Association Between Mutations in DNA Damage Response Genes and Efficacy of Immune Checkpoint Inhibitor Therapy in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Background: Immunotherapy has improved outcomes in non-small cell lung cancer (NSCLC), but reliable predictive biomarkers remain limited. DNA damage response (DDR) gene mutations may enhance tumor immunogenicity and response to immune checkpoint inhibitors (ICIs), yet clinical findings remain inconsistent. We aimed to systematically evaluate the association between DDR gene mutations and ICI outcomes in NSCLC. Methods: PubMed and Embase were searched for eligible studies. Data on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were extracted and pooled using random-effects models. Subgroup analyses were performed by treatment regimen. Results: A total of 13 studies involving 5989 patients were included from 606 records. The pooled RR for ORR comparing DDR wild-type with DDR-mutated patients was 0.63 (95% CI: 0.49–0.82, p < 0.001), indicating higher ORR in the DDR-mutated group. DDR mutations were also associated with improved PFS (HR = 0.56, 95% CI: 0.43–0.74, p < 0.001) and OS (HR = 0.82, 95% CI: 0.68–0.98, p < 0.05). In subgroup analyses, benefits were more consistent with ICI monotherapy, including improved PFS (HR = 0.59, 95% CI: 0.44–0.79, p < 0.001) and ORR (RR = 0.60, 95% CI: 0.44–0.82, p = 0.001), while OS showed a nonsignificant trend. Evidence in the ICI-plus-chemotherapy subgroup remained inconclusive because of the limited number of available studies and substantial between-study heterogeneity. Conclusions: DDR gene mutations were associated with improved clinical outcomes in NSCLC patients treated with ICIs, particularly in the ICI monotherapy setting.