Baseline Neutrophil‐To‐Lymphocyte Ratio as a Risk Stratification Marker for Severe Checkpoint Inhibitor Pneumonitis in Patients With Non‐Small Cell Lung Cancer: A Two‐Cohort Study With Retrospective Discovery and Prospective Validation

BACKGROUND AND OBJECTIVE: Severe checkpoint inhibitor pneumonitis (CIP), particularly when it develops within 6-12 weeks, is a potentially fatal adverse event in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs). Although neutrophil-to-lymphocyte ratio (NLR) has been reported to predict immune-related adverse events, its role in severe CIP remains unclear. METHODS: The discovery cohort retrospectively enrolled 102 patients with NSCLC treated with ICI monotherapy at Hiroshima University Hospital. The validation cohort prospectively enrolled 191 NSCLC patients receiving first-line treatment, including ICI, at 15 institutions. Severe CIP was defined as grade 3-5 pneumonitis occurring within 3 months of treatment initiation. The cut-off level of the baseline NLR was identified by receiver operating characteristic curve analysis in the discovery cohort, and the predictive accuracy was analyzed and confirmed in both cohorts. RESULTS: Severe CIP was observed in seven (6.9%) and 11 (5.8%) patients in the discovery and validation cohorts, respectively. In the discovery cohort, the baseline NLR was higher in patients with severe CIP than in those without (17.29 [4.76-20.73] vs. 3.70 [2.64-6.68], p = 0.006), and the cut-off level of the baseline NLR was set at 4.75 (AUC 0.81; sensitivity 85.7%, specificity 64.2%). The incidence of severe CIP was significantly higher in patients with higher baseline NLR levels (≥ 4.75) than in those without, in both cohorts (discovery: 15.0% vs. 1.6%, p = 0.009; validation: 10.3% vs. 3.3%, p = 0.046). CONCLUSION: Baseline NLR is a promising risk stratification marker for severe CIP.