Sex-Based Efficacy Variations of Immune Checkpoint Inhibitors in Advanced Non-Small Cell Lung CancerImmune checkpoint inhibitors show different survival benefits for men and women

This meta-analysis evaluates the efficacy of immune checkpoint inhibitors (ICIs) compared to standard chemotherapy in a large cohort of 25,827 patients with advanced non-small cell lung cancer (NSCLC). The primary focus of the analysis is to determine if sex-based differences exist in treatment response, specifically regarding overall survival (OS) and progression-free survival (PFS). The study provides critical data for clinicians managing NSCLC, where personalized treatment pathways are increasingly prioritized.

In the primary analysis, both male and female patients demonstrated statistically significant improvements in OS and PFS when treated with ICIs compared to chemotherapy. For male patients, the hazard ratios for OS and PFS were 0.74 and 0.59, respectively. For female patients, the hazard ratios were 0.83 and 0.76. While both groups showed clinical benefit, the magnitude of the effect appeared more pronounced in the male demographic.

Statistical interaction analyses revealed significant sex-based differences in treatment outcomes. The interaction for OS showed a significantly greater benefit in males (HR 0.90, 95% CI 0.84-0.97, P = 0.01). Similarly, the interaction for PFS showed a significantly greater benefit in males (HR 0.82, 95% CI 0.73-0.92, P = 0.0006). These findings suggest that while ICIs are effective for both sexes, the relative gain over chemotherapy may be more substantial for men.

When examining ICI monotherapy specifically, the data indicated significant sex-based differences in PFS. After False Discovery Rate (FDR) correction, the results remained significant for monotherapy (P = 0.001), anti-PD-1 agents (P = 0.001), and patients with PD-L1 levels $\geq$50% (P = 0.004). However, the sex-based differences in OS for monotherapy did not maintain significance after FDR correction, suggesting a more nuanced interpretation of survival data in this specific subgroup.

In contrast, when ICIs were combined with chemotherapy, no statistically significant sex-based differences were observed in OS or PFS. This suggests that the addition of cytotoxic agents may homogenize the response rates between males and females. This finding is clinically relevant for determining whether combination therapies might mitigate the observed disparity in monotherapy outcomes.

Several limitations must be considered when interpreting these results. The meta-analysis noted imbalances in baseline confounders and a notable underrepresentation of female patients in the original trials included in the analysis. These factors may influence the precision of the sex-based interaction estimates. Furthermore, the lack of significance in OS after FDR correction for monotherapy suggests that survival data may be less robust than PFS data in identifying sex-specific trends.

Clinicians should interpret these findings with caution. While the data suggests a potential attenuation of PFS benefits in females compared to males under monotherapy, these results require confirmation in future randomized controlled trials specifically designed to investigate sex-based differences. Current evidence suggests that while ICIs are a cornerstone of NSCLC treatment, the magnitude of benefit may vary by sex, necessitating careful patient selection and monitoring.