Abstract
Background
Belzutifan is an orally administered small molecule inhibitor of HIF-2-alpha that has been approved for use in von Hippel-Lindau (VHL)-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuro-endocrine tumors. While use of the drug for treatment of VHL-associated retinal hemangioblastomas (RH) remains off-label, numerous case reports, case series, and a clinical trial sub-analysis have demonstrated excellent results in using the drug to control these tumors.
Summary
We review the literature that has been published on the use of belzutifan for RH in patients with VHL. These studies have described good efficacy for treating RH and preventing the development of new ocular tumors. The efficacy for juxtapapillary and macular tumors that can be difficult to treat has been particularly promising. Dose reductions are commonly required due to side effects which most commonly include anemia and fatigue.
Key Messages
While early reports are encouraging, the optimal dose of the drug for controlling RH along with the duration of therapy, role as a neoadjuvant, and ways to incorporate use of the drug into the treatment and screening paradigms for VHL-associated ocular disease are evolving.
Keywords: Belzutifan, von Hippel-Lindau, Retinal hemangioblastoma
Introduction
Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited condition that results in tumor formation in multiple systems including the adrenal glands, central nervous system (CNS), eyes, and kidneys [1]. The molecular pathophysiology of the disease was described in the 1990s when it was determined that the disease is caused by a mutation in the VHL gene on chromosome 3, leading to loss of the VHL tumor suppressor protein [2]. In the absence of functional VHL, HIF-1-alpha is not degraded, and there is continuous activation of HIF target genes. This then leads to aberrant angiogenesis with uncontrolled expression of HIF target genes like VEGF, PDGF, and EPO which promotes tumor growth (Fig. 1, reproduced from Lozano et al. [3]) [1–5]. Common tumors formed in response to this mutation include clear cell renal cell carcinoma (RCC), pheochromocytoma, and hemangioblastoma of the retina and CNS [1, 3].
Fig. 1.
Activation of the hypoxia inducible pathway with mutated VHL or under hypoxic conditions. VHL cannot bind to HIF-alpha in the presence of pathogenic mutations or lack of hydroxylation in hypoxia. Consequently, HIF-alpha is not degraded and translocates to the nucleus where it induces expression of hypoxia-response genes. The drug belzutifan binds to HIF-2-alpha and decreases the expression of HIF-2-alpha target genes. Reproduced from Lozano et al. [3] 2025.
Patients with this condition face morbidity and increased mortality from their tumors [1]. In the eye, the characteristic tumor is the retinal hemangioblastoma (RH) (Fig. 2) [1]. While benign, these tumors are vision-threatening, particularly when they occur in difficult-to-treat areas such as surrounding the optic nerve or in the macula. Strategies for treatment can include laser photocoagulation, photodynamic therapy, cryotherapy, brachytherapy, radiation, pars plana vitrectomy, and adjunct anti-VEGF or steroid injections [1, 6]. However, these treatments can be locally destructive and sometimes result in vision loss particularly for macular and juxtapapillary tumors [1, 6].
Fig. 2.
RH. Typical appearance of RH with tortuous and dilated feeding arteriole and draining venule.
It is with excitement that the drug belzutifan (Welireg™ Merck and Co, Inc., Rahway, NJ, USA), a small molecule inhibitor of HIF-2-alpha, was developed as a targeted therapy for this disease and was US FDA-approved for use in VHL-associated RCC in 2022 [7, 8]. The mechanism of action of this drug is via binding to HIF-2-alpha, and in conditions of hypoxia, the drug prevents the interaction of HIF-2-alpha and HIF-1. This leads to reduced transcription and expression of HIF-2-alpha target genes and the slowing or halting of VHL-related tumor growth [7–9]. The drug has now been US FDA-approved for use in additional VHL-associated tumors (CNS hemangioblastomas and pancreatic neuro-endocrine tumors) and non-VHL-associated advanced RCC [7, 10, 11].
While off-label, there has been a growing body of literature on the use of this drug for the treatment of VHL-associated RH with good success. However, the drug often has systemic side effects at full dose, including anemia, fatigue, dyspnea, nausea, dizziness, and elevated transaminases [10, 12]. Furthermore, there are many questions that remain unknown including the optimal dosing for patients with isolated ocular tumors, the duration of therapy, the role of the drug as a neoadjuvant agent, the possibility of drug resistance over time, and the need for changes to screening paradigms for patients treated with the drug. In this review, we aim to summarize the current literature on the use of belzutifan for VHL-associated ocular tumors and suggest directions for future work to optimize the use of this drug in the ocular setting.
Review
Table 1 summarizes the published literature on the use of belzutifan for treatment of VHL-associated RH. The LITESPARK-004 clinical trial, where RCC response to belzutifan was the primary outcome measure, led to insight into the response of RH. In the subgroup analysis of 12 patients (16 eyes) with RH, with a median 37.3-month follow-up, all tumors responded, and no new tumors developed while on treatment [8, 10]. Of note, these were smaller tumors with an average tumor area of 0.81 mm2 and an average of two tumors per eye. There was a mean area reduction of 15% by 12 months and 30% by 24 months measured on fundus photography [8]. Importantly, 4 patients had to discontinue therapy because of side effects or progression of RCC. Among those who discontinued belzutifan, two demonstrated worsening of RH at 3 weeks and 3 months after treatment cessation, respectively [8].
Table 1.
Summary of published work using belzutifan to treat VHL-associated RH
| Study | N | Indication | Dose, mg | Age, years | Gender | Dose adjustments for side effects | Ocular tumor response | Visual acuity last follow- up | Follow-up on drug, months |
|---|---|---|---|---|---|---|---|---|---|
| Aykut et al. [13], 2024 | 1 | RH | 120 | 15 | F | No | Resolved fluid in one eye, stabilized lesions in periphery of second eye with some reduction in size (mild) | 20/25 | 12 |
| HM (from 20/300) | |||||||||
| Cotton et al. [14], 2023 | 1 | RH | 120, 80 | 71 | F | Anemia | 30% reduction tumor size at 3 months (120 mg). 50% reduction by 1 year at 80 mg | NLP (baseline). Monocular patient) | 12 |
| Dameron et al. [15], 2024 | 1 | RCC, Pheo, RH | 120 | 63 | F | No | Significant reduction in bilateral peripapillary tumor with improved macula edema and vision | 20/60 OD | 6 |
| 20/20 OS | |||||||||
| Duan et al. [16], 2024 | 5 | CNS, orbital, RH | 40–120 | 10–17 | 3 M | Fatigue | All cases responded. One case was orbital and 4 were RH | Improvement to 20/20 (from 20/50) and 20/25 from 20/30 in 2 patients. Others not reported | 14–32 |
| 2 F | Anemia | ||||||||
| | Nausea | ||||||||
| | Headaches | ||||||||
| | Dizziness | ||||||||
| Ercanbrack et al. [17], 2024 | 3 | CNS, pNET, RH | 120 | 23 | M | Discontinued due to anemia and dyspnea at 4 months | Tumor reduced by 33% at 4 months and remained stable 2 months without any therapy | 20/20 OD, 20/50-2 OS | 21 |
| No new lesions at 21 months | |||||||||
| CNS, RH | 120, 80 | 32 | M | Anemia and fatigue | Tumors decreased in size, 2 months at 120 then 1 month at 80 mg | 20/20-1 OD, 20/20-1 OS | 3 | ||
| CNS, RH | 120, 40 | 44 | M | Dyspnea and anemia | Rapid reduction of dose from 120 mg to 40 mg. About 50% reduction by 7 months | NLP OD (baseline), 20/20 OS | 7 | ||
| Fairbanks et al. [18], 2023 | 1 | RH | NR | 24 | M | N/A | Mild reduction in size and number of tumors, significant tortuosity reduction | NR | 6 |
| Grimes et al. [19], 2024 | 2 | CNS, RH | 120 | 40 | M | No | Decreased size, reduction in tortuosity and exudation | NR | 1 |
| | RCC, RH | 120 | 66 | F | N/A | Decrease in size and fluid | NR | 30 | |
| Jamshidi et al. [20] 2024 | 7 | RCC, CNS, pNET | 40–120 | 15–50s | 5 F | Fatigue | Involution in 3 (9–12 months). All patients except 1 had ablative therapy. 1 of 7 did not experience side effects | NR | 4–24 |
| 2 M | Anemia | ||||||||
| | Nausea | ||||||||
| | Headaches | ||||||||
| | Dizziness | ||||||||
| Jones et al. [21], 2024 | 1 | RH | 120 | 15 | M | No | Regression in tumor size and vascularity | OD NR, 20/30 OS | 12 |
| Meade et al. [22], 2024 | 1 | RH | 120 | 18 | F | No | 25% reduction in height at 2 months, improved edema | 20/20 | 24 |
| Mohammadi et al. [23], 2024 | 1 | CNS, RH | NR | 24 | F | N/A | PVR s/p multiple surgeries before treatment, 2 months later with resolution on drug | NLP OD | 2 |
| Mustafi et al. [24], 2024 | 1 | RH | 120, 80 | 11 | F | Anemia | Decreased size, vascular tortuosity, and exudative detachment | OD NR, 20/400 OS (baseline) | 6 |
| Wiley et al. [8], 2024 | 12* | RCC | 120–40 | 24–63 | 6 M | Anemia | All participants responded. Median time to response was 2.7 months | 20/12-20/125 | Median 37.3 |
| 6 F | Fatigue | ||||||||
| | Dizziness | ||||||||
| | Myalgia | ||||||||
| | Arthralgia | ||||||||
| | Dyspnea | ||||||||
| | Other less common side effects |
N, number of patients; RCC, renal cell carcinoma; pNET, pancreatic neuro-endocrine tumor; RH, retinal hemangioblastoma; Pheo, pheochromocytoma; NR, not reported.
*Study for use in renal cell carcinoma, 12 patients with ocular tumors.
The second largest series reported 7 patients (12 eyes) including eyes with high disease burden and juxtapapillary cases. In 3 cases, belzutifan was initiated due to severity of ocular disease and imminent threat to vision [20]. All 3 patients demonstrated notable reductions in the size of their tumors [20]. One patient with bilateral juxtapapillary disease, whose dose of medication had to be reduced from 120 mg daily to 80 mg daily because of side effects, had a remarkable near complete involution of her juxtapapillary tumors with resolution of associated macular edema at 9 months (Fig. 3, reproduced from Jamshidi et al. [20]). It is important to note that in this study, 6 out of 7 patients developed side effects most commonly anemia and fatigue and dose adjustments were frequent [20].
Fig. 3.
Response to belzutifan in an adult female patient with VHL-associated bilateral RH. Right eye (a) and left eye (b): color fundus photographs and optical coherence tomography (OCT) of bilateral optic disc angiomas with associated cystoid macular edema that had been treated with a combination of PDT laser, focal laser, intravitreal anti-VEGF, intravitreal and sub-tenon’s steroids to both eyes and external beam radiation to the right eye. Right eye (b) and left eye (c): color fundus photographs and OCT images of the patient after starting treatment with systemic belzutifan with regression of the tumors and marked improvement in the cystoid macular edema on OCT. Reproduced from Jamshidi et al. [20] 2024. The final, published version of this article is available at https://www.karger.com/?doi=10.1159/000539434.
Dameron et al. [15] also reported use of belzutifan in a patient with bilateral juxtapapillary tumors. This patient had slow growing tumors involving 50% of the nerve in the right eye and 25% of the nerve in the left eye [15]. Over time, she developed worsening macular edema from exudation of the juxtapapillary tumors [15]. At 120 mg daily, both tumors had significant decrease in size with improvement in macular edema in the 6-month interval of treatment [15]. Vision improved from 20/150 to 20/50 in the right eye and from 20/25 to 20/20 in the left eye [15].
Cotton and colleagues described perhaps the largest treated tumor (2 × 1.2 cm on MRI) which had a 9 mm extrascleral extension [14]. This tumor had a 30% size reduction at 3 months on 120 mg, and 50% reduction by 1 year at 80 mg. The dose adjustment was made because of anemia [14]. Ercanbrack et al. [17] reported a case where 33% reduction in tumor size occurred at 4 months, and there was no growth 2 months after stopping the treatment. The tumor was then treated with laser ablation. No new tumors developed off of belzutifan 21 months after stopping the treatment in this patient [17].
With regard to pediatric dosage, Duan et al. [16] reported the largest case series of pediatric patients with 5 patients between the ages of 10 and 17. Reduced dosing was used in younger patients in keeping with package recommendations for weight-based dosing in pediatric patients (package comments only on use in children 12-years and older) with patients over 40 kg being started on 120 mg oral daily and patients under 40 kg receiving 80 mg orally once daily [9, 16]. A dose of 120 mg daily was used for a 16- and a 17-year-old patient while 40 mg daily and 80 mg daily were used for 10- and 11-year-old patients [16]. Within 1 year of treatment, all patients had a response [16]. Three of the 5 patients were started on belzutifan because of vision loss secondary to worsening RH and all three had improvement in their visual acuity at 1 year [16].
These studies suggest great promise for the use of belzutifan to control ocular disease in patients who would otherwise slowly lose vision over time from RH. However, much remains to be learned regarding the use of this drug in the ocular setting. In particular, it is imperative that criteria for ocular use be more clearly defined. This review highlights many cases of successful treatment in individuals with juxtapupillary angiomas, macular tumors, and those with a high disease burden who normally would have experienced significant visual morbidity as sequelae of treatment [20]. Given the systemic side effects of the drug and lack of long-term safety data, many individuals with peripheral tumors would still likely do well with local treatment. As evidenced by Table 1, the criteria and reporting of tumor response is incredibly heterogenous, and more standardized ways to report tumor size and response would be useful in designing future studies. While Ercanbrack et al. [17] demonstrated neoadjuvant application of belzutifan in the treatment of the case of a small tumor, the role of the drug as a neo-adjuvant therapy to shrink larger tumors followed by definitive local therapy has not been studied [15]. Consensus recommendations for the use of the drug in the ocular setting will need to be developed in the future.
Another important question is the optimal dosing and duration of belzutifan treatment for RH. Given the potential for anemia, the current package guidelines recommend monitoring for anemia prior to starting the drug and periodically while on therapy with a dose hold recommended for hemoglobin levels dropping below 8 g/dL [9]. It is also recommended that oxygen saturation be measured prior to starting therapy and periodically during treatment with consideration of a dose hold for significant decline in oxygen saturation levels with exercise (pulse oximeter readings <88%) or for decreased oxygen saturation at rest [9]. Practically, many oncologists monitor with complete blood count with differential and pulse oximetry prior to drug initiation and monthly while patients remain on treatment [25]. The standard starting dose of belzutifan is 120 mg PO daily. However, in many reported cases in the ophthalmic setting, a dose reduction was required due to side effects, most commonly anemia (Table 1). In the reported cases, a dose of 80 mg was frequently reported to control the ocular tumors with a reduction in side effects (Table 1) [20]. One pediatric patient required a dose reduction to 40 mg five days a week which also initially controlled the ocular disease with fewer side effects, but she later developed new tumors. As experience with the drug expands, optimal dosing will hopefully be refined for specific indications. However, current literature indicates that a lower dose may control most ocular tumors with fewer systemic side effects.
The durability of therapy over time for ocular disease also requires further study. Several reports have shown that ocular tumors recur when the drug is held, suggesting that sustained therapy is necessary for long-term control of ocular tumors [8]. Control of ocular tumors has been reported for up to 30 months, but patients have been shown to develop resistance to other small molecule inhibitors used in an oncologic setting, and the durability of beluzutifan over time is not known [26]. This mirrors the lack of long-term data in the use of the drug for other indications such as the CNS hemangioblastomas, given the only relatively recent approval of the drug for this indication [27, 28].
Given the propensity for VHL-associated RH to develop in younger individuals, it is critical to counsel patients regarding the safety of belzutifan use during pregnancy [29]. It is documented as a pregnancy category D risk for teratogenicity, and it may decrease the efficacy of other drugs metabolized through the CYP3A pathway such as oral contraceptives [12]. Thus, a careful discussion of these risks when starting patients of reproductive age on belzutifan is imperative, and management of tumors during pregnancy requires careful consideration while the patient is off of the drug. Pregnancy testing must be completed prior to starting the drug, and it is recommended that females of reproductive age use nonhormonal contraception while on the drug and for 1 week after the final dose [9]. The drug may also impair fertility in both males and females and this should also be discussed prior to starting treatment [9].
Additional studies of other novel targeted therapies for VHL-associated tumors as well as the use of belzutifan in combination with other drugs are underway. AB521 is a HIF-2 alpha inhibitor being evaluated in a phase I trial for RCC, NKT2152 is a selective HIF-2 alpha inhibitor in phase 1/2 study for RCC, and DFF332 is a small molecule inhibitor targeting the transcriptional activity of HIF-2 alpha transcription in RCC that is in phase 1 study [30]. Drugs that target HIF-2 alpha for degradation are another potential drug mechanism that may play a role in the future [31]. Studies of belzutifan in combination with drugs such as the tyrosine kinase inhibitors cabozantinib and lenvatinib are also being conducted for the treatment of RCC [30]. Combination of belzutifan with VEGF inhibitors and PD-1/PD-L1 antibodies is another area of study [31]. These drugs may one day provide more targeted therapy with fewer systemic side effects for patients with VHL-associated RH and other tumors.
Conclusion
The drug belzutifan is a promising tool for the management of VHL-associated RH. Prospective studies are needed to determine the optimal treatment paradigm for this tumor type. We are optimistic that the results of this work will lead to improved visual outcomes for patients with VHL-associated RH. Additional therapies targeting the HIF-2-alpha pathway may also provide ways to treat VHL-associated RH in the future with fewer systemic side effects.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was supported by the University of Iowa Medical Scientists Training Program (T32 GM139776).
Author Contributions
Each author meets the ICMJE requirements for authorship. Data acquisition/research execution: F.J., S.T., L.L., H.C.B., and E.B.; data analysis/interpretation: F.J., S.T., and E.B.; and manuscript preparation: F.J., S.T., L.L. H.C.B., and E.B.
Funding Statement
This study was supported by the University of Iowa Medical Scientists Training Program (T32 GM139776).
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