Sex-based differences in effectiveness of immune checkpoint inhibitors in the treatment of advanced non-small-cell lung cancer: systematic review and meta-analysis

BACKGROUND: Sex-based differences in immune response are well established, but whether men and women derive comparable benefit from immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) remains uncertain. This systematic review and meta-analysis aimed to investigate sex-related differences in effectiveness of ICI for the treatment of advanced NSCLC. METHODS: A systematic review and meta-analysis of randomised controlled trials (RCTs) was conducted to compare overall survival (OS) and progression-free survival (PFS) between men and women treated with ICIs versus chemotherapy for stage III-IV NSCLC. Eligible studies compared programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) inhibitors with chemotherapy and reported sex-specific OS and/or PFS outcomes. HRs were pooled using random-effects models, and secondary analyses incorporated updated follow-up data where available. RESULTS: 55 RCTs comprising 28 550 adults (71.6% men; 28.4% women) were included. ICIs significantly improved OS in both men (HR=0.75, 95% CI 0.72 to 0.78) and women (HR=0.81, 95% CI 0.76 to 0.86; p=0.17 for difference). However, PFS benefits favoured men (HR=0.62, 95% CI 0.59 to 0.65) compared with women (HR=0.76, 95% CI 0.70 to 0.81; p=0.005). In analyses using the most recent follow-up data, women showed lower ICI effectiveness for both OS (p=0.043) and PFS (p=0.003). CONCLUSIONS: ICIs confer similar OS benefits in men and women with advanced NSCLC, but women show shorter PFS, particularly in PD-L1-positive and monotherapy settings. Further research should clarify the biological and clinical factors underlying these differences and ensure balanced representation and equitable evaluation in future trials. PROSPERO REGISTRATION NUMBER: CRD42024451670.