Role of Targeted Therapy in the Management of von Hippel-Lindau Disease-Associated Renal Cell Carcinoma: A Single-Proportion Meta-Analysis

Management of renal cell carcinoma (RCC) associated with von Hippel-Lindau (VHL) disease is challenging due to multifocality and the risk of renal failure from repeated surgery. Recent advances in targeted therapy directed at the hypoxia-inducible factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR) pathways offer new therapeutic options. This meta-analysis evaluated the overall response and toxicity of targeted therapy in VHL-associated RCC. A systematic literature search was conducted in PubMed, Embase, Cochrane, and Scopus databases from January 2000 to January 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies included clinical trials and retrospective analyses reporting the efficacy and adverse events of systemic targeted therapies in VHL-related RCC. Pooled response rates and confidence intervals (CI) were calculated using a random-effects model, with heterogeneity assessed by I² statistics. Five studies (188 RCC cases) met the inclusion criteria. The pooled overall response rate to targeted therapy was 42% (95% CI: 28-56). Subgroup analysis showed higher efficacy of HIF-2α inhibitors (belzutifan) compared to VEGFR inhibitors (62% vs. 44%; 95% CI: 49-74 and 30-59, respectively). Heterogeneity was moderate (I²=68%). Most adverse events were grades 1-2, with better tolerability in HIF-2α inhibitors. Targeted therapy focusing on the molecular pathogenesis of VHL-associated RCC provides meaningful disease control while preserving renal function. HIF-2α inhibitors demonstrate superior efficacy and lower toxicity compared with VEGFR-targeted agents, representing a promising non-surgical alternative for managing VHL-related RCC.