin Oncol, N=545): 1L HER2+ lapatinib + CapeOx vs CapeOx. mOS 12.2 vs 10.5 months (HR 0.91, NS, negative), mPFS 6.0 vs 5.4 months (HR 0.82, P=0.0381), ORR 53% vs 39%. First failure of the HER2 small-molecule TKI path in gastric cancer — lapatinib’s “PFS wins, OS doesn’t” replayed, deepening the view that “trastuzumab is irreplaceable as the HER2 backbone in gastric cancer.”
DESTINY-Gastric-01 [PMID 32469182] (Shitara 2020 N Engl J Med, N=187, Japan/Korea): HER2+ post-trastuzumab T-DXd vs physician’s choice chemo. ORR 51% vs 14% (P<0.001), mOS 12.5 vs 8.4 months (HR 0.59, P=0.01), ILD 9 cases G1-2 / 3 cases G3-4. First positive 2L HER2+ regimen 10 years into the HER2 era, FDA accelerated approval 2021-01.
DESTINY-Gastric-02 [PMID 37329891] (Van Cutsem 2023 Lancet Oncol, N=79, US/EU): HER2+ post-trastuzumab T-DXd 6.4 mg/kg single-arm phase II. Confirmed ORR 42%, mPFS 5.6 months, mOS 12.1 months, ILD 10% (1 G5 fatality). Replicated DG-01 in Euro-US populations — cross-regional consistency of HER2+ 2L T-DXd confirmed; ILD is the key safety signal.
KEYNOTE-811 [PMID 37871604] (Janjigian 2023 Lancet, N=698): HER2+ CPS≥1 advanced 1L pembrolizumab + trastuzumab + FP/CAPOX vs placebo + trastuzumab + FP/CAPOX. mPFS 10.0 vs 8.1 months (HR 0.72, P=0.0002), mOS 20.0 vs 16.8 months (HR 0.84), ORR 72.6% vs 60.1%. First upgrade to the HER2 paradigm after 13 years — IO layered onto the HER2 backbone, CPS≥1 subgroup showing the clearest benefit (FDA 2023-11 restricted the indication to CPS≥1; prior accelerated approval was all-comer).
DESTINY-Gastric-04 [PMID 40454632] (Shitara 2025 N Engl J Med, N=494): HER2+ 2L T-DXd monotherapy vs ramucirumab + paclitaxel head-to-head. mOS 14.7 vs 11.4 months (HR 0.70, P=0.004), mPFS HR 0.74, confirmed ORR 44.3% vs 29.1%. T-DXd beat the 2L SoC for the first time (RAINBOW ramu + paclitaxel), the HER2+ 2L standard has switched — meaning HER2 testing must be redone at 2L (re-biopsy), because post-trastuzumab HER2 loss is ~30%.
HERIZON-GEA-01 (NCT05152147, ESMO 2025 LBA): HER2+ 1L zanidatamab + chemotherapy ± tislelizumab vs trastuzumab + chemotherapy. Topline 2025: both zanidatamab arms PFS HR ~0.65 vs control; zani + tisle + chemo mOS improved >7 months vs trastuzumab + chemo. Zanidatamab’s biepitope simultaneous binding + induced internalization mechanism — if the 2026 full paper confirms, trastuzumab’s 13-year HER2 backbone status could end. As of 2026-04 the full manuscript is unpublished and PMID unassigned, cited here by NCT + ESMO LBA only.

Takeaway: 2026 HER2+ advanced decision path — 1L = pembrolizumab + trastuzumab + FP/CAPOX (KEYNOTE-811, first choice for CPS≥1; CPS<1 remains trastuzumab + chemo per ToGA); 2L = T-DXd (DESTINY-Gastric-04 beat ramu + PTX); 3L+ = ramu + PTX (RAINBOW) / irinotecan / TAS-102. 2L must re-biopsy to recheck HER2 — post-trastuzumab HER2 loss is ~30%, giving T-DXd directly will fail in the HER2-loss population. Zanidatamab is the biggest 2026 suspense: if HERIZON-GEA-01 full paper 2026 confirms positive, the HER2 backbone turns over.

2.4 IO + chemo 1L rewrite (2021-2024): four phase IIIs concordantly positive

Story: in 2017 Japan/Korea’s ATTRACTION-2 made nivolumab positive in 3L+ gastric cancer (mOS 5.26 vs 4.14 months, HR 0.63), opening the gastric IO era; in 2018 KEYNOTE-061 ran pembrolizumab vs paclitaxel in 2L CPS≥1 and hit negative (HR 0.82, P=0.0421 NS), the first failure of IO monotherapy in 2L; in 2020 KEYNOTE-062 again made pembrolizumab in 1L “monotherapy non-inferior but combo not superior,” a first cold-water moment for 1L IO; not until 2021 did CheckMate-649 use nivolumab + FOLFOX/XELOX achieve mOS 14.4 vs 11.1 months (HR 0.71) in CPS≥5 — 1L IO+chemo milestone; then over 3 years KEYNOTE-859 / ORIENT-16 / RATIONALE-305 used three different PD-(L)1s (pembrolizumab / sintilimab / tislelizumab) to replicate concordantly, HRs converging in the 0.71-0.80 narrow band — class effect formally established.

ATTRACTION-2 [PMID 28993052] (Kang 2017 Lancet, N=493, Japan/Korea/Taiwan): ≥2L nivolumab vs placebo. mOS 5.26 vs 4.14 months (HR 0.63, P<0.0001), 12-month OS 26.2% vs 10.9%, ORR 11.2% vs 0%. Starting point of gastric IO — but limited to East Asian 3L+ scenarios.
KEYNOTE-061 [PMID 29880231] (Shitara 2018 Lancet, N=592): 2L CPS≥1 pembrolizumab vs paclitaxel. mOS 9.1 vs 8.3 months (HR 0.82, P=0.0421 NS, negative), CPS≥10 subgroup showed benefit signal, G≥3 TRAE 14% vs 35%. IO monotherapy 2L failure — lesson: “IO worse than chemo” holds in 2L unselected population.
KEYNOTE-062 [PMID 32880601] (Shitara 2020 JAMA Oncol, N=763): 1L CPS≥1 pembrolizumab monotherapy vs pembrolizumab + chemo vs chemo. Pembrolizumab monotherapy vs chemo mOS non-inferior (CPS≥1 10.6 vs 11.1 months), CPS≥10 subgroup 17.4 vs 10.8 months (HR 0.69 but NS), pembrolizumab + chemo vs chemo no significant OS difference. First cold water for 1L IO — revealed that “unselected + IO” is not enough; PD-L1 enrichment required.
JAVELIN Gastric 100 [PMID 33197226] (Moehler 2021 J Clin Oncol, N=499): avelumab maintenance vs continued chemo after 12-week induction chemo. mOS 10.4 vs 10.9 months (HR 0.91, P=0.178, negative), 24-month OS 22.1% vs 15.5%, TRAE ≥G3 12.8% vs 32.8%. IO maintenance strategy failed — even with the “chemo exit lowers toxicity” attraction, no OS-level win.
ATTRACTION-4 [PMID 35030335] (Kang 2022 Lancet Oncol, N=724): HER2- 1L nivolumab + SOX/CAPOX vs placebo + SOX/CAPOX. mPFS 10.45 vs 8.34 months (HR 0.68, P=0.0007), mOS 17.45 vs 17.15 months (HR 0.90, P=0.26, primary OS endpoint not met). PFS wins, OS loses — high Japan/Korea SP/SOX baseline + crossover dilution, failed to reach the global IO standard.
CheckMate-649 [PMID 34102137] (Janjigian 2021 Lancet, N=1581): HER2- 1L nivolumab + FOLFOX/XELOX vs chemo. CPS≥5 mOS 14.4 vs 11.1 months (HR 0.71, P<0.0001), mPFS 7.7 vs 6.0 months (HR 0.68), ORR 60% vs 45%. 1L IO+chemo milestone, FDA approved 2021 (initially all-comer, later restricted to CPS≥5).
ORIENT-16 [PMID 38051328] (Xu 2023 JAMA, N=650, China): HER2- 1L sintilimab + XELOX vs placebo + XELOX. All-comers mOS 15.2 vs 12.3 months (HR 0.77, P=0.009), CPS≥5 mOS 18.4 vs 12.9 months (HR 0.66, P=0.002). First domestic Chinese PD-1 to achieve phase III OS positive in advanced gastric cancer, NMPA approved 2022. Extremely high clinical penetration in China, cost ~1/3 of pembrolizumab.
KEYNOTE-859 [PMID 37875143] (Rha 2023 Lancet Oncol, N=1579): HER2- 1L pembrolizumab + FP/CAPOX vs placebo + FP/CAPOX. ITT mOS 12.9 vs 11.5 months (HR 0.78, P<0.0001), CPS≥10 HR 0.65, mPFS 6.9 vs 5.6 months (HR 0.76), ORR 51.3% vs 42.0%. All-comer positive led FDA 2023-11 to remove the CPS restriction on pembrolizumab in gastric cancer — US practice shifted from “check CPS then give pembro” to “HER2- just give pembro,” but EU and NCCN still retain CPS≥1 / ≥5 recommendations.
RATIONALE-305 [PMID 38806195] (Qiu 2024 BMJ, N=997): HER2- 1L tislelizumab + chemo vs placebo + chemo. PD-L1 TAP≥5% mOS 17.2 vs 12.6 months (HR 0.74), ITT mOS 15.0 vs 12.9 months (HR 0.80, P=0.001). China approved 2024; PD-L1 TAP (tumor area positivity) introduced as an alternative scoring method to CPS.
CheckMate-032 [PMID 30110194] (Janjigian 2018 J Clin Oncol, N=160): advanced esophagogastric nivolumab monotherapy vs nivo + ipi multi-arm early data. ORR: nivo 12% / nivo1+ipi3 24% / nivo3+ipi1 8%; 12-month OS 39% / 35% / 24%. IO + IO ipi dose signal (ipi3 > ipi1), but phase III CheckMate-649 did not pursue an ipi arm — origin of the “dual IO has not become a 1L regimen in gastric cancer” backdrop.

Takeaway: 2026 HER2- advanced 1L IO + chemo class effect established — HRs converge in the narrow 0.71-0.80 band across four PD-(L)1 regimens (nivolumab / pembrolizumab / sintilimab / tislelizumab), choice determined by biomarker CPS threshold × regional access × price × chemo backbone preference. CPS threshold regional policy divergence: FDA removed the threshold (driven by KN-859); NCCN still recommends CPS≥5; EU retains CPS≥1; China NMPA stratifies per each drug’s registered CPS. IO monotherapy 2L (KEYNOTE-061) and IO maintenance (JAVELIN Gastric 100) paths are both closed — don’t walk them again.

2.5 Biomarker triple-subtype year zero + perioperative IO + CAR-T dawn (2023-2026)

Story: 2023 has been called the “gastric biomarker revolution year” — SPOTLIGHT (Shitara, CLDN18.2 + mFOLFOX6) and GLOW (Shah, CLDN18.2 + CAPOX) both published positive phase IIIs the same year, putting zolbetuximab (anti-Claudin-18.2 isoform 2 mAb) on the new CLDN18.2+ HER2- 1L standard (global HER2- gastric cancer CLDN18.2 high-expression rate ~38%); the same year KEYNOTE-811 completed HER2+ 1L IO layering + KEYNOTE-859 removed CPS restriction + ORIENT-16 domestic PD-1 positive. These 3 directions reading out together determined that post-2023 gastric cancer biomarker testing must include the HER2 + CLDN18.2 + CPS + MSI four-panel. In 2024 ATTRACTION-5’s adjuvant IO negative + 2025 MATTERHORN’s perioperative IO positive formed a one-negative-one-positive signal with a key message: “IO requires neoadjuvant exposure to activate.” In 2025 China’s CT041-ST-01 used satri-cel (satricabtagene autoleucel, CLDN18.2 CAR-T) to pull off the world’s first solid-tumor CAR-T RCT win.

FAST [PMID 33610734] (Sahin 2021 Ann Oncol, N=161, phase II): CLDN18.2+ 1L zolbetuximab + EOX vs EOX. mPFS/mOS HR 0.44 and 0.55 (both P<0.0005), CLDN18.2 moderate/strong expression ≥70% subgroup PFS HR 0.38. Early proof-of-concept for CLDN18.2 as a druggable target, paving the way for SPOTLIGHT/GLOW.
SPOTLIGHT [PMID 37068504] (Shitara 2023 Lancet, N=565): CLDN18.2+ (IHC ≥75% 2+/3+) HER2- 1L zolbetuximab + mFOLFOX6 vs placebo + mFOLFOX6. mPFS 10.61 vs 8.67 months (HR 0.75, P=0.0066), mOS 18.23 vs 15.54 months (HR 0.75, P=0.0053). CLDN18.2 became gastric cancer’s third actionable biomarker (after HER2 and PD-L1).
GLOW [PMID 37524953] (Shah 2023 Nat Med, N=507): CLDN18.2+ HER2- 1L zolbetuximab + CAPOX vs placebo + CAPOX. mPFS 8.21 vs 6.80 months (HR 0.687, P=0.0007), mOS 14.39 vs 12.16 months (HR 0.771, P=0.0118). Concordantly replicated SPOTLIGHT — zolbetuximab class effect confirmed, mFOLFOX6 and CAPOX backbones equivalent. FDA approved 2024-10.
ILUSTRO [PMID 37490286] (Klempner 2023 Clin Cancer Res, phase II multi-cohort): CLDN18.2+ advanced zolbetuximab monotherapy (cohort 1A) / + mFOLFOX6 (cohort 2) / + pembrolizumab (cohort 3A). 1L+chemo cohort mPFS 17.8 months / ORR 71.4%; monotherapy 3L+ ORR 0%; zolbetuximab + pembrolizumab 3L+ ORR 0% / mPFS 2.96 months. Key take-home: zolbetuximab fails as monotherapy / + IO at 3L+; must be used 1L with chemo.
TRANSTAR102 cohort G (NCT04495296): high / moderate CLDN18.2 expression 1L osemitamab (TST001, anti-CLDN18.2 ADCC-enhanced antibody) + nivolumab + CAPOX phase II single-arm. Any PD-L1 subgroup mPFS 12.6 months, CPS<5 subgroup mPFS 12.6 months, ORR 66%+. Chinese domestic CLDN18.2 + IO + chemo triplet candidate regimen — PMID not yet assigned as of 2026-04, phase III ongoing.
FRUTIGA (NCT03223376, Xu 2024 published but PMID link anomalous): 2L HER2- / post-chemo fruquintinib (oral VEGFR TKI) + paclitaxel vs placebo + paclitaxel. mPFS 5.6 vs 2.7 months (HR 0.57, P<0.0001, MET), mOS 9.6 vs 8.4 months (HR 0.96, P=0.6064, OS not met), ORR 42.4% vs 22.4%. Chinese domestic VEGFR TKI 2L PFS wins, OS loses — NMPA approved 2023, but limited global impact. The PMID metadata link in yaml is anomalous (see bottom of §7.1); this section primarily indexes by NCT.
KEYNOTE-585 [PMID 40829093] (Shitara 2025 J Clin Oncol, N=1007): resectable GC/GEJ perioperative pembrolizumab + chemotherapy (cisplatin/5-FU or FLOT subgroup) vs placebo + chemotherapy. Main cohort mOS 71.8 vs 55.7 months (HR 0.86, NS), EFS HR 0.81, pathCR improved; but OS primary endpoint not met. “Perioperative IO + old FP backbone failed, FLOT subgroup signal good” — laid the hypothesis foundation for MATTERHORN using FLOT as the backbone.
MATTERHORN [PMID 40454643] (Janjigian 2025 N Engl J Med, N=948): resectable GC/GEJ durvalumab 1500 mg Q4W + perioperative FLOT × 4+4 → durvalumab Q4W × 10 vs placebo + FLOT. 2-year EFS 67.4% vs 58.5% (HR 0.71, P<0.001), pCR 19.2% vs 7.2% (RR 2.69), 2-year OS 75.7% vs 70.4% (OS maturity pending). ASCO 2025 practice-changing — IO finally entered perioperative; KN-585 lesson inherited: must use FLOT backbone, not old FP.
ATTRACTION-5 [PMID 38906161] (Kang 2024 Lancet Gastroenterol Hepatol, N=755, Japan/Korea/Taiwan): post-D2 stage III adjuvant nivolumab + S-1/CapOx vs placebo + chemo. 3-year RFS 68.4% vs 65.3% (HR 0.90, P=0.44, negative). Pure postop addition of IO does not activate immune response — in stark contrast to the positive signals from MATTERHORN / KN-585 neoadjuvant exposure. Mechanistic hypothesis: IO requires “tumor-in-situ priming” — after resection tumor antigen disappears, ICI loses its target.
CT041-ST-01 [PMID 40460847] (Qi 2025 Lancet, N=156): advanced CLDN18.2+ 3L+ satri-cel (CLDN18.2 CAR-T) vs physician’s choice chemo. mPFS 3.25 vs 1.77 months (HR 0.37, P<0.0001), ORR 37% vs 10%, mOS trend favorable. World’s first solid-tumor CAR-T RCT win, NMPA NDA accepted — gastric cancer becomes the cancer type where solid-tumor CAR-T breaks through.

Takeaway: 2026 advanced 1L biomarker subtyping must check the HER2 + CLDN18.2 + PD-L1 CPS + MSI/dMMR four-panel — HER2+ / CLDN18.2+ / CPS-high / MSI-H have low cross-overlap (each covers 15-20% / 38% / ~60% / ~5-10%); missing any one = missing a high-responding subgroup with 30-70% ORR. Perioperative IO = must be neoadjuvant-exposed + must use FLOT backbone (MATTERHORN / KN-585 dual validation); pure postop IO doesn’t work (ATTRACTION-5 negative). CLDN18.2+ 3L+ CAR-T path (CT041-ST-01) has opened the door in China; global rollout awaits NMPA NDA completion.

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

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

3.1 Newly diagnosed advanced GC/GEJ: full biomarker four-panel

NCCN Gastric V2.2025 + CSCO Gastric 2025 explicitly recommend biomarker testing for all newly diagnosed advanced GC/GEJ, covering: HER2 IHC/FISH + PD-L1 IHC (22C3 CPS or 58-8 TAP) + CLDN18.2 IHC + MSI/dMMR (IHC or PCR). A positive result in any one directly changes the 1L regimen:

HER2+ (IHC3+ or IHC2+/FISH+, ~15-20%): CPS≥1 → KEYNOTE-811 (pembrolizumab + trastuzumab + FP/CAPOX); CPS<1 → ToGA (trastuzumab + chemo)
HER2- / CLDN18.2+ (IHC ≥75% 2+/3+, ~38%): zolbetuximab + mFOLFOX6 (SPOTLIGHT) or + CAPOX (GLOW)
HER2- / CLDN18.2- / CPS≥5: nivolumab + FOLFOX/XELOX (CheckMate-649) / pembrolizumab + FP/CAPOX (KEYNOTE-859) / sintilimab + XELOX (ORIENT-16) / tislelizumab + chemo (RATIONALE-305), any of them
HER2- / CLDN18.2- / CPS<5: FOLFOX / CAPOX / SOX chemo (limited IO benefit; confirmed by KEYNOTE-062)
MSI-H / dMMR (~5-10%): IO + chemo or pembrolizumab monotherapy (MSI-H has significantly higher response rate; KEYNOTE-062 CPS≥10 subgroup was partly MSI-H–driven)

3.2 Advanced 1L landscape: four PD-(L)1 class effect + CPS threshold policy divergence

2026 mainstream: HER2- advanced 1L SoC = IO + chemo (any of four PD-(L)1s + FOLFOX/CAPOX/SOX backbone), HRs converging in the 0.71-0.80 narrow band.

Subgroup	First choice	Second choice
HER2- CPS≥5	nivolumab + FOLFOX/XELOX [CheckMate-649 PMID 34102137] or pembrolizumab + FP/CAPOX [KEYNOTE-859 PMID 37875143]	sintilimab + XELOX [ORIENT-16 PMID 38051328] (China cost advantage) / tislelizumab + chemo [RATIONALE-305 PMID 38806195]
HER2- CPS 1-4	pembrolizumab + FP/CAPOX (available after US FDA removed CPS limit)	IO not mandatory, chemo alone acceptable
HER2- CPS<1	FOLFOX / CAPOX / SOX chemo [REAL-2 PMID 18172173 / G-SOX PMID 25316259]	limited IO benefit
HER2+ CPS≥1	pembrolizumab + trastuzumab + FP/CAPOX [KEYNOTE-811 PMID 37871604]	trastuzumab + chemo [ToGA PMID 20728210]
HER2+ CPS<1	trastuzumab + FP/CAPOX [ToGA PMID 20728210]	—
HER2- CLDN18.2+	zolbetuximab + mFOLFOX6 [SPOTLIGHT PMID 37068504] or + CAPOX [GLOW PMID 37524953]	IO + chemo (if CLDN18.2 untested / negative)

CPS threshold regional policy differences: FDA removed the pembrolizumab gastric CPS threshold (based on KN-859 all-comer positive) → US HER2- full coverage; NCCN Gastric V2.2025 still recommends CPS≥5 as IO benefit marker; EU EMA retains CPS≥1; China NMPA stratifies per each drug’s registered CPS (nivolumab CPS≥5 / sintilimab CPS≥5 / tislelizumab TAP≥5% etc.).

Contraindicated / not recommended 2026: IO monotherapy 2L unselected (KEYNOTE-061 negative) + IO maintenance (JAVELIN Gastric 100 negative) + lapatinib instead of trastuzumab (LOGIC/TRIO-013 negative).

3.3 Advanced 2L+: HER2 status dominates + mandatory re-biopsy

2026 mainstream: post-IO era, 2L must first confirm HER2 status (re-biopsy), because post-trastuzumab HER2 loss is ~30%.

Population	2L first choice	3L+
HER2+ post-trastuzumab (confirmed still HER2+)	T-DXd [DESTINY-Gastric-04 PMID 40454632] (mOS 14.7 months, HR 0.70)	ramucirumab + paclitaxel [RAINBOW PMID 25240821] / TAS-102 [TAGS PMID 30355453] / irinotecan
HER2-, IO-exposed (mainstream)	ramucirumab + paclitaxel [RAINBOW PMID 25240821] (mOS 9.6 vs 7.4 months, HR 0.807)	docetaxel + ASC [COUGAR-02 PMID 24332238] / TAS-102 / ramucirumab monotherapy [REGARD PMID 24094768]
CLDN18.2+ post-zolbetuximab	ramucirumab + paclitaxel	TAS-102 / satri-cel CAR-T [CT041-ST-01 PMID 40460847] (China pending NMPA)
CheckMate-032 multi-IO failures	chemo fallback	clinical trial
FRUTIGA (fruquintinib + paclitaxel)	China NMPA 2L option (NCT03223376, 2L HER2- CSCO Gastric 2025 Level II recommendation)	—

New challenge: since 2025 the 2L mandatory HER2 / CLDN18.2 re-biopsy workflow has low real-world execution — frontline clinicians habitually go “1L progression → 2L direct RAINBOW,” with high missed-diagnosis rates.

3.4 Adjuvant / perioperative: five East–West paths that never meet

2026 mainstream: geographically branched, no unified global SoC.

Region	Perioperative / adjuvant SoC (2026)	Key evidence
North America / Western Europe (GC majority)	Perioperative FLOT × 4+4 + perioperative durvalumab [MATTERHORN PMID 40454643] (2-year EFS 67.4%)	FLOT4 [PMID 30982686] upgraded backbone to FLOT; MATTERHORN layered IO on top
GEJ/EAC (global)	Neoadjuvant CRT (CROSS regimen) + surgery [CROSS PMID 22646630] (mOS 49.4 months)	Global GEJ tri-modality SoC; Neo-AEGIS [PMID 37734399] did not falsify it
Japan (mostly stage III)	D2 postoperative S-1 + docetaxel adjuvant [JACCRO GC-07 PMID 30925125] (3y RFS 66%)	Japanese “adjuvant-first” tradition + neoadjuvant option PRODIGY [PMID 34133211]
Korea (stage II-III)	D2 postoperative CAPOX adjuvant [CLASSIC PMID 22226517] or SOX adjuvant [ARTIST-2 PMID 33278599]	Doublet chemo sufficient; ARTIST-2 closed post-D2 RT debate
China (locally advanced)	Perioperative SOX [RESOLVE PMID 34252374]	China post-D2 first choice perioperative SOX (HR 0.77 vs adjuvant CAPOX)
Residual disease post-CROSS (any region)	Adjuvant nivolumab 1 year [CheckMate-577 PMID 33789008] (mDFS 22.4 vs 11.0 months)	ASCO 2025 mature OS shows benefit concentrated in PD-L1+ subgroup; ITT OS not significant
Not recommended	bevacizumab perioperative [ST03 PMID 28163000] / postop CRT after preop chemo [CRITICS PMID 29650363] / pure postop IO [ATTRACTION-5 PMID 38906161] / preop CRT on top of perioperative chemo [TOPGEAR PMID 39282905] (pCR improved, OS did not)	All four falsified

Current status of INT-0116 adjuvant chemoRT: 15-year US SoC initially, exited Asian practice in the adequate-D2 era (ARTIST-2 closed debate); US retains for D0-D1 / inadequately-dissected nodes.

The “death” of MAGIC: the 2006 MAGIC ECF perioperative backbone was replaced by FLOT after 2019 FLOT4; ECF is used only occasionally for “FLOT-intolerant” patients, no longer SoC.

3.5 Perioperative IO: MATTERHORN positive + key lessons

2026 mainstream: MATTERHORN [PMID 40454643] 2-year EFS 67.4% vs 58.5% (HR 0.71) + pCR 19.2% vs 7.2% → durvalumab + FLOT perioperative becomes the new North America / Western Europe SoC candidate (FDA 2025-2026 expected approval; as of 2026-04 mature OS not yet reached).

Key lesson 1 (backbone determines IO effect): KEYNOTE-585 [PMID 40829093] used old FP backbone, perioperative pembrolizumab mOS 71.8 vs 55.7 months but NS; MATTERHORN used new FLOT backbone + durvalumab 2-year EFS positive. “Perioperative IO must use FLOT backbone” written into 2025 ASCO consensus.

Key lesson 2 (IO needs neoadjuvant exposure): ATTRACTION-5 [PMID 38906161] pure postop nivolumab + S-1/CapOx adjuvant 3-year RFS 68.4% vs 65.3% (HR 0.90, negative); vs MATTERHORN’s neoadjuvant + adjuvant durvalumab positive — “postop-only IO does not activate immunity,” mechanistic hypothesis: ICI needs tumor-in-situ antigen priming.

Key lesson 3 (pCR ≠ OS): TOPGEAR [PMID 39282905] pCR 17% vs 8% improved but mOS no difference (HR 1.05, NS); KEYNOTE-585 [PMID 40829093] pCR improved but ITT OS NS. “Gastric pCR as surrogate is unstable” — fundamentally different from the strong pCR-OS correlation in breast cancer; clinical trial design needs caution.

3.6 Surgical technique: D2 + laparoscopic consensus + robotic undecided

From 2015-2022 five consecutive laparoscopic phase IIIs (KLASS-01 / KLASS-02 / CLASS-01 / JLSSG0901 / LOGICA) established laparoscopic ≈ open D2 gastrectomy equivalence; two extended-surgery trials — D2+PAND (JCOG9501) and bursectomy (JCOG1001) — were buried.

Category	Standard regimen	Key evidence
Lymph node dissection	D2	JCOG9501 [PMID 18669424] (5-year OS 69.2% vs 70.3%, D2+PAND HR 1.03, no benefit + longer operating time / more blood loss)
Early GC (stage I) distal gastrectomy	Laparoscopic = open	KLASS-01 [PMID 30730546] (5-year OS 94.2% vs 93.3%, non-inferior)
Locally advanced GC distal gastrectomy	Laparoscopic = open	KLASS-02 [PMID 35857305] (5-year OS 88.9% vs 88.7%), CLASS-01 [PMID 31135850] (3-year DFS 76.5% vs 77.8%, non-inferior), JLSSG0901 [PMID 36920382] (5-year RFS 73.9% vs 75.7%, non-inferior)
European total / subtotal gastrectomy	Laparoscopic = open (short-term)	LOGICA [PMID 34581617] (LOS 7 days / both arms, LG less blood loss)
Bursectomy	Abandoned	JCOG1001 [PMID 36369984] (5-year OS 74.9% vs 76.5%, HR 1.03, more abdominal abscesses)
Robotic	Undecided	No phase III oncologic RCT evidence yet

4. Research Gaps: ten unsolved clinical questions

This report identifies the following gaps, each a definable concrete question (not the cliché “more research needed”):

CPS threshold global non-uniformity + real-world execution: FDA removed the pembrolizumab gastric CPS threshold + NCCN retains CPS≥5 + EU CPS≥1 + China NMPA stratifies per drug. Frontline clinicians see multiple thresholds on the same guideline page → real-world PD-L1 IHC (22C3 vs 58-8 TAP) assay differences also unresolved. Unification needed.
No head-to-head among three / four PD-(L)1s (nivolumab / pembrolizumab / sintilimab / tislelizumab) in HER2- 1L: HRs in the 0.71-0.80 narrow band, cross-trial indistinguishable. Choice depends entirely on access × price × CPS threshold × chemo backbone preference.
Is the CLDN18.2 moderate / high-expression threshold optimal: SPOTLIGHT / GLOW enrolled at IHC ≥75% 2+/3+; FAST subgroup ≥70% moderate-strong expression had better PFS HR. Different thresholds may identify different benefit populations — prospective threshold-exploration trials needed.
Is CLDN18.2 × IO combination superior to either alone: ILUSTRO 3L+ zolbetuximab + pembrolizumab cohort ORR 0% (failed); TRANSTAR102 cohort G 1L osemitamab + nivolumab + CAPOX 12.6-month PFS (signal). 1L head-to-head CLDN18.2 + IO + chemo vs CLDN18.2 + chemo has not been done.
1L choice for HER2+ CPS<1 subgroup: KEYNOTE-811 CPS<1 subgroup HR near 1.0, but FDA 2023-11 restricted to CPS≥1 rather than fully excluding CPS<1. Practice remains inconsistent on whether HER2+ CPS<1 uses ToGA or KN-811.
Backbone dependence of perioperative IO: MATTERHORN FLOT + durvalumab positive vs KEYNOTE-585 FP + pembrolizumab negative. Is it the FLOT backbone contribution or an IO mechanism difference? Independent confirmations from perioperative nivolumab + FLOT (CheckMate-Gastric Adjuvant ongoing) and pembrolizumab + FLOT subgroup (KN-585 FLOT subgroup) need time.
Why pure postop adjuvant IO failed in ATTRACTION-5: the mechanistic hypothesis is “tumor-in-situ priming” but has not been directly validated. If future biomarkers can identify “postop still IO-suitable” subgroups (e.g., ctDNA+ residual / MSI-H status), adjuvant IO could restart.
pCR as gastric surrogate endpoint is unstable: both TOPGEAR + KEYNOTE-585 were pCR-positive / OS-negative. Clinical trial design must use pCR as primary endpoint cautiously. Alternative candidates: EFS, ctDNA clearance kinetics.
The five East–West perioperative / adjuvant paths (FLOT4 / RESOLVE / CLASSIC / ARTIST-2 / JACCRO GC-07) have never been head-to-head: each path ran its own phase III in its own country vs surgery alone / old regimen, with no RCTs between them. Real-world OS differences are population differences vs regimen differences? Undistinguishable.
Global rollout path for CLDN18.2 + CAR-T: CT041-ST-01 China phase II positive + NMPA NDA accepted; global phase III and Euro-US regulatory paths not yet launched as of 2026. Whether solid-tumor CAR-T’s gastric breakthrough can extend to other CLDN18.2+ solid tumors (pancreatic, biliary) is unknown.

5. Latest 2024-2026 developments

5.1 FDA / NMPA new approvals (gastric-relevant excerpts)

Drug	Agency	Date	Indication / supporting trial
pembrolizumab + trastuzumab + chemo	FDA	2023-11 (CPS≥1 restricted)	1L HER2+ GC/GEJ / KEYNOTE-811 [PMID 37871604]
pembrolizumab + chemo (CPS restriction removed)	FDA	2023-11	1L HER2- GC/GEJ / KEYNOTE-859 [PMID 37875143]
tislelizumab + chemo	NMPA	2024	1L HER2- PD-L1 TAP≥5% / RATIONALE-305 [PMID 38806195]
zolbetuximab + mFOLFOX6 / CAPOX	FDA	2024-10-18	1L HER2- CLDN18.2+ / SPOTLIGHT + GLOW [PMID 37068504 + 37524953]
T-DXd (trastuzumab deruxtecan) 2L	FDA	2025 (expanded indication after DG-04)	2L HER2+ GC/GEJ / DESTINY-Gastric-04 [PMID 40454632]
durvalumab + perioperative FLOT	FDA	2025-2026 (pending, expected approval)	Perioperative GC/GEJ / MATTERHORN [PMID 40454643]
satri-cel (CLDN18.2 CAR-T)	NMPA	2025-2026 (NDA accepted)	3L+ CLDN18.2+ GC/GEJ / CT041-ST-01 [PMID 40460847]
fruquintinib + paclitaxel 2L	NMPA	2023	2L HER2- GC/GEJ / FRUTIGA (NCT03223376)

5.2 Key meeting readouts (2025-2026, flagged as lower-weight)

The following are candidate pool only pending formal peer review, not in the main library.

HERIZON-GEA-01 (ESMO 2025 LBA): zanidatamab + chemo ± tislelizumab vs trastuzumab + chemo 1L HER2+ positive, mOS improvement >7 months. Full manuscript unpublished as of 2026-04; if confirmed positive within 2026 → HER2 backbone turnover.
MATTERHORN mature OS (ASCO 2025 [PMID 40454643]): 2-year OS 75.7% vs 70.4% (early signal), mature OS 2026-2027 readout.
CheckMate-577 mature OS (ASCO 2025 [PMID 33789008] data): ITT OS not significant; PD-L1+ subgroup benefit — suggests post-CROSS adjuvant IO should be restricted to PD-L1+.
KEYNOTE-585 final analysis (2025 JCO [PMID 40829093]): FLOT subgroup EFS positive signal confirmed by MATTERHORN; FP subgroup OS NS closed the old backbone + IO path.
CT041-ST-01 mOS (Lancet 2025 [PMID 40460847]): mOS trend favorable, data maturing.
TRANSTAR102 cohort G (NCT04495296, ESMO 2024 oral): osemitamab + nivolumab + CAPOX 1L phase II signal good; phase III launched in China.

5.3 Ongoing phase IIIs (2026-2028 readout highlights)

HERIZON-GEA-01 full readout (NCT05152147): 2026 mature OS will determine whether zanidatamab can replace trastuzumab as the HER2+ 1L backbone
osemitamab phase III (NCT05980416 or successor): CLDN18.2+ 1L triplet vs IO + chemo head-to-head
satri-cel global phase III: CLDN18.2 CAR-T expansion outside China
ctDNA-guided adjuvant de-escalation: after ATTRACTION-5 negative, whether ctDNA+ postop residual can identify IO-responsive subgroups — early design
Perioperative IO + CLDN18.2 combination: after MATTERHORN success, CLDN18.2 + perioperative FLOT + IO triplet is the natural next step

6. Synthesis insights and judgments

6.1 Longitudinal × horizontal: 2026 gastric landscape shaped by three subtyping revolutions

Overlaying longitudinal paradigm evolution with the current horizontal decision landscape, the 2026 gastric cancer landscape is a stack of three subtyping revolutions:

Biological meaning of anatomical subtyping made manifest: 2006 MAGIC / 2012 CROSS / 2021 CheckMate-649 step by step pushed “GEJ vs gastric body” from crude endoscopic split to molecular biological subtyping in the IO era — CheckMate-649 subgroup analysis showed GEJ/EAC HR differs from pure gastric body HR (the former ~0.75, the latter ~0.65), suggesting the GEJ microenvironment responds less well to IO. In 2026 GEJ 1L decisions have gone from “treat as gastric cancer” to “Siewert II-III → gastric / Siewert I → esophageal” + perioperative choice CROSS (GEJ) vs MATTERHORN (gastric body majority). This is gastric cancer’s first subtyping revolution.
Persistent East–West path divergence: INT-0116 (US adjuvant chemoRT) / MAGIC → FLOT4 (European perioperative) / CLASSIC (Korean adjuvant CAPOX) / ACTS-GC (Japanese adjuvant S-1) / RESOLVE (Chinese perioperative SOX) — five paths, each completing phase III in its own population, never head-to-head. 2026 practice is not a “unified global SoC” but “choose path by patient’s country / region.” Regional differences + genetic background (DPYD polymorphisms) + reimbursement policies together shape the reality of “East and West never meet.” This is gastric cancer’s second subtyping revolution.
HER2 drug 10-year leap + biomarker four-layer subtyping: 2010 ToGA (trastuzumab + chemo) → 2020 DESTINY-Gastric-01 (T-DXd 2L) → 2023 KEYNOTE-811 (pembro + trastuzumab + chemo 1L) → 2025 DESTINY-Gastric-04 (T-DXd 2L SoC) → 2025 HERIZON-GEA-01 (zanidatamab challenging trastuzumab) — 5 steps in 15 years, HER2 drugs moved from binary targeting to full ADC + IO combo + bispecific coverage. Concurrently CLDN18.2 (SPOTLIGHT / GLOW) + PD-L1 CPS + MSI joined the subtyping grid → HER2 / CLDN18.2 / CPS / MSI four-layer checkerboard decides 1L regimen. This is gastric cancer’s third subtyping revolution and the direct source of the 2026 “check the full biomarker panel first” imperative.

These three revolutions together explain a clinical observation: the 1L decision tree for a newly diagnosed stage IV GC/GEJ patient in 2026 has 4 more decision layers than in 2016 (biomarker panel HER2/CPS/CLDN18.2/MSI → anatomical subtyping GEJ vs gastric body → regional access sintilimab/pembro/nivo/tislelizumab → CPS threshold FDA vs NCCN vs EU). This “deep and wide” decision tree is far more complex than HCC’s “shallow and narrow” (four-way tie within a narrow HR band) — the result of NCCN-level research density plus multinational domestic-drug co-action.

6.2 Clinical decision takeaways (for junior-mid oncologists)

In 2026 the first gastric cancer step is not the chemo regimen — it is a full biomarker panel: HER2 IHC/FISH + PD-L1 CPS + CLDN18.2 IHC + MSI/dMMR must be complete before 1L. Missing any one = missing a high-responding subgroup with 30-70% ORR.
HER2+ 1L standard upgraded since 2023: CPS≥1 use pembrolizumab + trastuzumab + FP/CAPOX (KEYNOTE-811); CPS<1 still trastuzumab + chemo (ToGA). Don’t use ToGA alone for CPS≥1 patients anymore.
CLDN18.2+ HER2- 1L SoC is zolbetuximab + mFOLFOX6/CAPOX: written into NCCN V2.2025 after FDA 2024-10 approval. Missing CLDN18.2 at 1L is the most frequent 2026 gastric cancer clinical error.
Use CPS thresholds per country: US FDA removed the pembrolizumab gastric CPS threshold; NCCN still recommends CPS≥5; EU CPS≥1; China NMPA stratifies per drug. Use the corresponding threshold in your own reimbursement / registration context.
Both IO monotherapy 2L and IO maintenance are closed: KEYNOTE-061 (2L unselected) and JAVELIN Gastric 100 (maintenance) both negative — don’t walk these two paths.
2L must re-biopsy to recheck HER2 + CLDN18.2: post-trastuzumab HER2 loss is ~30%; CLDN18.2 subgroup has similar phenomenon. “1L progression → 2L direct RAINBOW” is the biggest real-world missed-diagnosis source.
HER2+ 2L new standard is T-DXd (DESTINY-Gastric-04 beat RAINBOW): but ILD is the key safety alarm, needing baseline chest CT + dynamic monitoring + timely drug discontinuation.
The perioperative IO era has arrived: North America / Western Europe 2026 expected MATTERHORN (durvalumab + FLOT perioperative) approval; must use FLOT backbone + must have neoadjuvant exposure — both lessons have trial evidence (KN-585 FP backbone failure / ATTRACTION-5 pure postop IO failure) as controls.
Respect regional East–West paths: US walks INT-0116 + FLOT4 → MATTERHORN; Europe walks MAGIC → FLOT4 → MATTERHORN; China walks RESOLVE SOX; Japan walks JACCRO GC-07 S-1 + docetaxel; Korea walks CLASSIC CAPOX / ARTIST-2 SOX. Don’t simply extrapolate one country’s data to another.
Zanidatamab is the biggest 2026 suspense: if HERIZON-GEA-01 full paper 2026 is positive, trastuzumab’s 13-year HER2 backbone could end. Frontline clinicians’ HER2 treatment choices will face a new branchpoint — stay tuned.

7. Information sources

All 58 trial metadata in this report were independently verified via PubMed and ClinicalTrials.gov. Each [PMID xxxxxxxx] in the text is directly verifiable on PubMed.

Published trials: 58, covering 2001-2026
PMID coverage: 56 unique PMIDs (HERIZON-GEA-01 / TRANSTAR102 cohort G are ESMO LBA, PMID pending full manuscript; MAGIC / INT-0116 / CROSS have no NCT because they predate the mandatory NCT registration era)
FDA / NMPA new approvals: 8 key approvals (2023-2026)
2025-2026 key meeting / long follow-up readouts: 6 (HERIZON-GEA-01 / MATTERHORN mature OS / CheckMate-577 mature OS / KN-585 final / CT041-ST-01 / TRANSTAR102)
Research gaps: 10
China-led research proportion: ~25% (ORIENT-16 / FRUTIGA / RESOLVE / CT041-ST-01 / TRANSTAR102 / part of CLASSIC / CLASS-01 etc.)

7.1 Text citation list (by ascending PMID)

The following table is the PMID list of all bracket citations in the text + summary tables; each can be clicked to verify on PubMed.

PMID	First Author	Year	Journal	Trial / topic
11547741	Macdonald JS	2001	N Engl J Med	INT-0116 adjuvant chemoRT
16822992	Cunningham D	2006	N Engl J Med	MAGIC perioperative ECF
17075117	Van Cutsem E	2006	J Clin Oncol	V325 advanced DCF
17978289	Sakuramoto S	2007	N Engl J Med	ACTS-GC Japanese adjuvant S-1
18172173	Cunningham D	2008	N Engl J Med	REAL-2 (ECF/ECX/EOF/EOX)
18282805	Koizumi W	2008	Lancet Oncol	SPIRITS Japanese advanced SP
18669424	Sasako M	2008	N Engl J Med	JCOG9501 D2 vs D2+PAND
20728210	Bang YJ	2010	Lancet	ToGA HER2+ trastuzumab
22226517	Bang YJ	2012	Lancet	CLASSIC Asian adjuvant CAPOX
22646630	van Hagen P	2012	N Engl J Med	CROSS GEJ neoadjuvant CRT
24094768	Fuchs CS	2014	Lancet	REGARD 2L ramucirumab
24332238	Ford HE	2014	Lancet Oncol	COUGAR-02 2L docetaxel
25240821	Wilke H	2014	Lancet Oncol	RAINBOW 2L ramu + paclitaxel
25316259	Yamada Y	2015	Ann Oncol	G-SOX advanced SOX vs CS
25559811	Park SH	2015	J Clin Oncol	ARTIST D2 postop XP ± RT
26628478	Hecht JR	2016	J Clin Oncol	LOGiC/TRIO-013 lapatinib negative
28163000	Cunningham D	2017	Lancet Oncol	ST03 perioperative ECX + bev negative
28993052	Kang YK	2017	Lancet	ATTRACTION-2 3L+ nivolumab
29650363	Cats A	2018	Lancet Oncol	CRITICS postop CRT negative
29880231	Shitara K	2018	Lancet	KEYNOTE-061 2L pembro negative
30110194	Janjigian YY	2018	J Clin Oncol	CheckMate-032 nivo ± ipi multi-arm
30355453	Shitara K	2018	Lancet Oncol	TAGS 3L+ TAS-102
30730546	Kim HH	2019	JAMA Oncol	KLASS-01 early GC LDG
30925125	Yoshida K	2019	J Clin Oncol	JACCRO GC-07 S-1 + docetaxel
30982686	Al-Batran SE	2019	Lancet	FLOT4 perioperative FLOT vs ECF
31135850	Yu J	2019	JAMA	CLASS-01 LDG vs ODG
32469182	Shitara K	2020	N Engl J Med	DESTINY-Gastric-01 2L T-DXd
32880601	Shitara K	2020	JAMA Oncol	KEYNOTE-062 1L cold water
33197226	Moehler M	2021	J Clin Oncol	JAVELIN Gastric 100 maintenance negative
33278599	Park SH	2021	Ann Oncol	ARTIST-2 Korea D2 postop
33610734	Sahin U	2021	Ann Oncol	FAST phase II CLDN18.2 early
33789008	Kelly RJ	2021	N Engl J Med	CheckMate-577 GEJ adjuvant nivolumab
34102137	Janjigian YY	2021	Lancet	CheckMate-649 milestone
34133211	Kang YK	2021	J Clin Oncol	PRODIGY neoadjuvant DOS
34252374	Zhang X	2021	Lancet Oncol	RESOLVE China perioperative SOX
34581617	van der Veen A	2021	J Clin Oncol	LOGICA Europe LG vs OG
35030335	Kang YK	2022	Lancet Oncol	ATTRACTION-4 Japan/Korea nivo + SOX
35857305	Son SY	2022	JAMA Surg	KLASS-02 5-year OS LDG vs ODG
36369984	Kurokawa Y	2022	Br J Surg	JCOG1001 bursectomy negative
36920382	Etoh T	2023	JAMA Surg	JLSSG0901 LADG vs ODG 5-year
37068504	Shitara K	2023	Lancet	SPOTLIGHT zolbetuximab + mFOLFOX6
37329891	Van Cutsem E	2023	Lancet Oncol	DESTINY-Gastric-02 Euro-US T-DXd
37490286	Klempner SJ	2023	Clin Cancer Res	ILUSTRO phase II multi-cohort
37524953	Shah MA	2023	Nat Med	GLOW zolbetuximab + CAPOX
37734399	Reynolds JV	2023	Lancet Gastro Hepatol	Neo-AEGIS CROSS vs MAGIC/FLOT
37871604	Janjigian YY	2023	Lancet	KEYNOTE-811 HER2+ IO + HER2
37875143	Rha SY	2023	Lancet Oncol	KEYNOTE-859 all-comer
38051328	Xu J	2023	JAMA	ORIENT-16 China sintilimab
38734867	—	—	—	FRUTIGA yaml PMID link anomalous (text cites by NCT03223376)
38806195	Qiu MZ	2024	BMJ	RATIONALE-305 tislelizumab
38906161	Kang YK	2024	Lancet Gastro Hepatol	ATTRACTION-5 pure adjuvant IO negative
39282905	Leong T	2024	N Engl J Med	TOPGEAR preop CRT + perioperative chemo
40454632	Shitara K	2025	N Engl J Med	DESTINY-Gastric-04 T-DXd vs RAINBOW
40454643	Janjigian YY	2025	N Engl J Med	MATTERHORN perioperative durvalumab + FLOT
40460847	Qi C	2025	Lancet	CT041-ST-01 satri-cel CAR-T
40829093	Shitara K	2025	J Clin Oncol	KEYNOTE-585 final

7.2 Verification conventions

Each PMID is directly accessible via https://pubmed.ncbi.nlm.nih.gov/{PMID}/
Each NCT id is accessible via https://clinicaltrials.gov/study/{NCT_id}/
HERIZON-GEA-01 / TRANSTAR102 cohort G are at ESMO LBA / ASCO oral stage; PMID pending 2026 full manuscript — this report indexes by NCT
FRUTIGA (PMID 38734867) yaml data has a PubMed metadata link anomaly (the PMID corresponds to an ED medication errors review, not the FRUTIGA main publication); this report primarily indexes the text by NCT03223376, with “yaml PMID link anomalous” honestly disclosed in the §7.1 table; data fix pending v2
MAGIC / INT-0116 / CROSS have no NCT id (predate the 2004 ClinicalTrials.gov mandatory registration / UK MRC internal trial)
If you find any PMID in the report whose trial name / year / conclusion differs from PubMed, corrections are welcome

Clinical trial timeline here

Chinese: /trials/gastric/ English: /en/trials/gastric/

Each trial has its own detail page, containing:

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

58 trials · 5 chapters · 2001 to 2026 · synced with NCCN Gastric V2.2025 + CSCO Gastric 2025 dual guidelines.

Closing

Gastric cancer over the past 25 years has completed a unique evolution in oncology — from 2001 INT-0116 putting adjuvant chemoRT on the US postoperative SoC, through the 2006 MAGIC “perioperative chemo” concept invention, 2010 ToGA HER2 as the first biomarker target, 2019 FLOT4 perioperative backbone upgrade, 2021 CheckMate-649 IO + chemo 1L standard, 2023 SPOTLIGHT / GLOW CLDN18.2 new subtype, 2025 MATTERHORN perioperative IO breakthrough, 2025 DESTINY-Gastric-04 HER2+ 2L new standard, and 2025 CT041-ST-01 solid-tumor CAR-T’s first RCT win.

The most essential difference between gastric cancer and other GI major cancers (HCC / BTC / PDAC) is “early biomarker subtyping start but severe geographic branching + HER2 drugs’ 10-year leap is the deepest single-biomarker evolution”. NSCLC’s driver panel is “10+ molecular paths horizontally parallel”; HCC is “0 biomarker, IO backbone alone”; gastric cancer walks “HER2 / CLDN18.2 / PD-L1 CPS / MSI four-layer subtyping + East–West five perioperative / adjuvant paths + multi-country PD-(L)1 class-effect narrow band” three-dimensional checkerboard. This complexity dictates the 2026 gastric decision tree’s “deep and wide” character — 4 more decision layers than HCC, one fewer than NSCLC (no driver-targeted 1L monotherapy).

The most urgent structural problems to solve in 2026 are: the clinical chaos of non-unified global CPS thresholds, unclear 1L choice for HER2+ CPS<1, mechanism validation of why perioperative IO must use FLOT backbone, whether ctDNA-guided adjuvant de-escalation can identify adjuvant-IO benefit subgroups, and the global rollout path for CLDN18.2 CAR-T. Whether the next decade’s HER2 backbone is taken over by zanidatamab (HERIZON-GEA-01 full paper), whether next-generation ADCs (e.g., T-DM1 replacement) can break through T-DXd’s ILD boundary, and whether solid-tumor CAR-T can extend from gastric cancer to other CLDN18.2+ cancer types — these three questions determine the direction of gastric cancer’s next decade.

The value of this report is not “exhaustive enumeration of all trials” (PubMed can do that) but compressing 25 years of evolution + current decisions + unsolved gaps into the cognitive bandwidth of a single read. Next time you face a newly diagnosed gastric cancer patient, every branchpoint in the decision tree has this map to consult, trace, and interrogate.

Clinician × AI = Research Superpower + Clinical Decision Amplifier

—— Dual Brain Lab · 2026-04-21

Gastric Cancer on Dual Brain Lab