Episode 11: The efficacy of belzutifan on PFS and ORR in metastatic ccRCC: Litespark-005

In this episode of ‘What’s New Doc’ in GU cancer, Prof Emmanuel Seront from UCL Louvain and Prof Christof Vulsteke from Maria Middelares Gent will discuss the findings of belzutifan in metastatic ccRCC, as conducted in the LITESPARK-005 study.

In over 90% of clear cell renal carcinomas, HIF levels increase, leading to excessive angiogenesis. Belzutifan, a novel drug with a unique mechanism of action, inhibits HIF-2α, providing the rationale for its use.

The LITESPARK-005 study evaluated the efficacy of belzutifan in patients with unresectable locally advanced or metastatic clear cell RCC that had progressed following treatment with both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF-TKI.

This heavily pretreated population, with a poor prognosis, was randomized 1:1 to receive either 120 mg of belzutifan or 10 mg of everolimus once daily. The primary endpoints were PFS and OS.

Belzutifan demonstrated a clear benefit in PFS. Although the median PFS of 6 months was similar in both treatment groups, the HR of belzutifan was 0.74, indicating a 25% reduction in the risk of death. The effect on PFS remained consistent during various interim analyses. In terms of ORR, belzutifan achieved 20% compared to only 3% with everolimus. OS data are still immature.

The most common side effects of belzutifan treatment are anaemia, fatigue, and hypoxia, which are related to its mechanism of action. However, these side effects are well-tolerated and manageable. The positive outcome on PFS and ORR, combined with its safety, positions belzutifan as a new standard of care in metastatic renal cell carcinoma after failure on TKIs and immune checkpoint inhibitors.

The low ORR of 3% in the comparative arm underscores belzutifan’s superiority. While greater benefits might have been anticipated given its mechanism of action, it’s important to note that this heavily pretreated population progressed on various treatments. In this trial, 30% of patients experienced progressive disease on belzutifan, suggesting that some patients may be independent of angiogenesis for cancer progression and development. Thus, in addition to offering an alternative treatment option for patients, this study contributes to the understanding of the pathogenesis of renal cell carcinoma.