Early monitoring of derived neutrophil-to-lymphocyte ratio (dNLR) as a predictive biomarker of benefit to immune checkpoint inhibitors (ICI) in advanced clear cell renal cell carcinoma (ccRCC).

Abstract

562 Background: Baseline high derived neutrophil-to-lymphocyte ratio (dNLR>3) has been associated with poor outcomes to ICIs in several tumor types, including RCC. However, the clinical value of early and dynamic dNLR changes during treatment remains unclear. In the era of ICI–ICI and TKI–ICI combinations, exploring early dNLR as an accessible biomarker of benefit is clinically relevant. Methods: Patients with advanced ccRCC treated with ICIs between March 2023 and June 2025 were retrospectively analyzed, dNLR was calculated as neutrophils/(leukocytes−neutrophils), and evaluated at four timepoints: pre-baseline (≥1 month before C1), baseline (prior C1), preC2 (prior C2), and postC4 (after C4);a cutoff of dNLR >3 was used to define high-dNLR for all analyses, while in Cohort B (pretreated population) an additional cutoff of dNLR >2 was explored to define high-dNLR; progression-free survival (PFS) and overall survival (OS) were the primary endpoints. Results: A total of 56 patients with advanced ccRCC were included. Cohort A comprised 25 patients treated with first-line ipilimumab plus nivolumab (I+N) (56% male; median age 67 years), ECOG PS ≥1 70%, and IMDC risk was intermediate in 56% and poor in 44%. Median follow-up was 13.3 months, with median PFS and OS of 6.6 months (95% CI, 4.1–19.6) and 13.3 months (95% CI, 4.8–21.2), respectively. High-dNLR at pre-baseline was seen in 8 patients, 25% of whom discontinued I+N due to early progression. High-dNLR at pre-baseline showed a trend toward poorer OS (HR 1.53, p=0.57), and at baseline toward shorter PFS and OS (HR 3.08, p=0.08; HR 2.3, p=0.24). PreC2 high-dNLR predicted worse OS (HR 4.83, p=0.026). Regarding dynamics, 5/8 pre-baseline high-dNLR remained high and 3 became low, while of 15 pre-baseline low, 2 became high. Between baseline and preC2, 7 patients were high; 3 changed to low and 1 died. Of 20 baseline low, 16 remained low and 3 became high. Two patients with high-dNLR at C4 developed grade 3 immune toxicity. Cohort B included 29 patients treated with nivolumab beyond first line (62% second-line, 34.5% third-line). Sixty-two percent were male, ECOG PS≥1 66%, and IMDC risk good/intermediate/poor in 31%/59%/7%.Median follow-up was 12 months, with median PFS and OS of 3.9 months (95% CI, 2.3–9.7) and 11.3 months (95% CI, 9.1–15.8), respectively. Only 3 patients showed high-dNLR at pre-baseline, all on prior-line treatment. With a lower cutoff (dNLR >2), 10 patients (34%) were high. PreC2 high-dNLR was linked to shorter PFS and OS (HR 7.33 and 2.50; p<0.005 and 0.12). Conclusions: Monitoring early changes in dNLR may provide insight into primary resistance to immunotherapy and early progression, supporting timely clinical intervention in selected patients.