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No approved systemic therapy exists for von Hippel-Lindau disease, an autosomal dominant disorder with pleiotropic organ manifestations that include clear cell renal cell carcinomas; retinal, cerebellar, and spinal haemangioblastomas; pheochromocytomas; pancreatic serous cystadenomas; and pancreatic neuroendocrine tumours. We aimed to assess the activity and safety of pazopanib in patients with von Hippel-Lindau disease. In this non-randomised, single-centre, open-label, phase 2 trial, adult patients with clinical manifestations of von Hippel-Lindau disease were recruited from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and were treated with pazopanib (800 mg orally daily) for 24 weeks, with an option to continue treatment if desired by the patient and treating physician. Primary endpoints were the proportion of patients who achieved an objective response and safety in the per-protocol population. The objective response was measured for each patient and each lesion type. Radiographic assessments were done at baseline and every 12 weeks throughout the study. Activity and safety were assessed with continuous monitoring and a Bayesian design. This study is registered with ClinicalTrials.gov, number NCT01436227, and is closed to accrual. Between Jan 18, 2012, and Aug 10, 2016, we screened 37 patients with genetically confirmed or clinical features consistent with von Hippel-Lindau disease, of whom 31 eligible patients were treated with pazopanib. The proportion of patients who achieved an objective response was 42% (13 of 31 patients). By lesion sites responses were observed in 31 (52%) of 59 renal cell carcinomas, nine (53%) of 17 pancreatic lesions, and two (4%) of 49 CNS haemangioblastomas. Seven (23%) of 31 patients chose to stay on the treatment after 24 weeks. Four (13%) of 31 patients withdrew from the study because of grade 3 or 4 transaminitis, and three (10%) discontinued study treatment because of treatment intolerance with multiple intercurrent grade 1–2 toxicities. Treatment-related serious adverse events included one case each of appendicitis and gastritis and one patient had a fatal CNS bleed. Pazopanib was associated with encouraging preliminary activity in von Hippel-Lindau disease, with a side-effect profile consistent with that seen in previous trials. Pazopanib could be considered as a treatment choice for patients with von Hippel-Lindau disease and growing lesions, or to reduce the size of unresectable lesions in these patients. The safety and activity of pazopanib in this setting warrants further investigation. Novartis Inc and NIH National Cancer Institute core grant.

The autosomal dominantly inherited disorder von Hippel–Lindau disease (VHL) is caused by germline mutations in the VHL tumour suppressor gene (TSG). VHL mutations predispose to the development of a variety of tumours (most commonly retinal and central nervous system haemangioblastomas, clear cell renal carcinoma and phaeochromocytomas). Here, we review the clinical and genetic features of VHL disease, briefly review the molecular pathogenesis and outline clinical management and tumour surveillance strategies.

Abstract In February 2025, the European Commission granted approval for belzutifan (Welireg) as a treatment for certain von Hippel–Lindau (VHL) disease-associated tumors. This is the first medicinal product in Europe for pharmacological management of VHL, a rare, hereditary condition characterized by the development of multiple tumors across various organs. Belzutifan is an oral inhibitor of hypoxia-inducible factor-2α (HIF-2α), a protein involved in the pathogenesis of VHL-associated tumors. This approval, which is based on the results of the pivotal phase 2 clinical trial MK-6482-004 (LITESPARK-004) offers a therapeutic approach to managing certain VHL disease-associated tumors. This article describes the clinical data supporting belzutifan approval in the EU, focusing on the VHL disease indication and its mechanism of action.

Increasing accessibility to genetic screening for cancer risk can lead to earlier surveillance and prevention, but with this comes the caveat of incidental identification of germline pathogenic gene variants. Here, we report a single institution case series of 6 otherwise healthy individuals with “incidental” Von Hippel Lindau (VHL) disease. These patients were found to have pathogenic germline variants in the VHL gene, after undergoing genetic testing for other purposes (5 for familial breast cancer risk and 1 to determine ancestry) but no VHL disease-associated tumors. The penetrance and expressivity of such incidental variants are not currently known, and therefore, no surveillance guidelines exist. Nevertheless, the association of these variants historically with high disease penetrance compels us to currently recommend active surveillance of their carriers with annual imaging of the brain, spine, and abdomen.

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

The cause of von Hippel–Lindau disease is excess activity of the HIF-2α pathway. A total of 61 patients with renal cell carcinoma and other proliferative manifestations of the hypoxia-induced signaling pathway received belzutifan, which inhibits the HIF-2α pathway. Nearly half the patients with renal cell carcinoma had a response to treatment, and 98% had disease control.

The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7–40·1). In approach 1, 22 of 50 patients (44% [95% CI 30–59]) had an objective response. In approach 2, 19 of 25 patients (76% [55–91] had an objective response. 23 (46%) of 50 patients had a grade 3–5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.

The identification in 1993 of inherited mutations in the von Hippel–Lindau ( VHL ) gene in families with VHL disease was a seminal finding. This and subsequent discoveries have given the VHL tumour suppressor gene a central role in our understanding of the mechanisms of cellular oxygen sensing and in the pathobiology of clear-cell renal cell carcinoma. Since the Von Hippel–Lindau (VHL) disease tumour suppressor gene VHL was identified in 1993 as the genetic basis for a rare disorder, it has proved to be of wide medical and scientific interest. VHL tumour suppressor protein (pVHL) plays a key part in cellular oxygen sensing by targeting hypoxia-inducible factors for ubiquitylation and proteasomal degradation. Early inactivation of VHL is commonly seen in clear-cell renal cell carcinoma (ccRCC), and insights gained from the functional analysis of pVHL have provided the foundation for the routine treatment of advanced-stage ccRCC with novel targeted therapies. However, recent sequencing studies have identified additional driver genes that are involved in the pathogenesis of ccRCC. As our understanding of the importance of VHL matures, it is timely to review progress from its initial description to current knowledge of VHL biology, as well as future prospects for novel medical treatments for VHL disease and ccRCC.

Abstract Background Von Hippel-Lindau syndrome (VHL) is a rare hereditary neoplastic disorder caused by mutations in the VHL gene. Treatment options for patients are limited to multiple surgeries dispersed between regular scans, watchful waiting, and treatments that preserve organ function. Methods An international, cross-sectional survey comprising patients in the United States (USA), Canada (CA), the United Kingdom (UK), France (FR), and Germany (DE) was conducted. Patients were recruited via the VHL Alliance; data were collected between Dec 2021 and May 2022. For inclusion, patients must have renal cell carcinoma, pancreatic neuroendocrine tumors, and/or central nervous system hemangioblastoma. Results In all, 220 patients (68.2% female, median age 40.0, median disease duration 15.8 years) in the USA (n = 108), CA (n = 37), the UK (n = 21), FR (n = 3), and DE (n = 51) completed the study. In this sample, n = 205 (93.2%) patients had experienced surgery; n = 171 (77.7%) had experienced multiple surgeries (median number of surgeries, 4.0); 166 (n = 75.5%) patients recorded data on their most recent surgery. Of these, patients reported that their most recent surgery worsened (scored 1-3) their fatigue (51.8%, n = 86), mental health (51.2%, n = 85), and ability to go about daily life (45.2%, n = 75). Approximately, 47.3% (n = 104) of patients selected reducing the number of surgeries as a top treatment goal, whereas 73% (n = 161) of patients indicated they would prefer to take a pill which would possibly delay the time until surgery. Conclusion Surgery negatively impacts the lives of patients, leading to a worsening in their fatigue, mental health, and ability to go about daily life.

Abstract von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in VHL deficiency and the potential formation of cerebellar hemangioblastomas, which resemble embryonic hemangioblast proliferation and differentiation processes. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structural elements (DASEs), consistently involve the cerebellar molecular layer in VHL patients, indicating the tumor site of origin. Unlike hemangioblastomas, however, cerebellar DASEs do not express brachyury, a mesodermal marker for hemangioblasts. In this study, neuronal progenitors occupying the molecular layer were investigated as tumor cells of origin. By immunohistochemistry, cerebellar DASEs and hemangioblastomas lacked immunoreactivity with antibody ZIC1 (Zic family member 1), a granule cell progenitor marker with concordance from oligonucleotide RNA expression array analyses. Rather, cerebellar DASEs and hemangioblastomas were immunoreactive with antibody PAX2 (paired box 2), a marker of basket/stellate cell progenitors. VHL cerebellar cortices also revealed PAX2-positive cells in Purkinje and molecular layers, resembling the histological and molecular development of basket/stellate cells in postnatal non-VHL mouse and human cerebella. These data suggest that VHL deficiency can result in the developmental arrest of basket/stellate cells in the human cerebellum and that these PAX2-positive, initiated cells await another insult or signal to form DASEs and eventually, tumors.