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Clinical Trial
. 2025 May;26(5):571-582.
doi: 10.1016/S1470-2045(25)00099-3. Epub 2025 Apr 12.

Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study

Ramaprasad Srinivasan  1 , Othon Iliopoulos  2 , Kathryn E Beckermann  3 , Vivek Narayan  4 , Benjamin L Maughan  5 , Stephane Oudard  6 , Tobias Else  7 , Jodi K Maranchie  8 , Ane B Iversen  9 , Jerry Cornell  10 , Rodolfo F Perini  10 , Yanfang Liu  10 , W Marston Linehan  1 , Eric Jonasch  11
Affiliations
Clinical Trial

Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study

Ramaprasad Srinivasan et al. Lancet Oncol. 2025 May.

Erratum in

Abstract

Background: Hypoxia-inducible factor-2α inhibitor belzutifan is approved for von Hippel-Lindau disease-associated renal cell carcinoma, CNS haemangioblastomas, and pancreatic neuroendocrine tumours, based on previously published initial results from the LITESPARK-004 study. Updated results are presented here after a median follow-up of nearly 50 months.

Methods: In this single-arm, phase 2 study, participants were enrolled at 11 centres in Denmark, France, the UK, and the USA. Oral belzutifan 120 mg once daily was given to eligible adults aged 18 years or older with a diagnosis of von Hippel-Lindau disease (based on germline VHL alterations), at least one measurable renal cell carcinoma tumour, no tumour larger than 3 cm that necessitated immediate surgery, no metastatic disease, no previous systemic anticancer treatment, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. The primary endpoint was the proportion of participants with an objective response in von Hippel-Lindau disease-associated renal cell carcinoma per Response Evaluation Criteria in Solid Tumours, version 1.1, determined by an independent review committee, and assessed in all participants who received at least one dose of belzutifan. This ongoing study is no longer recruiting and is registered at ClinicalTrials.gov, NCT03401788.

Findings: Between May 31, 2018, and Mar 29, 2019, 61 participants were enrolled; 36 (59%) were continuing treatment as of April 3, 2023. The median age of all enrolled participants was 41·0 years (IQR 29·0-51·0); 32 (52%) of 61 participants were male and 29 (48%) were female; most were White (n=55; 90%). Median study follow-up was 49·9 months (IQR 48·9-52·2). 41 (67%; 95% CI 54-79) of 61 participants with renal cell carcinoma had an objective response; seven (11%) had a complete response and 34 (56%) a partial response. 13 grade 3 treatment-related adverse events occurred in 11 (18%) participants (anaemia: seven [11%]; fatigue: three [5%]; urinary tract infection: one [2%]; hypoxia: one [2%]; and blister: one [2%]). None of the participants had a grade 4 or 5 treatment-related adverse event. Four (7%) participants had serious treatment-related adverse events (one participant each: anaemia, urinary tract infection, intracranial haemorrhage, and hypoxia).

Interpretation: Updated results support the use of belzutifan as systemic treatment for von Hippel-Lindau disease-associated renal cell carcinoma.

Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA; the Intramural Research Program of the National Institutes of Health, National Cancer Institute Center for Cancer Research; and a grant from the National Cancer Institute.

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Conflict of interest statement

Declaration of interests RS reports that this study was conducted under a Cooperative Research and Development Agreement between the National Cancer Institute and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA; received support for manuscript writing from Merck & Co; support (to the institution) to partially defray the costs of a clinical study from Nikang; and other financial or non-financial interests with support to his institution from Pfizer, Genentech, and Novartis (provision of investigational agent for study conduct). OI received consulting fees (personal) from Merck & Co and honoraria (personal) for lectures in biology and treatment of von Hippel-Lindau disease: updates from King Feisal Hospital, Saudi Arabia, and University of Buenos Aries, Buenos Aires, Argentina. KEB received funding (institution) from Aravive, ArsenalBio, Merck & Co, and Pionyr, and received consulting fees from Alpine Biosciences, Aravive, AstraZeneca, Aveo, Bristol Myers Squibb, Eisai, Exelexis, Merck & Co, Nimbus, Sanofi, Seagen, and Xencor. VN received support (institution) for current manuscript from Merck & Co; received consulting fees from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Janssen, Pfizer, Regeneron, Sanofi, Terns Pharmaceuticals, and Xencor; received honoraria from Pfizer; received research support (institution) from Bristol Myers Squibb, Janssen, Pfizer, Regeneron, and Xencor; and participates on a committee for Myovant Sciences. BLM received financial compensation as a paid consultant/advisor to AbbVie, Astellas, AVEO Oncology, Bristol Myers Squibb, Bayer Oncology, Clovis, DAVA Oncology, Eisai, Exelixis, Janssen, Lilly, Merck, Peloton Therapeutics, Pfizer, Sanofi, Tempus, Telix, and Xencor; received research funding (to the Huntsman Cancer Institute) from Bavarian-Nordic, Bristol Myers Squibb, Clovis, Exelixis, Genentech, and Merck & Co for correlative studies and investigator-sponsored clinical trials; and was a member of a drug safety monitoring board for AVEO Oncology. SO received honoraria (personal) from Bayer, Bristol Myers Squibb, Eisai, Ipsen, Merck & Co, and Pfizer; received research funding (institution) from AstraZeneca, Bayer, Ipsen, and Sanofi; received travel, accommodations, and expenses from Bayer, Ipsen, Janssen, and Pfizer; and participates on a data safety monitoring board or advisory board for Incyte and Roche. TE received support (institution) and consulting fees from Merck & Co. JKM received support (institution) for the current manuscript from Merck & Co; received research support (institution) from Janssen; received travel support from International Kidney Cancer Symposium and Kidney Cancer Research Summit, and Society of Urologic Oncology; and holds a leadership role on a board or committee for The Northeastern Section of the American Urological Association (president). ABI received research funding and medical writing support from Merck Sharp & Dohme, a subsidiary of Merck & Co. JC is an employee of, and received travel support from, Merck Sharp & Dohme, a subsidiary of Merck & Co. RFP is an employee of, and owns stock in, Merck Sharp & Dohme, a subsidiary of Merck & Co. YL is an employee of, owns stock in, and received travel support from Merck Sharp & Dohme, a subsidiary of Merck & Co. EJ received support for the current manuscript from Merck; received grants (institution) from Arrowhead, Merck & Co, NiKang, and Novartis; received consulting fees (personal) from Aveo, Eisai, Exelixis, Ipsen, Merck & Co, and NiKang; received honoraria (personal) from DAVA; participates on a data safety monitoring board or advisory board for Novartis; and holds a leadership role on a board or committee at the National Comprehensive Cancer Network. WML declares no competing interests.

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