Belzutifan monotherapy in Chinese patients (pts) with von Hippel-Lindau (VHL) disease–associated tumors: Results of LITESPARK-015 study.
Authors: Jianhui Qiu, Jingcheng Zhou, Lin Cai, Wen Kong, Wei Xue, Jin Zhang, Pei Dong, Jie Liu, Wanyu Li, Nan Li, Girish S. Naik, Kan Gong
Journal: Journal of Clinical Oncology (2025)

534 Background: Pts with VHL disease are at risk of developing malignant tumors such as renal cell carcinoma (RCC) due to VHL gene inactivation, leading to activation of hypoxia-inducible factors (HIFs). In the phase 2 LITESPARK-004 study, HIF-2α inhibitor belzutifan (MK-6482) demonstrated antitumor activity and a manageable safety profile in pts with VHL disease–associated tumors; however, the study did not include pts from Asia. We present results for pts from mainland China with VHL disease–associated localized tumors enrolled in cohort B1 of the phase 2, open-label, single-arm LITESPARK-015 study (NCT04924075). Methods: Eligible pts were aged ≥18 yrs with localized VHL disease–associated tumors diagnosed by local germline testing and/or clinically (per family history and ≥1 VHL-related tumor, ≥2 retinal/central nervous system [CNS]-hemangioblastomas [HBs], or 1 retinal/CNS-HB and ≥1 VHL-related visceral tumor [except renal/epididymal cysts]), and with ≥1 measurable pheochromocytoma/paraganglioma (PPGL), pancreatic neuroendocrine tumor (pNET), or RCC per RECIST v1.1 by blinded independent central review (BICR) not requiring immediate surgery. Pts received belzutifan 120 mg orally QD until PD or unacceptable toxicity. A primary endpoint for cohort B1 was ORR per RECIST v1.1 by BICR in VHL disease–associated RCC in patients from China. Secondary endpoints included disease control rate (DCR), time to response (TTR), duration of response (DOR), PFS (BICR), OS, and safety. Results: 23 pts from China enrolled and treated in cohort B1 had ≥1 primary tumor: RCC, n=18; CNS-HB (solid component), n=7; CNS-HB (solid + cystic components), n=10; pNET, n=12; and PPGL, n=4. Median study follow-up was 14.9 (range, 12.0–17.1) months at data cutoff (May 23, 2024). ORR in pts with RCC was 83% (95% CI, 59%–96%); 15 pts achieved PR. All 4 pts with PPGL had SD. Additional data are shown in the Table. No PFS or OS events had occurred. All-cause AEs occurred in all 23 pts (100%), most commonly (incidence ≥20%) anemia, ALT increased, AST increased, asthenia, URI, and GGT increased. Grade 3 AEs occurred in 9 pts (39%; no grade 4–5), serious AEs in 3 pts (13%). AEs that led to treatment discontinuation occurred in 1 pt (treatment-related tumor hemorrhage of kidney). Conclusions: Belzutifan showed a favorable benefit/risk profile for VHL disease–associated localized tumors in pts from China, with a clinically meaningful response rate, durable responses, and manageable safety profile. Clinical trial information: NCT04924075 . RCCN = 18 a CNS-HB (Solid)N = 7 a CNS-HB (Solid + Cystic)N = 10 a pNETN = 12 a ORR (95% CI), % 83(59–96) 100(59–100) 60(26–88) 67(35–90) DCR (95% CI), % 100(82–100) 100(59–100) 100(69–100) 100(74–100) TTR, median (range), mo 5.6(2.7–11.1) 2.8(2.6–3.0) 2.9(2.6–5.6) 5.6(2.5–8.4) DOR, median (range), mo NR(2.7+ to 11.1+) NR(8.1+ to 14.1+) NR(5.6+ to 14.1+) NR(2.8+ to 11.3+) a Pts may have had ≥1 primary tumor type.