From surgery to systemic therapy in von Hippel-Lindau disease: insights from extended follow-up of LITESPARK-004

The management of von Hippel-Lindau (VHL) disease has undergone a remarkable transformation in recent years. For decades, treatment revolved around vigilant surveillance and repeated surgeries, an approach that effectively delayed metastasis but often came at the cost of significant cumulative morbidity. With the advent of belzutifan, a first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor, the paradigm has shifted dramatically. For the first time, clinicians can offer a systemic therapy that directly targets the molecular driver of disease rather than relying solely on surgical control. The recently reported long-term outcomes for patients in the LITESPARK-004 trial not only confirm the durability of belzutifan-associated tumor responses and treatment tolerability but also raise important questions about optimal timing, duration, and breadth of use. In this commentary, we review these updated data and explore their implications for clinical practice, patient quality of life, and future research directions for both hereditary and sporadic renal cell carcinoma (RCC).

VHL disease is a rare, inherited, multisystem cancer syndrome caused by germline mutations in the VHL tumor suppressor gene (1). This genetic alteration confers a lifetime predisposition to a spectrum of both malignant and benign tumors, most prominently RCCs, pancreatic neuroendocrine tumors (pNETs), and central nervous system (CNS) hemangioblastomas, but also including retinal hemangioblastomas, endolymphatic sac tumors, epididymal cystadenomas, and pheochromocytomas (2,3). Although some of these tumors are termed benign, lesions such as CNS hemangioblastomas often lead to substantial neurologic morbidity (2). The lifetime risk of RCC approaches 70%, with tumors often presenting as multifocal, bilateral clear cell lesions and carrying a high probability of progression and metastasis (4-6). Indeed, RCC progression remains the leading cause of mortality in VHL disease (7). Before the availability of belzutifan, the median life expectancy for patients with VHL disease was about 50 years (8,9) with RCC management relying on repeated surgical resections or local ablative therapies when the largest renal lesion approached 3 cm, a threshold used to reduce metastatic risk but associated with significant cumulative morbidity (10).

The reliance on surgery as the primary modality to manage VHL disease began to shift in 2021 when belzutifan received US Food and Drug Administration (FDA) approval as the first and only systemic therapy for VHL-associated RCC, CNS hemangioblastomas, and pNETs (11) and more recent United Kingdom (UK) [Medicines and Healthcare products Regulatory Agency (MHRA), 2022] and European [European Medicines Agency (EMA), 2025] approvals for patients in whom local therapy is unsuitable (12,13). Regulatory approval was based on outcomes from the LITESPARK-004 trial observed after a median follow-up of 21.8 months, which established belzutifan as a targeted option capable of reducing or delaying the need for surgery (14). LITESPARK-004 was a single-arm, phase 2 study conducted at 11 sites in the United States, UK, Denmark, and France. The trial enrolled 61 adults with germline VHL mutations, at least one measurable non-metastatic RCC lesion ≤3 cm, Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and no prior systemic therapy. Patients with larger renal tumors or those requiring immediate surgical intervention were excluded. All participants received belzutifan 120 mg orally once daily. The primary endpoint was objective response rate (ORR) in VHL-associated RCC as determined by an independent review committee. The secondary endpoints included response assessments in VHL-associated CNS hemangioblastomas, pNETs, and other extrarenal lesions, as well as safety and tolerability outcomes.

In the initial LITESPARK-004 analysis with 21.8 months median follow-up, the ORR for RCC tumors was 49% with no complete responses (CRs) (14). The updated LITESPARK-004 results recently published by Srinivasan et al. in Lancet Oncology with a median follow-up extending to 49.9 months demonstrated an increased ORR in RCC tumors to 67% (see Table 1) (15). The most recent update, presented at the American Society of Clinical Oncology (ASCO) 2025 annual meeting with a median follow-up of 61.8 months, showed a further increase in ORR to 70% (16). Notably, the CR rate also rose over time, reaching 11% with longer follow-up (Table 1). Most patients achieving CR had smaller tumors at the start of belzutifan treatment measuring <2 cm (16). The median time to response lengthened from 8.2 months in earlier reports to 11.1 months with longer follow-up, reflecting that responses often emerged late, sometimes 2–3 years after therapy initiation (14,15). Thus, the tempo of belzutifan-mediated RCC regression appears gradual, with responses in many patients deepening over years rather than months. The median duration of response has not been reached, with 71.5% of patients maintaining a response beyond 42 months. These findings demonstrate that belzutifan provides durable disease control of RCC tumors for the majority of treated patients. The extended time to maximal response and higher CR rates in smaller RCC lesions suggest earlier use might improve outcomes. However, early initiation also requires readiness for long-term treatment, underscoring the need to individualize decisions based on potential benefit versus the burden of prolonged therapy in asymptomatic patients.

While all patients enrolled in LITESPARK-004 had measurable RCC, belzutifan also demonstrated substantial activity in extrarenal lesions. In CNS hemangioblastomas (n=50), ORR increased from 30% in early analysis to 50% at 5 years, with tumor shrinkage in 97% of patients and most responses lasting beyond 3 years (14-17). Among pNETs (n=22), ORR rose from 77% to 91%, including three CRs; all responders maintained benefit beyond 36 months (14-16,18). Notably, no patients required pancreas-related surgery after starting belzutifan, underscoring its potential to preserve organ function. Retinal hemangioblastomas responded in 13 of 14 patients (93%), with sustained effects for more than 2 years (15,19). Although only three patients with pheochromocytomas were enrolled in LITESPARK-004, all achieved stable disease following belzutifan initiation (11). Taken together, these findings indicate that belzutifan’s efficacy extends to all the common VHL-associated tumor types driven by the same underlying molecular pathway.

Perhaps the most striking measure of belzutifan’s success is its impact on the need for surgical intervention. Historically, management of VHL-associated tumors relied almost entirely on repeated procedures, but with belzutifan, that paradigm has shifted. In the 4 years preceding their study enrollment, 75% of patients underwent at least one tumor-reducing procedure. After treatment initiation, this rate fell sharply to 26%, with most interventions occurring in patients who had discontinued therapy. The marked reduction in surgical burden suggests a meaningful decrease in long-term morbidity and preservation of organ function for belzutifan treated patients (15,20). Overall, these findings underscore belzutifan’s potential to significantly lessen the cumulative invasive treatment burden associated with VHL disease.

At 49.9 months median follow-up, 36 of 61 patients (59%) remained on treatment (15). Acquired resistance to belzutifan was an uncommon cause of treatment failure. Ten patients (16%) developed progressive disease, with time to progression ranging from 19 to 52 months. Although progression patterns were not fully described, six patients underwent local procedures yet continued belzutifan, indicating that isolated resistant lesions could be treated surgically while other sites remain adequately controlled by belzutifan. This supports the feasibility and potential benefit of combining or sequencing systemic therapy with local interventions. Seven patients who discontinued treatment required a subsequent tumor-reducing procedure with a median time from discontinuing belzutifan of 3.3 months. This relatively short interval underscores a need to maintain ongoing multidisciplinary oversight for many patients.

Overall, belzutifan was well tolerated, with most adverse events graded 1–2 in severity. The most frequent treatment-related adverse event was anemia (89%), followed by fatigue (66%), dizziness (25%), and nausea (25%). Grade 3 events were uncommon, occurring in 11 (18%) patients, including 7 (11%) patients with anemia, 3 (5%) with fatigue, and 1 (2%) with hypoxia. No grade 4 or 5 treatment-related events were reported, and only 3% of patients permanently discontinued belzutifan due to toxicity. Serious adverse events were rare. During the study, one grade 2 intracranial hemorrhage was reported. However, there have been three additional post-marketing cases reported of early hemorrhagic events in CNS hemangioblastomas (21). Such observations underscore the importance of ongoing vigilance and long-term safety monitoring, particularly in a rare disease setting where available safety data represent a small study cohort. Dose interruptions (21%) and reductions (13%) were primarily used to manage anemia and fatigue, while transfusion and erythropoiesis-stimulating agent (ESA) use remained infrequent. The most common reason for treatment discontinuation was elective withdrawal (18%) which may indicate that the chronicity of low-grade side effects was less appealing than risk of episodic surgical interventions for a subset of patients.

Belzutifan-associated anemia represents an expected on-target effect of HIF-2α inhibition, as this transcription factor directly regulates erythropoetin (EPO) production in the kidney (14). Physiologic EPO replacement in this context represents an attractive strategy to manage belzutifan-associated anemia and fatigue, which differs biologically from the supraphysiologic ESA exposure historically used for refractory cancers or chemotherapy-related cytopenias. In advanced cancer, including RCC, prior ESA use has been linked to increased mortality, thromboembolic events, and possible tumor progression (22,23). In RCC specifically, concern arises from preclinical data showing that exogenous erythropoietin may stimulate tumor growth in vitro, as RCC frequently expresses EPO and its receptor (EPOR), driven in part by HIF activation in the setting of a VHL mutation (24). However, much of the EPO-associated safety concerns occurred in patients receiving high-dose cytotoxic chemotherapy, where ESA-associated neutropenia, treatment breaks, and dose reductions likely reduced chemotherapy intensity, potentially explaining progression risk (25,26). In a post hoc analysis of LITESPARK-004, ESA use (n=15) did not alter response rates or accelerate progression compared to non-ESA patients (24,27). While current evidence does not suggest that ESA exposure alters tumor biology or accelerates resistance, the limited sample size, non-metastatic population, and prolonged therapy warrant caution. Alternatives to ESA support include dose reduction or treatment interruption of belzutifan and red blood cell transfusions. Reducing belzutifan dose intensity can improve anemia but may compromise anti-tumor efficacy. Transfusions offer rapid symptomatic relief, but the associated risk of allosensitization is a serious concern particularly relevant for VHL patients who may ultimately require renal transplantation after bilateral nephrectomies for management of RCC (28). Thus, the optimal approach to anemia management in belzutifan-treated patients remains to be defined. Continued follow-up of belzutifan-treated patients from both VHL syndrome and sporadic RCC cohorts will be essential to clarify the long-term impacts on safety and tumor control for these anemia management strategies.

Gaps remain in our understanding of the optimal implementation of belzutifan for VHL disease. Data on less common VHL-associated tumors such as endolymphatic sac tumors, pheochromocytomas, and epididymal cystadenomas are limited to isolated case reports (29,30). In addition, with a median patient age of 41 years from the LITESPARK-004 cohort, fertility and reproductive health considerations emerge as particularly important. Preclinical studies noted in the FDA package insert report irreversible male reproductive toxicity and embryo-fetal lethality but without adverse effects on female reproductive organs identified in animal testing at or below human-equivalent doses (31). No human data on fertility or pregnancy outcomes have been reported to date. However, it is important to recognize for patient counseling that belzutifan may reduce the efficacy of some hormonal contraceptives (11,31). Real-world registries are urgently needed to help fill this knowledge gap regarding reproductive risks. Belzutifan’s success in reducing surgical morbidity supports its use earlier in the disease course, targeting smaller lesions or even as a preventative approach before lesions emerge. While this strategy may enhance disease control, it also extends treatment during a life stage when many patients are making family-planning decisions. This creates a tension between the potential benefits of deeper, earlier responses and the personal consequences of therapy on fertility, pregnancy, and life planning. Longer treatment durations will also accentuate the need for improved strategies to maintain tolerability and quality of life over time. Balancing efficacy with these reproductive risks will require careful counseling, integration of fertility preservation strategies, and open discussions about family planning (21). Future research should evaluate whether planned treatment breaks or intermittent dosing can sustain long-term benefit while mitigating cumulative toxicity. Collection of real-world safety data and prospective patient-reported outcomes data may help guide the optimization of long-term disease control and quality of life in belzutifan-treated patients. In weighing earlier and prolonged use of belzutifan in a younger patient population, it is also important to consider the economic impact. Prolonged therapy may impose a significant financial toxicity of cumulative drug cost, although these expenses may be partly offset by reductions in surgical interventions and prevention of end-stage organ dysfunction such as kidney failure and associated dialysis and renal allografting costs.

The favorable efficacy data for belzutifan treatment of RCC tumors arising in patients with VHL disease may carry important implications for sporadic clear cell RCC (ccRCC), where VHL inactivation and HIF-2α activation are also early oncogenic events (32). In the LITESPARK-005 trial, belzutifan monotherapy for patients with heavily pretreated, sporadic, metastatic ccRCC was compared to everolimus and demonstrated superior activity with an ORR of 21.9%, though an overall survival benefit has not yet been demonstrated (33). Plausible explanations for the discrepant belzutifan response data for RCC tumors arising in VHL disease versus sporadic RCC include the more advanced disease stage at which sporadic RCC is often treated or reduced dependence on the VHL-HIF pathway in patients who have progressed after VEGF-targeted therapy. Belzutifan treatment earlier in the disease course may be more compelling, possibly before alternative oncogenic pathways dominate. In the LITESPARK-003 trial, front-line belzutifan plus cabozantinib for sporadic ccRCC achieved an ORR of 70% and disease control rate of 98% (34), surpassing the response rates seen with front-line cabozantinib as a single agent in CABOSUN (20%) or with the cabozantinib-nivolumab regimen in CheckMate 9ER (55.7%) (35,36). Although these data support the promise of earlier-line therapy, the combination approach complicates interpretation of belzutifan’s independent contribution. Ongoing phase 3 studies will also be informative: LITESPARK-012 is evaluating the pembrolizumab plus lenvatinib doublet versus triplet therapy in combination with belzutifan or the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor quavonlimab as first-line treatment regimens for advanced ccRCC (37), while LITESPARK-022 is assessing belzutifan plus pembrolizumab versus placebo plus pembrolizumab as adjuvant therapy following nephrectomy (38). Collectively, these studies are poised to significantly broaden the role for belzutifan in earlier lines of therapy for treatment of advanced, sporadic RCC.

In summary, follow-up from LITESPARK-004 confirms belzutifan as a highly effective and generally well-tolerated therapy for VHL-associated RCC and other VHL-related neoplasms, offering tumor control, reduced surgical burden, and meaningful preservation of organ function. These findings support early initiation and prolonged treatment in appropriate patients. However, longer-term outcomes remain uncertain beyond the current median follow-up of 5 years, highlighting the need for continued longitudinal surveillance to clarify long-term safety, durability of response, and quality of life trade-offs. These factors warrant careful attention in future studies, particularly as efforts to extend HIF-2α inhibition strategies to a larger population of patients with advanced, sporadic RCC continue.

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.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-637/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-637/coif). L.M.T. reports research funding (institution) from Seagen, Merck, and Erasca; travel support from ASCO Merit Award; advisory board/consultant role from American Journal of Managed Care’s Institute for Value-Based Medicine; and honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from OncLive/MJH Life Sciences and CancerNetwork. S.S.T. reports a consulting role from FirstWord, Bristol-Myers Squibb, AVEO Oncology and Exelixis; honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from OncLive/MJH Life Sciences, Targeted Oncology, CancerNetwork, and Topline Bio; support for attending meetings/travel from DAVA Oncology and KidneyCAN; and research funding (institution) from Xencor, Merck, AVEO Oncology, Bristol-Myers Squibb, Exelixis, Pfizer, Iovance Biotherapeutics and HiberCell. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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