Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor

Simple Summary A high PD-L1 expression in a tumor tissue biopsy qualifies lung cancer patients to treatment with an immune checkpoint inhibitor. However, tumor tissue is highly heterogeneous, and many patients progress early, despite having qualified for treatment. Thus, reliable biomarkers are lacking. Using blood samples, we aim to identify predictive biomarkers for responses to immune checkpoint-inhibitor treatment. Immune-related plasma proteins in lung cancer patients were quantified, and Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) were demonstrated to be associated with response and survival. In addition, combining these results with the quantity of circulating tumor DNA enabled us to identify a patient subgroup with prolonged survival. Liquid biopsies are a minimally invasive test, and our results demonstrate that they hold a predictive value supplementing the current eligibility criteria for treatment.Abstract Immunotherapy has altered the therapeutic landscape for patients with non-small-cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1/PD-L1 signaling axis and produces durable clinical responses, but reliable biomarkers are lacking. Using 115 plasma samples from 42 pembrolizumab-treated patients with NSCLC, we were able to identify predictive biomarkers. In the plasma samples, we quantified the level of 92 proteins using the Olink proximity extension assay and circulating tumor DNA (ctDNA) using targeted next-generation sequencing. Patients with an above-median progression-free survival (PFS) had significantly higher expressions of Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) at baseline than patients with a PFS below the median. A Kaplan-Meier analysis demonstrated that high levels of FASLG and ICOSLG were predictive of longer PFS and overall survival (OS) (PFS: 10.83 vs. 4.49 months, OS: 27.13 vs. 18.0 months). Furthermore, we identified a subgroup with high expressions of FASLG and ICOSLG who also had no detectable ctDNA mutations after treatment initiation. This subgroup had significantly longer PFS and OS rates compared to the rest of the patients (PFS: 25.71 vs. 4.52 months, OS: 34.62 vs. 18.0 months). These findings suggest that the expressions of FASLG and ICOSLG at baseline and the absence of ctDNA mutations after the start of treatment have the potential to predict clinical outcomes.

Automated summary

By using blood samples, this study aimed to identify predictive biomarkers for responses to immune checkpoint-inhibitor treatment in lung cancer patients. The expressions of Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) were found to be associated with response and survival. Combining these results with the quantity of circulating tumor DNA enabled the identification of a patient subgroup with prolonged survival.