Belzutifan: A Breakthrough in Targeted Therapy for ccRCC

Gejia Tian

doi:10.54254/2753-8818/2025.AU26578

Theoretical and Natural ScienceOpen access

Belzutifan: A Breakthrough in Targeted Therapy for ccRCC

Research Article

Open Access

Belzutifan: A Breakthrough in Targeted Therapy for ccRCC

Gejia Tian ^1*

¹ Johns Hopkins University

^*Corresponding author: Gtian2@jh.edu

Published on 9 September 2025

TNS Vol.135

ISSN (Print): 2753-8826

ISSN (Online): 2753-8818

ISBN (Print): 978-1-80590-371-0

ISBN (Online): 978-1-80590-372-7

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Abstract

Belzutifan, a novel orally bioavailable small-molecule inhibitor of hypoxia-inducible factor 2α (HIF-2α), represents a mechanistically distinct and clinically promising therapy for clear cell renal cell carcinoma (ccRCC), particularly in patients with von Hippel–Lindau (VHL) disease. By selectively disrupting the VHL–HIF–2α signaling axis, Belzutifan effectively inhibits hypoxia-driven transcriptional programs that promote tumor progression. Unlike traditional therapies such as VEGF inhibitors and immune checkpoint blockade, Belzutifan directly targets a core oncogenic pathway unique to VHL-deficient tumors. Clinical trials have demonstrated encouraging response rates and manageable safety profiles, both as monotherapy and in combination with agents like cabozantinib. However, emerging resistance, limited efficacy in pre-treated populations, and concerns about long-term toxicity highlight areas that require further investigation. This article reviews the underlying molecular mechanism, clinical trial data, therapeutic advantages, and key limitations of Belzutifan, while also exploring its future potential in broader contexts of renal cell carcinoma and in rational combination strategies.

Keywords:

Belzutifan, HIF-2α inhibition, clear cell renal cell carcinoma, VHL disease, targeted therapy

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References

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References

[3]. Kaelin, W. G., Jr. (2017). The VHL tumor suppressor gene: Insights into oxygen sensing and cancer. Transactions of the American Clinical and Climatological Association, 128, 298–307.

[4]. Wallace, E. M., Rizzi, J. P., Han, G., et al. (2016). A small-molecule antagonist of HIF 2α is efficacious in preclinical models of renal cell carcinoma. Nature, 539(7627), 112–117.

[5]. U.S. Food and Drug Administration. (2021, August 13). FDA approves first HIF-2α inhibitor for von Hippel–Lindau disease–associated tumors.

[7]. Jonasch, E., Donskov, F., Iliopoulos, O., et al. (2021). Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. New England Journal of Medicine, 385(21), 2036–2046.

[8]. Choueiri, T. K., et al. (2025). Belzutifan plus cabozantinib as first-line treatment for advanced ccRCC (LITESPARK-003). Lancet Oncology, 26(1), 64–73.

[9]. Silas, D. (2023, February 17). Belzutifan/lenvatinib combination shows auspicious signals in RCC. Tar.

Cite this article

Tian,G. (2025). Belzutifan: A Breakthrough in Targeted Therapy for ccRCC. Theoretical and Natural Science,135,1-6.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

About volume

Volume title: Proceedings of ICBioMed 2025 Symposium: AI for Healthcare: Advanced Medical Data Analytics and Smart Rehabilitation

ISBN: 978-1-80590-371-0(Print) / 978-1-80590-372-7(Online)

Editor: Alan Wang

Conference website: https://2025.icbiomed.org/auckland.html

Conference date: 17 October 2025

Series: Theoretical and Natural Science

Volume number: Vol.135

ISSN: 2753-8818(Print) / 2753-8826(Online)

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