Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC)

Abstract

5012 Background: The clinical response to VEGF-targeted therapy in metastatic RCC is robust, yet variability in outcome exists. VHL is often mutated in RCC, but the relation to therapeutic outcome is unclear. Identification of tumor molecular characteristics associated with outcome would aid in patient selection and interpretation of clinical trials. Materials and Methods: Patients with metastatic, clear-cell RCC with available baseline frozen or paraffin-embedded tumor samples who received VEGF-targeted monotherapy with sunitinb, sorafenib, axitinib or bevacizumab at Cleveland Clinic or University of California San Francisco, were included. Patient characteristics, VHL gene status (mutated or not mutated) and objective response rate (ORR) were documented. ORR was investigator-assessed per RECIST criteria. Fisher’s exact test and logistic regression models were used to assess ORR in univariate and multivariate analyses, respectively. Results: One-hundred twenty-three patients were evaluable. The ORR was 36.5% for the entire cohort. VHL mutation was found in 48% of patients and was seen across all three exons. Patients with VHL mutation had an ORR of 46% versus 28% for pts without a mutated VHL gene (p=0.06). In multivariate analysis, presence of a VHL mutation remained an independent prognostic factor associated with improved ORR (p=.02) when multiple clinical prognostic factors (ECOG PS, hemoglobin, corrected calcium, LDH, prior radiation, prior therapy and number of metastatic sites) were also considered. Conclusion: This is the first large study testing the impact of VHL mutation on response to VEGF-targeted agents in metastatic RCC. Although objective responses were more likely among patients with mutated VHL gene, lack of VHL mutation did not preclude a response. Additional tissue analysis and identification of biomarkers relevant to response to VEGF-targeted agents in metastatic RCC are warranted. [Table: see text]