32 Inflamed Eosinophilic Phenotype Predicts Improved Outcomes Without Excess Immune-Related Adverse Events in First-Line Ici-Treated Metastatic Renal Cell Carcinoma

Background Blood biomarkers predicting benefit and toxicity from first-line (1L) immune checkpoint inhibitor (ICI) therapy in metastatic RCC (mRCC) remain limited. Eosinophils facilitate T-cell activation while neutrophils reflect systemic inflammation. We hypothesized an “inflamed eosinophilic” phenotype – characterized by low baseline neutrophil-to-eosinophil ratio (NER) with on-treatment eosinophil rise – identifies patients with favorable outcomes without increased immune-related adverse events (irAEs). Methods We retrospectively analyzed 117 mRCC patients receiving 1L ICI-based therapy at the University of Virginia (ICI/ICI 68%, ICI/tyrosine kinase inhibitor (TKI) 17%, ICI monotherapy 15%). Baseline absolute eosinophil count (AEC), NER, and neutrophil-to-lymphocyte ratio (NLR) were tested in multivariable Cox models adjusted for treatment regimen. Change in AEC (ΔAEC) was defined as percent change from baseline within 12 weeks; AEC trajectories over 12 weeks used linear mixed-effects models. Patients were classified into three predefined phenotypes: inflamed eosinophilic (IE: NER ≤40 and ΔAEC ≥10%), inflamed non-eosinophilic (INE: NER ≤40 and ΔAEC <10%), and non-inflamed (NI: NER >40). The 10% ΔAEC threshold was pre-specified based on prior nivolumab-treated mRCC data. Phenotype analysis required a calculable baseline NER (AEC >0) and at least one post-baseline AEC measurement. Associations with progression-free survival (PFS), overall survival (OS), and irAEs were assessed using Cox and logistic regression. Receiver operating characteristic (ROC) analysis was performed for 1-year OS. Results Higher baseline AEC independently predicted improved PFS (hazard ratio [HR] 0.02 per 1 K/μL, p=0.004). Elevated baseline NER was associated with inferior PFS (HR 1.008/unit, p=0.001) and OS (HR 1.006/unit, p=0.008). Optimal baseline NER cutoff for 1-year OS was 39.25 (area under the curve [AUC] 0.71). Baseline AEC trended higher in patients developing irAEs (p=0.08), whereas baseline NER and NLR were not associated with irAEs. AEC trajectories did not significantly differ by regimen and were not independently associated with survival. The IE phenotype demonstrated superior OS versus INE (HR 3.63, 95% CI 1.10-11.96, p=0.034) and NI (HR 2.88, 95% CI 1.06-7.88, p=0.039); median OS was not reached in IE vs 601 and 900 days, respectively. Median PFS was longest in IE (658 vs 460 vs 306 days). Rates of irAEs were similar across phenotypes (51.5% vs 50.0% vs 34.8%, p=0.44). Of 117 analyzed patients, 51 were excluded from phenotype analysis due to missing baseline NER or post-baseline AEC. These missing data were primarily due to baseline eosinophil counts of 0 (which prevented NER calculation) or a lack of routine post-baseline lab draws, rather than early mortality. Excluded patients did not differ significantly from included patients in baseline characteristics. Conclusions Low baseline NER with early eosinophil mobilization suggests a composite “inflamed eosinophilic” phenotype that may help identify patients with superior survival and acceptable toxicity in 1L ICI-treated mRCC. This composite approach requires validation in larger studies, but has the potential to enhance precision immunotherapy and improve patient outcomes in the expanding first-line mRCC treatment landscape.