Inflammatory–Molecular Clusters as Predictors of Immunotherapy Response in Advanced Non-Small-Cell Lung Cancer

Background/Objectives: Immunotherapy has improved outcomes for selected patients with advanced non-small-cell lung cancer (NSCLC), yet the predictive value of individual biomarkers such as PD-L1 remains limited. Systemic inflammatory indices derived from routine blood tests may complement molecular and immunohistochemical features, offering a broader view of host–tumor immunobiology. Methods: We conducted a retrospective study of 298 patients with stage IIIB–IV NSCLC treated with immune checkpoint inhibitors (ICIs) at a tertiary oncology center between 2022 and 2024. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune–inflammation index (SII) were collected alongside PD-L1 expression and molecular alterations (EGFR, KRAS, ALK, TP53). Patients were stratified into inflammatory–molecular clusters integrating these parameters. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan–Meier and multivariate Cox analyses. Results: Four distinct inflammatory–molecular clusters demonstrated significantly different outcomes (p < 0.001). Patients with low NLR and high PD-L1 expression (Cluster A) showed the highest ORR (41%), longest median PFS (13.0 months), and OS (22.5 months). The EGFR/ALK-driven, inflammation-dominant cluster (Cluster C) exhibited poor response (ORR 7%) and shortest survival (PFS 4.3 months). High NLR (HR 2.12), PD-L1 < 1% (HR 1.91), and EGFR mutation (HR 2.36) independently predicted shorter PFS. A combined model incorporating NLR, PD-L1, and molecular status outperformed individual biomarkers (AUC 0.82). Conclusions: Integrating systemic inflammatory indices with PD-L1 expression and molecular alterations identifies clinically meaningful NSCLC subgroups with distinct immunotherapy outcomes. This multidimensional approach improves prediction of ICI response and may enhance real-world patient stratification, particularly in settings with limited access to extended molecular profiling.