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

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).