Unveiling distinct features of long-term benefit in metastatic NSCLC patients undergoing immune checkpoint blockade

Abstract

Introduction: Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits observed in a select group of patients. Despite widespread use of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet. Methods: A total of 49 metastatic NSCLC patients treated with ICB were included. Long-term (LTR) and Short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before treatment initiation and early-on treatment (before cycle 2 – at 3rd week). Plasma ctDNA NGS panel and serum proteomics were performed. Standard diagnostic workup included PD-L1 immunohistochemistry and NGS in tumor tissue. Tumor tissue RNAseq panel focused on immune related genes was performed in a subset of patients. Results: Our analysis revealed specific characteristics of long-term patients compared with short term benefit, namely higher PD-L1 in tumor cells (p=0.005) and higher incidence of irAEs (p=0.001). Genomic features that associated with lack of benefit to ICB included cooccurrence of mutations in KRAS/STK11, KRAS/KEAP1 and TP53/KMT2D (p<0.05). At a serum proteomic level, LTR patients exhibited higher abundance of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteosome, processing of MHC class I (S100A4, PSMD9, RNF41) and immunehomeostasis (HAVCR1, ARG1) (p<0.05 for all proteins). In line with peripheral immunological features, transcriptional analysis of tumor samples showed that LTR patients displayed higher levels of genes linked with T cell recruitment/trafficking (CXCL11) and T cell effector functions (GMZB) within the tumor microenvironment (p<0.05). Finally, a longitudinal analysis identified a set of proteins that presented opposite dynamics in LTR compared to STR, making them interesting candidates for treatment efficacy evaluation. Conclusions: Our comprehensive analysis of metastatic NSCLC patients treated with ICB has unveiled distinct clinicopathological and immunological features associated with long-term benefit, highlighting the presence of a pre-existing antitumor immunity as a stronger predictor of long-term benefit. These findings offer insights into potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC. Keywords: Lung neoplasms; Immunotherapy; Long-term responders; Serum proteomics; blood-based biomarkers.