ABSTRACT Immune checkpoint inhibitors (ICIs) have improved outcomes in metastatic non-small cell lung cancer (NSCLC), and providers may now choose between multiple first-line ICI-based regimens including ICI monotherapy and ICI with chemotherapy. However, this increase in options has complicated clinical management, with few biomarkers to guide upfront ICI treatment selection, and incomplete metrics for early on-treatment assessment of response to ICI therapy. Hence, there is an urgent need for novel analytics tools to optimize and personalize immunotherapy treatment strategies. While prior biomarker efforts have focused largely on tissue-based molecular profiling, these have demonstrated limited predictive power and are difficult to implement due to practical limitations in acquiring pre- and on-treatment tissue. In contrast, imaging and blood-based assays offer a unique and non-invasive mechanism by which the biology of the tumor and the changes on treatment can be studied and modeled. Thus, we propose an integrated radiomic-blood analysis to develop predictors of pre- and on-treatment response to guide the clinical management of NSCLC. Our primary goal is to develop radiomic- blood signatures for precision immunotherapy in advanced NSCLC by leveraging our expertise in data science, thoracic oncology, cancer genomics, computational oncology, clinical assay development, and established research collaborations. Our preliminary data demonstrates our success in utilizing multi-parametric profiling of circulating tumor DNA to identify molecular phenotypes associated with ICI outcome and disease recurrence, and in developing novel radiomic subtyping techniques with superior outcome prediction and demonstrated association with underlying lung cancer biology. Hence, we hypothesize that coupling radiomic and blood-based metrics can non-invasively inform therapeutic decision-making in NSCLC management while advancing our understanding of NSCLC biology. To advance this hypothesis, we have assembled a unique set of cohorts of metastatic NSCLC patients treated with ICI regimens with high-quality radiographic scans, blood samples, and molecular and clinical data: our in-house lung cancer database (GEMINI, n=5000); a validation dataset from our collaboration with the Massachusetts General Hospital (MGH) Cancer Center (MGH, n=600); the multicenter collaborative Stand Up 2 Cancer/Mark Foundation cohort (SU2C, n=400), and a prospective phase III ICI trial (LONESTAR, n=300). Our proposal builds on these unique cohorts and our promising preliminary data to construct predictive models to guide up-front ICI therapy selection and improve on-treatment response assessment, while complementary investigations will uncover the biology underlying these clinical predictors. A major strength of our proposal is our interdisciplinary team’s expertise in developing, validating, and translating these innovative predictive models toward highly relevant clinical questions. The dev...