Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) improve survival in advanced non-small cell lung cancer (NSCLC), yet current biomarkers such as programmed death-ligand 1 (PD-L1) expression and response criteria (Response Evaluation Criteria in Solid Tumors, RECIST, V.1.1) align poorly with long-term survival. Radiomics has been proposed as a source of novel biomarkers, but standard radiomic approaches suffer from limited biological interpretability and poor generalizability across treatment settings. We address these gaps by developing the Quantitative Vessel Tortuosity (QVT) score, a biologically interpretable imaging biomarker that quantifies tumor vascular complexity-a known mediator of immune evasion-from routine imaging. We hypothesized that QVT score would improve prognostication and enable treatment response monitoring in ICI-treated NSCLC, independent of current biomarkers. METHODS: This retrospective, multicenter study analyzed 1,301 CT scans from 682 patients with ICI-treated NSCLC. An automated pipeline segmented lesions and tumor-associated vasculature within each scan, extracting 910 QVT features measuring vascular shape and complexity. Unsupervised clustering of these features in a discovery cohort (N=375) was performed to identify fundamental vascular phenotypes. A continuous QVT score was then derived using regularized logistic regression to map patients along this phenotypic spectrum. QVT score was externally validated in ICI monotherapy (N=172) and chemoimmunotherapy (N=135) cohorts. In a longitudinal cohort (n=143), early on-treatment QVT score changes were evaluated for overall survival (OS) association. RESULTS: Two robust vascular phenotypes emerged in the discovery cohort: a highly vascularized, chaotic "QVT High" phenotype with poor post-ICI OS and a "QVT Low" phenotype with normalized vasculature and improved ICI outcomes. The continuous QVT score was prognostic for ICI monotherapy (HR=1.17 per 0.1 increase, p=0.0028) and chemoimmunotherapy (HR = 1.23 per 0.1 increase, p = 4.9×10⁻⁵). High QVT status remained prognostic for both treatments after adjustment for PD-L1 and clinical variables (adjusted HR range: 2.13-2.38, p≤0.002). Early decreases in QVT score during therapy, indicating vascular normalization, were associated with improved OS (HR=1.93, p=0.0022) independent of RECIST best overall response and tumor volume change. CONCLUSIONS: QVT score is a novel, biologically interpretable imaging biomarker that quantifies vascular complexity. It enables automated, non-invasive prediction and monitoring of ICI outcomes by capturing treatment-induced vascular remodeling. Integrating QVT score into clinical decision-making and drug development can address critical gaps in precision oncology.