ABSTRACT Non-small cell lung cancer (NSCLC) is a major disease burden in the United States and worldwide. Most patients are diagnosed at an advanced stage. For unresectable locally advanced NSCLC, the standard of care is definitive concurrent chemoradiotherapy. Unfortunately, the majority of patients will develop local-regional or distant failure with standard treatment. High-dose radiotherapy or consolidation chemotherapy may reduce local or distant recurrence, but are also associated with significant toxicity leading to morbidity and even mortality. Several randomized phase III trials failed to show a survival benefit with intensified treatment given to unselected, locally advanced NSCLC populations, highlighting the limitations of current `one-size-fits-all' treatment. A biomarker-driven approach would allow rational treatment selection based on individualized assessment of risks of local-regional versus distant failure. However, current imaging and genomic markers lack sufficient accuracy in predicting relevant outcomes. The goal of this project is to develop and validate quantitative imaging biomarkers to evaluate early response and integrate with circulating tumor DNA analysis to predict patterns of treatment failure in locally advanced NSCLC. Previously, we developed a novel tumor partitioning method based on FDG-PET and CT images, which revealed spatially distinct tumor subregions with predictive significance in NSCLC. In this project, we will further improve our tumor partitioning method to identify robust subregions, and propose novel image features to characterize intratumoral spatial heterogeneity via spatially explicit analysis. A rigorous qualification procedure will be employed to identify repeatable and reproducible image features for biomarker discovery. We will develop a predictive imaging biomarker by incorporating pre and mid-treatment scans in a retrospective patient cohort, and independently test it in two prospectively collected cohorts including a national randomized phase II trial. Finally, we will combine imaging with circulating tumor DNA analysis in a unifying model to further improve predictive accuracy. We anticipate that the integrated biomarker will allow reliable, early prediction of local-regional vs distant failure, which has important implications for deciding treatment between high-dose RT vs intensive systemic therapy. If successful, the proposed biomarkers will afford a rational approach to individualized therapy and ultimately improve outcomes in locally advanced NSCLC.