Exploring the efficacy of belzutifan in the treatment of renal cell carcinoma associated with von Hippel-Lindau disease: A comparative analysis with external control arm.

469 Background: Randomized controlled trials are the gold standard for demonstrating treatment efficacy but are not feasible in certain disease settings. In such cases, external control arm (ECA) analysis can be an effective way to interpret experimental treatment results. Our aim, based on a natural history study (NHS), was to develop an ECA for a Phase 2 single-arm trial (LITESPARK [LS]-004) for belzutifan in 61 patients with VHL disease-associated RCC. With a median follow-up of 37.8 months in LS-004, the objective response rate (ORR) for VHL RCC patients was 64% (95%CI: 50.6, 75.8) and the median time to surgery (TTS) was not reached. Methods: The ECA was developed using NHS data for VHL RCC patients undergoing active surveillance at the US National Cancer Institute with up to 5 years of follow-up. Key LS-004 eligibility criteria (e.g., no prior systemic therapy or metastasis) were applied. Propensity score (PS) weighting was used to balance baseline characteristics (age, sex, number and size of RCC, prior surgery and time from prior surgery, VHL mutation status) between LS-004 and ECA, with balance evaluated using standardized mean difference (SMD). PS adjusted point estimates and 95% CI for ORR, assessed by independent blinded committee review using RECIST 1.1, and TTS were estimated. For the ECA, the ORR was evaluated among patients with ≥3 serial scans to allow the opportunity for a confirmed response. Results: The ECA included 244 patients with 178 patients in the ORR analysis. Prognostic factors were well balanced between the ECA and LS-004 with a SMD<0.1 for all covariates. The PS adjusted ORR (95% CI) for LS-004 and the ECA was 63.9% (51.9, 76.0) and 1.5% (0.0, 3.3), respectively. Median (95% CI) TTS was 44.4 (35.7, 51.1) months in the ECA, and not yet reached in LS-004. Conclusions: The magnitude of the treatment effect with belzutifan is large compared with the ECA. Although residual confounding is still possible, including effects of unmeasured confounders, observing such a large effect is unlikely due to chance. The results support the demonstrated antitumor activity and efficacy of belzutifan in the treatment of VHL RCC.