Background: Immune checkpoint inhibitor (ICI) therapy is standard-of-care for treatment of mutation-negative advanced non-small cell lung cancer (NSCLC). However, given known inaccuracy of PD-(L)1 markers, there is an unmet need to better identify patients most likely to derive clinical benefit from ICI. We developed and externally validated a generalizable CT imaging-based biomarker to predict response to ICI. Methods: We developed and validated a deep learning radiomic biomarker using an internally curated real-world dataset (RWD) of 2,010 stage IV NSCLC patients treated with PD-(L)1 ICIs in academic and community settings from US and Europe. Patients with missing baseline imaging, missing follow-up data, or EGFR/ALK oncogenic driver mutations were excluded, resulting in a total of 1,188 subjects. This RWD consisted of a discovery cohort (Dataset A, N=844) and a temporally distinct holdout cohort (Dataset B, N=344), which were used to generate performance metrics of the biomarker. To test generalizability, we validated our biomarker in a prospective clinical trial dataset evaluating Sasanlimab in PD-(L)1 therapy-naïve, advanced NSCLC patients (NCT02573259, Dataset C, N=54). We utilized a two-stage learning approach to model 6-month PFS. First, we used an independent multi-task deep-learning feature extractor trained on 19,184 whole chest CT scans. Second, we input the extracted features into a Cox proportional hazard (CoxPH) model along with age, sex, and baseline lesion measurements (sum of longest diameter and distant metastases counts), and the model generated a time-dependent PFS function and a response score. We performed 6-fold cross-validation on Dataset A to train and evaluate the models, which were subsequently ensembled and applied to independent Datasets B and C. To assess independence from PD-L1 status and key demographic covariates, we herein report multivariate adjusted hazard ratios (HR) for the group identified as low-risk based on the biomarker. Results: In Dataset A, the biomarker showed a cross-validation PFS adjusted HR of 0.49 (95% CI 0.38-0.63) in the all-comers cohort and 0.28 (0.17-0.46) in the first-line ICI monotherapy cohort (1LMono). In Dataset B, the PFS adjusted HRs were 0.54 (0.35-0.83) in all-comers and 0.18 (0.05-0.61) in 1LMono. In Dataset C, the adjusted HRs were 0.30 (0.14-0.68) for PFS, 0.29 (0.10-0.83) for OS, 0.31 (0.14-0.72) for TTP. Conclusions: In our validations in RWD and clinical trial cohorts, a deep-learning radiomic biomarker based on routine pre-treatment CT scans predicted response to ICI and stratified patients independently from PD-L1 status. This tool may inform clinical decision-making, such as to help guide whether concomitant chemotherapy may not be needed. In future work, we plan to further validate our approach in larger prospective datasets and expand its use to new indications.