PROJECT SUMMARY In 2022, an estimated 236,740 patients in the US are expected to be diagnosed with non-small cell lung cancer (NSCLC) and 130,180 deaths. In 2019 and 2020, the Veteran Health Administration estimates 8,352 and 6,111 new lung cancer diagnoses and 4,284 and 2,344 deaths from lung cancer, respectively. Management of Stage III unresectable NSCLC underwent a monumental change with the NEJM publication of the PACIFIC trial in 2017. Maintenance immunotherapy after chemoradiation became the standard with median overall survival (mOS) nearly doubling to 47.5 months compared to chemo-radiation alone. While with durvalumab, the progression-free survival (PFS) rate at 60 months was 33.1%, compared to placebo (i.e. chemoradiation alone) which was 19.0%, the findings suggest that 1 in 2 patients is likely to not receive added benefit from durvalumab. The problem then becomes, who should receive immunotherapy over and above chemoradiation? By identifying only those Veterans who will receive benefit will result in a significant cost savings for the VA health care system. Second, many Veterans within the VA Healthcare System travel > 50 miles for their treatments. By eliminating unnecessary trips for inefficacious therapy, the quality of life of our Veterans will be enhanced. Similarly, given the cost and associated toxicity of these IO based regimens there is a need to identify which patients will benefit from a short treatment duration (i.e. 6 months versus the typical 1 year duration). Finally, there is a need to identify which patients are likely to suffer from immune related adverse events (irAEs), specifically pneumonitis, seen in approximately 1/3 of lung cancer patients treated with IO. Our group has pioneered the development of novel artificial intelligence (AI) based radiomic (computer extracted) features of the tortuosity of the nodule vasculature and textural patterns both inside and outside the nodule on CT scans, and demonstrated strong association between these features with response to (1) durvalumab+chemoradiation in Stage III NSCLC, (2) in first line chemo+IO and (3) overall survival in NSCLC patients treated with IO. In recent work published in the J of Immunotherapy for Cancer (JITC), our group showed that intra- and peritumoral radiomic texture features were associated with disease free survival (DFS) in Stage III NSCLC patients treated with durvalumab+chemoradiation. The radiomic features were associated with clinical outcome in both the low and high PD-L1 groups. More recently, in work to be presented at ASCO 2022, we have shown that radiomic features on CT scans can distinguish radiation induced from IO induced pneumonitis. In this project, we aim to develop and validate RadIO, a novel radiomic toolkit to (1) predict at baseline which Veterans will receive added benefit from durvalumab over chemo-radiation alone, (2) determine when a disease stable status has been achieved so that an IO duration prediction can be made (6 ...