Tumor‐Informed ctDNA in Guiding First‐Line Immunochemotherapy in Advanced Non‐Small Cell Lung Cancers

Tumor‐informed circulating tumor DNA (ctDNA) analysis identifies patients with advanced non‐small cell lung cancer (NSCLC) who benefit from first‐line immunotherapy plus chemotherapy. Longitudinal ctDNA monitoring further reflects therapeutic response and predicts prognosis beyond imaging. These findings support ctDNA as a practical and dynamic biomarker to guide treatment selection and real‐time assessment of clinical benefit in advanced NSCLC. Abstract Predictive biomarkers are urgently needed for first‐line immune checkpoint inhibitors plus chemotherapy (ICI‐chemo) in advanced non‐small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) reflects tumor burden and immunogenicity, potentially identifyinging of patients suitable for ICI‐chemo. In this study, pre‐ and on ‐ treatment tissue and plasma samples are prospectively collected and analyzed from the randomized phase III CHOICE‐01 trial comparing ICI ‐ chemo versus chemotherapy alone in advanced NSCLC. Pre‐treatment tissue and plasma samples, as well as on‐treatment plasma samples, are prospectively collected. Tumor‐informed ctDNA detection is based on tissue‐identified mutations. Among patients with tumor‐informed ctDNA positivity, those receiving ICI‐chemo experienced significantly improved‐free survival (PFS) and overall survival (OS) compared to those receiving chemotherapy alone (PFS: HR 0.45, 95% CI 0.34–0.60; OS: HR 0.66, 95% CI 0.49–0.88; p = 0.0045). In contrast, no significant differences in PFS or OS are observed between treatment arms in the ctDNA‐negative subgroup. The predictive value of tumor‐informed 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‐rank p = 0.0004 for OS and p = 0.044 for PFS). Tumor-informed circulating tumor DNA (ctDNA) analysis identifies patients with advanced non-small cell lung cancer (NSCLC) who benefit from first-line immunotherapy plus chemotherapy. Longitudinal ctDNA monitoring further reflects therapeutic response and predicts prognosis beyond imaging. These findings support ctDNA as a practical and dynamic biomarker to guide treatment selection and real-time assessment of clinical benefit in advanced NSCLC. Abstract Predictive biomarkers are urgently needed for first-line immune checkpoint inhibitors plus chemotherapy (ICI-chemo) in advanced non-small cell lung cancer (NSCLC). Circulating tumor DNA (ctDNA) reflects tumor burden and immunogenicity, potentially identifyinging of patients suitable for ICI-chemo. In this study, pre- and on - treatment tissue and plasma samples are prospectively collected and analyzed from the randomized phase III CHOICE-01 trial comparing ICI - chemo versus chemotherapy alone in advanced NSCLC. Pre-treatment tissue and plasma samples, as well as on-treatment plasma samples, are prospectively collected. Tumor-informed ctDNA detection is based on tissue-identified mutations. Among patients with tumor-informed ctDNA positivity, those receiving ICI-chemo experienced significantly improved-free survival (PFS) and overall survival (OS) compared to those receiving chemotherapy alone (PFS: HR 0.45, 95% CI 0.34–0.60; OS: HR 0.66, 95% CI 0.49–0.88; p = 0.0045). In contrast, no significant differences in PFS or OS are observed between treatment arms in the ctDNA-negative subgroup. The predictive value of tumor-informed 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-rank p = 0.0004 for OS and p = 0.044 for PFS). Advanced Science, Volume 12, Issue 48, December 29, 2025.