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Henry Wiley, Hanna R. Coleman, Eric Jonasch, Ramaprasad Srinivasan, Frede Donskov, Anders Kruse, Jodi K. Maranchie, Jay Chhablani, Tobias Else, Hakan Demirci, Benjamin L. Maughan, Mary Elizabeth Hartnett, Rodolfo F. Perini, Eric K. Park, Emily Y Chew; Oral HIF-2α inhibitor belzutifan for ocular von Hippel-Lindau (VHL) disease. Invest. Ophthalmol. Vis. Sci. 2021;62(8):32.
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VHL disease is a rare hereditary disorder caused by VHL gene mutation, resulting in overexpression of hypoxia-inducible factors (HIFs) and tumorigenesis. We report results for retinal hemangioblastomas (RH) in patients with VHL disease-associated clear cell renal cell carcinoma (VHL-RCC) receiving small molecule HIF-2α inhibitor belzutifan (MK-6482).
In this open-label, single-arm, phase 2 study (NCT03401788), patients with VHL-RCC received belzutifan, 120 mg orally daily. Evaluations included visual acuity assessment, ophthalmic exam, and imaging every 3 months for patients with baseline active ophthalmic disease. The primary endpoint was objective response rate (ORR) of VHL-RCC by Response Evaluation Criteria In Solid Tumours (v1.1). Efficacy for RH was a secondary endpoint, measured as an eye-level best overall response by an independent reading center (DARC, Great Neck, NY) based on assessment of color fundus imaging. Each eye was evaluated for RH number/size/location; degree of feeding/draining vessel dilation; and presence of intraretinal/preretinal/vitreous hemorrhage, exudation, and/or fibrosis. Eyes were assigned a summary grade of improved, stable, or progressed at last follow up.
61 patients were enrolled between 2018 and 2019. As of June 2020, median follow-up was 69 weeks (range, 18–105). Confirmed ORR for VHL-RCC was 36% (95% CI, 24–49), with a disease control rate of 98% (95% CI, 91–100). The most common adverse events were anemia (90%) and fatigue (61%) for the entire study population. Color fundus images were obtained for 29 eyes (16 patients) having ≥1 RH. 16/29 eyes (55%) were graded as improved, 12/29 eyes (41%) were stable, and 1/29 eyes (3%) was not evaluable (poor image quality). No eye was graded as progressed and no new RH occurred. 1/29 eyes (3%) had a decrease in visual acuity >15 letters equivalent, secondary to retinal detachment in the setting of RH, epiretinal membranes, and myopia.
Belzutifan demonstrated promising activity, including reduction in size, vascularity, and/or exudation in a subset of RH, in addition to beneficial effects on RCC in patients with VHL disease.
This is a 2021 ARVO Annual Meeting abstract.
Figure. A. Baseline: Small RH (diameter=1 mm). Photocoagulation scars from prior treatment are visible, but RH appearance suggests viability. B. Week 49 on belzutifan: RH is less visible, with diminished feeding/draining vessels. Eye received no other treatment.
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