Hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan in von Hippel-Lindau (VHL) disease–associated neoplasms: 5-year follow-up of the phase 2 LITESPARK-004 study

Background:The HIF-2α inhibitor belzutifan is approved for the treatment of patients with VHL disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNETs), not requiring immediate surgery based on previously reported results from the ongoing open-label phase 2 LITESPARK-004 study (NCT03401788). Updated results are presented after a minimum of 5 years of follow-up.

Methods: Adults 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 participant (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 61.8 mo (range, 60.2-70.1). As of the April 1, 2024 data cutoff date, 35 pts (57%) remained on treatment. ORR was 70% for RCC, 50% for CNS HB, and 90% for pNETs. Additional efficacy results are in the Table. Among 14 pts (n = 18 eyes) with retinal HB, 100% (95% CI, 82-100) of eyes showed improvement per ophthalmologic assessment; median DOR for retinal HBs was not reached (NR; range, 8.5-61.0+ mo). At baseline, 59 of 61 pts (97%) had ≥1 prior VHL-related surgery. Within the 5 years before starting belzutifan, 46 of 61 pts (75%) had ≥1 surgery. Since starting belzutifan, 19 of 61 pts (31%) underwent VHL-related surgeries; 4 underwent surgery while on treatment and subsequently discontinued treatment, 8 underwent surgery after discontinuing treatment, and 7 are continuing treatment as of the data cutoff date. Grade 3 treatment-related adverse events (TRAEs) (most commonly anemia [n = 7; 11%]) were reported in 11 pts (18%). No grade 4 or 5 TRAEs occurred. Belzutifan was discontinued in 2 pts (3%) due to TRAEs (grade 1 dizziness and grade 2 intracranial hemorrhage).Conclusions:After 5 years of follow-up, belzutifan continues to demonstrate durable antitumor activity and a manageable safety profile, consistent with prior reports. Most pts remain on treatment after this period. Results continue to support the use of belzutifan in pts with VHL disease–related RCC, CNS HB, and pNETs who do not require immediate surgery.