Biomarkers and Gene Signatures to Predict Durable Response to Pembrolizumab in Non-Small Cell Lung Cancer

SIMPLE SUMMARY: Not all patients with advanced or metastatic non-small cell lung cancer (NSCLC) respond to pembrolizumab, even if their tumor expresses PD-L1. This is a monocentric study aimed at identifying potential predictive biomarkers for pembrolizumab first-line treatment. Tumor microenvironment was characterized by gene expression analysis in 46 tumor samples from 25 NSCLC patients with and 21 without durable clinical benefit. As expected, patients achieving clinical benefit had a greater infiltration of immune cells. In particular, CD8 T-cell and NK cell scores were strongly associated with durable benefit. Single immune cell markers such as XCL1/2 showed a high performance in predicting durable response to pembrolizumab with an AUC of 0.85. In the same series PD-L1 expression levels had an AUC equal to 0.61. Identified predictive biomarkers can improve patients’ selection, thus optimizing treatment definition. ABSTRACT: Pembrolizumab has been approved as first-line treatment for advanced Non-small cell lung cancer (NSCLC) patients with tumors expressing PD-L1 and in the absence of other targetable alterations. However, not all patients that meet these criteria have a durable benefit. In this monocentric study, we aimed at refining the selection of patients based on the expression of immune genes. Forty-six consecutive advanced NSCLC patients treated with pembrolizumab in first-line setting were enrolled. The expression levels of 770 genes involved in the regulation of the immune system was analysed by the nanoString system. PD-L1 expression was evaluated by immunohistochemistry. Patients with durable clinical benefit had a greater infiltration of cytotoxic cells, exhausted CD8, B-cells, CD45, T-cells, CD8 T-cells and NK cells. Immune cell scores such as CD8 T-cell and NK cell were good predictors of durable response with an AUC of 0.82. Among the immune cell markers, XCL1/2 showed the better performance in predicting durable benefit to pembrolizumab, with an AUC of 0.85. Additionally, CD8A, CD8B and EOMES showed a high specificity (>0.86) in identifying patients with a good response to treatment. In the same series, PD-L1 expression levels had an AUC of 0.61. The characterization of tumor microenvironment, even with the use of single markers, can improve patients’ selection for pembrolizumab treatment.