Head-to-head comparison of composite and individual biomarkers to predict clinical benefit to PD-1 blockade in non-small cell lung cancer

Abstract

Background The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab. Methods Pretreatment samples from 135 patients receiving nivolumab were used to evaluate the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1T TILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were randomly assigned to a training (n = 55) and validation cohort (n = 80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m). Results In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) compared to individual biomarkers PD-1T TILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Additionally, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) demonstrated inferior predictive performance compared to PD-1T TILs and TIS alone. PD-1T TILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1T TILs could more accurately discriminate patients with no long-term benefit, as specificity was substantially higher compared to TIS (74% versus 39%). Conclusion Composite biomarkers did not show improved predictive performance compared to PD-1T TILs and TIS alone for both the 6- and 12-month endpoints. PD-1T TILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1T TILs.