A high neutrophil-to-lymphocyte ratio (NLR; ≥4.75) at baseline appears to contribute to an elevated risk of developing severe checkpoint inhibitor pneumonitis (CIP) in patients with nonsmall cell lung cancer (NSCLC), suggests a study.
“Baseline NLR is a promising risk stratification marker for severe CIP,” said the investigators, led by Dr Tetsu Hirakawa, Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
Hirakawa and colleagues retrospectively enrolled 102 patients with NSCLC treated with immune checkpoint inhibitor (ICI) monotherapy at Hiroshima University Hospital in the discovery cohort. They also prospectively enrolled 191 NSCLC patients receiving first-line treatment, including ICI, at 15 institutions in the validation cohort.
Severe CIP was characterized by grade 3‒5 pneumonitis occurring within 3 months of treatment initiation. The baseline NLR cutoff level was identified by receiver operating characteristic curve analysis in the discovery cohort, while the predictive accuracy was evaluated and validated in both cohorts.
Seven patients (6.9 percent) in the discovery cohort and 11 (5.8 percent) in the validation cohort developed severe CIP. [Respirology 2026;31:922-932]
The baseline NLR in the discovery cohort was substantially higher in patients with severe CIP than in those without (17.29 vs 3.70; p=0.006). The cutoff level of baseline NLR was 4.75 (AUC 0.81, sensitivity 85.7 percent, specificity 64.2 percent).
Similarly, the incidence of severe CIP was significantly higher in patients with higher NLR at baseline than in those without, both in discovery (15.0 percent vs 1.6 percent; p=0.009) and validation cohorts (10.3 percent vs 3.3 percent; p=0.046).
“This association was consistently observed in the two independent cohorts, including the multicentre prospective validation cohort,” the investigators said.
“These findings suggest that the baseline NLR may serve as a readily available and promising risk stratification marker for identifying patients at high risk of severe CIP; however, further external validation in larger cohorts is needed,” they added.
Lung injuries
In previous studies, elevated NLR correlated with the incidence of severe acute lung injuries, including acute exacerbation of idiopathic pulmonary fibrosis, acute respiratory distress syndrome, COVID-19-related pneumonia, and radiation pneumonitis. [J Clin Med 2023;12:7446; Front Oncol 2021;11:698832; Oncotarget 2017;8:81387-81393; Int J Clin Pract 2021;75:e14596; BMC Pulm Med 2022;22:314]
“These findings suggest that an elevated NLR may reflect a systemic inflammatory state that contributes to the development of serious pulmonary damage,” the investigators said.
By contrast, other studies did not identify high baseline NLR as a risk factor for CIP. However, several reports stated that NLR increases at CIP onset from baseline and is elevated in severe CIP compared with mild disease at diagnosis. [Sci Rep 2021;11:1324]
“This discrepancy is likely attributable to previous studies assessing the association between baseline NLR and the risk of CIP without specifically accounting for disease severity,” the investigators said. [Clin Lung Cancer 2019;20:442-450.e4; Thorac Cancer 2021;12:153-164; Lung Cancer 2022;170:74-84]
“Our analysis revealed that the baseline NLR was significantly higher in patients with severe CIP than in those without, whereas no such association was observed when analysed by focusing on cases of mild CIP,” they added.
“Severe CIP, particularly when it develops within 6–12 weeks, is a potentially fatal adverse event in patients with NSCLC receiving ICIs,” according to the investigators.