VHL mutations predict survival of patients with renal cell carcinoma in response to the therapy of immune checkpoint inhibitors

Abstract Purpose: To identify a predictive biomarker of immune checkpoint inhibitor (ICI) therapies for renal cell carcinoma (RCC). Methods: Survival analysis of mutations in a panel of 468 cancer-related genes in a cohort of 151 RCC patients who underwent the ICI treatment using Cox regression model univariate or multivariate analysis in publicly available datasets. Results: We found that VHL mutations were the only promising independent predictor for overall survival (OS) (HR=0.44, 95% CI=0.25-0.77 and P=0.004). More specifically, compared with 26 months of survival in the wildtype patients, metastatic RCC patients carrying truncated VHL mutations had a significantly longer survival time of nearly 70 months (HR=0.45, 95% CI=0.25-0.82 and P=0.008) in the presence of the ICI therapy. This survival benefit was also observed in another cohort of 35 patients with clear cell RCC from Dana-Farber Cancer Institute (DFCI): compared with 29 months in the wildtype patients, patients with VHL truncated mutations also had a longer median OS of 33 months (HR=0.59, 95% CI=0.24-1.44 and P=0.243). These observed survival benefits were independent of VHL expression and tumor infiltration immune cells in The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA KIRC). Conclusion: VHL mutational inactivation may have an effect on the RCC response to ICI therapy, likely by the upregulation of PD-L1 via attenuating degradation of HIF-1α. To our knowledge, this is the first report of VHL mutations as an independent predictive biomarker for the ICI therapy in RCC, which, once validated by larger clinical trials, may help improve clinical decision-making in individualized treatment of RCC patients.