BACKGROUND: Belzutifan is a first-in-class HIF-2α inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed death receptor (or ligand)-1 (PD-[L]1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether belzutifan dose could be optimized is unclear.
METHODS: The phase 2 LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after 1-3 prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1:1 to receive belzutifan 120 mg or 200 mg once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). Median follow-up was 20.1 months (range 14.8-28.4). ORR was 23.7% vs 23.1% for the 120 mg and 200 mg groups, respectively (P = 0.5312; -0.5% [95% CI, -14.0 to 12.9]. Median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS (HR 0.94 [95% CI 0.63-1.40]) or OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group.
CONCLUSIONS: The efficacy of belzutifan was similar between the 120-mg dose and the 200-mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.

UNASSIGNED: The systemic HIF-2 alpha inhibitor, belzutifan, has been approved for use in patients with von Hippel-Lindau disease (VHL)-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors. This drug has also shown promise in controlling VHL retinal hemangioblastomas (RHs), but little work has been published on the use of the drug in this setting.
UNASSIGNED: We conducted a retrospective review of patients with VHL-associated RHs followed by the retina service at our institution who were treated with systemic belzutifan. Patient age, gender, genotype, presence of systemic tumors, indication for the drug, initial dose, adjusted dose, side effects, and tumor response were recorded. We also conducted a literature search for all manuscripts describing the effect of belzutifan on VHL-associated ocular tumors.
UNASSIGNED: We identified 12 eyes of 7 patients with VHL-associated ocular tumors who were treated with belzutifan at our institution. Of these, 5 eyes of 3 patients had progressing ocular tumors when belzutifan was started. Of the 7 total patients, 2 were treated for renal cell carcinoma, 2 for CNS hemangioblastomas, 2 for RHs, and one for pancreatic neuroendocrine tumors. Initial dose was 120 mg PO daily in 6 patients and 80 mg PO daily in 1 patient. The dose was reduced in all but 1 patient due to side effects. The ocular tumors were controlled in all patients with an average follow-up of 13 months (range 4-24 months). Literature review identified 7 manuscripts that described belzutifan-mediated control of ocular tumors in patients with VHL-associated RHs in 21 patients.
UNASSIGNED: The drug belzutifan shows great promise for controlling RHs and preventing vision loss in patients with VHL. Further work needs to address the optimal dose, role of the drug as a neoadjuvant therapy, and long-term efficacy and tolerability of the drug in a larger cohort of patients with ocular tumors.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder that predisposes patients to develop multiple cysts and tumors, such as hemangioblastomas (HBs) and clear cell renal cell carcinoma (ccRCC), due to mutations in the VHL tumor suppressor gene. While treatment of HBs varies based on their characteristics and has improved patient survival, it still involves high morbidity and mortality, leading to ongoing debates and studies to refine therapy strategies. Recent developments include the emergence of Belzutifan, a novel inhibitor targeting hypoxia-inducible factor 2α (HIF-2α), which has shown promising results in ongoing trials, particularly for patients not immediately requiring surgery.
METHODS: This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of Belzutifan for treating HBs associated with VHL disease. Search was conducted across Medline, Embase, Cochrane, and Web of Science databases. Statistical Analysis was performed, with proportions and 95 % confidence intervals. Statistical analyses were carried out using R Studio.
RESULTS: Ten studies were selected, comprising 553 patients. The population mean age was 40 (24-65), and 50 % of the population was formed by males. In terms of proportion, 6 analyses were performed: Disease Stability of 31 % [95 %CI:14 %-47 %; I2 = 2 %]; Disease Progression of 2 %[95 %CI:0 %-9 %; I2 = 0 %]; Partial Response of 75 % [95 %CI:54 %-96 %; I2 = 58 %]. Complete response of 1 % [95 %CI:0 %-7 %; I2 = 0 %];and Side effects, anemia 81 % rate [95 % CI:54 %-100 %; I2 = 94 %], and fatigue rate of 79 % [95 % CI:54 %-100 %;I2 = 94 %].
CONCLUSIONS: Results indicate that Belzutifan effectively stabilizes disease, reduces tumor progression, and achieves significant therapeutic responses, although side effects like anemia and fatigue were noted.

OBJECTIVE: To highlight the neurosurgical implications of the hypoxia-inducible factor-2α- targeting agent belzutifan in the management of both von-Hippel Lindau (VHL)-associated and sporadic hemangioblastomas (HBLs).
METHODS: The literature was queried for VHL, HBLs, and belzutifan. A summary of recent uses of belzutifan and currently ongoing clinical trials that are investigating the use of belzutifan in the treatment of HBLs is presented.
RESULTS: VHL disease occurs as a result of germline mutations in the VHL tumor suppressor gene on chromosome 3p25-p26, leading to growth of benign and malignant tumors such as HBLs. The possibility of intermittent growth in HBLs indicates that it is important to avoid hasty surgical interventions. Belzutifan is the first nonsurgical food and drug administration-approved treatment for VHL disease-related tumors that may delay or circumvent the need for surgery or radiation therapy by inhibiting HIF-2α, an important component of cellular hypoxic response. There is limited real-world experience of belzutifan in patients with HBLs as a primary indication, though there are 2 phase II clinical trials investigating the use of belzutifan in the treatment of HBLs.
CONCLUSIONS: There is limited experience regarding the use of belzutifan for CNS hemangioblastoma. While its application has been limited to a small group of clinical cases, it has exhibited significant efficacy in reducing the size and consequences of HBLs. Based on the promising outcomes observed in individual patient experiences and ongoing clinical trials, we infer that further exploration and integration of belzutifan into neurosurgical treatment plans for both sporadic and VHL-associated HBLs are warranted.

Renal cell carcinoma (RCC) is a heterogenous disease which the incidence is increasing worldwide. The identification and understanding of the role of the Von Hipple Lindau (VHP) in regulating the hypoxia-inducible factor signaling pathway has revolutionized the treatment of this disease. Belzutifan is an oral hypoxia-inducible factor (HIF)-2α inhibitor, which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease and for the treatment of adults with RCC who experienced disease progression after PD-1/PD-L1- and VEGFR-targeted therapies. One of the most common adverse effect of this drug is anemia; however, it is treatment is not well known. This review summarizes role of the VHL-HIF pathway in ccRCC aroused the interest of targeting HIF activity, the history of belzutifan development and their relationship to anemia as well as propose a management algorithm.

Recently, the treatment landscape for metastatic pheochromocytomas and paragangliomas (MPPGL) has seen both progress and setbacks. We provide an up-to-date review of the multimodality management of MPPGL and discuss novel opportunities and current challenges in the treatment landscape. Given the unique clinical presentation of MPPGL, we discuss the management of hormone-related clinical sequelae and traditional modalities of therapy. Advances in the understanding of the molecular biology of these diverse tumors have enabled novel strategies such as augmenting DNA damage by targeted delivery of radionuclides such as 131I and 177Lu, abrogating tumor angiogenesis, hypoxia resistance, and DNA damage repair. Despite progress, we address the significant challenges still faced by patients and researchers engaged in efforts to improve outcomes in these rare cancers.

OBJECTIVE: To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study.
METHODS: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study.
METHODS: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible.
METHODS: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity.
METHODS: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator\'s preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography.
RESULTS: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 μm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24.
CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The identification of the VHL gene and its role in regulating the hypoxia-inducible factor signaling pathway has helped to revolutionize the treatment of renal cell carcinoma (RCC). Belzutifan is a novel small-molecule inhibitor of hypoxia-inducible factor 2α which has demonstrated efficacy in treating von Hippel-Lindau (VHL) disease, earning regulatory approvals for this indication. There is also early evidence for efficacy in sporadic RCC. Belzutifan has a favorable safety profile. Several clinical trials are currently ongoing, which should help in identifying this promising drug\'s role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.
The novel drug belzutifan was developed after years of research in identifying the VHL gene and how genetic abnormalities in VHL may result in tumor growth. Belzutifan has been approved for use in patients with VHL disease – a rare familial disorder first described in the 19th century that presents with a variety of cancerous and noncancerous tumors, including kidney cancer. Growing evidence supports belzutifan’s use in non-familial kidney cancer as well. This is important because most patients eventually develop resistance to the currently available cancer treatments, highlighting the need for drugs with a different mechanism of action. Belzutifan works by blocking a protein called HIF-2a, which causes tumor growth in patients with VHL disease. Belzutifan is well tolerated, with the most common side effects being low energy, hemoglobin and blood oxygen. This review summarizes the history, mechanism of action and research evidence to date supporting the use of belzutifan in VHL disease and cancer treatment. We also discuss future directions, including remaining clinical questions and areas of ongoing research.

Von Hippiel-Lindau (VHL) disease is a rare genetic disorder characterized by a variety of benign and malignant neoplastic growths arising in multiple different organ systems. About 60%-84% of patients develop hemangioblastomas, benign tumors comprised of newly formed blood vessels that often occur in the central nervous system (CNS) and retinas. Treatment options for this disease were limited before the Food and Drug Administration (FDA) approval of belzutifan, a HIF2α inhibitor. We present a case of a 25-year-old woman with VHL who underwent treatment with belzutifan over 18 months. It was noted that her CNS lesions decreased significantly in size over the course of her treatment, and she had minimal adverse effects. Her excellent and sustained therapeutic response to the treatment highlights the real-world clinical benefit of belzutifan and the possibility that this could play a crucial role in treating VHL by postponing or completely avoiding repeated surgical and radiotherapeutic intervention and their associated comorbidities.

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.