Research in Context

Research in Context is a structured summary that editors at The Lancet’s journals ask all authors to provide when submitting an original research article. Read more

A collaboration with

Ongoing phase 2 follow-up shows durable belzutifan activity in VHL disease-associated neoplasms

In the ongoing phase 2 LITESPARK-004 study, nearly 50 months of follow-up showed durable responses and a continued low need for surgical intervention in participants with VHL disease-associated lesions.

  • Ramaprasad Srinivasan, MD; Othon Iliopoulos, MD; Kathryn E Beckermann, MD; Vivek Narayan, MD; Benjamin L Maughan, MD; Stephane Oudard, MD; et al.

  • April 11, 2025

  • The Lancet Oncology
  • The Lancet Oncology, Volume 26, Issue 5, Pages 571–582
  • 10.1016/S1470-2045(25)00099-3

Share

Evidence before this study

We searched PubMed on Nov 14, 2023, using the keywords “von Hippel-Lindau disease”, and “hypoxia inducible factor”, and “von Hippel-Lindau disease management”, including abbreviations, with no date or language restrictions. Results from the published literature showed that the number of systemic treatment options for von Hippel-Lindau disease is limited, and patients with von Hippel-Lindau disease are commonly treated using observation followed by surgical procedures when indicated. Hypoxia-inducible factor 2α (HIF-2α) plays an important part in manifestations of von Hippel-Lindau disease, including clear cell renal cell carcinoma, CNS haemangioblastomas, and pancreatic neuroendocrine tumours. Inactivation of the VHL gene results in accumulation of HIF-2α, inducing the downstream upregulation of genes associated with cancer growth, proliferation, angiogenesis, and metabolism. We hypothesised that targeting the underlying pathophysiology of von Hippel-Lindau disease with an HIF-2α inhibitor would be associated with durable antitumour activity in von Hippel-Lindau disease-related renal cell carcinoma and other tumour types associated with von Hippel-Lindau disease.

Added value of this study

Belzutifan is the first HIF-2α inhibitor approved by the US Food and Drug Administration and the only approved systemic therapy for participants with von Hippel-Lindau disease. In the initial results of the ongoing phase 2 LITESPARK-004 study, belzutifan showed promising antitumour activity in participants with von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms. With longer follow-up of nearly 50 months, results showed the durability of response and additional responses in renal cell carcinoma, pancreatic lesions, and haemangioblastomas in the CNS and retina. The need for surgical intervention to manage von Hippel-Lindau disease-related lesions also remained low. These results show the long-term antitumour activity and safety of belzutifan in Hippel-Lindau disease-associated neoplasms and reinforce the clinical utility of belzutifan in treatment of this patient population.

Implications of all the available evidence

Updated results from this study showed that belzutifan continued to be well tolerated and that it had a higher response rate in von Hippel-Lindau disease-associated renal cell carcinoma than observed in the primary analysis; belzutifan was also associated with durable antitumour activity in participants with von Hippel-Lindau disease-associated renal cell carcinoma, CNS and retinal haemangioblastomas, and pancreatic neuroendocrine tumours, and seemed to delay or preclude the need for surgical intervention. These results support the continued use of belzutifan in von Hippel-Lindau disease as an alternative to surgical intervention, and as a standard against which future therapies can be assessed.

Source: The Lancet Oncology

Your research deserves a global audience

The Lancet Group reaches millions of clinicians and researchers worldwide.

Publish with The Lancet Group

Related Content

TiNivo-2: first phase 3 data on PD-1 rechallenge in advanced renal cell carcinoma.

Investigators reported no efficacy for PD-1 rechallenge with tivozanib plus nivolumab after progression on previous ICI combination therapy, while the authors noted clinical activity for full-dose tivozanib monotherapy in this setting.

  • by Toni K Choueiri, MD; Laurence Albiges, MD; Philippe Barthélémy, MD; Roberto Iacovelli, MD; Sheik Emambux, MD; Javier Molina-Cerrillo, MD; et al.

  • September 13, 2024

Illustration of kidneys with a highlighted lesion.
FASTRACK II: non-randomised trial of SABR in inoperable or high-risk renal cell carcinoma

Investigators reported no local progression during the study period and said the findings justify a randomised trial of surgery versus SABR.

  • by Shankar Siva, MBBS PhD; David Pryor, MBBS; Jarad Martin, PhD DMed; Nicholas Hardcastle, PhD; Daniel Moon, MBBS; Tomas Kron, PhD; et al.

  • May 17, 2026

Patient undergoing radiation therapy beneath a treatment machine.