Sex-Related Predictive Value of Circulating Inflammatory Biomarkers in NSCLC Patients Treated with Immune Checkpoint Inhibitors: A Prospective Real-World Study

Background: While Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in advanced NSCLC lacking targetable alterations, response heterogeneity persists and PD-L1 fails to fully capture treatment benefit. Sex-specific variations in immune regulation and ICI responsiveness are emerging as critical, yet underexplored, factors that may inform the development of tailored immunotherapy approaches. Methods: This prospective, single-center translational study aims to enroll 100 patients (target: 50 men, 50 women) with advanced or unresectable EGFR/ALK-wildtype NSCLC (ECOG 0–2), initiating first-line ICI monotherapy or ICI plus platinum-doublet chemotherapy in a real-world setting. Peripheral blood is collected at baseline, first imaging assessment, and at progression. A panel of nine cytokines (IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNFα) is measured using the Q-Plex Human Cytokine Inflammation Panel. The primary endpoint is the association between baseline cytokine levels and objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), immune-related adverse events (irAEs), and cytokine dynamics, with a predefined focus on sex-specific correlates. Results: As of this interim analysis, 35 patients have been enrolled: 15 (43%) females; 28 (80%) with adenocarcinoma; 27 (77%) received pembrolizumab plus chemotherapy and 8 (23%) ICI monotherapy. Enrollment and biospecimen collection are ongoing. Cytokine and outcome analyses will be performed following cohort completion and adequate follow-up. Conclusions: This study aims to define sex-specific circulating immune-inflammatory profiles associated with response to first-line immune checkpoint inhibition in advanced NSCLC. By integrating cytokine profiling with longitudinal clinical outcomes in a sex-balanced cohort, the results are expected to contribute to the identification of predictive biomarkers that reflect differential immune dynamics by sex. These findings may ultimately support more refined, biomarker-driven treatment algorithms and promote sex-informed personalization of immunotherapy strategies in routine clinical practice. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany