83P Comprehensive molecular profiling of tumor tissue and liquid biopsy in NSCLC patients treated with immune-checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) represent the standard of care for patients with Non-Small Cell Lung Cancer (NSCLC) lacking actionable genomic alterations.However, the absence of robust and reproducible biomarkers limits patient stratification and clinical outcome prediction in ICI-based strategies. Methods:We retrospectively analyzed 75 advanced NSCLC patients treated with a first-line ICI-based approach (n=17 received ICI monotherapy and n=58 received ICI plus chemotherapy).Comprehensive genomic profiling was performed on tumor tissue DNA (tDNA) at baseline and circulating tumor DNA (ctDNA) both at baseline and at progression of disease (PD) using the TruSight Oncology 500 panel (Illumina).This panel provides the evaluation of 523 cancer-related genes, as well as genomic patterns such as microsatellite instability (MSI) and tumor mutational burden (TMB).Clinical, pathological, and molecular variables were correlated with progression-free survival (PFS) and overall survival (OS).Results: Among 52 patients with available FFPE tumor tissue, the most common alterations included TP53 (60%), BARD1 (25%), LRP1B (24%), SMARCA4 (24%), and KRAS (22%).Significant co-mutation occurred in KEAP1/SMARCA4 (p<0.01) and NOTCH3/TP53 (p<0.01).Median TMB was 9.3 mut/Mb and all patients were MSI stable (median MSI score: 1.77).Alterations in LRP1B were significantly associated with improved PFS and OS (p=0.02 and p=0.005 respectively).In 8 patients with ctDNA samples available at baseline and PD, median VAF increased significantly from 1.41% at baseline to 8,41% at PD (p = 0.02).TMB in ctDNA did not change between baseline and PD samples (10.8 mut/Mb and 11.7 mut/Mb respectively).The analysis of ctDNA mutational status and its association with patient prognosis is currently ongoing. Conclusions:Our findings suggest LRP1B mutations as a promising prognostic biomarker in metastatic NSCLC with potential integration into molecular diagnostic workflows to improve patient stratification.ctDNA dynamics could be useful to monitor disease progression and treatment response.Larger prospective cohorts and functional studies are needed to elucidate the biological and clinical relevance of LRP1B in NSCLC.