Recurrent Macular Edema Associated With Belzutifan Therapy for Metastatic Renal Cell Carcinoma

Abstract

Purpose: To report a case of rapidly reversible cystoid macular edema (ME) associated with belzutifan therapy. Methods: A single case was reviewed. Results: A 70-year-old man with sporadic metastatic renal cell carcinoma developed acute symptomatic cystoid macular edema (CME) within 2 weeks of initiating belzutifan therapy. The CME began to improve within 1 week after treatment cessation and resolved completely thereafter. Belzutifan was subsequently restarted at a lower dose, following which CME recurred within 2 weeks. Conclusions: This is the first reported instance of rapidly reversible CME associated with the use of belzutifan in a real-world clinical setting, highlighting the need for ophthalmic monitoring in patients receiving hypoxia-inducible factor-2α inhibitors.

Introduction

Belzutifan is a hypoxia-inducible factor-2α inhibitor that was initially approved by the US Food and Drug Administration for treating von Hippel–Lindau disease-associated tumors, including renal cell carcinoma. ¹ More recently, it has been approved as a second-line treatment option for patients with advanced sporadic renal cell carcinoma.^1,2

Through inhibition of the hypoxia-inducible factor-2α transcription factor, belzutifan prevents dimerization of hypoxia-inducible factor-2α and hypoxia-inducible factor-1β, ultimately blocking the transcription of downstream oncogenic targets. ¹ Ongoing phase III trials are investigating belzutifan in combination therapies for the treatment of advanced clear cell renal cell carcinoma, the most common histological subtype, accounting for approximately 70% of renal cell carcinomas.^1,3

In the eye, hypoxia-inducible factor-mediated angiogenesis is critical for both the normal development of retinal vasculature and the pathogenesis of various retinal ischemic diseases. ⁴ Few ocular toxicities resulting from belzutifan have been previously reported. In a phase II clinical trial, up to 16% of enrolled patients reported blurred vision after initiation of belzutifan therapy. ⁵ Despite this relatively high incidence, these patients did not undergo subsequent ophthalmologic evaluation, and the underlying mechanism for the decrease in visual acuity (VA) was not further elucidated.

In addition to its use in treating renal cell carcinoma, belzutifan has also been investigated for the treatment of ocular lesions related to von Hippel–Lindau disease. A prospective subgroup analysis of the phase II LITESPARK-004 study demonstrated the efficacy of belzutifan in ocular von Hippel–Lindau disease, including sustained control of retinal hemangioblastomas with effects sustained for more than 2 years with ongoing treatment. ⁶ Notably, macular edema (ME) was not reported as an adverse effect of belzutifan in this study.

In this article, we present the case of a patient who was treated with belzutifan for sporadic metastatic clear cell renal cell carcinoma who developed rapidly reversible unilateral ME.

Case Report

A 70-year-old man with a history of sporadic metastatic clear cell renal cell carcinoma presented to our eye clinic with a 1.5-month history of blurred vision in the left eye. He had previously undergone a left nephrectomy without local recurrence and had been treated with 2 other systemic chemotherapy agents that were discontinued by his medical oncologist due to systemic side effects. He was subsequently started on belzutifan 120 mg daily for metastatic disease and first noted the onset of blurred vision in the left eye within 2 weeks of initiating therapy. Belzutifan was discontinued 4 days before his first ophthalmologic evaluation, and the patient subjectively reported improvement in vision after cessation of the medication.

At the patient’s initial visit, 4 days after discontinuation of belzutifan, his VA was 20/30 OD and 20/40 OS. There was no afferent pupillary defect. Intraocular pressure was 11 mm Hg OD and 6 mm Hg OS. Anterior segment examination revealed mild cataracts in both eyes. Dilated posterior segment examination was unremarkable in the right eye. The left eye demonstrated cystoid ME (CME) and a small single dot-blot hemorrhage just inferior to the optic nerve (Figures 1A and 2A). Notably, there was no clear evidence of retinal vein occlusion, as retinal vascular tortuosity was absent and only a single hemorrhage was observed. Fluorescein angiography (FA) was not performed at this time due to concerns regarding renal dysfunction.

Figure 1.

Optical coherence tomography images of the patient’s left eye since initial presentation. (A) Improving cystoid macular edema (CME) 4 days after belzutifan cessation at initial examination. (B) Further improvement in CME nearly 2 weeks after belzutifan cessation. (C) Completely resolved CME 1 month after cessation of treatment. (D) Recurrence of CME with new subretinal fluid while on a reduced dose of belzutifan. (E) Nearly resolved CME 2 weeks after stopping treatment. (F) Completely resolved CME 1.5 months after belzutifan cessation.

Figure 2.

Ultra-widefield fundus (Optos) images of the patient’s left eye. (A) Initial presentation demonstrating cystoid macular edema (CME) and a single dot-blot hemorrhage. (B) Recurrence of CME while on a reduced dose of belzutifan. (C) Completely resolved CME 1.5 months after belzutifan cessation.

After discussion with the patient’s medical oncologist, belzutifan therapy remained withheld. Follow-up evaluation 1 week later demonstrated improvement in CME (Figure 1B) with complete resolution 1 month after discontinuation (Figure 1C). After additional consultations with the oncologist, belzutifan was restarted at a lower dose of 80 mg daily. Follow-up examination conducted 3 weeks after restarting belzutifan revealed significant recurrence of CME with new subretinal fluid (SRF) in his left eye only, confirmed by optical coherence tomography (Figures 1D and 2B). At that time, the VA was 20/100 OS and 20/25 OD. Belzutifan was again discontinued, and topical ketorolac and prednisolone acetate were initiated in the left eye 4 times daily. About 2 weeks after repeat cessation of the drug, CME was nearly resolved (Figure 1E), with corresponding improvement in VA to 20/30 OU. The topical medications were subsequently tapered. Follow-up visit 1 month later demonstrated completely resolved CME (Figures 1F and 2C), with final VA of 20/25 OU.

Conclusions

Belzutifan is a second-generation hypoxia-inducible factor-2α inhibitor that selectively disrupts heterodimerization of the hypoxia-inducible factor transcription complex, thereby preventing downstream target gene transcription and resultant oncogenesis. ⁷ It demonstrates improved pharmacologic properties relative to the first-generation compound MK-3795 ⁵ and is currently the only hypoxia-inducible factor-2α inhibitor approved by the US Food and Drug Administration for the treatment of von Hippel–Lindau-associated and advanced sporadic metastatic renal cell carcinoma. ⁸ This decision was largely based on the phase III LITESPARK-005 trial, which demonstrated the superiority of belzutifan over everolimus in patients with locally advanced or metastatic clear cell renal cell carcinoma after 1 to 3 prior systemic therapies.^2,9 Few, if any, ocular adverse effects were reported in this trial, with the most common adverse reactions being anemia, fatigue, and musculoskeletal pain. ²

We report a case of reversible unilateral acute CME associated with oral belzutifan use. CME developed within 2 weeks of treatment initiation and began to improve within 1 week of discontinuation of the treatment, with complete CME resolution observed 1 month after cessation. Documentation of retinal adverse events associated with belzutifan therapy remains limited. As the first reported case of rapidly reversible CME associated with belzutifan use, our study adds to the existing literature by offering a potential explanation for patients who experienced blurred vision after belzutifan in recent phase II clinical trials.^5,10 Retinal detachment and central retinal vein occlusion were each reported in 1 patient in phase II trials and were considered unrelated to treatment.^5,10 Other studies investigating the efficacy of belzutifan for treating von Hippel–Lindau-associated retinal hemangioblastomas did not demonstrate any new retinal hemangioblastomas or ocular disease progression.^6,11,12 Interestingly, one of these studies ⁶ found that edema associated with von Hippel–Lindau lesions subsided, particularly in juxtapapillary tumors, with recurrence upon belzutifan withdrawal. However, ME was not reported as an adverse effect in any of these studies.^6,11,12

Although we strongly believe this patient’s CME is a direct adverse effect of belzutifan for metastatic renal cell carcinoma, several limitations should be acknowledged. First, chronic retinal vein occlusion cannot be definitively excluded, as retinal venous tortuosity may have subsided during the 1.5 months when the patient experienced blurred vision. The patient also had a history of acute hypertension secondary to his prior chemotherapy agent before switching to belzutifan. FA was not performed owing to concerns regarding renal dysfunction. Nevertheless, the striking temporal relationship between initiation and cessation of belzutifan and the recurrence and resolution of CME strongly suggests a drug-related etiology, as ME secondary to retinal vein occlusion would not be expected to demonstrate such rapid and reproducible fluctuation with exposure to oral medication.

Second, the patient’s CME was unilateral, whereas many reported drug-induced ocular adverse effects are bilateral. However, unilateral ocular complications related to chemotherapy for genitourinary, ovarian, and breast malignancies have been previously reported.^13–18 These include unilateral optic disc papilledema from carboplatin, ¹³ unilateral hemianopsia after paclitaxel, ¹⁴ unilateral acute SRF accumulation from futibatinib, ¹⁵ unilateral vision loss from ifosfamide, ¹⁶ and unilateral palpebral ptosis during vinblastine therapy. ¹⁷ Such uncommon unilateral presentations may be explained by age-dependent susceptibility, ¹⁷ a weaker blood–ocular barrier, anatomic predisposition of 1 eye, or differential drug distribution to each optic nerve.

Despite these proposed explanations, unilateral ocular complications from chemotherapy remain rare, and their underlying mechanisms remain unclear. Further research on the etiology and pathophysiology of chemotherapy-induced ocular adverse effects is warranted. Despite these limitations, we believe that this patient’s rapidly reversible CME was directly induced by belzutifan, given the close temporal relationship between belzutifan exposure and CME occurrence. FA may be considered in the future if diagnostic uncertainty persists, pending stabilization of the patient’s renal function.

Given the concerns regarding recurrent ME associated with belzutifan, shared decision-making discussions among the patient, his medical oncologist, and the retinal specialist were ongoing at the time of writing this report to determine whether belzutifan should be restarted at a lower dose or an alternative systemic therapy should be initiated. These discussions take into account that life-preserving treatments are likely of highest importance, even if pursued at the expense of visual quality. If belzutifan is restarted at a lower dose, ¹⁹ consideration may be given to adjunctive therapy with topical anti-inflammatory agents or antivascular endothelial growth factor (anti-VEGF) injections to mitigate recurrent edema.

As VEGF is a downstream target of hypoxia-inducible factor-2α, ⁵ one proposed mechanism for CME induced by belzutifan-induced CME is the disruption of VEGF homeostasis, which plays an important role in maintaining the integrity of the blood–retinal barrier.^20,21 Belzutifan may cause retinal capillary dysfunction by interfering with VEGF signaling, leading to increased vascular permeability. Another possible mechanism is localized macular inflammation resulting from the altered response to hypoxia due to inhibition of hypoxia-inducible factor-2α. The findings of this study emphasize the need for further research on the pathogenesis of belzutifan-induced macular edema.

Hypoxia-inducible factor-2α inhibitors such as belzutifan may offer a more favorable safety profile compared with other antiangiogenic agents, which are often associated with cardiovascular toxicity, hepatotoxicity, and metabolic and hematologic disturbances.^22–24 Belzutifan monotherapy and combination therapy are currently being investigated for a wide range of cancers, such as advanced gastrointestinal stromal tumors, ovarian cancer, and various other solid tumors. Notably, several recent case reports have demonstrated the potential use of belzutifan for treating von Hippel–Lindau disease-related retinal hemangioblastomas.^11,12

In a 2024 case series, Ercanbrack et al ¹¹ reported 3 patients with von Hippel–Lindau disease who showed significant regression of retinal hemangioblastomas when treated with belzutifan in conjunction with photocoagulation therapy. Another case report described the use of belzutifan to successfully reduce a complicated retinal hemangioblastoma with extrascleral extension, with minimal systemic side effects, ultimately reducing the need for enucleation. ¹² As the indications for belzutifan continue to expand, further research into the pathophysiology of its ocular adverse effects is warranted.

This study reports the first case of rapidly reversible CME associated with belzutifan use. As belzutifan utilization increases with broader indications for advanced cancers, close and careful coordination between oncologists and ophthalmologists is needed for safe dosage optimization and early recognition and management of potential ocular toxicities. A better understanding of the underlying mechanisms will help physicians and patients prevent and promptly manage these complications, ultimately preventing permanent retinal damage and vision loss in these patients.