Head-to-head comparison of composite and individual biomarkers to predict clinical benefit to PD-1 blockade in Non-Small Cell Lung Cancer

Abstract

AbstractBackgroundTreatment with PD-(L)1 blocking agents has demonstrated durable efficacy in advanced NSCLC, but only in a minority of patients. Multiple biomarkers for predicting treatment benefit have been investigated, but their combined performance has not been extensively studied. Here, we assess the combined predictive performance of multiple biomarkers in a series of NSCLC patients treated with nivolumab.MethodsPretreatment samples from 135 patients treated with nivolumab were used to assess the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1TTILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were assigned to a training (n=55) and validation set (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).ResultsIn 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%) than the individual biomarkers PD-1TTILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Also, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) showed less predictive performance compared to PD-1TTILs and TIS alone. PD-1TTILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1TTILs could better discriminate patients with no long-term benefit, since specificity was substantially higher as compared to TIS (74% versus 39%).ConclusionComposite biomarkers did not show improved predictive performance compared to PD-1TTILs and TIS alone for both the 6- and 12-months endpoint. PD-1TTILs 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-1TTILs.