Belzutifan 40mg tablets

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.

Abstract licence: CC BY

BackgroundRandomized controlled trials are the gold standard for demonstrating treatment efficacy. When infeasible, external control arm (ECA) analysis is an effective way to interpret treatment arm results. We developed an ECA for a single-arm trial (LS-004) for a HIF-2α inhibitor (belzutifan) in 61 patients with VHL renal cell carcinoma (RCC) to help interpret results. With a median follow-up of 37.8 months in LS-004, the ORR was 64% (95% CI = 50.6 to 75.8); median time to surgery was not reached.MethodsThe ECA was developed using natural history study data for VHL RCC patients undergoing active surveillance with ≤5 years of follow-up. Key LS-004 eligibility criteria were applied. Propensity score (PS) weighting was used to balance prognostic factors, with balance evaluated using standardized mean difference (SMD). PS adjusted point estimates and 95% CI for ORR and time to surgery (TTS) are presented. For the ECA, ORR was evaluated among patients with ≥3 scans to allow opportunity for a confirmed response.ResultsThe ECA included 244 patients (167 for ORR analysis). Prognostic factors were balanced with SMD ConclusionsThe belzutifan treatment effect is large compared with the ECA, supporting belzutifan efficacy in VHL RCC. Although residual confounding is possible, the large effect is unlikely due to chance.

Abstract licence: CC BY