{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:30:56Z","timestamp":1782487856159,"version":"3.54.5"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Locally advanced gastric\/gastroesophageal junction (G\/GEJ) adenocarcinoma faces high recurrence risks despite radical surgery. Perioperative chemotherapy (e.g., FLOT regimen) improves survival but has limited pathological complete response (pCR) rates and significant toxicity. Immunotherapy and anti-angiogenic agents show promise in advanced G\/GEJ cancer. This trial evaluates fruquintinib (a VEGFR-1\/2\/3 inhibitor), sintilimab (PD-1 inhibitor), and SOX (oxaliplatin+S-1) as perioperative therapy for resectable locally advanced G\/GEJ adenocarcinoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This prospective, single-arm, phase II trial (N = 25) enrolls treatment-na\u00efve adults (18\u201375 years) with histologically confirmed, resectable cT3-4aN+M0 G\/GEJ adenocarcinoma (AJCC 8th edition). Patients receive 3 cycles of neoadjuvant therapy:Fruquintinib:4 mg orally, days 1\u201314 (21-day cycle). S-1: 80\u2013120 mg orally twice daily (based on BSA), days 1\u201314. Oxaliplatin: 130 mg\/m\u00b2 IV, day 1. Sintilimab: 200 mg IV, day 1.Radical gastrectomy with D2 lymphadenectomy follows 4\u20136 weeks post-neoadjuvant therapy. Adjuvant therapy (3 cycles of sintilimab for pCR patients; 3 cycles of preoperative regimen for non-pCR) starts 4\u20136 weeks post-surgery. Endpoints: Primary: pCR rate (ypT0\/Tis ypN0 per CAP criteria). Secondary: R0 resection rate, major pathological response (MPR, \u226410% residual tumor), 2-year event-free survival (EFS), 2-year overall survival (OS), safety (NCI CTCAE v5.0). Exploratory: Biomarker analysis of tumor microenvironment. Statistical Analysis: Sample size (25 patients) was calculated using Fisher\u2019s exact test (one-sided \u03b1 = 0.05, power = 80%), assuming pCR improvement from 5% (historical control) to 20%. Efficacy analyses use intention-to-treat (ITT) population; safety analyses include patients receiving \u22651 neoadjuvant dose.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This is the first trial combining fruquintinib, sintilimab, and SOX in perioperative G\/GEJ cancer. If successful, it may expand treatment options for locally advanced disease. Limitations include single-arm design and small sample size.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>Chinese Clinical Trial Registry (ChiCTR2400084194)<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1638316","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T05:21:27Z","timestamp":1753766487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Fruquintinib and sintilimab plus SOX as perioperative therapy for locally resectable advanced gastric\/gastroesophageal junction adenocarcinoma: study protocol for a prospective, single-arm, phase II clinical 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