Real-world outcomes and toxicity with belzutifan in the treatment of Von Hippel–Lindau disease: A single centre Canadian experience.

e22620 Background: Von Hippel–Lindau (VHL) disease is an autosomal dominant disorder caused by mutations in the VHL gene, predisposing individuals to the development of various neoplasms, including but not limited to cerebellar and spinal hemangioblastomas (CHB and SHB, respectively), pheochromocytomas, pancreatic neuroendocrine tumours (pNET), and renal cell carcinoma (RCC). Belzutifan, an oral HIF-2α inhibitor, offers a novel systemic approach to manage VHL-associated lesions. This study aimed to evaluate the real-world effectiveness and safety of belzutifan in patients with VHL disease at the provincial British Columbia (BC) Cancer VHL Clinic in Vancouver, Canada. Methods: We undertook a retrospective review of patient records between April 2022 and December 2024. Patient demographics, types of VHL related tumors, treatment responses, and adverse events were collected and recorded in a centralized database. Tumor response was assessed according to RECIST 1.1 criteria, categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Additionally, treatment toxicity and dose reductions were evaluated. Results: Twenty seven patients were started on belzutifan between August 2022 and October 2024. Median age was 37 years (range 21-64). Amongst these, 52% (n = 14) were females and 48% (n = 13) were males. The most common subtype was type 1 VHL (85%; n = 23). In patients with CHB (n = 25), objective response rate (ORR) was 68% (all PR, no CR) and SD was seen in 24% (n = 6). One patient had progression of the cystic component of their CHB. In those with SHB (n = 24), ORR was 54% (46% PR, 8% CR) with SD seen in 46%. In pancreatic lesions (including pNET and cystadenomas; n = 24), ORR was 71% (all PR; no CR). In patients with solid renal lesions (n = 22) ORR was 73% (PR 68% [n = 15] and CR 5% [n = 1]) and SD 27% (n = 6). No patients developed new lesions in any affected areas while on belzutifan. The most common side effects experienced were grade 1 anemia (59%; n = 16) and fatigue (52%; n = 14). Grade 2 hypoxia was reported in 14.8% (n = 4). Dose reductions or temporary treatment break were required in 62.5% of patients (n = 15), most often for anemia (40%; n = 6) and fatigue (53%; n = 8). Amongst these 15 patients, 2 were able to re-escalate to full dose without recurrence of side effects. No patients required permanent treatment discontinuation. Conclusions: Our real-world outcomes demonstrate that belzutifan is effective in treatment of VHL disease and generally being well-tolerated. Further research into long-term outcomes, efficacy for other VHL-associated lesions, such as pheochromocytomas and delineation of mechanism of resistance may expand its therapeutic utility.