Long-term HIF-2α inhibition in von Hippel-Lindau disease: insights from LITESPARK-004

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor‑predisposition syndrome caused by germline pathogenic variants in VHL gene, characterized by the formation of highly vascular tumors across multiple organ systems (1,2). Typical manifestations include clear‑cell renal cell carcinoma (ccRCC) along with retinal and central nervous system (CNS) hemangioblastomas, pheochromocytomas/paragangliomas, pancreatic neuroendocrine tumors (pNETs) and cysts, and endolymphatic sac tumors of the inner ear. Loss of VHL protein stabilizes hypoxia-inducible factor-2α (HIF-2α), a transcription factor, enabling sustained activation of angiogenic and metabolic gene programs. The resulting upregulation of angiogenic factors such as vascular endothelial growth factor (VEGF) and erythropoietin drives the hallmark hypervascular phenotype of the syndrome. Belzutifan is an oral, selective smallmolecule inhibitor of HIF-2α. It received Food and Drug Administration (FDA) approval on August 13, 2021, for adults with VHL disease who require treatment for associated ccRCC, CNS hemangioblastomas, or pNET that do not require immediate surgical intervention. The decision was supported by the LITESPARK-004 trial (NCT03401788) (3). LITESPARK-004 was a multicenter, single-arm, phase 2 study of belzutifan 120 mg daily in non-metastatic ccRCC (≤3 cm) associated with VHL disease. The primary endpoint was objective response rate (ORR). After a median follow-up of 21.8 months, belzutifan demonstrated an ORR of 49% (30 of 61) in VHL-associated renal cell carcinoma (RCC), with no patients experiencing progressive disease (PD). The median duration of response was not reached (NR). In addition, the ORR was 77% for pancreatic lesions and 30% for CNS hemangioblastomas.

This updated analysis of LITESPARK-004, with a median followup of nearly 50 months, provides updated efficacy, safety, the durability of benefit, and the trial’s practical implications for managing VHL-associated neoplasms (4). With longer follow-up, the antitumor activity of belzutifan has deepened (Table 1). The ORR in RCC rose from 49% in the primary analysis to 67% including 11% of complete response (CR). Primary disease progression rate remained at 0%. The median progression-free survival (PFS) reached 49.8 [95% confidence interval (CI): 49.8–NR] months, with an estimated 42-month PFS rate of 79%. The median duration of response was not reached. Of note, the median time to response increased from 8.2 to 11.1 months.

Table 1. Efficacy outcomes of belzutifan in VHL-associated RCC.

Endpoints	Median follow-up
	21.8 months	49.9 months
ORR (95% CI) (%)	49 (36–62)	67 (54–79)
PD (%)	0	0
PFS (95% CI)	24-month PFS: 96% (87–89%)	42-month PFS: 79% (65–88%). Median PFS: 49.8 (49.8–NR) months
Median time to response (95% CI) (months)	8.2 (2.7–19.1)	11.1 (6.2–16.5)
Median duration of response (95% CI) (months)	NR (2.8–22.3)	NR (41.3–NR)

CI, confidence interval; NR, not reached; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; VHL, von Hippel-Lindau.

Durable responses were observed across hallmark VHL manifestations with prolonged follow-up. In CNS hemangioblastomas (n=50), ORR was 48% (95% CI: 34–63%) including 8% CR, and virtually all evaluable patients experienced some tumor shrinkage. pNETS (n=22) were particularly sensitive, with a 91% ORR (95% CI: 71–99%) and 50% CR; all pNETs had some reduction in target burden. Retinal hemangioblastomas improved in 93% (95% CI: 66–100%) of participants (n=14) with evaluable eyes. The broad anti-tumor activity across diverse VHL-associated neoplasms validates the clinical advantage of targeting HIF-2α, the central molecular driver of this hereditary tumor syndrome. Additionally, one of the most clinically meaningful outcomes is the reduction in procedure burden. In the four years preceding belzutifan treatment, 46 of 61 participants underwent 86 procedures (39 renal, 33 CNS hemangioblastomas, nine retinal, three pancreatic, two other). Following treatment initiation, only 18 procedures were performed across 16 participants (13 renal, three CNS, and two retinal). Median time to surgery was not reached for any organ system. While no formal statistical comparison was planned, this substantial reduction suggests that sustained HIF-2α inhibition can significantly delay or defer the need for surgery or other invasive interventions. Such delay has important implications for long-term preservation of renal function, reduction of cumulative neurologic and ocular risks, and overall improvement in patient quality of life.

Belzutifan has also demonstrated antitumor activity in the individualized management of a patient with polycythemia and multiple paragangliomas (Pacak-Zhuang syndrome), leading to durable tumor control and control of hypertension, headaches, and polycythemia (5). In addition, a rapid cardiovascular benefit has been reported in catecholamine-related hypertensive emergencies, with prompt reductions in blood pressure and catecholamine levels in pheochromocytoma and paraganglioma (6). Together, these findings suggest that belzutifan may have broader therapeutic applications beyond VHL-associated tumors, particularly in the management of catecholamine-mediated complications in pheochromocytoma and paraganglioma. In the phase 2, multicohort LITESPARK-015 trial, belzutifan demonstrated clinically meaningful activity in patients with advanced pheochromocytoma or paraganglioma, achieving a 26% ORR and a median response duration of approximately 20 months. Notably, approximately one-third (19 out of 60) of patients were able to sustainably reduce their antihypertensive medications, reflecting improvement in catecholamine-related symptoms. These findings highlighted both durable tumor control and functional benefit, leading the FDA to approve belzutifan for adults and adolescents (≥12 years) with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma—the first oral systemic therapy available for this rare disease (7).

The extended safety profile of belzutifan remains consistent with class effects and is overall reassuring. Anemia (89%; grade 3: 11%) and fatigue (66%; grade 3: 5%) were the most common adverse events; grade 3 hypoxia was rare (2%). Dose interruptions and reductions occurred in 21% and 16% of patients, respectively. Anemia was often managed with erythropoiesis-stimulating agents (ESAs) or transfusions, without apparent negative impact on outcomes. Rates of high-grade anemia were lower than in heavily pretreated RCC populations, reflecting the healthier and younger VHL cohort. An increasingly recognized side effect was weight gain, reported in 16% of patients with CNS hemangioblastomas in LITESPARK-004 (8).

In addition to its activity in VHL-associated neoplasms, belzutifan has demonstrated clinical benefit in sporadic ccRCC. Based on results from the phase 3 LITESPARK-005 trial (9), the FDA approved belzutifan on December 14, 2023, for patients with advanced RCC who have received prior programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and VEGF-targeted therapy (10). At final analysis (median follow-up of 35.8 months) (11), belzutifan significantly improved PFS compared to everolimus (median PFS: 5.6 vs. 5.6 months; hazard ratio =0.75; 95% CI: 0.63–0.88). Landmark PFS rates at 12 and 24 months were 33.7% and 17.5% for belzutifan, vs. 17.6% and 4.1% for everolimus, respectively. The ORR was 23% with belzutifan compared to 3.5% with everolimus, with a median duration of response of approximately 19.3 months. Notably, a significant improvement in overall survival was not observed. Belzutifan was generally well tolerated, reinforcing its role as a non-VEGF-directed, oral therapeutic option in the post-immune checkpoint inhibitor/VEGF-tyrosine kinase inhibitor (TKI) setting. Notably, belzutifan monotherapy is associated with a relatively high rate of PD in the refractory setting (34% in LITESPARK-005) (11), underscoring the need for more effective strategies to achieve early disease control. Combining belzutifan with VEGF-targeted therapy may enhance both the onset and durability of response (Table 2). In the phase 2 single-arm LITESPARK-003 study, belzutifan plus cabozantinib demonstrated an ORR of 70% and a median PFS of 30.3 months in treatment-naïve patients, with durable responses and a manageable safety profile (12,13). In the post-immunotherapy cohort, the same combination yielded an ORR of 31% and median PFS of 13.8 months. Separately, in KEYMAKER-U03 substudy 03B, the belzutifan plus lenvatinib combination showed notable activity in a heavily pretreated population, achieving an ORR of 47%, median PFS of 12.5 months, and a median duration of response of 22.1 months (14). Both combinations exhibited encouraging efficacy and tolerability, supporting the continued exploration of HIF-2α inhibition in rational VEGF-directed doublet strategies for ccRCC. LITESPARK-011 (NCT04586231) is an ongoing phase III, randomized trial evaluating belzutifan plus lenvatinib versus cabozantinib in patients with advanced ccRCC previously treated with PD-1/PD-L1 (15). Another phase III study, LITESPARK-012, is investigating pembrolizumab + lenvatinib with or without belzutifan, and includes a third arm of pembrolizumab + lenvatinib + quavonlimab [a cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor] in patients with advanced ccRCC in the first-line setting. In the adjuvant setting, the LITESPARK-022 is investigating belzutifan in combination with pembrolizumab vs. pembrolizumab in resected high-risk ccRCC (16).

Table 2. Efficacy of belzutifan with/without VEGF-TKI in refractory RCC.

Trials	Setting	ORR (95% CI) (%)	PD (%)	Median PFS (95% CI) (months)	Median DOR (95% CI) (months)
Belzutifan (LITESPARK-005)	Post-IO/VEGF-TKI	23 (19–27)	34	5.6 (3.8–6.5)	19.3 (1.9–40.1)
Belzutifan + cabozantinib (LITESPARK-003, cohort 2)	Post-IO	31 (19–45)	6	13.8 (9.2–19.4)	30.4 (4.2–45.6)
Belzutifan + lenvatinib (KEYMAKER-U03-03B, arm B5)	Heavily pretreated	47 (34–60)	11	12.5 (5.9–26.3)	22.1 (2.6–25.6)

CI, confidence interval; DOR, duration of response; IO, immunotherapy; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; RCC, renal cell carcinoma; VEGF-TKI, vascular endothelial growth factor-tyrosine kinase inhibitor.

Ongoing clinical trials are investigating other HIF-2α inhibitors, including casdatifan (NCT05536141) and NKT2152 (NCT05119335). As monotherapy, casdatifan achieved an ORR of 33% and a disease control rate of 85% at the 100 mg once-daily dose (n=29), with a tolerable safety profile characterized primarily by anemia (79%; ≥ grade 3: 17%) and hypoxia (14%; ≥ grade 3: 10%) (17). Building on these results, an expansion cohort of the ARC-20 trial evaluated casdatifan in combination with cabozantinib (60 mg daily) in previously treated ccRCC (n=42), demonstrating a 46% ORR, including a 4% CR and only 4% PD at a median follow-up of 5.3 months (18). These encouraging data form the basis for the ongoing phase 3 PEAK-1 trial (NCT07011719), which is investigating casdatifan plus cabozantinib vs. cabozantinib alone in patients previously treated with immune checkpoint inhibitors. In parallel, the eVOLVE-RCC (NCT07000149) phase 1b/III trial is investigating casdatifan in combination with volrustomig, a PD-1/CTLA-4 bispecific antibody, as first-line therapy in advanced RCC. In a recent phase 1/2 trial of NKT2152 in heavily pretreated patients with advanced ccRCC, the ORR was 20% among 100 efficacy-evaluable patients, with a median PFS of 7.4 months. Two loading/maintenance dose regimens are being further evaluated in the ongoing dose-expansion phase (19).

At a median follow-up of 50 months, LITESPARK-004 demonstrated that sustained HIF-2α inhibition with belzutifan provides durable, multi-organ disease control in VHL-associated tumors while substantially reducing the need for invasive procedures. Therapeutic responses of belzutifan may require prolonged treatment duration, underscoring the importance of ongoing treatment and clinical monitoring. Anemia remains the most common adverse event but is generally manageable with supportive care. Building on this success, the role of belzutifan is expanding into sporadic ccRCC, where aberrant HIF-2α signaling is a defining molecular feature. Ongoing trials are evaluating belzutifan in combination with VEGF-TKIs and immune checkpoint inhibitors at various settings, aiming to enhance efficacy through synergistic mechanisms. These combination strategies seek to improve outcomes across multiple treatment settings and support the integration of belzutifan as a foundational component of systemic therapy for sporadic ccRCC.

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