Abstract 3377: The impact of gender and age on real-world progression-free survival (rwPFS) in patients without a smoking history with NSCLC treated with checkpoint inhibitors

Abstract Introduction: While the emergence of checkpoint inhibitors has changed the treatment landscape of non-small cell lung cancer (NSCLC), most never-smokers derive little benefit. This lack of benefit is due to many never-smokers possessing oncogene-driven cancers (e.g. EGFR, ALK, ROS1, etc.) that have “cold” tumor microenvironments (TME) that poorly respond to anti-PD-1(-L1). However, being female and young are also associated with inferior responses to immunotherapy in several cancer types, possibly due to these patients having more endogenous hormones that may be immunosuppressive. To our knowledge, the impact of gender and age on the efficacy of anti-PD-1(-L1) has not been studied in NSCLCs that occur in never-smokers. Such an investigation is particularly relevant given the frequency of this diagnosis in young women. Methods: A nationwide de-identified EHR-derived database (Flatiron Health) was used to evaluate patients without a smoking history with advanced NSCLC treated with single-agent anti-PD-1(-L1). De-identified data originated from approximately 280 US cancer clinics (∼800 sites of care). Kaplan-Meier curves estimated rwPFS (based on clinician documentation of progression) in months (m) with gender and age comparisons evaluated using the log-rank test and multivariable Cox regression. Results: In our cohort of 1535 patients, 1029 (67%) were female, 836 (55%) had a tumor oncogene, 144 (9%) were <55 years of age (yoa), 782 (51%) were 55-75 yoa, and 609 (40%) were >75 yoa. Real-world PFS did not differ between females (2.9 m, 95% CI 2.8-3.1) and males (2.8 m, 95% CI 2.7-3.2) (p=0.52). However, among female patients, those < 55 yoa had shorter rwPFS (2.1 m, 95% CI 1.9-2.7) than females 55-75 yoa (2.9 m, 95% CI 2.7-3.2) and >75 yoa (3.2 m, 95% CI 2.9-3.6) (p=0.001). In a Cox regression model that adjusted for performance status, race, therapy line, and presence of a tumor oncogene, female patients >75 yoa (HR 0.74, 95% CI 0.58-0.95) and 55-75 yoa (HR 0.82, 95% CI 0.65-1.03) were at lower risk for disease progression as compared to females < 55 yoa (reference group). Differences by age in rwPFS were not observed in males. Conclusion: Our analysis revealed that among women without a smoking history, young patients < 55 yoa with NSCLC experience especially poor survival with anti-PD-1(-L1). Research is needed to elucidate the biological mechanisms underlying this disparity. While data on menopausal status were not available for this analysis, most women < 55 yoa are pre- or perimenopausal. The contribution of greater levels of endogenous estrogens to immunosuppression in the lung TME warrants further study. (Supported by a Flatiron-FCCC Academic Partnership Research Grant Award) Citation Format: Hye Sung Kim, Li Zhang, Margie L. Clapper, Jill Hasler, Tia Nicolas, Hossein Borghaei, Martin J. Edelman, Joseph Treat, J. Nicholas Bodor. The impact of gender and age on real-world progression-free survival (rwPFS) in patients without a smoking history with NSCLC treated with checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3377.