DNA Damage Response Alterations Stratify Response to ICI-Based Therapy in Advanced NSCLC with High PD-L1 Expression

Background: Although high PD-L1 expression correlates with improved outcomes to immune checkpoint inhibitor (ICI), it remains an imperfect predictive biomarker. DNA damage response (DDR) pathway alterations are closely associated with antitumor immunity, shaping tumor immunogenicity and the immune microenvironment. This study evaluates the distribution and clinical impact of DDR alterations in advanced Non-small cell lung cancer (NSCLC) with Programmed death-ligand 1 (PD-L1) ≥ 50%, providing insights for personalized treatment selection and response prediction. Experimental Design: Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received first-line ICI-based therapy were retrospectively enrolled. Tumor tissue samples underwent targeted next-generation sequencing using a comprehensive cancer panel, with a predefined 35-gene DDR panel used to identify and classify pathogenic or likely pathogenic DDR alterations. The associations between genomic DDR alteration status, clinicopathologic characteristics, cytokine profiles, and immunotherapy outcomes were evaluated. Results: Among 121 patients, 72 (59.5%) were classified as DDR-positive and 49 (40.5%) as DDR-negative based on genomic DDR alterations. DDR-positive patients exhibited a higher burden of DDR alterations and TMB, and DDR-positive status remained independently associated with improved outcomes after adjustment for clinical factors and TMB. DDR-positive patients had higher DCB rates and IL-2 levels, whereas TNF-α and IL-6 levels were elevated in DDR-negative patients. DDR-positive status was associated with longer PFS than DDR-negative status (median, 12.7 vs. 8.9 months), with the benefit of chemo-immunotherapy mainly observed in DDR-positive patients. Conclusions: Genomic DDR alterations are associated with distinct immune profiles and may represent a potential biomarker for immunotherapy stratification. DDR-positive patients may derive greater benefit from chemo-immunotherapy, supporting further prospective investigation.