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Circulating tumor DNA (ctDNA) reflects tumor burden and immunogenicity, potentially identifyinging\u00a0of patients suitable for ICI\u2010chemo. In this study, pre\u2010 and on \u2010 treatment tissue and plasma samples are prospectively collected and analyzed from the randomized phase III CHOICE\u201001 trial comparing ICI \u2010 chemo versus chemotherapy alone in advanced NSCLC. Pre\u2010treatment tissue and plasma samples, as well as on\u2010treatment plasma samples, are prospectively collected. Tumor\u2010informed ctDNA detection is based on tissue\u2010identified mutations. Among patients with tumor\u2010informed ctDNA positivity, those receiving ICI\u2010chemo experienced significantly improved\u2010free survival (PFS) and overall survival (OS) compared to those receiving chemotherapy alone (PFS: HR 0.45, 95% CI 0.34\u20130.60; OS: HR 0.66, 95% CI 0.49\u20130.88; p = 0.0045). In contrast, no significant differences in PFS or OS are observed between treatment arms in the ctDNA\u2010negative subgroup. The predictive value of tumor\u2010informed ctDNA is independent of other immune biomarkers and superior to other ctDNA metrics. Validation in a combined cohort from RATIONALE 304\/307 trials shows similar results. Furthermore, ctDNA clearance during treatment correlates with better clinical outcomes (log\u2010rank p = 0.0004 for OS and p = 0.044 for PFS).<\/jats:p>","DOI":"10.1002\/advs.202506565","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T08:53:27Z","timestamp":1764060807000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Informed ctDNA in Guiding First\u2010Line Immunochemotherapy in Advanced Non\u2010Small Cell Lung Cancers"],"prefix":"10.1002","volume":"12","author":[{"given":"Kailun","family":"Fei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Molecular Oncology CAMS Key Laboratory of Translational Research on Lung Cancer Department of Medical Oncology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing P. R. 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