Advances in predictive biomarkers associated with immunotherapy in extensive-stage small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is a highly malignant and poor-prognosis cancer, with most cases diagnosed at the extensive stage (ES). Amidst a landscape marked by limited progress in treatment modalities for ES-SCLC over the past few decades, the integration of immune checkpoint inhibitors (ICIs) with platinum-based chemotherapy has provided a milestone approach for improving prognosis, emerging as the new standard for initial therapy in ES-SCLC. However, only a minority of SCLC patients can benefit from ICIs, which frequently come with varying degrees of immune-related adverse events (irAEs). Therefore, it is crucial to investigate predictive biomarkers to screen potential beneficiaries of ICIs, mitigate the risk of side effects, and improve treatment precision. This review summarized potential biomarkers for predicting ICI response in ES-SCLC, with a primary focus on markers sourced from tumor tissue or peripheral blood samples. The former mainly included PD-L1 expression, tumor mutational burden (TMB), along with cellular or molecular components related to the tumor microenvironment (TME) and antigen presentation machinery (APM), molecular subtypes of SCLC, and inflammatory gene expression profiles. Circulating biomarkers predominantly comprised circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines, plasma autoantibodies, inflammation-related parameters, and blood TMB. We synthesized and analyzed the research progress of these potential markers. Notably, investigations into PD-L1 expression and TMB have been the most extensive, exhibiting preliminary predictive efficacy in salvage immunotherapy; however, consistent conclusions have yet to be reached across studies. Additionally, novel predictive markers developed based on TME composition, APM, transcriptomic and genomic features provide promising tools for precision immunotherapy. Circulating biomarkers offer the advantages of convenience, non-invasiveness, and a comprehensive reflection of tumor molecular characteristics. They may serve as alternative options for predicting immunotherapy efficacy in SCLC. However, there is a scarcity of studies, and the significant heterogeneity in research findings warrants attention.