Clinical Utility of Broad-Panel Profiling in Non-Small Cell Lung Cancer: Pairwise Co-Mutational Gene Patterns and PD-L1 Associations Define Stage-Specific Prognosis

Objectives: Precision medicine has improved outcomes in advanced lung cancer, but its implementation remains limited. The prospective LANTERN project (NCT05802771) involves comprehensive clinical and multi-omics data collection. Here, we report preliminary genomic findings, focusing on the prognostic impact of gene mutations, pairwise co-mutational patterns, and their stage-specific association with PD-L1 analysis on patients speciments. Methods: This prospective, multicenter observational study enrolled 271 consecutive patients between March 2023 and December 2024, including 137 with stage I–III and 134 with stage IV disease. Comprehensive genomic profiling was performed using the TruSight Oncology 500 High Throughput assay to assess single nucleotide variants, insertions/deletions, copy number alterations, tumor mutational burden and microsatellite instability. The prognostic role of mutations and co-mutations was evaluated, together with associations between genomic alterations and PD-L1 expression. Results: At least one Tier I–II alteration was identified in 84% of patients. TP53 (39%), KRAS (27%), EGFR (15%), and STK11 (11%) were the most frequently altered genes. Several co-mutations were associated with worse overall survival, including TP53/STK11, STK11/LRP1B, STK11/RB1 and RB1/LRP1B, and with reduced disease-free survival, particularly TP53/KRAS, TP53/STK11, KRAS/STK11 and STK11/LRP1B. In advanced disease, STK11 and KEAP1 mutations were associated with low PD-L1 expression, whereas PIK3CA, PTEN and ARID1A mutations correlated with higher PD-L1 expression in early-stage tumors. Conclusions: Comprehensive genomic profiling reveals substantial molecular heterogeneity across lung cancer stages and identifies co-mutational patterns with prognostic and immune-related relevance, supporting broader molecular testing at diagnosis.