China’s National Medical Products Administration (NMPA) has granted approval to belzutifan (Welireg) for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery. This decision marks the 17th global approval for this indication, offering a new systemic treatment option for Chinese patients with VHL disease.
The approval is primarily based on data from the phase 2 LITESPARK-004 trial (NCT03401788), which evaluated the efficacy and safety of belzutifan in patients with VHL-associated tumors. LITESPARK-004 was a multicenter, open-label, single-arm study conducted across sites in the United States, Denmark, France, and the United Kingdom.
Efficacy Data from LITESPARK-004
The LITESPARK-004 trial demonstrated clinically significant objective response rates (ORR) and duration of response (DOR) across different VHL-associated tumor types. In patients with VHL-associated RCC (n = 61), the ORR was 49% (95% CI, 36%-62%), with all responses being partial responses. The median DOR was not reached (NR; range, 2.8+ to 22.3+ months), and 17 of 30 responding patients maintained a response for at least 12 months.
For patients with VHL-associated CNS hemangioblastomas (n = 24), the ORR was 63% (95% CI, 41%-81%), including a complete response (CR) rate of 4%. The median DOR was NR (range, 3.7+ to 22.3+ months), with 73% of responders maintaining a response for at least 12 months. Among patients with VHL-associated pNETs (n = 12), the ORR was 83% (95% CI, 52%-98%), with a CR rate of 17%. The median DOR was NR (range, 10.8+ to 19.4+ months), and 50% of responders maintained a response for at least 12 months.
Belzutifan: A Novel HIF-2α Inhibitor
Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor. By selectively blocking HIF-2α, belzutifan disrupts the signaling pathways that drive tumor growth and angiogenesis in VHL-associated tumors. This mechanism of action provides a targeted approach to managing these tumors, offering an alternative to surgery for eligible patients.
Marjorie Green, MD, senior vice president and head of oncology and global clinical development at Merck Research Laboratories, noted, “This approval of belzutifan brings the first and only systemic therapy to adult patients in China with certain VHL disease–associated tumors who, to date, have not had access to a nonsurgical treatment option to help manage manifestations of VHL disease.”
Prior Approvals and Ongoing Research
Belzutifan was initially approved by the FDA in August 2021 for VHL disease-associated RCC, CNS hemangioblastomas, or pNETs, based on the LITESPARK-004 trial findings. In December 2023, the FDA further approved belzutifan for advanced RCC after prior therapy with a PD-1 or PD-L1 inhibitor and a VEGF TKI, supported by the phase 3 LITESPARK-005 trial (NCT04195750). Belzutifan is currently under investigation in advanced RCC and other tumor types, both as a monotherapy and in combination regimens, across multiple phase 2 and 3 studies.
Study Design and Patient Population
The LITESPARK-004 trial enrolled adult patients with VHL disease-associated RCC and other associated neoplasms. Eligible patients were required to have a germline VHL alteration, at least one measurable RCC tumor per RECIST 1.1 criteria, no RCC tumor larger than 3 cm requiring immediate surgical intervention, no evidence of metastatic disease, no prior exposure to systemic anticancer therapy, and an ECOG performance status of 0 or 1. All patients received oral belzutifan at 120 mg once daily until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was independent review committee–assessed ORR per RECIST 1.1 criteria, with secondary endpoints including DOR, time to response, and progression-free survival.
