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This dose escalation exploratory study is aimed to determine the maximum tolerated dose (MTD) of lenvatinib plus\u00a0paclitaxel as second\u2010line treatment in AGC and to explore molecular biomarkers using dynamic network biomarker (DNB) analysis. Eligible patients are treated with lenvatinib plus paclitaxel (135\u00a0mg\u00a0m\n                    <jats:sup>\u22122<\/jats:sup>\n                    , q3w). Dose escalation of lenvatinib adopts a \u201c3 + 3\u201d design. DNB analysis is performed based on Olink proteomics data using serial blood samples. Eleven patients are treated. No dose\u2010limiting toxicities are observed, and the MTD of lenvatinib is determined as 16\u00a0mg. White blood cells decreased (45.5%, 5\/11) is the most common adverse event. Grade \u22653 adverse event rate is 18.2% (2\/11). Objective response rate is 36.4% (4\/11), and median overall survival is 7.4 months. A DNBscore associated with patient prognosis and response to multitarget tyrosine kinase inhibitor (TKI) plus paclitaxel is established. Infiltration of cancer\u2010associated fibroblasts in tumor microenvironment is positively associated with the DNBscore. In summary, lenvatinib plus paclitaxel is well tolerant and shows promising efficacy as a second\u2010line regimen in AGC. The DNBscore can be a biomarker for multitarget TKI plus paclitaxel and provide critical clues for future research\u00a0.\n                  <\/jats:p>","DOI":"10.1002\/advs.202506678","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T18:23:57Z","timestamp":1754936637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lenvatinib Plus Paclitaxel as Second\u2010Line Therapy for Advanced Gastric Cancer Patients: A Dose Escalation Exploratory Study"],"prefix":"10.1002","volume":"12","author":[{"given":"Chenfei","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Oncology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinling","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Oncology Ruijin Hospital Shanghai Jiao Tong University 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Shanghai 200025 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Ji","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Digestive Surgery Shanghai Jiao Tong University School of Medicine Shanghai 200025 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2527-8212","authenticated-orcid":false,"given":"Feng","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Oncology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China"},{"name":"Shanghai Key Laboratory of Gastric Neoplasms Shanghai 200025 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