Background: CM227 (NCT02477826) is a large multi-center phase 3 trial that evaluated the benefit of immunotherapy (IO) over chemotherapy (Ch) as first line therapy in stage IV NSCLC. While PD-L1 and tumor mutational burden (TMB) initially emerged as promising biomarkers, CM227 showed benefit of IO over Ch regardless of PD-L1 or TMB status. There is an unmet clinical need for predictive biomarkers to identify patients (pts) who will respond to IO. In this study, we report initial blinded validation results of a CT-derived biomarker combining change in textural radiomics (Δ-Rad) and quantitative vessel tortuosity (Δ-QVT) between baseline and 6-week post-treatment for predicting response and survival outcome of IO and Ch alone in a subset of patients enrolled in CM227. Methods: This retrospective study included baseline (B) and 6-week post-treatment (TP1) CT scans from (a) a multi-center training set (D_tr, N=110) of first line IO-treated mNSCLC pts and (b) a validation set consisting of a subset of mNSCLC from CM227 (D_v, N=224), of which 178 pts were treated with IO (D_v^IO) and 36 pts (D_v^Ch) with Ch. Intra-tumoral, peri-tumoral texture radiomic (Khorrami et al., Cancer Immunol Res 2020) and QVT (Alilou et al., Sci Adv 2022) features were extracted from up to the two largest measurable lung lesions on each CT using an in-house MATLAB pipeline. Δ-Rad and Δ-QVT features were computed as the feature difference between B and TP1. A best objective IO response classifier, M_Combo was trained on D_tr using a combination of Δ-Rad and Δ-QVT features. Kaplan-Meier analyses with log rank p-values, hazard ratio (HR) and its confidence interval (CI) were computed to assess the predictive benefit of M_Combo with overall survival (OS) and progression free survival (PFS) in D_v, D_v^IO and D_v^Ch. We also report area under the receiver operating characteristic (AUC) of IO response predictions compared against best overall response in D_v, D_v^IO and D_v^Ch. Results: M_Combo predicted best overall response with an AUC of 0.67, 0.68, 0.74 in D_v, D_v^IO, and D_v^Ch, respectively. M_Combo was statistically significantly associated with OS and PFS in D_v and D_v^IO but not in D_v^Ch (Table). Conclusions: Our preliminary findings reveal that combination of CT-based textural and vessel tortuosity features are predictive of IO response over chemotherapy in a subset of CM227 pts. Validation on the entire CM277 cohort is warranted.