Baseline tumour vessel perfusion as a non-invasive predictive biomarker for immune checkpoint therapy in non-small-cell lung cancer.

Objective: Current biomarkers for predicting immunotherapy response in non-small-cell lung cancer (NSCLC) are derived from invasive procedures with limited predictive accuracy. Thus, identifying a non-invasive predictive biomarker would improve patient stratification and precision immunotherapy. Methods and analysis: In this retrospective multicohort study, the discovery cohort included 205 NSCLC patients screened from ORIENT-11 and an external validation (EV) cohort included 99 real-world NSCLC patients. The 'onion-mode segmentation' method was developed to extract 'onion-mode perfusion' (OMP) from contrast-enhanced CT images. The predictive performance of OMP or its combination with the PD-L1 Tumour Proportion Score (TPS) was evaluated by the area under the curve (AUC). Results: High baseline OMP was associated with significantly longer survival and predicted patient response to combination anti-PD-(L)1 therapy in the discovery and EV cohorts. OMP complemented the PD-L1 TPS with superior predictive sensitivity (p=0.02). In the PD-L1 TPS<50% subgroup, OMP achieved an AUC of 0.77 for the estimation of treatment response (95% CI 0.66 to 0.86, p<0.0001). A simple bivariate model of OMP/PD-L1 robustly predicted therapeutic response in both the discovery (AUC 0.82, 95% CI 0.74 to 0.88, p<0.0001) and EV (AUC 0.80, 95% CI 0.67 to 0.89, p<0.0001) cohorts. Conclusion: OMP, derived from routine CT examination, could serve as a non-invasive and cost-effective biomarker to predict NSCLC patient response to immune checkpoint inhibitor-based therapy. OMP could be used alone or in combination with other biomarkers to improve precision immunotherapy.