Phase 2 trial of belzutifan in participants from China and Japan with von Hippel-Lindau disease-associated tumors: Results from LITESPARK-015 cohort B1.

494 Background: Von Hippel-Lindau (VHL) disease manifests with tumors including renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS-HB), pancreatic neuroendocrine tumors (pNET), pheochromocytomas/paragangliomas (PPGL), and retinal hemangioblastomas (R-HB). The LITESPARK-004 trial conducted in the US and Europe demonstrated robust clinical activity of belzutifan in VHL disease-associated RCC, CNS-HB and pNET. We report the results of China and Japan participants (pts) with VHL disease-associated tumors from Cohort B1 of LITESPARK-015 trial. Methods: This global single-arm phase 2 trial enrolled adult pts with VHL disease-associated localized tumors with ≥1 measurable RCC, pNET or PPGL to receive 120 mg belzutifan Q1D until disease progression, unacceptable toxicity, or withdrawal. For R-HB, ophthalmic evaluations including color fundus photography were performed. The primary endpoint was objective response rate (ORR) for VHL disease-associated RCC per RECIST v1.1 by blinded independent central review (BICR) in pts from China and Japan; the hypothesis was ORR >15% tested once at 20 months (mo). Other key endpoints included duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) (RECIST 1.1, BICR), time to surgery by tumor type, overall survival (OS) and safety. Results: At data cut-off (April 22, 2025), 44 pts (23 China, 21 Japan) were enrolled and treated. The median age was 38 years, 59% pts had family history of VHL disease, and 59% had type 1 VHL disease. Overall, 34 (77%) pts had RCC, 22 (50%) solid and cystic CNS-HB, 16 (36%) solid CNS-HB, 21 (48%) pNET and 6 (14%) PPGL. Seven pts had ≥1 R-HB by BIRC at baseline. At median follow-up of 25.1 mo (range, 20.7 to 28.1), the primary endpoint was met with ORR of 88.2% (95% CI, 72.5-96.7; p <0.001) in pts with RCC. ORR was 90.5% (95%CI, 69.6-98.8) in pNET, 59.1% (95% CI, 36.4-79.3) in solid and cystic CNS-HB, 81.3% (95% CI, 54.4-96.0) in solid CNS-HB, and 16.7% (95% CI, 0.4,64.1) in PPGL. DCR was 100% in all pts. The best overall response at pt level for R-HB was “improved” in 71% pts. Median DOR and PFS were not reached for all pts, with 24-mo PFS rates of 88.1% (RCC), 88.4% (pNETs), 90.4% (solid and cystic CNS-HB), 100% (solid CNS-HB), and 100% (PPGL). No pts had VHL tumor specific surgery or radiation while treated with belzutifan. All pts (100%) had a treatment-related adverse event (TRAE), with a serious TRAE in 1 (2%) pt. One (2%) pt discontinued and 28 (64%) had dose reduction due to TRAE. Nine (21%) pts had grade 3 TRAEs; the most common were increased alanine aminotransferase (9%) and anemia (4%). There were no grade 4 or 5 TRAEs. Conclusions: Belzutifan provided robust and clinically meaningful antitumor activity with durable responses in pts from China and Japan with VHL disease-associated tumors. Belzutifan had a manageable safety profile with no new safety signals. Clinical trial information: NCT04924075 .