Extended follow-up (6 years) of the phase 2 LITESPARK-004 study of belzutifan in participants with von Hippel-Lindau disease–associated neoplasms.

Abstract

4550 Background: Belzutifan, a potent and selective hypoxia-inducible factor 2α inhibitor, is indicated for treatment of patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery based on prior results from the open-label phase 2 LITESPARK-004 study (NCT03401788). We report results from LITESPARK-004 after a minimum of 6 years of follow-up. Methods: Participants (pts) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor >3 cm that required immediate surgery, no metastatic disease, no prior anticancer systemic treatment, and an ECOG PS of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. The primary end point was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent review committee (IRC). Secondary end points included safety, ORR in non-RCC neoplasms, duration of response (DOR), and progression-free survival (PFS) per RECIST v1.1 by IRC. Results: Overall, 61 pts received ≥1 dose of belzutifan. Median study follow-up was 73.8 months (range, 72.1-82.1). As of the data cutoff date (April 1, 2025), 34 pts (56%) remained on treatment. ORR was 70% for RCC, 52% for CNS HB, and 91% for pNETs. Additional efficacy results are shown in the Table. Among 14 pts (n = 18 affected eyes by ophthalmic evaluation), retinal HBs in 100% (95% CI, 81-100) of eyes showed improvement. Median DOR in pts with retinal HBs was not reached (NR; 95% CI, 8.5-NR). Within 5 years prior to initiating belzutifan, 46 of 61 pts (75%) had ≥1 VHL-related tumor reduction procedure (surgery or radiation therapy; 43 RCC, 39 CNS HB, 12 retinal HB, 3 pNET, 2 other). Since initiating belzutifan treatment, 22 of 61 pts (36%; 14 during treatment and 8 after discontinuing treatment) underwent 25 VHL-related tumor reduction procedures (16 RCC, 3 CNS HB, 5 retinal HB, 1 pNET). Grade 3 treatment-related adverse events (TRAEs) were reported in 12 pts (20%); the most common grade 3 TRAE was anemia (11%). No grade 4 or 5 TRAEs occurred. No additional pts discontinued belzutifan due to TRAEs since the previous analysis. Conclusions: After 6 years of follow-up, belzutifan continues to show durable antitumor activity and a manageable safety profile in pts with VHL-associated RCC, CNS HB, and pNETs who do not require immediate surgery. These results continue to support the use of belzutifan in this patient population. Clinical trial information: NCT03401788 . RCCn = 61 CNS HBn = 50 pNETsn = 22 ORR (95% CI), % 70 (57-81) 52 (37-66) 91 (71-99) Best overall response, n 8 CR35 PR 17 SD0 PD1 NE 7 CR19 PR20 SD3 PD1 NE 14 CR6 PR2 SD0 PD0 NE DOR, median (range), months NR (5.8+ to 69.1+) NR (0.0+ to 74.3+) NR (11.0+ to 71.8+) 48-month DOR rate 78% 84% 90% PFS, median (95% CI), months NR (71.5-NR) NR (NR-NR) NR (NR-NR) 48-month PFS rate 79% 80% 90%