When is belzutifan the right option for von Hippel-Lindau disease-associated hemangioblastomas?—a critical review of LITESPARK-004 results

Von Hippel-Lindau (VHL) disease is a tumor predisposing condition associated with an autosomal dominant inheritance pattern caused by germline mutations in the VHL gene on chromosome 3p25 (1-3). VHL is associated with a variety of tumors, including clear cell renal cell carcinomas (RCC), pheochromocytomas, pancreatic neuroendocrine tumors (pNET), retinal capillary hemangioblastomas, endolymphatic sac tumors of the middle ear, and central nervous system (CNS) hemangioblastomas (4).

CNS hemangioblastomas related to VHL most frequently involve the posterior fossa and the spinal cord, but can develop anywhere along the neuroaxis (5). These tumors are benign but can cause significant morbidity based on their location, leading to symptoms such as ataxia, gait difficulty, and brainstem dysfunction (6). Historically, CNS hemangioblastomas associated with VHL have been managed with expectant surveillance, surgical resection, and radiation therapy, including stereotactic radiosurgery (SRS) (7,8). Surveillance is a viable strategy for individuals with asymptomatic CNS hemangioblastomas that are not demonstrating rapid growth (5). CNS hemangioblastomas can have solid and cystic components (5,6). The cystic component of the tumor can undergo accelerated growth, rapidly enlarge and cause neurological deterioration, requiring urgent surgical intervention (6). Surgical resection is associated with excellent local tumor control and should be considered for larger symptomatic tumors even in the absence of rapid progression (5,7). For lesions not amenable to surgery, SRS has been historically utilized. SRS is associated with a low risk of adverse events but diminishing long-term control (8). More recently, advancements in understanding of tumorigenesis associated with VHL have led to development of a systemic therapy option that can be used for treatment of CNS hemangioblastomas (9).

Tumor development in VHL is mediated through hypoxia inducible factor (HIF) 1α and 2α. Under conditions of normal oxygen tension, HIF1α is constitutively produced but undergoes proteosomal degradation mediated by the E3 ubiquitin ligase action of the VHL protein.(10) Among patients with VHL disease, HIF1α proteolysis is diminished, which leads to stabilization of HIF subunits and constitutive activation of HIF-mediated transcription pathways that regulate expression of vascular endothelial growth factor, cyclin D1, glucose transporter 1, and erythropoietin (9,11). Activation of these cell growth and angiogenesis pathways leads to development of the hypervascular tumors associated with VHL, including CNS hemangioblastomas (9,11). Belzutifan, previously called MK-6482 and PT2977, is a small molecule HIF-2α inhibitor that has demonstrated efficacy in treatment of VHL-associated tumors (9).

In a phase 1 trial of patients with advanced RCC, belzutifan was associated a favorable safety profile and demonstrated early evidence of efficacy (12). In the subsequent registrational, open-label, single arm, phase 2 LITESPARK-004 study, efficacy of belzutifan was evaluated among patients with VHL-associated RCC (9). LITESPARK-004 enrolled adult patients with VHL who had at least one measurable RCC that did not require immediate surgical intervention. In this single-arm study, patients were treated with belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. Sixty-one patients with VHL-related RCC were treated. Objective responses were noted in thirty patients, all of which were classified as partial responses (PR) defined as at least 20% reduction in tumor size. Median time to response was 8 months and median duration of response was not reached at the time of the initial study report.

In addition to RCC, responses for pNETs and CNS hemangioblastomas were evaluated among the participants (9). Pancreatic lesions associated with VHL may be cystic or solid tumors consistent with pNET. The prevalence of pNETs in VHL has been reported as 9–17% (13). Historically, management of these tumors has included expectant surveillance and surgical resection, with decision making influenced by lesion size VHL genotype. In the LITESPARK-004 study, 22 patients had measurable pNETs. Among these patients, the objective response rate (ORR) was 91%. Seventeen PRs and three complete responses (CRs) were noted. Median time to response for pNET was 8 months.

Fifty patients had measurable CNS hemangioblastomas. Among these patients, ORR was 30% with 12 PR and 3 CR reported. Median time to response for CNS hemangioblastomas was 3 months, with 73% of patients experiencing a response duration of at least 12 months. Median follow up at the time of the initial study report was 22 months.

Based on the results of the phase 2 clinical trial, belzutifan was granted approval by the United States Food and Drug Administration (FDA) in 2021 for RCC, pNET, and CNS hemangioblastomas associated with VHL not requiring immediate surgery (14). Since initial approval, additional clinical studies have evaluated use of belzutifan in the real-world setting for VHL-associated tumors (15-18). Potential efficacy of the agent for treatment of retinal capillary hemangioblastomas related to VHL has also been suggested, but this is not an indication currently included as part of the FDA label (19,20).

In September 2024, additional results from the LITESPARK-004 study for use of belzutifan for treatment of CNS hemangioblastomas were published (21). In this subsequent analysis, CNS hemangioblastoma responses were evaluated using two approaches. In approach one, investigators evaluated all measurable and non-measurable lesions at baseline, including both solid and cystic components. A measurable lesion was defined as a lesion that was at least 1 cm across its maximum diameter. In approach two, only lesions with at least 1 cm solid component were included. Fifty patients with at least one CNS hemangioblastoma were followed for a median of 38 months. Twenty-two of fifty patients (44%, 4 CR, 18 PR) had an objective response using approach one. Median time to response was 5.4 months and median duration of response was not reached at the time of the report. Only 25 patients had at least one CNS hemangioblastoma with a solid component measuring 1 cm or greater. Among these patients, evaluated under approach two, 19 of 25 (76%, 1 CR, 18 PR) had an objective response. Median time to response was 3.1 months and median duration of the response was not reached.

The original results from LITESPARK-004 indicated an ORR of 30% for CNS hemangioblastomas. The updated results included 16 additional months of follow up data, with ORR improved to 44% (21). Median time to response increased from 3.2 to 5.4 months, indicating CNS responses may occur over a longer period than initially suggested. Once obtained, responses tended to be durable, with most patients experiencing duration of response for at least 36 months. Further, treatment with belzutifan was associated with a reduction in need for CNS-related surgeries (21). Prior to participation in the clinical trial, more than half the patients with CNS hemangioblastomas underwent at least one neurosurgical intervention. Following participation, only one individual underwent a CNS-related surgery.

Updated results also indicate that responses are more likely to occur in the setting of solid tumors rather than tumors with cystic components (21). This finding is consistent with two retrospective studies reporting objective responses in patients with VHL-associated CNS hemangioblastomas (15,18). LITESPARK-004 investigators proposed that the agent may target solid components of hemangioblastomas, directly reducing the size of such tumors. Decrease in size of the cystic component may lag, caused indirectly by decreased exudation into the peritumoral cyst (21). However, since tumors with solid components were more likely to demonstrate a radiographic response in the study, careful surveillance would be recommended during this anticipatory lag suggested by the investigators. Since median time to response was reported as 5.4 months, individuals with symptomatic cystic lesions should be considered for potential surgical interventions as systemic therapy may not provide a clinically meaningful reduction in tumor size in a timely manner.

The clinical trial results are overall promising and indicate that belzutifan is a viable treatment option for individuals with CNS tumors. However, the systemic therapy does have associated toxicities. In the initial clinical trial report, the most common adverse events were anemia and fatigue, affecting 90% and 66% of participants, respectively (9). Hypoxia has also been noted in up to 29% of patients taking the agent (9,14,15,21). Individuals taking the medication should be screened for anemia prior to initiation of treatment and monitored continuously throughout therapy. Patients should also be assessed for hypoxia prior to starting belzutifan and monitored throughout therapy. In the event that clinically significant or symptomatic anemia or hypoxia occurs, dose reduction or drug discontinuation may be needed (14).

Many patients with VHL and associated tumors are of reproductive age (7). According to animal studies, belzutifan is associated with embryo-fetal toxicity (14). Use of this agent during pregnancy is absolutely contraindicated. Coadministration of belzutifan with CYP3A4 substrates decreases concentration of CYP3A4 substrates, which can render oral contraceptives ineffective. Individuals taking the medication must be counseled on the potential embryo-fetal risk and recommended effective non-hormonal contraception. Belzutifan is also contraindicated during lactation. Further, the agent may impair fertility in males and females of reproductive potential and this effect may be irreversible (14). Individuals taking the agent must be counseled of this risk and referred accordingly for fertility preservation. In addition, LITESPARK-004 only enrolled adult patients (21). Efficacy and tolerability of belzutifan in pediatric patients is unknown.

The ORRs and durable responses to treatment reported as part of the LITESPARK-004 trial are encouraging, though limited by the single-arm nature of the study design with no prospectively followed comparison arm. To date, belzutifan does represent the only systemic therapy option with clinically meaningful efficacy in treatment of VHL-associated tumors. However, progression free survival and overall survival benefits of the agent remain unknown. Potential utility of the medication in preventing development of additional VHL-related tumors is also unknown. While the medication is well tolerated, there are potentially serious toxicities such as anemia and hypoxia that require monitoring and intervention. Embryo-fetal risks and concerns regarding impaired fertility require consideration prior to treatment initiation. Further, the clinical trial data to date suggest the agent is more effective in producing objective responses for solid CNS tumors as opposed to cystic tumors.

Many patients with VHL have stable disease and can be managed effectively with expectant surveillance without risking potential toxicities associated with systemic therapy. Further, since the median time to response was reported as 5.4 months for CNS hemangioblastomas and 8 months for RCC and pNET, in accordance with belzutifan’s FDA label, use of this systemic therapy agent is not appropriate for individuals who need immediate surgery for VHL-related tumors. Surgical resection and stereotactic radiation therapy remain options for management of VHL-related CNS hemangioblastomas (22). Ablation techniques can be considered as minimally invasive alternatives to surgery for VHL-associated RCC and pNET (23,24). Based on available clinical trial data, patients who are experiencing progression of their tumors but not in need of urgent surgical intervention currently represent ideal candidates for treatment. The promising data with this agent also lends optimism to future additional disease-modifying therapeutics for other tumor-predisposing conditions.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2478/prf

Funding: This publication was supported by the National Center for Advancing Translational Sciences (NCATS) (No. UL1 TR002377). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2478/coif). U.S. received one-time consulting fees from Alexion Pharmaceuticals and Servier Pharmaceuticals; and one-time speaker fee from Merck & Co., Inc. The other author has no conflicts of interest to declare.

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