Retrospective comparison of belzutifan versus natural history control in Von Hippel-Lindau associated renal cell carcinoma

Randomized 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 result. The single-arm LS-004 trial evaluated belzutifan (HIF-2α inhibitor) in 61 patients with Von Hippel-Lindau associated renal cell carcinoma (VHL RCC). With a median follow-up of 37.8 months, the objective response rate (ORR) was 64% (95% CI 50.6-75.8), whereas median time to surgery (TTS) was not reached. An ECS was developed using natural history study data for 244 VHL RCC patients. Propensity score (PS) weighting was used to balance prognostic factors, with standard mean differences < 0.1 for all covariates. PS adjusted ORR for LS-004 and ECA was 63.9% (95% CI 51.9-76.0) and 1.5% (0.0-3.3), respectively. Median TTS was not yet reached in LS-004 versus 51.3 months (95% CI 43.8-not yet reached) in ECA. The authors conclude that the belzutifan treatment effect was large compared with ECA. Although residual confounding is possible, the large effect is unlikely due to chance.