From surgery to systemic therapy: long-term lessons of belzutifan in von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant syndrome resulting from a germline mutation in the VHL tumor suppressor gene on chromosome 3p25 (1). The syndrome predisposes affected individuals to a diverse set of benign and malignant neoplasms across multiple organ systems, most commonly clear cell renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors, and retinal hemangioblastomas (2). Multi-organ tumors often develop by the third decade, requiring vigilant surveillance and surgical intervention guided by size thresholds such as the 3 cm cutoff for renal lesions to balance metastatic risk with surgical morbidity (1). This paradigm, while effective in preventing metastasis in many cases, comes at the cost of numerous invasive procedures over a patient’s lifetime, with associated risks including vision loss, renal function impairment, neurological deficits and reduced quality of life.

The underlying pathophysiology of VHL disease involves inactivation of the VHL protein, which impairs oxygen-dependent ubiquitination and degradation of hypoxia-inducible factors, particularly hypoxia-inducible factor 2-alpha (HIF-2α), leading to constitutive activation of downstream transcriptional programs that drive angiogenesis, cell proliferation, and metabolic reprogramming (3). The development of an HIF-2α inhibitor, has therefore offered an attractive disease-specific therapeutic strategy for patients with VHL disease. Belzutifan is the first such agent to gain regulatory approval, supported by initial data from the single-arm phase 2 LITESPARK-004 trial, which demonstrated marked antitumor activity in VHL-associated neoplasms. The updated analysis from Srinivasan et al., with a median follow-up approaching 50 months, now provides the most mature dataset to date on the long-term efficacy, durability, and safety of belzutifan in this population (4).

LITESPARK-004 enrolled 61 adults with genetically confirmed VHL disease, at least one measurable RCC tumor, no metastatic disease, and no prior systemic anticancer therapy. Participants received oral belzutifan at 120 mg daily (4). The baseline cohort was relatively young (median age 41 years), with excellent performance status [82% Eastern Cooperative Oncology Group (ECOG) 0], and nearly all (97%) had undergone at least one prior VHL-related surgery, underscoring the recurrent procedural burden typical of this disease. Median follow-up was 49.9 [interquartile range (IQR), 48.9–52.2] months, and 59% of participants remained on treatment at data cutoff, with a median treatment duration of 48.7 months (4).

In VHL-associated RCC, the objective response rate (ORR) was 67% (41 of 61), including complete responses in 11% and partial responses in 56%, an improvement from the 49% ORR reported in the initial analysis (4). Ninety-two percent of patients experienced any reduction in the sum of target lesion diameters. Median time to response was 11.1 (IQR, 6.2–16.5) months, suggesting that meaningful tumor regression may occur well beyond the early months of therapy. Median duration of response was not reached [95% confidence interval (CI): 41.3 months to not reached], with 71.5% of responders maintaining benefit at 42 months by Kaplan-Meier estimate. Median progression-free survival (PFS) was 49.8 months, with an estimated 42-month PFS rate of 79%.

Activity extended beyond the kidney. Among 50 patients with evaluable CNS hemangioblastomas, the ORR was 48% (up from 30% in the primary analysis), with complete responses in 8%. Nearly all evaluable patients (97%) demonstrated some degree of lesion shrinkage. In 22 patients with pancreatic neuroendocrine tumors, the ORR was an impressive 91%, with half achieving complete responses. For 14 patients with evaluable retinal hemangioblastomas, 93% showed improvement. Across all non-RCC lesion types, median duration of response was not reached, indicating ongoing benefit at last follow-up (4).

One of the most clinically meaningful findings is the reduced surgical burden. In the 4 years before belzutifan, 75% of participants had at least one tumor reduction procedure, totaling 86 interventions (39 RCC, 33 CNS hemangioblastomas, nine retinal, three pancreatic, two “other”). After initiating belzutifan, only 26% required any such procedures, with a total of 18 interventions performed. While the study was not designed to formally quantify surgical avoidance, this sharp reduction suggests that systemic HIF-2α inhibition can substantially delay, and in some cases eliminate, the need for surgery, an important goal in preserving renal function and reducing cumulative morbidity in VHL patients.

The long-term safety profile was consistent with earlier reports, with no new safety signals. Anemia was the most common treatment-related adverse event, affecting 89% of patients, but was predominantly grade 1 or 2 and managed with erythropoiesis-stimulating agents or transfusion. Grade 3 anemia occurred in 11%, fatigue in 5%, and other grade 3 events were rare. Only a small percentage (3%) of participants discontinued due to adverse events (4). This tolerability profile is particularly relevant for a therapy intended for long-term, potentially indefinite administration in a chronic genetic syndrome.

Taken together, these data reinforce belzutifan’s position as the first systemic therapy capable of providing durable, multi-organ tumor control in VHL disease while meaningfully reducing procedural burden. They also support a paradigm shift from reactive, surgery-driven management toward proactive, systemic disease suppression. For patients, the implications extend beyond tumor shrinkage: fewer operations, preserved organ function, and a reduction in the physical and psychological toll of repeated interventions.

The translational significance is equally notable. VHL disease offers a model for precision oncology, where a single germline alteration drives tumorigenesis via a defined molecular pathway. The consistent activity of belzutifan across RCC, CNS, pancreatic, and retinal lesions underscores the centrality of HIF-2α in VHL pathophysiology and validates it as a unifying therapeutic target. This experience illustrates the potential for rationally designed, pathway-specific inhibitors to alter the natural history of hereditary cancer syndromes, setting a benchmark for drug development in similarly well-defined molecular contexts.

At the same time, several limitations warrant consideration. The single-arm, phase 2 design without a comparator arm limits definitive conclusions about relative efficacy versus surgery alone or alternative therapies. The trial’s modest sample size (n=61) and strict eligibility criteria, which excluded patients with metastatic disease or those needing immediate surgery, resulted in a selected population with earlier-stage disease, younger age, and fewer comorbidities than the broader VHL cohort in routine practice (4). These factors may influence both the observed efficacy and tolerability, and caution is warranted in extrapolating results to all VHL patients.

Important questions remain. The durability of benefit beyond 50 months, and its translation into improved overall survival, will require extended follow-up. The optimal sequencing of belzutifan, whether to start at first detection of eligible lesions or reserve for specific scenarios, remains undefined. Similarly, the potential for combination strategies, either with other targeted agents or immunotherapy, remains unexplored in this setting. Understanding mechanisms of acquired resistance to HIF-2α inhibition will be crucial in informing subsequent therapy for patients who progress on belzutifan. The impact of treatment on patient-reported outcomes and quality of life, particularly given the apparent reduction in surgical burden, remains to be quantified and should be a priority for future studies. Finally, prospective, controlled studies assessing surgical avoidance and organ preservation as explicit endpoints would help solidify belzutifan’s value in reshaping the natural history of VHL disease.

The nearly 50-month follow-up from LITESPARK-004 establishes belzutifan as a cornerstone in the systemic management of VHL-associated neoplasms. By directly targeting the molecular driver of disease, it achieves durable tumor control across multiple organs, reduces surgical burden, and does so with a safety profile compatible with long-term administration. For a patient population long managed with cycles of surveillance and surgery, this represents a meaningful shift in therapeutic philosophy. As ongoing research addresses unanswered questions around durability, sequencing, resistance, and quality of life, belzutifan’s success offers both a tangible clinical benefit for patients with VHL and a proof-of-concept for the broader potential of pathway-targeted therapy in hereditary cancer syndromes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

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