1473P - Efficacy of anti-PD1/PDL1 antibody monotherapy in patients with advanced non-small cell lung cancer with increased hepcidin expression

Background

T cell-promoted tumor ferroptosis, a form of iron-induced regulated cell death, is involved in the anti-tumor activities of immune checkpoint inhibitors (ICIs). The Efficacy of ICIs on advanced non-small cell lung cancer (aNSCLC) with iron metabolism disorders is unknown. Iron is an essential factor in metabolic pathways. However, iron facilitates the production of oxygen radicals, which may result in ferroptosis. This study explored the efficacy of anti-PD1/PDL1 monotherapy on survival in patients with aNSCLC with increased hepcidin expression.

Methods

A retrospective observational study was conducted in histologically confirmed aNSCLC patients with samples for hepcidin immunohistochemical staining. Eligible patients initiated nivolumab, pembrolizumab, or atezolizumab monotherapy as any line of treatment; the data cutoff was May 6, 2023. The hazard ratio for death was estimated with the use of the Kaplan–Meier method. Between-group comparisons were performed with the use of the log-rank test. Effects of hepcidin on ferroptosis induced by IFNg were examined using a lung cancer cell line.

Results

The 45 eligible patients included 39 (86.7%) men; the median age was 72 years (range, 36-83 years); 3 (6.7%) of 45 patients with driver gene mutations. The median patient follow-up was 15.3 months (26 days to 87.8 months). The median time to death was 69.6 (95% CI, not reached) and 15.3 months (95% CI, 0.94 – 29.7) for hepcidin High (TPS ≥ 50%) and None or Moderate (TPS < 50 %), respectively. The hazard ratio and p-value for OS with hepcidin High versus None or Moderate were 0.55 (95% CI, 0.23 to 1.34) and p = 0.19. The cytotoxicity of IFNg on A549 cells was enhanced by hepcidin with increasing levels of endogenous reactive oxygen species, a feature of ferroptosis.

Conclusions

In our cohort, aNSCLC patients with increased hepcidin expression and anti-PD1/PDL1 antibody monotherapy showed a longer survival time, but statistically insignificant probably due to a small sample size. Further study with a larger sample size is required to validate the effect of hepcidin on anti-PD1/PDL1 monotherapy. The potency of anti-PD1/PDL1 monotherapy enhancement by modulation of iron metabolism-related factors needs to be explored.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

JSPS Kakenhi grant: 20K08571.

Disclosure

All authors have declared no conflicts of interest.