•  
  •  
 

Article Type

Article

Abstract

Background: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in metastatic non–small cell lung cancer (NSCLC), yet durable clinical benefit (DCB) is achieved in only a subset of patients. Established biomarkers such as PD-L1 expression and tumor mutational burden (TMB) incompletely predict response, while emerging evidence suggests that gut microbiome composition may further modulate immunotherapy efficacy. We conducted a prospective multi-center study in China to evaluate the independent and integrated predictive value of PD-L1, TMB, and microbiome signatures for durable immunotherapy response. Methods: In this prospective cohort study, 286 patients with metastatic NSCLC receiving PD-1/PD-L1 inhibitors were enrolled across three tertiary cancer centers in China. Pretreatment tumor samples underwent PD-L1 immunohistochemistry and targeted next-generation sequencing for TMB assessment. Baseline stool samples were analyzed using 16S rRNA sequencing to evaluate microbial diversity and taxonomic composition. Durable clinical benefit was defined as response or stable disease lasting ≥ 12 months. Multi-omic integration was performed using canonical correlation analysis and machine-learning–based predictive modeling. Results: Durable clinical benefit was observed in 32.2% of patients. PD-L1 TPS ≥ 50% was associated with improved progression-free survival (median 14.8 months; HR 0.56; P = .001). High TMB (≥ 10 mut/Mb) correlated with increased DCB rates (47.4% vs 26.2%; P = .002). Responders demonstrated significantly higher microbial diversity (Shannon index 4.08 vs 3.22; P < .001) and enrichment of Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bifidobacterium longum. Integrated multi-omic modeling outperformed individual biomarkers in predicting DCB, identifying biologically distinct subgroups with markedly different survival outcomes. Conclusion: In this Chinese multi-center cohort, PD-L1 expression, tumor mutational burden, and gut microbiome composition represent complementary predictors of durable immunotherapy response in metastatic NSCLC. Multi-omic integration significantly enhances predictive precision and may inform personalized treatment strategies. These findings support incorporation of multidimensional biomarker profiling into precision oncology practice in China.

Keywords

Non–small cell lung cancer, Immunotherapy, PD-L1 expression, Tumor mutational burden, Gut microbiome, Durable clinical benefit, Multi-omics, Precision oncology

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Download

Share

COinS