Background: Angiogenesis inhibitors, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), are standard of care therapy (alone and in combination) for several advanced cancers, including RCC. There is an unmet need for a biomarker to identify patients with RCC most likely to benefit from VEGFR TKIs to guide individualized treatment decision making. Hence, we sought to develop and validate a biomarker for predicting single-agent systemic VEGFR TKI benefit in patients with RCC. Methods: Candidate biomarkers were selected by co-expression patterns in VEGFR TKI sensitive/resistant tumor types from pan-solid tumor TCGA expression profiling data and the literature. The angiogenesis inhibitor treatment response score (Angio TRS) was developed as a multivariate expression-based algorithm from RNA-based quantitative transcriptional profiling (qTP) performed in parallel with clinical FFPE tumor based comprehensive genomic profiling, with the Angio TRS High/Low threshold set at the median of clear cell RCC samples. The locked Angio TRS (and High/Low status) was then validated in a cohort of adult RCC patients treated with a systemic line of single agent VEGFR TKI therapy within a prospective observational trial; group outcomes (by time to next therapy [TTNT]) were compared by univariate analysis, Cox proportional hazards modeling (adjusting for age, biologic sex, histology, nuclear grade [incorporating sarcomatoid features], therapy line, and TKI type), and unadjusted Kaplan Meier analysis. Laboratory information for IMDC risk group status was not available. Results: Across 3,721 solid tumor tissue samples, median Angio TRS was highest in known VEGFR TKI sensitive tumors (RCC, thyroid carcinoma, sarcoma). Angio TRS was then validated in a separate cohort of 86 patients with RCC treated with single agent systemic VEGFR TKI (median follow-up 29.2 months; 76% male, 77% clear cell, 14% with sarcomatoid features, 84% 1^st line, and 71% treated with sunitinib, pazopanib or axitinib); 52% of patients were Angio TRS High. By univariate analysis, Angio TRS status (p=0.008) and nuclear grade 4 (with or without sarcomatoid features; p=0.06 & 0.07) were most significantly associated with VEGFR TKI TTNT; by multivariate analysis, only Angio TRS status was significantly associated with TTNT (High vs. Low median TTNT 15.8 vs. 5.6 months, adjusted hazard ratio 0.46, p=0.012). Conclusions: Angio TRS is a multivariate expression-based algorithm performed on FFPE tumor tissue, validated to be prognostic of clinical outcome for patients with RCC treated with single agent VEGFR TKI when controlling for clinical factors. Angio TRS may support individualized treatment decision making in patients with advanced RCC. Additional independent validation in a cohort of Kaiser Permanente patients will be presented. Clinical trial information: NCT03061305.