Background
Sex-based differences in survival have been reported in non-small cell lung cancer (NSCLC). Traditional analyses using hazard ratios can be difficult to interpret in clinical terms because they do not directly convey absolute survival differences such as months of survival. Restricted mean survival time (RMST) offers a clinically interpretable measure of survival differences over a fixed time period. Additionally, attributable fraction (AF) analysis allows quantification of the contribution of a factor, such as sex, to cumulative mortality, providing complementary insight into sex-related survival disparities.

Objectives
To evaluate sex-based differences in overall survival among patients with primary NSCLC using RMST derived from flexible parametric survival models and to quantify the proportion of deaths attributable to excess mortality associated with male sex.

Methods
In this retrospective observational study, we identified adults diagnosed with primary NSCLC from 2011 to 2019, using Cancer Registry of the Aga Khan University Hospital (Karachi, Pakistan). Flexible parametric survival models were used to estimate sex-specific RMST (in months). Both unadjusted and adjusted models were fitted, with adjustment for relevant demographic and clinicopathological factors. Subgroup analyses were performed among patients with metastatic NSCLC. Sensitivity analyses using multivariable Cox proportional hazards models were conducted to assess robustness of findings. AF analyses were performed within the flexible parametric framework. AF was interpreted etiologically as the proportion of deaths attributable to excess mortality associated with male sex. All the analyses were conducted using Stata version 17.0.

Results
Among 867 primary NSCLC patients, females comprised 26.00% (n=225). Age at diagnosis, tobacco use, alcohol use, and tumor histology differed between sexes. In the overall NSCLC cohort, females consistently had longer survival than males across all time points. At 12 months, adjusted RMST was 10.19 months for females versus 9.47 months for males, and at 60 months, 31.15 months versus 24.70 months, corresponding to an adjusted RMST difference of 0.72 months at 12 months and 6.45 months at 60 months. Similar patterns were observed in the metastatic subgroup, with adjusted RMST of 9.69 versus 8.90 months at 12 months, and 26.13 versus 20.36 months at 60 months (differences: 0.79 and 5.76 months, respectively). Sensitivity analyses using multivariable Cox regression confirmed these findings. In the overall cohort, males had a significantly higher hazard of death (HR 1.43; 95% CI: 1.07–1.92; p=0.017), while in metastatic patients, the hazard was directionally higher but borderline significant (HR 1.37; 95% CI: 0.99–1.91; p=0.058). In AF analysis, for the overall cohort, AF declined from 21% at 12 months to 8% at 60 months. In metastatic patients, AF decreased from 18% at 12 months to 5% at 60 months, indicating that male sex contributed to excess mortality early after diagnosis, with effects persisting over time.

Conclusions
In conclusion, across both overall and metastatic cohorts, adjusted RMST and Cox analyses consistently demonstrated longer survival for females, and AF analysis confirmed that male sex contributed to excess mortality. These findings underscore the need to account for sex as an integral variable in future lung cancer research and clinical decision-making.