Background: None of the current biomarkers for predicting response to checkpoint inhibitors (ICIT) for advanced NSCLC are associated with long-term benefits, such as improved OS. In this multi-agent (nivolumab, pembrolizumab, or atezolizumab) multi-site study (Cleveland Clinic, Univ. of Pennsylvania), we demonstrate that changes in computer-extracted textural patterns, from within and 30mm outside the nodules, between baseline and post-treatment CT following ICIT correlate with RECIST-derived responses, and are prognostic of OS. Methods: CT scans from 139 NSCLC patients both pre-, and post 2-3 cycles of ICIT were acquired from 2 sites. Patients with objective response/stable disease per RECIST v1.1 were defined as ‘responders’, and those with progressive disease were ‘non-responders’. The cohort was divided into a discovery (D1 = 50) and two validation sets (D2 = 62, D3 = 27). 454 intranodular texture (IT) features, and 7426 perinodular features (PT) were extracted from the temporalscans, Relative differences were computed to yield a set of ‘delta-radiomic’ descriptors. In D1, 8 features that evolved the most between baseline and post-treatment CT, and performed the best in identifying responders, were determined. These were then used with a Linear Discriminant Analysis classifier to identify the responders from the non-responders. We then computed a radiomic risk score (RRS) system and tested its prognostic ability in assessing differences in OS. Results: A combination of 5 IT, 3 PT delta radiomic features yielded an AUC of 0.88 ± 0.08 in D1 and a corresponding AUC = 0.85 and 0.81 in D2 and D3, respectively. Multivariate survival metrics are shown in Table. Conclusions: Delta-radiomic features, both from inside and outside the nodules, could be used to identify patients likely to derive clinical benefit from ICIT (eg: OS) beyond anatomic response.