Early dynamics of eosinophils and the neutrophil-to-lymphocyte ratio are associated with severe immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma

Background Reliable biomarkers for characterization of the risk of severe immune-related adverse events (irAEs) during immune checkpoint inhibition remain lacking. We hypothesized that early dynamics of complementary complete blood count (CBC)-based immune biomarkers may be associated with severe immune toxicity. We therefore evaluated longitudinal changes in absolute eosinophil count (AEC) and neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. Methods This multicenter retrospective study included 503 patients with mRCC receiving nivolumab monotherapy in the second or later treatment line. Biomarker analyses were performed using a prespecified 28-day landmark design. AEC and NLR were evaluated at baseline, month 1, and as dynamic Low→High phenotypes, defined as transition from below the baseline upper-quartile threshold to the highest month-1 quartile. Multivariable logistic regression adjusted for age, sex, ECOG performance status, IMDC risk group, and treatment line. Results Among 501 toxicity-evaluable patients, 57 (11.4%) developed grade 3–4 irAEs. Baseline AEC and NLR were not associated with severe irAEs. In contrast, the AEC Low→High phenotype was associated with severe irAEs after multivariable adjustment (adjusted odds ratio [aOR] 2.25, 95% confidence interval [CI] 1.02–4.97; P = 0.045), as was the NLR Low→High phenotype (aOR 2.77, 95% CI 1.25–6.17; P = 0.012). In a prespecified combined multivariable model, NLR remained independently associated with severe irAEs (aOR 2.81, 95% CI 1.25–6.30; P = 0.012), whereas the AEC association was attenuated (aOR 2.08, 95% CI 0.90–4.80; P = 0.085). Conclusions Early dynamics of eosinophils and NLR, rather than baseline biomarker values, were associated with severe irAEs during nivolumab therapy. These findings suggest that eosinophil expansion and inflammatory remodeling may reflect aspects of early immune activation associated with clinically significant immune toxicity. Longitudinal assessment of routinely available CBC-based immune biomarkers therefore warrants prospective validation in cohorts with time-resolved toxicity assessment.