Blood Based Biomarkers for Predicting Treatment Response to Immune Checkpoint Inhibitors After EGFR-TKI Resistance in Non-Small Cell Lung Cancer

Abstract

Background Immune checkpoint inhibitors (ICIs) have limited benefit in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). However, they are often tried after tumors develop resistance to EGFR tyrosine kinase inhibitors (TKIs). Because EGFR-TKI treatment alters the tumor microenvironment, biomarkers predictive of ICI response are ideally identified post-EGFR-TKI resistance, but obtaining repeat biopsies at this time can be challenging. The purpose of this study was to explore predictive biomarkers for ICI response using plasma samples collected after EGFR-TKI therapy.Methods This retrospective analysis included 28 patients with EGFR-mutant NSCLC treated with an ICI after developing resistance to EGFR-TKI. Plasma samples collected at TKI progression were profiled using an Olink Target 96 immune protein panel to identify differential protein expression. Candidate protein biomarkers were validated by immunohistochemistry in tumor tissue. Durable clinical response (DCB) was defined as patients achieving progression-free survival (PFS) >= 6 months during ICI therapy.Results Of the 28 patients, 6 (21.4%) achieved durable clinical benefit, with PFS >= 6 months. Proteomic analysis identified four plasma proteins that differed significantly between DCB and NCB. Gal-9 and GZMH levels were elevated in NCB, whereas IL-4 and IL-6 were elevated in DCB. Notably, PFS was significantly longer in patients with lower Gal-9 and higher IL-4 levels.Conclusions Plasma-based immune markers measured at the time of TKI resistance may help predict which patients with EGFR-mutant NSCLC will respond to subsequent ICI therapy. Such biomarkers could guide immunotherapy decision-making in this clinically challenging population.