Delta-He as a Novel Predictive and Prognostic Biomarker in Patients With NSCLC Treated With PD–1/PD-L1 Inhibitors

Background

Lung cancer treatment has rapidly advanced, particularly with immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1. However, there are variable responses, such as immune-related adverse events. Several factors predicting the prognosis of lung cancer ICI treatment have been studied so far, but they have limitations, leaving an unmet need. This study aims to investigate delta-He, a novel marker reflecting the iron availability and inflammation through the difference in hemoglobin content between reticulocytes and erythrocytes, as a potential prognostic factor in patients with NSCLC undergoing PD-1/PD-L1 inhibitor therapy.

Methods

This research was conducted at Chungnam National University Hospital, analyzing 79 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors. The study population had a mean age of 70 years, with the majority being male (82.3%) and former or current smokers (84.8%). Blood samples collected before therapy initiation were examined for hematological parameters, including delta-He, using Sysmex XN-550 and XN-20 analyzers. The study employed receiver operating characteristic (ROC) curves and Kaplan–Meier curves for the statistical analysis, using SPSS version 26 (IBM Corp., USA) and MedCalc version 22 (MedCalc Software Ltd., Belgium) to evaluate the sensitivity and specificity of delta-He, and to analyze progression-free survival (PFS) and overall survival (OS).

Results

The study revealed that delta-He is a significant prognostic marker in patients with NSCLC treated with PD-1/PD-L1 inhibitors. A delta-He cutoff value of 3.3 pg was identified based on ROC analysis. Patients with high delta-He values (> 3.3 pg) showed significantly longer median PFS (9.6 vs. 3.0 months, p = 0.024) and OS (not reached vs. 12.2 months, p = 0.010) than those with low values. The high delta-He group also had higher objective response rate (41.4% vs. 26.0%) and disease control rate (86.2% vs. 52.0%). Multivariate analysis highlighted higher delta-He (> 3.3 pg), along with other factors such as FEV1 and smoking status, as important predictors of survival, underscoring its potential role in guiding therapeutic decisions of ICIs in NSCLC (PFS: HR 0.874, 95% CI 0.264-0.874, p = 0.016; OS: HR 0.327, 95% CI 0.150-0.715, p = 0.005).

Conclusion

Our study shows delta-He as a promising prognostic biomarker for lung cancer patients treated with PD-1/PD-L1 inhibitors, highlighting its potential to guide therapeutic decisions and improve patient management in a non-invasive manner. Further research is necessary to validate delta-He's predictive and prognostic value across broader populations and in combination with other biomarkers, emphasizing its role in advancing personalized oncology.