Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2026 Aug 8.
Published in final edited form as: Ophthalmology. 2024 Jun 6;131(11):1324–1332. doi: 10.1016/j.ophtha.2024.05.024

Oral Hypoxia-Inducible Factor 2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease

Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study

Henry E Wiley 1, Ramaprasad Srinivasan 2, Jodi K Maranchie 3, Jay Chhablani 4, Ane Bundsbæk Bøndergaard Iversen 5, Anders Kruse 6, Eric Jonasch 7, Dan S Gombos 8, Tobias Else 9, Hakan Demirci 10, Benjamin L Maughan 11, M Elizabeth Hartnett 12,13, Hanna R Coleman 14,15, Wei Fu 16, Rodolfo F Perini 16, Yanfang Liu 16, W Marston Linehan 17, Emily Y Chew 1, for the LITESPARK-004 Investigator Group - Ocular VHL
PMCID: PMC13448648  NIHMSID: NIHMS2192944  PMID: 38849055

Abstract

Purpose:

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.

Design:

Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study.

Participants:

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.

Main Outcome Measures:

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.

Financial Disclosure(s):

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Belzutifan, HIF-2α, Retinal hemangioblastoma, von Hippel-Lindau

von Hippel-Lindau (VHL) disease is characterized by a propensity for the development of tumors in multiple organs and is caused by germline pathogenic variants in the VHL tumor suppressor gene. Manifestations of VHL disease in the eye include retinal hemangioblastoma (RH) and retinal vascular proliferation.1 Retinal hemangioblastomas represent one of the most common features of the disease, present in 1 or more eyes in 335 of 890 patients (38%) in a large cross-sectional cohort.2 These tumors can threaten vision by causing exudation, hemorrhage, scarring, and retinal detachment. Currently, they are treated primarily with ablative therapy if the location and size of the tumor are favorable, or in rare cases, with surgical removal. Juxtapapillary (associated with the optic nerve) RHs and RHs that involve a large proportion of the retina are not amenable to the available ablative therapies, although the latter sometimes can be removed with vitrectomy.3

von Hippel-Lindau protein (pVHL) plays a key role in regulating the cellular response to oxygen levels via its interaction with transcription factors known as hypoxia-inducible factors (HIFs).4 In normoxic conditions, HIF-α subunits (including HIF-2α) are targeted for proteasomal degradation by hydroxylation and binding with a ubiquitin ligase complex via pVHL. In the absence of functional pVHL, HIF-2α evades degradation, heterodimerizes with HIF-1β, and translocates into the nucleus to modulate the expression of hundreds of genes normally involved in the cellular response to hypoxia.4 Hypoxia-inducible factor 2α is present in the kidney, lung, liver, and endothelial cells, where it is known to exert effects on cell proliferation and angiogenesis.5–7 Hypoxia-inducible factor 2α over-expression is associated with the growth of clear cell renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors (pNETs), and paragangliomas or pheochromocytomas.8–17 Expression levels of HIF-2α in RHs are not known, but elevated HIF levels more generally have been documented.18 The location and the cell type responsible for the pathogenesis of RH have been investigated previously. Studies of surgical specimens from VHL disease-associated hemangioblastomas in the brain and spine indicated that the cell of origin is likely a mesoderm-derived, embryologically arrested hemangioblast.19–21 Other researchers found expression of stem cell markers in RH lesions associated with VHL disease in autopsied eyes,22 and subsequently developed a murine model of VHL disease-associated RH by inactivating VHL in a hemangioblast population in a transgenic mouse line.23 Thus, the hemangioblast is a likely candidate for cell of origin for hemangioblastomas in the CNS.

Belzutifan (MK-6482; previously called PT-2977) is a first-in-class small-molecule inhibitor of HIF-2α approved in the United States, Great Britain, Canada, Australia, and several other countries for certain patients with VHL disease-associated RCC, CNS hemangioblastomas, or pNETs. The approval was based on the single-arm LITESPARK-004 study (ClinicalTrials.gov identifier, NCT03401788), which evaluated oral belzutifan therapy in these patients.24 At a median follow-up of 37.8 months, 39 of 61 participants showed an objective response to belzutifan in RCC by Response Evaluation Criteria in Solid Tumors version 1.1 guidelines (objective response rate, 64%; 95% confidence interval [CI], 50.6%–75.8%).25 More recently, belzutifan was approved in the United States for patients with advanced RCC after a programmed death receptor-1 or ligand-1 inhibitor and a VEGF tyrosine kinase inhibitor, based on the phase 3 LITESPARK-005 study (ClinicalTrials.gov identifier, NCT04195750).26

Secondary outcomes of the LITESPARK-004 study included assessment of response for pNETs, CNS hemangioblastomas, and RHs. A qualitative analysis of 12 participants with 16 eyes with evaluable active RHs on color fundus images at baseline previously reported improvement in ocular VHL disease in 100% of participants and eyes by an independent reading center (IRC).24 Herein, we expand on the ocular findings of this study with longer follow-up and a detailed qualitative analysis of VHL disease-associated RHs.

Methods

Study Design and Participants

LITESPARK-004 is a phase 2, single-arm, open-label trial that enrolled participants at 11 sites in the United States, the United Kingdom, France, and Denmark between May 31, 2018, and March 29, 2019, for which methods and primary results have been reported elsewhere.24 Briefly, written informed consent was obtained from all participants, the study complied with the Health Insurance Portability and Accountability Act, and was conducted according to Good Clinical Practice guidelines and the tenets of the Declaration of Helsinki. The National Institutes of Health (NIH) Institutional Review Board provided approval for this clinical trial to be conducted. The trial is registered at www.ClinicalTrials.gov (identifier, NCT03401788). Key eligibility criteria included age 18 years or older, diagnosis of VHL disease confirmed by genetic testing, presence of 1 or more measurable RCC tumor, and no RCC tumors of more than 3.0 cm or other VHL tumors of any size requiring immediate surgical intervention (trial protocol in Supplemental Material, available at www.aaojournal.org). No eligibility criteria were related to the status or features of the eyes.

Treatment

Participants received oral belzutifan 120 mg once daily until disease progression, unacceptable treatment-related toxicity, participant or physician decision to discontinue therapy, protocol noncompliance, pregnancy, or death. Dose reduction to 80 mg daily, and then to 40 mg daily, was permitted to manage adverse events. Dose re-escalation was permitted on consultation with the study sponsor.

Assessments

Ophthalmic evaluation was performed at baseline, every 12 weeks for a minimum of 3 years, and every 24 weeks thereafter for participants judged by the investigators to manifest 1 or more active and evaluable VHL disease-associated RHs. Eye assessments included dilated fundus examination, color fundus photography, and best-corrected visual acuity. Color fundus images obtained using several camera systems across study sites documenting ocular disease at baseline and follow-up visits were submitted to the IRC (VOIANT, Boston, MA). Some sites collected measurements of intraocular pressure at the investigator’s discretion. The IRC determined whether participants had active RH evaluable for response based on image quality and visibility of the tumor. Individual eyes and participants were assessed by certified IRC readers with a qualitative grade of improved, stable, or progressed relative to baseline and to prior images for each eye at each visit. Criteria for determining IRC grade at each visit are provided in Table S1A (available at www.aaojournal.org). The overall best response at the eye and participant level was determined using the grades assigned by the IRC based on guidelines shown in Table S1B (available at www.aaojournal.org). Earlier results of eye-level and participant-level response rate (RR) were reported alongside the primary results of the trial.24 Best-corrected visual acuity score at each time point was determined from the number of letters correctly identified in a Snellen or equivalent chart, performed by the ophthalmologist at each trial site.

At the NIH site (Bethesda, MD), standardized multimodal imaging was performed for all participants with active ocular VHL disease in evaluable eyes at baseline and at months 6, 12, and 24, with discretionary images obtained to document notable findings observed at follow-up visits every 12 weeks. Imaging included spectral-domain OCT of the macula (Cirrus HD-OCT; Carl Zeiss Meditec) and color fundus photography (standard fundus camera [Topcon TRC 50-DX; Topcon Medical Systems] and an ultra-widefield scanning laser ophthalmoscope [Optos P200DTx; Optos, Inc]) performed at baseline, at months 6, 12, and 24, and at select follow-up visits and ultra-widefield fluorescein angiography performed at baseline and month 24.

Adverse events were collected for all participants who received 1 or more doses of study treatment and reported from the first administration of belzutifan up to 30 days after the last dose. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Outcomes

The primary end point was the objective response rate (partial and complete response) for VHL disease-associated RCC as defined by Response Evaluation Criteria in Solid Tumors version 1.1 guidelines, as reported previously.24,25 The effect of belzutifan treatment on ocular VHL disease was a secondary end point and included eye-level and participant-level RR (defined as the proportion of participants or eyes assessed as improved per IRC), duration of response (defined as the time from first assessment of improved status per IRC until a response assessment of progressed or death resulting from any cause), and time to response (defined as the time from start of study treatment to the first assessment of improved status). Safety also was a secondary end point. Individual RH size change and qualitative changes in exudation from images over time for participants enrolled at the NIH site was a post hoc exploratory analysis.

Statistical Analysis

Data for the subgroup of participants with RH in LITESPARK-004 were summarized descriptively. The Clopper Pearson method was used to calculate exact binomial 95% CIs for RR to belzutifan at both the eye and participant levels. Median duration of response was estimated using the Kaplan-Meier method. All descriptive statistical analyses related to prespecified trial end points were performed using SAS version 9.4 software (SAS Institute).

Image analysis of individual RH size for participants with available data at the NIH site was conducted as follows: viable, evaluable RHs or RH complexes (defined as a lesion containing one or more viable RHs in combination with fibrosis obscuring discrete RH borders) measuring 500 μm or more in greatest linear diameter (GLD) at baseline were analyzed further. These lesions were selected because they could be measured reproducibly and, depending on location, were more likely to have clinical significance. The clearest 50° color fundus photograph was selected for each RH at each time point (baseline, month 3 [when available], month 6, month 12, and month 24). Three retina specialists independently performed grading of all RHs. Each RH at each time point was ranked qualitatively by vascularity (color, visibility of internal vasculature) and, separately, by appearance of feeding or draining vessel caliber or tortuosity on fundus photographs. Exudation was assessed using OCT images for RHs at the posterior pole and color fundus photographs (evaluating lipid exudates) for peripheral RHs. Grading for size (area) on color fundus photographs was performed using ImageJ version 1.53 software (NIH). Graders manually traced the border of each RH or complex on the color image, allowing for reference to its red-free filtered image, and the area was calculated. When present, the total area encompassing lipid exudation also was traced. Area measurements from all 3 graders were averaged. Images presented in the results underwent contrast, brightness, and color balancing to optimize comparison of images within each series. All post hoc exploratory analyses at the NIH site were performed using R statistical software version 4.1.2 (R Foundation for Statistical Computing) and figures were produced using the package ggplot2.

Results

Among 61 total participants enrolled in the LITESPARK-004 study, 16 participants (26.2%) showed active RHs by investigator assessment that were imaged and sent to the IRC for evaluation (Fig S1, available at www.aaojournal.org). A total of 12 participants (19.7%) had 16 eyes with active RH at baseline evaluable for response by IRC assessment and were included in the present analysis. The median number of RHs was 2.5 (range, 1–5 RHs) per participant and 2 RHs (range, 1–4 RHs) per eye. Baseline characteristics were consistent with those of the total enrolled population (Table S2, available at www.aaojournal.org).24 All 12 participants (100.0%) had undergone prior surgery for at least one VHL disease-associated tumor, including 3 participants (25.0%) who underwent prior eye laser surgery and 1 participant (8.3%) who underwent prior eye enucleation. The median time from initiation of study treatment to the data cutoff date of April 1, 2022, was 37.3 months (range 36.2–46.1 months) for the 12 participants with active and evaluable RH. Participants continued to receive study treatment for a median of 37.0 months (range, 16.6–46.1 months; Table S3, available at www.aaojournal.org). As of the data cutoff date, 8 participants (66.7%) continued to receive treatment. The reasons for treatment discontinuation included progression of VHL disease-associated RCC (n = 1 [8.3%]), adverse event (n = 1 [8.3%]), participant decision to discontinue therapy (n = 1 [8.3%]), and other (n = 1 [8.3%]).

All 12 participants and all 16 eyes showed a response of improved per the IRC (RR, 100.0% [95% CI, 73.5%–100.0%] and 100.0% [95% CI, 79.4%–100.0%], respectively; Table 4). No new RHs were reported as of the data cutoff date. The median duration of response at the participant level was not reached (range, 14.3+ months–33.3+ months), and no cases of disease progression at the participant or eye level had been reported per the IRC at the data cutoff date. The median time to response was 2.7 months (range, 2.5–8.3 months). Visual acuity scores for eyes with active RH generally remained consistent from baseline across time points up to 193 weeks (approximately 44 months; Fig 2).

Table 4.

Best Overall Response by the Independent Reading Center in Participants with Retinal Hemangioblastoma

Variable Belzutifan
Total participants 12 (100.0)
 Improved 12 (100.0)
 Stable 0
 Improved plus stable 12 (100.0)
 Progressed 0
 Not evaluable 0
 No assessment 0
Response rate, % (95% CI) 100.0 (73.5–100.0)
Duration of response (mos) NE (14.3+−33.3+)
Time to response (mos) 2.7 (2.5–8.3)
Total eyes 16 (100.0)
 Improved 16 (100.0)
 Stable 0
 Improved plus stable 16 (100.0)
 Progressed 0
 Not evaluable 0
 No assessment 0
 Response rate, % (95% CI) 100.0 (79.4–100.0)
Open in a new tab

Data are presented as no. (%) or median (range) unless otherwise indicated.

CI = confidence interval; NE = not estimable.

Figure 2.

Figure 2.

Open in a new tab

Graph showing visual acuity scores over time by eye in participants with retinal hemangioblastoma (RH). Each colored line represents an individual study eye. Participants in boldface in the above legend were enrolled at the National Institutes of Health site. The visual acuity score is the number of letters converted from Snellen visual acuity values and is presented only for eyes with active RHs.

All 12 participants (100.0%) experienced any-grade treatment-related adverse events and 4 participants (33.3%) experienced grade 3 or higher treatment-related adverse events (Table S5, available at www.aaojournal.org). The most common events of any grade were anemia in 11 participants (91.7%; grade ≥ 3 in 3 participants [25.0%]) and fatigue in 10 participants (83.3%; grade ≥ 3 in 1 participant [8.3%]). No participants experienced a treatment-related hypoxia event. One participant required vitrectomy shortly after study treatment initiation because of rhegmatogenous retinal detachment in the setting of rapidly progressing RH at baseline and comorbid high myopia and epiretinal proliferation; no recurrence of retinal detachment during the study was documented. The retinal detachment was not considered attributable to study treatment by the investigator and was repaired successfully by vitrectomy during a brief hold of belzutifan. Study treatment was interrupted for approximately 4 weeks because of the event.

Nine participants with active RH were enrolled at the NIH site, one of whom was considered nonevaluable by investigators because of phthisis bulbi in one eye and media opacity in both eyes (Fig S1). Among the remaining 8 participants, 12 eyes with 24 viable RHs or RH complexes were identified at baseline. Among them, 6 participants and 8 eyes harbored 10 RHs measuring 500 βm or more in GLD at baseline, meeting criteria for inclusion into the post hoc exploratory longitudinal analysis. All 6 participants were also included in the response analysis per the IRC described above. Baseline and follow-up characteristics by participant and eye included in this study are presented in Table S6 (available at www.aaojournal.org). At baseline, median RH size was 0.808 mm2 (interquartile range, 0.507–0.926 mm2; range, 0.314–11.0 mm2). The largest RH represented a complex, whereas the rest were single discrete RHs.

Color fundus photographs of the 10 RHs included in the exploratory longitudinal analysis are shown at baseline, month 12, and month 24 in Figure 3. The RH area at each time point and change relative to baseline are shown in Table S7 (available at www.aaojournal.org). As of April 1, 2022, all RHs showed a reduction in area of 10% or more (average, 40%; standard deviation, 18%) by month 6, 15% or more (average, 46%; standard deviation, 17%) by month 12, and 30% or more (average, 51%; standard deviation, 14%) by month 24 (Fig 4). All 10 RHs showed a reduction in vascularity at months 6, 12, and 24 compared with baseline. Among 8 RHs with feeding or draining vessels apparent at baseline, all showed a decrease in caliber or tortuosity of vessels at months 6, 12, and 24. The effect on feeding or draining vessels plateaued at month 12 in 6 of 8 RHs and continued to decrease in the remaining 2 RHs. Among 5 viable RHs with available color fundus photographs at month 3, investigator assessment suggested improvements in RH appearance from baseline frequently were apparent at this early time point, including reduction in size, vascularity, and feeding or draining vessels (Fig S5, available at www.aaojournal.org). Ultra-widefield fluorescein angiography images obtained at baseline and month 24 for the 8 eyes with viable and evaluable RHs or complexes are shown in Figure S6 (available at www.aaojournal.org). Fluorescein angiography leakage of viable RHs generally decreased at month 24 compared with baseline, but a quantitative analysis was not performed. The exudation associated with juxtapapillary (per investigator assessment) RH in participant B at baseline was improved at month 12 and decreased further at month 24, as documented on OCT (Fig S7A, available at www.aaojournal.org). For completeness of data on these vision-threatening tumors, 1 and 2 more juxtapapillary RHs were treated at the NIH site and other sites. These, too, demonstrated reduction in size, vascularity, and tortuosity of the blood vessels (Fig S7B, available at www.aaojournal.org).

Figure 3.

Figure 3.

Open in a new tab

Color fundus photographs of 10 RHs with GLD of 500 μm or more at baseline, month 12, and month 24 in participants at the National Institutes of Health site. aAt month 6, new lipid exudation not present at baseline was noted surrounding the RH. Lipid exudates were first visible at month 6, peaked at month 12, and improved at month 24 in the absence of any overt subretinal fluid at any visit. GLD = greatest linear diameter; OD = right eye; OS = left eye; RH = retinal hemangioblastoma.

Figure 4.

Figure 4.

Open in a new tab

Graph showing the percent change in size for 10 retinal hemangioblastomas with greatest linear diameter of 500 μm or more over time in participants at the National Institutes of Health site.

Two participants examined after a period off belzutifan therapy at later study time points (after 24 months) exhibited increases in RH size and vascularity, suggesting at least some reversibility of effects (Fig 8). Participant B manifested a modest increase in size, exudation, and vascularity of RHs at month 36, after discontinuing the study and belzutifan at month 33 (Fig 8A–B; Fig S6). Participant E manifested a perceptible increase in size and vascularity of a solitary peripheral RH at month 30, compared with prior follow-up, after having had belzutifan held for approximately 3 weeks preceding this visit (Fig 8C).

Figure 8.

Figure 8.

Open in a new tab

Color fundus photographs of retinal hemangioblastoma activity after cessation of belzutifan therapy. OD = right eye.

Discussion

The development of small-molecule HIF-2α inhibitors and the 2021 Food and Drug Administration approval of belzutifan for the treatment of VHL disease-associated RCC, CNS hemangioblastomas, or pNETs not requiring immediate surgery represent a milestone in rational design of pharmacotherapy for this condition. Targeting of specific downstream mediators of HIF dysregulation has not been proven effective to date in VHL disease-associated RH. Intravitreal anti-VEGF agents demonstrated a variable effect on the exudative effects of RHs, but did not reduce RH size, vascularity, or the sequelae of exudation reliably.27,28 Sunitinib malate, an oral tyrosine kinase inhibitor blocking multiple receptor tyrosine kinases, including VEGF receptors and platelet-derived growth factor receptors, showed similar variable effects on exudation, but did not produce a decrease in tumor size in a small prospective trial.29 The status of HIFs as master regulators of the cellular hypoxia response affecting the expression of hundreds of genes implies that neoplasia arising in the setting of HIF dysregulation may depend on a broad array of downstream mediators. In particular, HIF-2α blockade is expected to exert effects at the nexus of pVHL dysregulation. The proof-of-concept HIF-2α antagonist MK-3795 (formerly PT2385) was documented to have short-term measurable effects on a subset of 3 participants with very small RHs in a single-arm clinical trial.30

The phase 2, single-arm, open-label LITESPARK-004 study evaluated the HIF-2α antagonist belzutifan in 61 participants with VHL disease-associated RCC. Herein, we report durable improvement in ocular VHL disease with belzutifan therapy in all 12 participants included in the study who had evaluable RHs on color fundus images, as determined by an independent qualitative assessment. Visual acuity generally was maintained across all 16 affected evaluable eyes. Safety findings for belzutifan in these 12 participants were consistent with the total population, including the frequency of treatment-related adverse events such as anemia. The larger phase 3 LITESPARK-005 study (374 participants in the belzutifan group) and the phase 2 LITESPARK-013 study (154 participants) in advanced RCC have shown a consistent safety profile for belzutifan as observed in LITESPARK-004.31,32 In an exploratory analysis conducted at a single study site that performed standardized multimodal imaging at key time points, all 10 RHs with GLD of 500 μm or more at baseline showed durable and continued decrease in size across 6 participants and 8 eyes during belzutifan treatment. In addition to size decrease, reductions in vascularity and visibility of associated feeding or draining vessels also were documented with high-resolution color photographs among participants at NIH site.

Limitations of this analysis include the small sample size and the absence of a comparator group in the study. Randomized controlled trials are not practical or feasible for ocular VHL disease, but further information from retrospective case series or prospective uncontrolled studies with comparison with historic cohorts documenting natural history could be useful to understand better the efficacy and safety of belzutifan and other HIF inhibitors for RH. Selecting the threshold RH size of GLD of 500 μm or more for the single-site analysis allowed for reliable visualization and reproducible grading of RH features and borders on color fundus photography, but confined the evaluation to only 6 participants. Another limitation included the differences in high-resolution retina imaging capabilities among trial sites. This precluded the IRC from performing more quantitative RH grading and potentially may have led to missing some RHs that were difficult to visualize. Finally, the durability of response in RH or other VHL disease-associated tumors has not yet been documented extensively beyond belzutifan cessation.

Belzutifan demonstrated consistent, clinically meaningful, and durable efficacy across multiple tumors, including RCC, CNS hemangioblastomas, pNETs, and RHs in participants with VHL disease in the LITESPARK-004 study. This is in line with the notion that these VHL tumors share common underlying biological features of VHL deficiency with consequent HIF-2α hyperactivity.25 In this small subgroup of participants with gradable ocular VHL disease, all participants and all eyes were classified as having improved while receiving belzutifan therapy. The observed RR, durability of responses, and the relatively short time to response reported herein provide encouraging preliminary evidence for the efficacy of belzutifan for containing growth of RHs over a period of more than 2 years. Given the demonstrated correlation between lesion size and success of ablative therapy, it remains to be explored whether belzutifan could enable safer and more effective destruction of RHs by laser photocoagulation and other methods. Significant decrease in RH area and sustained effect were achieved even for large RHs and RHs that cannot be managed readily by current standard-of-care therapy, such as juxtapapillary RHs. In conclusion, patients receiving belzutifan therapy as approved for VHL disease-associated RCC, pNETs, or CNS hemangioblastomas also may expect to experience clinical benefit in RHs. Additional studies could evaluate further the role of belzutifan specifically for the treatment of ocular VHL.

Supplementary Material

1

Supplemental material available at www.aaojournal.org.

Acknowledgments

The authors thank the patients and their families and caregivers and all primary investigators and their site personnel, with special thanks to the National Institutes of Health and National Eye Institute investigators and ophthalmologists for their expertise and site subgroup analysis.

Supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ. This project has also been supported by the intramural program at the National Institutes of Health (National Cancer Institute and National Eye Institute), and by federal funds from the National Eye Institute, National Institutes of Health, Department of Health and Human Services.

Abbreviations and Acronyms:

CI

confidence interval

CNS

central nervous system

GLD

greatest linear diameter

HIF

hypoxia-inducible factor

IRC

independent reading center

NIH

National Institutes of Health

pVHL

von Hippel-Lindau protein

pNET

pancreatic neuroendocrine tumor

RCC

renal cell carcinoma

RH

retinal hemangioblastoma

RR

response rate

VHL

von Hippel-Lindau

Footnotes

Disclosure(s):

All authors have completed and submitted the ICMJE disclosures form. The author(s) have made the following disclosure(s):

H.E.W.: Financial support – Genentech, Inc.; Royalties or licenses – National Institutes of Health

R.S.: Nonfinancial support – Nikang, Pfizer, Genentech, Novartis

J.K.M.: Financial support – American Urological Association (AUA) Summit; Leadership or fiduciary role – Northeastern Section of the AUA, IKCS International Kidney Cancer Symposium 2024 for travel and registration

E.J.: Consultant – Aveo, Eisai, Exelixis, Ipsen, Novartis, Merck, NiKang, Takeda, GSK; Financial support – Aveo, Corvus, Arrowhead, ProfoundBio, Merck, NiKang, Telix, AbbVie, Lecturer – DAVA Oncology; Data Safety Monitoring Board or Advisory Board - Novartis

T.E.: Consultant – Merck, Lanthaeus, HRA

H.D.: Advisory board – Castle Bioscience

B.L.M.: Consultant – AbbVie, Pfizer, AVEO Oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, TEMPUS, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, Merck, Peloton Therapeutics; Financial support – Exelixis, Bavarian-Nordic, Clovis, Bristol-Myers Squibb; Data Safety Monitoring Board or Advisory Board – AVEO Oncology

M.E.H.: Consultant – JNJ (Janssen), Feliqs, Regeneron, Genentech; Lecturer – Cincinnati Children’s Hospital, University of California, Los Angeles; Financial support – Michael F. Marmor, M.D. Professor of Retinal Science and Disease endowment, Knights Templar Eye Foundation, AOS Council; Royalties – Wolters Kluwer Lippincott; Patents – WO2015123561A2, WO2021062169A1; Leadership or fiduciary role – Women’s Eye Health, Jack McGovern Coats’ Disease Foundation, Macula Society

W.F.: Employee – Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Dr Wiley is currently at Genentech, Inc., South San Francisco, CA, USA.

Emily Y. Chew, MD, an Associate Editor of this journal, was recused from the peer-review process of this article and had no access to information regarding its peer-review.

A list of the LITESPARK-004 Investigator List – Ocular VHL Analysis is available at www.aaojournal.org.

HUMAN SUBJECTS: Human subjects were included in this study. The National Institutes of Health (NIH) Institutional Review Board (IRB) provided approval for this randomized clinical trial to be conducted. Written informed consent was obtained from all participants.

No animal subjects were included in this study.

Data Sharing Statement:

Merck Sharp & Dohme LLC (MSD), a subsidiary of Merck & Co., Inc. (Rahway, NJ), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. Merck Sharp & Dohme LLC is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

References

  • 1.Wiley H, Schachat A, Chew E. Hemangioblastoma of the retina and von Hippel-Lindau disease. Ryan’s Retina 6th ed. Philadelphia, PA: Elsevier; 2018:2427–2437. [Google Scholar]
  • 2.Wong WT, Agron E, Coleman HR, et al. Clinical characterization of retinal capillary hemangioblastomas in a large population of patients with von Hippel-Lindau disease. Ophthalmology. 2008;115(1):181–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Wiley HE, Krivosic V, Gaudric A, et al. Management of retinal hemangioblastoma in von Hippel-Lindau disease. Retina. 2019;39(12):2254–2263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer. 2015;15(1):55e64. [DOI] [PubMed] [Google Scholar]
  • 5.Hu CJ, Wang LY, Chodosh LA, et al. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–9374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Raval RR, Lau KW, Tran MG, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol. 2005;25(13):5675–5686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Carroll VA, Ashcroft M. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res. 2006;66(12):6264–6270. [DOI] [PubMed] [Google Scholar]
  • 8.Kondo K, Klco J, Nakamura E, et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell. 2002;1(3):237–246. [DOI] [PubMed] [Google Scholar]
  • 9.Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45(8):860–867. [DOI] [PubMed] [Google Scholar]
  • 10.Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23(1):18–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature. 2016;539(7627):112–117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Cho H, Du X, Rizzi JP, et al. On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature. 2016;539(7627):107–111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Wallace EM, Rizzi JP, Han G, et al. A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491–5500. [DOI] [PubMed] [Google Scholar]
  • 14.Mandriota SJ, Turner KJ, Davies DR, et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell. 2002;1(5):459–468. [DOI] [PubMed] [Google Scholar]
  • 15.Pollard PJ, El-Bahrawy M, Poulsom R, et al. Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab. 2006;91(11):4593–4598. [DOI] [PubMed] [Google Scholar]
  • 16.Flamme I, Krieg M, Plate KH. Up-regulation of vascular endothelial growth factor in stromal cells of hemangioblastomas is correlated with up-regulation of the transcription factor HRF/HIF-2alpha. Am J Pathol. 1998;153(1):25–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Speisky D, Duces A, Bieche I, et al. Molecular profiling of pancreatic neuroendocrine tumors in sporadic and von Hippel-Lindau patients. Clin Cancer Res. 2012;18(10):2838–2849. [DOI] [PubMed] [Google Scholar]
  • 18.Chan CC, Lee YS, Zhuang Z, et al. Von Hippel-Lindau gene deletion and expression of hypoxia-inducible factor and ubiquitin in optic nerve hemangioma. Trans Am Ophthalmol Soc. 2004;102:75–79. discussion 79–81. [PMC free article] [PubMed] [Google Scholar]
  • 19.Vortmeyer AO, Frank S, Jeong SY, et al. Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res. 2003;63(21):7051–7055. [PubMed] [Google Scholar]
  • 20.Park DM, Zhuang Z, Chen L, et al. von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells. PLoS Med. 2007;4(2):e60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Glasker S, Li J, Xia JB, et al. Hemangioblastomas share protein expression with embryonal hemangioblast progenitor cell. Cancer Res. 2006;66(8):4167–4172. [DOI] [PubMed] [Google Scholar]
  • 22.Chan CC, Chew EY, Shen D, et al. Expression of stem cells markers in ocular hemangioblastoma associated with von Hippel-Lindau (VHL) disease. Mol Vis. 2005;11:697–704. [PMC free article] [PubMed] [Google Scholar]
  • 23.Wang H, Shepard MJ, Zhang C, et al. Deletion of the von Hippel-Lindau gene in hemangioblasts causes hemangioblastoma-like lesions in murine retina. Cancer Res. 2018;78(5):1266–1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. New Engl J Med. 2021;385(22):2036–2046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Srinivasan R, Iliopoulos O, Rathmell WK, et al. LBA69—belzutifan, a HIF-2α inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: 36 months of follow-up of the phase II LITESPARK-004 study. Ann Oncol. 2022;33:S808–S869. [Google Scholar]
  • 26.Sharp Merck & Dohme LLC. Welireg (belzutifan): U.S. prescribing information Rahway, NJ: Merck Sharp & Dohme LLC; December 2023. [Google Scholar]
  • 27.Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina. 2007;27(2):150–158. [DOI] [PubMed] [Google Scholar]
  • 28.Wong WT, Liang KJ, Hammel K, et al. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology. 2008;115(11):1957–1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Knickelbein JE, Jacobs-El N, Wong WT, et al. Systemic sunitinib malate treatment for advanced juxtapapillary retinal hemangioblastomas associated with von Hippel-Lindau disease. Ophthalmol Retina. 2017;1(3):181–187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Wiley HE, Srinivasan R, Linehan M, et al. Ocular findings in a phase 2 trial testing the first-in-class oral HIF-2α inhibitor, PT2385, for renal cell carcinoma in von Hippel-Lindau disease. Invest Ophthalmol Vis Sci. 2019;60:2782. [Google Scholar]
  • 31.Albiges L, Rini BI, Peltola K, et al. LBA88—belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study; Madrid, Spain. Annals Oncology. 2023;34:2. [Google Scholar]
  • 32.Agarwal N, Brugarolas J, Ghatalia P, et al. 18810—safety and efficacy of two doses of belzutifan in patients (pts) with advanced RCC: results of the randomized phase II LITESPARK-013 study. Ann Oncol. 2023;34(suppl_2):S1013–S1031. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS2192944-supplement-1.zip (1.5MB, zip)

Data Availability Statement

Merck Sharp & Dohme LLC (MSD), a subsidiary of Merck & Co., Inc. (Rahway, NJ), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. Merck Sharp & Dohme LLC is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

RESOURCES