Denoised VEGFR2 expression relates to sunitinib efficacy in advanced Clear Cell Renal Cell Carcinoma

ABSTRACT Short summary Personalized biomarkers can facilitate decision making upon multiple therapeutic options in ccRCC. VEGFR2 expression denoised with 37 normal and tumor gene-expressions relates to sunitinib effect whereas raw VEGFR2 expression doesn’t relate to sunitinib effect. Background Several studies suggested that molecular analysis of patients with advanced clear cell renal cell carcinoma (ccRCC) could indicate whether a patient is susceptible of benefiting from sunitinib in first-line systemic treatment compared to immunotherapies. However, data remain conflicting and no predictive biomarker is validated so far to decipher if sunitinib could still represent a good therapeutic option in first line setting and beyond. Methods PREDMED ® denoised the tumor RNA expression of 37 genes including KDR (encoding VEGFR2) estimated by RT-qPCR, by normalizing it on the expression of normal kidney tissue and cell types. We investigated the performance of PREDMED ® VEGFR2-scoring to predict the clinical effect of sunitinib for patients affected by ccRCC. Results Among the 34 ccRCC patients’ samples retrospectively retrieved from the UroCCR project ( NCT03293563 ), high VEGFR2 scores were associated with objective clinical responses under sunitinib treatment and low scores with stable disease or progression with a sensitivity of 86%, a specificity of 67% and an AUC of 72.5% (95%CI[50.1–94.9]; p=0.04). VEGFR2 scores were significantly and positively related to progression-free survival (HR = 0.465; 95%CI[0.221–0.978]; p=0.0311) and overall survival (HR = 0.400; 95%CI[0.192–0.834]; p=0.0134) under sunitinib treatment. In our cohort, raw VEGFR2 expression (before PREDMED ® processing) was not related to the above mentioned outcomes. Conclusion We describe a gene-expression based algorithm that is accurately related to the effect of sunitinib for patients with ccRCC. We further plan a validation of PREDMED ® for combinatorial strategies involving antiangiogenics and immune-checkpoint blockers.