Oral HIF-2α inhibitor belzutifan for ocular von Hippel-Lindau (VHL) disease

Abstract

Purpose : 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).

Methods : 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.

Results : 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.

Conclusions : 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.