Circulating Biomarkers of Response and Toxicity of Immunotherapy in Advanced Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

SIMPLE SUMMARY: Although immunotherapy has dramatically revolutionized non-small cell lung cancer (NSCLC) treatment, not all the patients will benefit from this innovative therapy. The identification of potential biomarkers able to predict efficacy and toxicity of immunotherapy represents an urgent need for tailored treatment regimens. Liquid biopsy is a minimally invasive and economical tool that could provide important information about patients’ selection and treatment monitoring. Currently, several blood biomarkers are under investigation (circulating immune and tumor cells, soluble immunological mediators, peripheral blood cells). Prospective clinical trials are needed to validate their use in clinical practice. ABSTRACT: Immune checkpoint inhibitors (ICIs) targeting the programmed cell death (PD)-1 protein and its ligand, PD-L1, and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, have revolutionized the management of patients with advanced non-small cell lung cancer (NSCLC). Unfortunately, only a small portion of NSCLC patients respond to these agents. Furthermore, although immunotherapy is usually well tolerated, some patients experience severe immune-related adverse events (irAEs). Liquid biopsy is a non-invasive diagnostic procedure involving the isolation of circulating biomarkers, such as circulating tumor cells (CTC), cell-free DNA (cfDNA), and microRNAs (miRNAs). Thanks to recent advances in technologies, such as next-generation sequencing (NGS) and digital polymerase chain reaction (dPCR), liquid biopsy has become a useful tool to provide baseline information on the tumor, and to monitor response to treatments. This review highlights the potential role of liquid biomarkers in the selection of NSCLC patients who could respond to immunotherapy, and in the identification of patients who are most likely to experience irAEs, in order to guide improvements in care.