Background: Biomarkers are needed to identify pts responsive to I-O therapies. IL-8 is a proinflammatory chemokine that promotes tumor immune escape. High serum IL-8 levels are associated with poor prognosis (Sanmamed et al. Clin Cancer Res. 2014); changes in serum IL-8 levels were associated with response to anti?PD-1 therapy in a small cohort of pts with melanoma (MEL) and NSCLC (Sanmamed et al. Ann Oncol. 2017). Here we report a large, cross-study, retrospective association analysis of baseline (BL) serum IL-8 levels with clinical efficacy and biomarkers in pts receiving nivolumab (NIVO)-based therapy. Methods: Data were analyzed from ≈2000 pts with MEL, NSCLC, and renal cell carcinoma enrolled in 8 clinical trials. Serum IL-8 was measured using an immunoassay platform (Myriad RBM, Austin, TX). Correlative efficacy metrics included BL tumor burden, overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Receiver operating characteristic (ROC) curve analyses for 12-month OS were used to determine IL-8 cutoffs associated with response. Additional tumor and peripheral correlative markers were assessed. Results: Quartile stratification of serum IL-8 levels showed that elevated BL IL-8 was associated with poor OS. ROC analysis of NIVO-based therapy from pooled study data identified 23 pg/mL as an IL-8 threshold that could be used to enrich for pts who may be more likely to benefit from I-O. Additional IL-8 correlates were identified, including elevated tumor CXCL8 mRNA and peripheral neutrophil count, but these were not statistically significant across all indications. Detailed analyses in pts with MEL showed the correlation of BL IL-8 with OS was independent of BL tumor burden or PD-L1 tumor expression. Absolute BL and post-BL IL-8 levels were more strongly associated with OS, PFS, and ORR than changes from BL. Conclusions: Association of serum IL-8 with response to NIVO-based therapy suggests that IL-8 may serve as a clinically useful biomarker to select for pts who can benefit from I-O therapy. We hypothesize that IL-8 neutralization in pts with elevated BL IL-8 may restore sensitivity to anti?PD-1 therapy; this will be tested clinically with an anti?IL-8 antibody (NCT03400332).