Belzutifan: a novel therapeutic for the management of von Hippel–Lindau disease and beyond

Abstract

The identification of the VHL gene and its role in regulating the hypoxia-inducible factor signaling pathway has helped to revolutionize the treatment of renal cell carcinoma (RCC). Belzutifan is a novel small-molecule inhibitor of hypoxia-inducible factor 2α which has demonstrated efficacy in treating von Hippel–Lindau (VHL) disease, earning regulatory approvals for this indication. There is also early evidence for efficacy in sporadic RCC. Belzutifan has a favorable safety profile. Several clinical trials are currently ongoing, which should help in identifying this promising drug’s role in RCC and beyond. This review summarizes the history, pharmacology and clinical evidence for belzutifan use to date, and also explores unanswered questions as they relate to this novel therapeutic agent.

Plain language summary

The novel drug belzutifan was developed after years of research in identifying the VHL gene and how genetic abnormalities in VHL may result in tumor growth. Belzutifan has been approved for use in patients with VHL disease – a rare familial disorder first described in the 19th century that presents with a variety of cancerous and noncancerous tumors, including kidney cancer. Growing evidence supports belzutifan’s use in non-familial kidney cancer as well. This is important because most patients eventually develop resistance to the currently available cancer treatments, highlighting the need for drugs with a different mechanism of action. Belzutifan works by blocking a protein called HIF-2a, which causes tumor growth in patients with VHL disease. Belzutifan is well tolerated, with the most common side effects being low energy, hemoglobin and blood oxygen. This review summarizes the history, mechanism of action and research evidence to date supporting the use of belzutifan in VHL disease and cancer treatment. We also discuss future directions, including remaining clinical questions and areas of ongoing research.

Plain language summary

Executive summary.

Introduction

• Although the last decade has ushered in a new era of systemic therapy options for the management of metastatic renal cell carcinoma (RCC), including molecular targeted therapies and immune checkpoint inhibitors, most patients will eventually develop disease progression. This emphasizes the need for therapeutics with alternative mechanisms of action in the management of metastatic RCC.

The VHL gene & its role in the cellular oxygen sensing pathway

• The VHL gene was identified in 1993, nearly a century after the first historical descriptions of von Hippel–Lindau (VHL) disease. VHL disease is caused by a germline variant in VHL, with an additional somatic inactivation/deletion of VHL in tumor cells.

• Variants in VHL may manifest in the absence of functional VHL protein, creating a cellular pseudohypoxic state whereby hypoxia-inducible factor (HIF) transcription factors are not degraded as they normally are in the presence of oxygen, ultimately leading to proangiogenic and tumorigenic gene expression.

Belzutifan clinical pharmacology

• Belzutifan (MK-6482) is a first-in-class, second-generation HIF-2α inhibitor that selectively disrupts the heterodimerization of the HIF transcription complex, preventing downstream target gene transcription and resultant oncogenesis.

• Evidence to date suggests that belzutifan has a well-tolerated toxicity profile. The most commonly experienced side effects include fatigue, anemia and hypoxia.

Clinical efficacy of belzutifan

• LITESPARK-001 was the first-in-human, phase I study of belzutifan that investigated its pharmacodynamics, pharmacokinetics and toxicity in 95 patients with locally advanced or metastatic solid tumors. In this study, belzutifan was well tolerated without dose-limiting toxicities, establishing 120 mg once daily as the recommended phase II dose.

• Belzutifan for VHL disease was first evaluated in the nonrandomized, phase II LITESPARK-004 study, in which 61 patients with VHL-associated, localized RCC were treated with belzutifan 120 mg orally daily. The demonstrated efficacy for RCC and non-RCC lesions led to the US FDA’s approval of belzutifan in 2021 for the treatment of adult patients with VHL disease, with Health Canada and other regulatory bodies following suit.

• The interim analysis of the phase III study LITESPARK-005 was presented at the European Society for Medical Oncology Congress in 2023, showing superior objective response rate and progression-free survival for belzutifan compared with everolimus in previously treated patients with advanced RCC.

Discussion

• To date, belzutifan has not been approved in any jurisdiction for treatment beyond VHL disease, for which the evidence is most robust. Growing evidence suggests belzutifan’s efficacy in sporadic RCC; however, its place in the treatment algorithm has not yet been clearly established due the paucity of phase III trial evidence.

• There are numerous phase III trials evaluating the safety and efficacy of belzutifan in combination with other treatments in the second- and first-line and adjuvant settings for RCC.

• If belzutifan finds its way into the armamentarium of systemic therapy for metastatic RCC, this agent could be practice-changing beyond the VHL population.

Renal cell carcinoma (RCC) is the most common renal neoplasm, accounting for 85% of all cases [1]. With increased axial imaging over the past few decades, the incidence of RCC has increased, with more disease being detected incidentally [2]. Yet up to 20% of patients present with metastatic disease at the time of diagnosis and 20–40% of surgically resected patients eventually develop recurrence [2,3]. Much of our understanding of the development of RCC has evolved around an understanding of the VHL gene and its role in regulation of the hypoxia-inducible factor (HIF) signaling pathway. The last decade has ushered in a new era of systemic therapy options for management of metastatic RCC (mRCC). Molecular targeted therapies, including VEGF tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), or a combination thereof, have been approved as first-line systemic treatments and have significantly improved survival [3]. Unfortunately, most patients will eventually develop disease progression on these combinations. Subsequent treatment involves the use of alternative VEGF TKIs or mTOR inhibitors. In both the first- and later-line settings, treatment resistance rates are high and virtually all patients will eventually develop progressive disease [4]. This emphasizes the need for therapeutics with alternative mechanisms of action in the management of mRCC. Belzutifan is a novel, second-generation, small-molecule inhibitor of HIF-2α and is considered by many to be a scientific success story rooted in over a century of knowledge translation, from historical clinical observations to the eventual identification of the VHL gene and HIF signaling pathway.

The VHL gene & its role in the cellular oxygen-sensing pathway

A familial pattern of retinal hemangioblastomas was first described by Collins and von Hippel in 1894 and 1904, respectively [5]. Neuropathologist Arvid Lindau identified the association of this disorder with an increased risk of both benign and malignant neoplasms, using the phrase ‘Angiomatosis des Zentralnervensystems’, and by 1936 the term von Hippel–Lindau (VHL) disease was officially coined [5]. Still, it would take another 60 years before the underlying gene abnormality was discovered [5].

The VHL tumor suppressor gene, identified in 1993 using positional cloning techniques, is located on the short arm of chromosome 3 at the locus 3p25–26 [6]. It consists of four exon regions encoding two isoforms of the 213 amino-acid VHL protein (pVHL): pVHL₃₀ and pVHL₁₉ [7,8]. As a tumor suppressor gene, loss or inactivation of both alleles is required for pathogenesis [3]. VHL disease is caused by a germline variant in the VHL gene, with an additional inactivation/deletion of the wild-type allele in tumor cells caused by a somatic event. Biallelic inactivation/deletion of the VHL gene is seen in >90% of sporadic clear-cell RCC (ccRCC) cases. In addition to variants in the gene, chromosomal loss and epigenetic abnormalities such as hypermethylation of the promoter have been observed [3].

By 1999, not only was the VHL gene identified, but it was also determined that HIF was an oxygen-dependent transcription factor. HIFs are transcription factors consisting of an unstable, oxygen-sensitive α-subunit and a stable β-subunit [4]. There are three isoforms of the α-subunit (HIF-1α, HIF-2α and HIF-3α). HIFα consists of an oxygen-dependent degradation domain which contains two proline residues, which are hydroxylated under normoxic conditions [9–11]. In the presence of oxygen, the hydroxylated proline residues are recognized by pVHL, which acts as an assembly for the ubiquitin ligase enzymes (i.e., elongin B and elongin C) [12]. Together, this is known as the VCB ubiquitin E3 ligase complex. With assistance from cullin 2 and the ring finger protein RBX1, the VCB complex results in the polyubiquitination and subsequent proteasomal degradation of HIFα subunits under normoxic conditions [13,14]. In contrast, under hypoxic conditions, the absence of HIFα proline hydroxylation results in downstream overexpression and accumulation of HIFα in the cell cytoplasm [7]. HIFα then forms a heterodimer with the constitutively expressed HIFβ, also known as aryl hydrocarbon receptor nuclear translocator. Together in the cell nucleus, the HIFα/HIFβ heterodimer binds to hypoxia-response elements and induces gene expression by acting as a transcription factor [15,16]. There are hundreds of HIF target genes that are responsible for physiological adaptations that enable cells to survive in hypoxic conditions, but may also drive tumor formation through various mechanisms. These include: TGFA, SLC2A1, CCND1 and CXCR4; VEGF and PDGF overexpression; erythropoiesis; and increased glucose uptake and metabolism via glucose transporters (i.e., GLUT1 and GLUT3) [3,7]. Doctors Kaelin Jr., Ratcliffe and Semenza were awarded the Nobel Prize in Physiology or Medicine in 2019 for their dedicated work in this area [5]. This pathway is summarized in Figure 1.

Figure 1.

Graphic representation of the VHL/HIF oxygen-sensing pathway.

HIF: Hypoxia-inducible factor; VHL: von Hippel–Lindau.

Created with BioRender.com.

In the tumors of patients with VHL disease and the vast majority of sporadic RCCs, pathogenic inactivation or deletion of VHL results in the absence of normal pVHL and an inability to form the VCB complex, leading to downstream HIF accumulation and resultant proangiogenic and tumorigenic gene expression [7,12]. These disease states mimic cellular pseudohypoxia, where VHL gene inactivation can be regarded as a driver mutation and HIFα as the executor of oncogenesis, independent of oxygen concentrations [3]. Downstream, the growth factor VEGF contributes to tumor-associated angiogenesis via the growth, migration and proliferation of vascular endothelial cells, as well as through inhibition of apoptosis and increasing vascular permeability [17]. Under normal physiological conditions, VEGF promotes wound healing, skeletal growth and embryogenesis [17]. VEGF has been long recognized as a major contributor to RCC pathogenesis, and inhibition of this pathway via VEGF TKIs remains a therapeutic target for affected patients. It also explains the highly vascular nature of renal cancer and commonly associated paraneoplastic erythrocytosis [18].

Clinical manifestations of VHL disease

VHL disease is an autosomal dominant, hereditary neoplastic condition, occurring in approximately 1 in 35,000 live births [19]. VHL disease phenotypically manifests with a variety of benign and malignant tumors including RCC, renal cysts, pancreatic cystadenomas and pancreatic neuroendocrine tumors (pNETs), pheochromocytomas, central nervous system (CNS) and retinal hemangioblastomas, endolymphatic tumors of the inner ear, and epididymal or broad ligament cystadenomas [20]. The phenotypic subtypes (type I and type 2A–C) are characterized by the presence or absence of typified lesions, as shown in Table 1 [7]. Patients with VHL disease have an up to 70% lifetime risk of developing RCC, usually the clear-cell subtype, and the risk of metastases increases once renal lesions are ≥3 cm [19]. Management of RCC in the context of VHL disease follows unique principles of treatment that are different from those of sporadic RCC [21]. Nephron-sparing interventions are preferred for lesions >3 cm in size or those demonstrating rapid growth of >5 mm per year [7]. Patients with VHL will undergo multiple such local interventions throughout their lives, with cumulative morbidity and risk for mortality. These invasive management strategies do not alter the natural history of the disease and are done with the goal of reducing the risk of further spread of disease and delaying symptomatic progression. As VHL-associated RCCs occur recurrently and bilaterally, the necessary repeated resection and ablation of these ultimately compromises renal function, leading to chronic renal impairment and a need for dialysis or renal transplantation [7]. Furthermore, there is an increased risk of mRCC. One of the leading causes of death in patients with VHL is complications from RCC [22]. Similarly, CNS and retinal disease, and the necessary local interventions to address them, can lead to significant end-organ dysfunction, including blindness, neurological deficits and reduced health-related quality of life [7]. Ideal treatment goals for this patient population are to achieve cytoreduction of existing tumors, halt the development of new lesions and prevent disease progression, thus reducing the need for multiple extensive surgical interventions. Additionally, treatment should reduce the risk for long-term sequelae of disease such as vision loss, renal impairment and neurological deficits. To that end, systemic therapies that address the underlying pathophysiology have been investigated to improve outcomes [19].

Table 1.

Phenotypic von Hippel–Lindau subtypes.

Subtype		Phenotype	HIF regulation	Genotype
1		Clear-cell RCC Hemangioblastomas Pancreatic tumors Endolymphatic sac tumors	Completely defective	Exon deletions Nonsense Frameshift missense
2	A	Pheochromocytomas Hemangioblastomas Endolymphatic sac tumors	Some present	Missense
	B	Clear-cell RCC Pheochromocytomas Hemangioblastomas Pancreatic tumors Endolymphatic sac tumors	Completely defective
	C	Pheochromocytomas	Maintained

HIF: Hypoxia-inducible factor; RCC: Renal cell carcinoma.

Past & present treatments for VHL disease

Targeting the VEGF pathway

Three VEGF TKIs have been evaluated in prospective clinical trials that enrolled patients with VHL disease: sunitinib, pazopanib and dovitinib. In an open-label, phase II clinical trial, 15 patients with VHL disease received sunitinib 50 mg oral daily for 28 days on, followed by 14 days off [23]. The primary end point of this trial was toxicity. Among those 15 patients, 67% required a dose reduction, and grade 3 toxicity was reported in 33% of patients. In the evaluation of tumor response, 33% of RCCs demonstrated a partial response (PR), while 67% had stable disease (SD) and 10% had progressive disease. Notably, there was no effect of sunitinib on non-RCC lesions, with 0% response rate in renal cysts, retinal hemangioblastomas, pNET and pancreatic cysts [23]. Based on these results, sunitinib was not widely adopted as a systemic therapy approach in patients with VHL disease. In another phase II clinical trial, pazopanib 800 mg orally daily was administered for 24 weeks in 31 patients with VHL disease [24]. The primary end point was objective response rate (ORR) and safety. An ORR in RCC tumors of 42% was reported (3% complete response [CR] rate); however, organ-specific response rates varied, with ORR in CNS hemangioblastomas of 4% and in pancreatic lesions of 53%. Treatment was generally well tolerated, but 22.6% of patients discontinued pazopanib due to treatment-related toxicity [24]. Finally, a nonrandomized trial of dovitinib was stopped early due to toxicity, and among the six patients who were enrolled, the best response was SD [25]. As a whole, VEGF TKIs have demonstrated disappointingly modest efficacy in the VHL disease, with unacceptable toxicity, as summarized in Table 2 [26]. Thus, their use has not been widely adopted, and effective systemic therapy for VHL disease has remained a critical unmet need in this patient population.

Table 2.

A summary of clinical trials investigating the treatment of patients with von Hippel–Lindau disease.

Study name	Publication year	Study size	Study arm	Design	End points		Results	Ref.
Pazopanib in patients with VHL disease: a single-arm, single-centre, phase II trial	2018	31	Pazopanib 800 mg orally daily	Single-arm, phase II	1°	ORR	Overall ORR 42% RCC ORR 52% pNET ORR 53% CNS ORR 4%	[24]
						Safety	68% required dose reduction or discontinuation for toxicity
Pilot trial of sunitinib therapy in patients with VHL disease	2011	15	Sunitinib 50 mg orally daily × 4 weeks then 2 weeks off	Single-arm, phase II	1°	Safety	67% required dose reduction for toxicity	[23]
					2°	ORR	ORR RCC 33% ORR non-RCC lesions 0%
Pilot study of dovitinib in patients with VHL disease	2018	6	Dovitinib 500 mg orally daily 5 days on, 2 days off	Single-arm, phase II	1°	Safety	50% discontinued due to toxicity	[25]
					2°	ORR	Best response stable disease
Belzutifan, a HIF-2a inhibitor, for VHL disease-associated neoplasms: 36 months of follow-up of the phase II LITESPARK-004 study	2022	61	Belzutifan 120 mg orally daily	Single-arm, phase II	1°	ORR RCC	ORR RCC 64%	[26]
					2°	ORR non-RCC lesions	ORR pNET 91% ORR CNS 44% ORR retinal 100%
						TTR	Median TTR 11.1 months
						DOR	Median DOR not reached
						Safety	Grade 3 TRAE 18%

DOR: Duration of response; ORR: Objective response rate; pNET: Pancreatic neuroendocrine tumor; RCC: Renal cell carcinoma; TRAE: Treatment-related adverse event; TTR: Time to response; VHL: von Hippel–Lindau.

First-generation HIF-2α inhibitors & the development of PT2977

Although HIF-1α and HIF-2α are structurally similar, they play different roles in tumorigenesis. There is accumulating evidence suggesting that HIF-1α functions as a tumor suppressor and HIF-2α functions as an oncogene [7]. Importantly, whereas HIF-2α expression is restricted to specific cell types, HIF-1α is expressed in all mammalian cells and is essential for normal cellular function. Not surprisingly, HIF-1α inhibitors have limited therapeutic use because of dose-limiting toxicity [27]. HIF-2α is therefore considered an attractive therapeutic target in the treatment of RCC and VHL disease.

The interaction surfaces of multiprotein complexes, such as HIFs, are challenging to disrupt with small molecules, due to their large size [28]. In 2009, Gardner et al. discovered a structural vulnerability within HIF-2α that was susceptible to allosteric inhibition by small molecules, thus paving the way for the development of small-molecule inhibitors [29]. This vulnerability is a small hydrophobic pocket that can bind small molecules in the PAS-B domain of HIF-2α, which disrupts the heterodimerization of the HIF transcription complex, preventing the activation of downstream target genes [29]. Several candidate small-molecule compounds were explored but had limited success due to unfavorable physical properties and modest cellular activity. A structure-based drug design process eventually led to the development of the first-generation HIF-2α inhibitors, PT2385 and PT2399, by Peloton Therapeutics in the 2010s [7].

PT2385 and PT2399 were tested in several in vivo RCC models, demonstrating a significant decrease in HIF-2α target gene expression and promising antitumor activity [30–32]. PT2385 was further tested in a phase I, first-in-human study of 26 heavily pretreated, sporadic and advanced ccRCC patients (NCT02293980) [33]. No dose-limiting toxicity was observed, and the most common grade 3 toxicities reported were anemia (10%) and peripheral edema (2%). An ORR of 14% was reported, and SD was achieved in 52% of patients. The VHL gene was mutated in five out of nine patients with available tissue samples, and VHL variants were enriched among patients with SD. Higher drug exposure (based on trough level ≥0.5 mg/ml) was associated with improved progression-free survival (PFS) [33]. This was attributed to high variability in drug exposure between patients due to extensive glucuronidation and resultant metabolism of PT2385 to PT2639, which limited efficacy [34]. To address this, PT2385 was subsequently modified into the second-generation compound PT2977. With decreased lipophilicity, the plasma protein binding decreased from 82 to 52%, improving its free fraction and availability efficacy [34]. Thus, the potency of PT2977 was increased by two to threefold. The manufacturer Peloton Therapeutics was acquired by Merck in 2019, and PT2977 was renamed MK-6482.

Belzutifan: clinical pharmacology

Chemical name: C₁₇H₁₂F₃NO₄S

Belzutifan is a first-in-class, second-generation HIF-2α inhibitor with a molecular weight of 383.34 Da. Its chemical structure is demonstrated in Figure 2. It is produced as 40 mg tablets for oral use and is administered at a dose of 120 mg orally daily (3 × 40 mg tablets) [35]. As previously explained, belzutifan selectively disrupts the heterodimerization of the HIF transcription complex, preventing downstream target gene transcription and resultant angiogenesis and oncogenesis [19].

Figure 2.

The chemical structure of belzutifan.

Belzutifan exposure increases proportionally across doses of 20–120 mg. Maximum concentration of 1.3 μg/ml is reached in 1–2 h and steady state is reached in approximately 3 days. The volume of distribution is 130 l at steady state. The plasma protein binding is 45%, with a blood-to-plasma concentration of 0.88. The mean clearance is 7.3 l/h and the mean elimination half-life is 14 h. Belzutifan can be taken with or without food [35].

Belzutifan is metabolized predominantly by UGT2B17 and CYP2C19 and to a lesser degree by CYP3A4 [35]. Inhibitors of UGT2B17 (e.g., imatinib) or CYP2C19 (e.g., fluoxetine, lansoprazole) increase plasma exposure of belzutifan, potentially augmenting the adverse effects of this agent. Coadministration of belzutifan with CYP3A4 substrates (e.g., midazolam, quetiapine) decreases their concentration, potentially resulting in therapeutic failure of those substrates [35]. No dose adjustments are required for mild-to-moderate renal impairment or mild hepatic impairment [36]. The effects of severe renal impairment and moderate-to-severe hepatic impairment are currently under evaluation (NCT04994522, NCT04995484) [37,38].

Safety profile

Evidence to date suggests that belzutifan has a well-tolerated toxicity profile. The side effects of belzutifan relate to reduced transcription of genes targeted by HIF-2α, including EPO, PDGFR, GLUT1 and VEGF [3,7. The most commonly experienced side effects include fatigue, anemia and hypoxia. These toxicities can be managed with dose modification (to either 80 or 40 mg) but in severe cases, belzutifan may need to be discontinued. Belzutifan also has important considerations for present and future fertility, as described below. The decision to resume treatment with belzutifan after a serious adverse event (AE) must be done on a case-by-case basis and is dependent on the severity of the AE, responsiveness to discontinuing/dose-modifying belzutifan, and patient input in a shared decision-making model.

Anemia

EPO is secreted by renal interstitial fibroblasts and is regulated by HIF-2α. Therefore, reductions in plasma EPO levels, which are dose- and exposure-dependent, serve as a pharmacodynamic measure of successful attenuation of the HIF-2α target gene expression [19]. Maximum EPO suppression typically occurs following 2 weeks of consecutive dosing of belzutifan, with a mean percentage decrease from baseline of approximately 60%. Mean EPO levels gradually return to baseline values after 12 weeks of treatment [39]. Anemia is therefore considered an ‘on-target’ side effect. If hemoglobin decreases to <90 nmol/l, belzutifan should be held until it rises to ≥90 nmol/l, when it can be resumed at a reduced dose or may need to be discontinued. In the clinical trial setting, erythropoiesis-stimulating agents (ESAs) were administered in 67% of patients with anemia in an effort to avoid dose reductions or discontinuations. However, there is a paucity of safety data available for this indication, and therefore ESAs should not be used for the treatment of belzutifan-induced anemia in clinical practice [39]. Importantly, some ccRCCs express the EPO receptor, and ESAs could theoretically promote RCC oncogenesis [40]. In summary, belzutifan-induced anemia is typically stabilized without intervention in most patients through dose modifications, and packed red blood cell transfusions can be safely administered if anemia is severe and/or symptomatic [26,39].

Hypoxia

The mechanism of hypoxia from HIF inhibition is somewhat poorly understood and is likely multifactorial. Potential etiologies include: reduced oxygen-carrying capacity from anemia; hypoventilation due to reduced hypoxic ventilatory response and inhibition of carotid body sensing; and impairment of pulmonary arterial response to ventilation/perfusion mismatch caused by HIF inhibition [41–44]. Due to the risk of hypoxia, patients must be advised to monitor their pulse oximeter readings while taking belzutifan [35]. In clinical practice, belzutifan should be held if oxygen saturation declines to <88%, and potential causes of pulmonary disease should be ruled out. If oxygen saturation rises to >88%, belzutifan may be resumed at either the same dose or a reduced dose, depending on the clinical scenario [35]. In cases of severe, persistent or life-threatening hypoxia, belzutifan should be discontinued.

Fertility

The effects of belzutifan upon fertility in humans are unknown, and verifying the pregnancy status of females of reproductive age prior to initiating treatment is recommended [35]. In an animal study of rats, belzutifan caused atrophy of the testes and hypospermia in males, which did not reverse by the end of the recovery period. There were no adverse effects upon the reproductive health of female rats. However, belzutifan did cause embryo-fetal lethality in pregnant rats during the period of fetal organogenesis [35]. Therefore, in humans, exposure to belzutifan during pregnancy may cause fetal harm, with a boxed warning to this effect included in the manufacturer’s prescribing information [35]. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding. Female patients of reproductive potential, and male patients with female partners of reproductive potential, are advised to use effective nonhormonal contraception during and for at least 1 week after the final dose of belzutifan therapy. Patients are advised not to breastfeed during treatment and for 1 week after the last dose, as the effects of belzutifan on a breastfed child are unknown. Safety and effectiveness of belzutifan have not been established in pediatric patients. Belzutifan has not been evaluated directly for carcinogenicity, but it was not considered to be mutagenic in an in vitro study [35]. Finally, belzutifan does not cause prolongation of the QT interval at the recommended dose [35].

Clinical efficacy of belzutifan

VHL disease

Belzutifan for VHL disease was first evaluated in the open-label, nonrandomized, phase II study LITESPARK-004, in which 61 patients with VHL-associated, localized RCC were treated with belzutifan 120 mg orally daily [26]. Eligible patients were those 18 years of age or older, with a germline VHL alteration and at least one RCC tumor measuring ≥10 mm (with or without histological confirmation), as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Eligibility further required no immediate need for surgery and Eastern Cooperative Oncology Group performance status 0 or 1. The primary end point was ORR (defined as either CR or PR on imaging, per RECIST v1.1) in VHL-associated RCC tumors [26]. Secondary end points included duration of response (DOR), time to response (TTR), PFS, safety and efficacy of belzutifan in non-RCC tumors, including retinal hemangioblastomas, CNS hemangioblastomas and pancreatic lesions including pNET. CNS lesions were evaluated by measuring both solid and cystic components separately [45]. Patients were monitored radiographically with either CT scan or MRI every 12 weeks for a minimum of 3 years, then every 24 weeks thereafter. All patients had localized RCC and pancreatic lesions, and 82% had CNS hemangioblastomas [26]. At 36 months of follow-up, ORR in RCC was 64% (95% CI: 50.6–75.8; 7% CR, 57% PR), with a median TTR (mTTR) of 11.1 months (range: 2.7–30.5) [46]. Median DOR (mDOR) was not reached, and 87% of patients had ongoing response to treatment at 36 months. Importantly, belzutifan also showed activity in non-RCC neoplasms. In pNET, the ORR was 91% (95% CI: 70.8–98.9; 31.2% CR, 59.1% PR), with mTTR 8.4 months (range: 2.5–19.1) and mDOR not reached [46]. In CNS hemangioblastomas, the ORR was 44% (n = 22; 95% CI: 30–59; 8% CR, 36% PR), disease control rate (DCR) was 90% (n = 45; 95% CI: 78–97), TTR was 5.4 months (range: 2.3–33.1) and the mDOR was not reached [45]. After starting belzutifan, the median linear growth rate for CNS lesions was -1.6 mm/year (range: -7.0–3.1). A further analysis categorizing response in CNS lesions, by solid (n = 25) or solid plus cystic (n = 50) components, was recently reported [45]. When evaluating only the solid component of CNS lesions, with a mTTR of 3.1 months, ORR was 76% (95% CI: 55–91), while in the solid plus cystic category, mTTR was 5.4 months and ORR was 44% (95% CI: 30–59). Finally, ORR was 100% for retinal disease, with mDOR not reached [46].

As of 1 April 2022, 38/61 patients (62%) remained on treatment, with primary reasons for treatment discontinuation being patient decision (n = 11; 18%) and disease progression (n = 6; 10%). Seven patients (18%) experienced grade 3 treatment-related adverse events (TRAEs), with the most common being anemia [46]. The safety profile remained consistent with prior results; there were no grade 4 or 5 TRAEs. Importantly, belzutifan use resulted in 87 and 98% reductions in the rate of RCC surgeries and non-RCC surgeries, respectively [47]. Only one patient underwent a CNS-related surgery after starting belzutifan [45]. The use of belzutifan is estimated to result in annual, per-patient cost reduction from US$57,259 to US$2536 owing to avoided surgeries and complications thereof [47].

These results represent a true paradigm shift in the management of VHL disease, leading to the US FDA’s approval of belzutifan in 2021 for the treatment of adult patients with VHL disease with nonmetastatic RCC, CNS hemangioblastomas or pNET, not requiring immediate surgery [35,48]. Belzutifan was approved by Health Canada in July 2022 for the treatment of adult patients with VHL disease who require therapy for nonmetastatic RCC, not requiring immediate surgery, and the approval was recently expanded to also include CNS hemangioblastomas and nonmetastatic pNET [49]. Finally, in the UK, the drug received Medicines and Healthcare Products Regulatory Agency approval in 2022 for the treatment of adult patients with VHL disease who require therapy for RCC, CNS hemangioblastomas or pNET, and for whom localized procedures are unsuitable/undesirable [50]. The European Medicines Agency has not yet approved belzutifan for VHL disease.

The most commonly reported AEs in the LITESPARK-004 trial were anemia (90% all grades, 8% grades 3–4), fatigue (66% all grades, 5% grades 3–4), headache (41% all grades, 0% grades 3–4) and dizziness (39% all grades, 0% grades 3–4) [26]. One patient experienced grade 3 transient hypoxia, which resolved with dose interruption for 1 week followed by dose reduction to 80 mg orally daily. Only one patient experienced a grade 4 AE (i.e., retinal detachment), which was unrelated to treatment, and there were no deaths due to treatment. TRAEs resulted in dose reductions in 15%, interruptions in 43% and permanent discontinuations in 2% of patients. Other less common TRAEs observed included nausea, constipation, abdominal pain, visual impairment, upper respiratory tract conditions, dyspnea, arthralgias/myalgias, hypertension, upper respiratory symptoms, blurred vision, abdominal pain, diarrhea, weight gain, peripheral edema and urinary tract infection [26]. The most commonly affected laboratory values included decreased hemoglobin, increased creatinine, increased glucose and increased alanine transaminase [26].

Adjuvant treatment of sporadic RCC

LITESPARK-022 is a multicenter, double-blind, randomized (1:1), phase III clinical trial evaluating the efficacy and safety of belzutifan (120 mg orally daily) in combination with the PD-1 inhibitor pembrolizumab (400 mg intravenously [iv.] every 6 weeks) compared with placebo and pembrolizumab in the adjuvant setting post nephrectomy for ccRCC (NCT05239728) [51]. At present, pembrolizumab is the most robust adjuvant treatment for high-risk localized RCC and thus combination with belzutifan in a multitargeted approach is an intriguing concept [52]. The biological rationale for combination therapies with belzutifan is explored below in the Discussion section. The estimated enrollment for LITESPARK-022 is 1600 patients who are treated with approximately 54 weeks of adjuvant therapy. The primary end point is disease-free survival (DFS), and secondary end points include overall survival (OS), disease recurrence-specific survival, safety and patient-reported outcomes [51]. No results have been published to date.

Treatment-naive, advanced, sporadic RCC

The phase II LITESPARK-003 is an ongoing clinical trial assessing the combination of belzutifan (120 mg orally daily) with cabozantinib (60 mg orally daily) in both treatment-naive (cohort 1) and pretreated (cohort 2) patients with advanced ccRCC (NCT03634540) [53,54]. In cohort 2, patients may have received a maximum of two previous treatment regimens. The primary end point was ORR per RECIST v1.1 by investigator review, and secondary end points include DOR, PFS, OS and safety. Data from both cohorts are now available. In cohort 2, nearly half of patients had been pretreated with ICI alone and half with ICI plus VEGF TKI. In this cohort, with a median follow-up of 24.6 months, the ORR was 30.8% (95% CI: 18.7–45.1), the mTTR 3.2 months (interquartile range: 1.9–7.3) and the mDOR 18.6 months (95% CI: 8.3–22.8), while the median PFS (mPFS) and median OS were 13.8 (95% CI: 9.2–19.4) and 24.1 months (95% CI: 20–37.4), respectively [53]. Only 19% of patients remained on treatment at data cutoff, and the most common reasons for discontinuing treatment were disease progression and AEs [53]. The authors concluded that the combination of an HIF-2α inhibitor and a TKI is tolerable and might offer more benefit than either drug as monotherapy. However, limitations in making this conclusion include the absence of a comparator group and the relatively small sample size [53]. In cohort 1 (treatment-naive patients), with a median follow-up of 14 months, the ORR was 57% with a mDOR of 28.6 months (range: 1.7+ to 28.6) [54]. The mPFS was 30.3 months (95% CI: 9.4 to not reached) and median OS was not yet reached. The estimated 12-month OS was 96% [54]. It is not surprising that the outcomes in the treatment-naive population are better than in the pretreated mRCC population. Acknowledging the limitations of cross-trial comparisons, the ORR of 31% in LITESPARK-003 and of 25% in LITESPARK-001 suggest a marginal benefit of adding belzutifan to cabozantinib. The LITESPARK-003 data again highlight the need for phase III evidence comparing belzutifan versus the standard of care in various lines of advanced RCC treatment.

When belzutifan was combined with cabozantinib in LITESPARK-003, the tolerability profile was consistent with those of the individual agents. In the treatment-naive patients, the most common any-grade TRAEs were anemia (71%) and diarrhea (71%) [54]. Grade 3 TRAEs occurred in 37% of patients, with the most common being hypertension (11%) and fatigue (9%). No patient discontinued belzutifan due to toxicity. In pretreated patients, 15% experienced grade 3 anemia, while 4% experienced grade 3 hypoxia [53]. TRAEs resulted in belzutifan dose reductions in 27% of patients, dose interruptions in 58% and treatment discontinuation in 19%. The most common reasons for discontinuation were fatigue and diarrhea [53]. In both cohorts, there were no grade 4 TRAEs [53,54]. In the pretreated cohort, one patient died from treatment-related respiratory failure, but had numerous contributing comorbidities including chronic obstructive pulmonary disease, pulmonary metastasis, pleural effusion and lymphangitic carcinomatosis [53].

NCT04736706 is an open-label, three-arm randomized (1:1:1), phase III clinical trial evaluating several novel combination therapies in the first-line setting for metastatic ccRCC. Arm A includes belzutifan (120 mg orally daily) in combination with lenvatinib (20 mg orally daily) and pembrolizumab (400 mg iv. every 6 weeks [Q6W]); arm B includes MK-1308A (quavonlimab 25 mg iv. plus pembrolizumab 400 mg iv., both given Q6W) and lenvatinib (20 mg orally daily); and arm C includes pembrolizumab (400 mg iv. Q6W) plus lenvatinib (20 mg orally daily) [55]. This combination builds on the evidence for antitumor activity observed in the KEYNOTE-581/CLEAR study, wherein pembrolizumab was combined with lenvatinib in the first-line treatment of advanced ccRCC [56]. The estimated enrollment is 1431 patients who are treated until evidence of disease progression, withdrawal, or another discontinuation event. Dual primary end points include PFS and OS for arms A and B compared with arm C, which is the standard-of-care combination of pembrolizumab and lenvatinib. Secondary end points include ORR, DOR, safety and patient-reported outcomes [55]. No results have been published to date for this study.

Pretreated, advanced, sporadic RCC

Early phase I/II studies have suggested the potential efficacy of HIF-2α inhibition in pretreated, advanced cases of sporadic ccRCC. LITESPARK-001 was the first-in-human, phase I study of belzutifan that investigated its pharmacodynamics, pharmacokinetics and toxicities in 95 patients with locally advanced or metastatic solid tumors, including 55 patients with mRCC [39]. The primary end point was safety. Secondary end points were ORR, DCR, PFS and DOR per RECIST v1.1 by investigator review. These patients were heavily pretreated, with prior use of ICI, VEGF TKI, or both. The median number of prior treatments received was three. In the dose-escalation phase, belzutifan was well tolerated. No dose-limiting toxicities were identified, and the maximum tolerated dose was not reached. Plasma EPO is a sensitive pharmacodynamic marker of HIF-2α inhibition and did not decrease beyond belzutifan doses of 120 mg daily. Therefore, the recommended phase II dose was 120 mg once daily [39]. An ORR of 25%, DCR of 80% and mPFS of 14.5 months have been reported at 36 months' follow-up [57]. The median DOR was not reached (range: 3.1+ to 37.9+ months). Though limited by small sample size, subgroup analyses showed better ORR and DCR in those with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk compared with intermediate/poor risk, and better ORR and DCR in patients who had not received prior VEGF TKI/ICI compared with those that did [57].Jonasch E, Bauer TM, Papadopoulos KP, et al. 4509 Poster Discussion Session Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: Update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. This analysis is limited by confounding factors, including inherently more indolent disease behavior in IMDC favorable-risk disease, and VEGF pathway resistance in heavily pretreated RCC. Some experts suggest the lack of durable response in LITESPARK-001 is possibly attributed to a proportion of ccRCC not driven by HIF-2α, by escape through genetic variants that interfere with belzutifan binding, or by other acquired mechanisms (e.g., R273H loss-of-function mutation in TP53) that confers resistance to HIF-2α inhibition [28].

The results of LITESPARK-001 provided the rationale to evaluate belzutifan monotherapy compared with everolimus in a phase III trial of previously treated, advanced ccRCC patients (NCT04195750, LITESPARK-005). In this study, patients with advanced sporadic RCC who had received one to three lines of treatment, including ICI and/or VEGF-targeted therapy, were randomized 1:1 to either belzutifan (120 mg orally daily) or everolimus (10 mg orally daily) [58]. The dual primary end points of this study were PFS and OS. The interim analysis of LITESPARK-005 was presented as a late-breaking abstract at the European Society for Medical Oncology Congress in 2023, showing superior ORR and mPFS for belzutifan compared with everolimus. OS did not reach statistical significance; however, the final analysis is pending. The safety profile of belzutifan was consistent with prior studies and no new safety signals were identified. The primary author concluded that LITESPARK-005 is the first positive phase III study in patients with advanced kidney cancer following ICI and antiangiogenic therapies [59].

Finally, early results from arm B5 (i.e., belzutifan 120 mg orally daily plus lenvatinib 20 mg orally daily) of the multiarm, open-label, phase I/II KEYMAKER-U03B study were recently presented at the 2023 American Society of Clinical Oncology Annual Meeting and showed promising ORR in a very heavily pretreated population of patients with advanced ccRCC (NCT04626518) [60]. Indeed, 53% of participants had received three or more prior lines of treatment, including PD-1 inhibitors and VEGF TKIs [60]. An ORR of 50% (n = 24; 95% CI: 29–71; all PRs) was reported, and responses appeared to be durable, with 74% of patients continuing on treatment for over 1 year [60]. Though 50% of patients experienced grade 3/4 TRAEs, the toxicity profile of the combination was well tolerated, with less than 10% of patients needing to discontinue study treatment due to AEs. While 43% of patients required dose reductions of lenvatinib, only 7% required such changes to belzutifan dosing [60]. The phase III LITESPARK-011 clinical trial is evaluating this combination in participants with advanced ccRCC who have progressed after ICI therapy (NCT04586231) [61].

Belzutifan beyond RCC

There are limited data on the efficacy of belzutifan in other cancers and nonmalignant conditions. Recruitment is underway for a phase II trial which is evaluating the efficacy and safety of belzutifan 120 mg orally daily in patients with locally advanced or metastatic pheochromocytoma/paraganglioma or pNET (NCT04924075) [62]. Although variants of genes involved in the VHL/HIF axis are frequently seen in pheochromocytomas and paragangliomas, it remains unclear whether dysfunction of the VHL/HIF axis drives their oncogenesis [63]. LITESPARK-016 (NCT04976634) is another phase II trial recruiting patients to evaluate the combination regimen of belzutifan (120 mg orally daily), pembrolizumab (400 mg iv. every 6 weeks) and lenvatinib (20 mg orally daily) in treating advanced solid tumors such as hepatocellular carcinoma, colorectal cancer, pancreatic ductal carcinoma and biliary tract cancer [64]. VHL variants have been reported in other cancer types, including colorectal cancer [65]. There are two studies evaluating belzutifan in prostate cancer: one in the neoadjuvant setting with abiraterone and leuprolide, and the other in metastatic castration-resistant prostate cancer (NCT05574712, NCT02861573) [66,67]. Application of HIF-2α inhibition beyond the malignant setting has been suggested, such as in hereditary erythrocytosis and pulmonary hypertension where HIF-2α inhibitors show potential in preclinical models [28]. Belzutifan has also been used to treat an adolescent patient with Pacak–Zhuang syndrome, a tumor predisposition syndrome caused by a mutation in the HIF-2α EPAS gene [68].

Discussion

To date, belzutifan has not been approved in any jurisdiction for treatment beyond VHL disease, for which the evidence is most robust. Growing evidence suggests belzutifan’s efficacy in sporadic RCC; however, its place in the treatment algorithm has not yet been clearly established due the paucity of phase III trial evidence. Robust data to guide treatment sequencing in advanced RCC is an important area of unmet need. Much of the data to date is based on real-world experience and retrospective reviews. If belzutifan does find its way into the armamentarium of systemic therapy for mRCC, this agent could be practice-changing beyond the VHL population. As described above, and as summarized in Table 3, the volume of trials currently underway demonstrates the potential implications of belzutifan as a backbone for combination regimens in cancer treatment.

Table 3.

Current trials with belzutifan.

NCT number	Status†	Disease	Intervention	Participants (n)
Phase I
NCT03445169	Completed	Healthy participants	Belzutifan	16
NCT04994522	Recruiting	Kidney failure, kidney impairment	Belzutifan	12
NCT02974738	Active	Advanced solid tumors including kidney cancer	Belzutifan	120
NCT04846920	Recruiting	Advanced ccRCC	Belzutifan	52
NCT05030506	Active	Advanced RCC	Belzutifan + lenvatinib	45
			Belzutifan + lenvatinib + pembrolizumab
NCT04995484	Recruiting	Moderate hepatic impairment	Belzutifan	16
NCT04627064	Recruiting	Advanced ccRCC	Abemaciclib	40
			Abemaciclib + MK-6482
Phase I/II
NCT04626479	Recruiting	Advanced ccRCC	Pembrolizumab/quavonlimab + lenvatinib	400
			Favezelimab/pembrolizumab + lenvatinib
			Belzutifan + lenvatinib
			Pembrolizumab + lenvatinib
			Vibostolimab/pembrolizumab + belzutifan
NCT04626518	Recruiting	Advanced ccRCC	Pembrolizumab/quavonlimab	370
			Favezelimab/pembrolizumab
			Pembrolizumab + MK-4830
			Pembrolizumab + belzutifan
			Belzutifan + lenvatinib
			Pembrolizumab + lenvatinib
NCT05468697	Recruiting	Advanced RCC	Belzutifan + palbociclib	180
NCT02861573	Recruiting	mCRPC	Pembrolizumab + olaparib	1200
			Pembrolizumab + docetaxel + prednisone
			Pembrolizumab + enzalutamide
			Pembrolizumab + abiraterone acetate + prednisone
			Pembrolizumab + lenvatinib
			Pembrolizumab/vibostolimab
			Pembrolizumab + carboplatin + etoposide
			Carboplatin + etoposide
			Belzutifan
			Belzutifan + pembrolizumab
Phase II
NCT05574712	Not yet recruiting	Prostate cancer	Belzutifan + abiraterone acetate + leuprolide acetate	30
NCT04489771	Active	Advanced ccRCC	Belzutifan	150
NCT03401788	Active	VHL disease-associated RCC	Belzutifan	50
NCT04924075	Recruiting	PPGL, pNET	Belzutifan	140
NCT04976634	Recruiting	Hepatocellular carcinoma, colorectal cancer, pancreatic ductal adenocarcinoma, biliary tract neoplasms	Pembrolizumab + belzutifan + lenvatinib	730
NCT03634540	Active	Advanced ccRCC	Belzutifan + cabozantinib	118
Phase III
NCT04195750	Active	Advanced ccRCC	Belzutifan	736
			Everolimus
NCT05239728	Recruiting	ccRCC	Belzutifan + pembrolizumab	1600
			Placebo + pembrolizumab
NCT04736706	Recruiting	Advanced ccRCC	Pembrolizumab + belzutifan + lenvatinib	1653
			Pembrolizumab/quavonlimab + lenvatinib
			Pembrolizumab + lenvatinib
NCT04586231	Recruiting	Advanced ccRCC	Belzutifan + lenvatinib	708
			Cabozantinib

Information from clinicaltrials.gov.

^†Status as of April 2023.

ccRCC: Clear-cell renal cell carcinoma; mCRPC: Metastatic castrate-resistant prostate cancer; pNET: Pancreatic neuroendocrine tumor; PPGL: Pheochromocytoma/paraganglioma; RCC: Renal cell carcinoma; VHL: von Hippel–Lindau.

Rationale for combination therapies with belzutifan

There is a biological rationale for combining a HIF-2α-targeting agent with VEGF TKI, mTOR inhibition, or ICI. As described, multiple active phase I/II studies are currently evaluating the safety and efficacy of belzutifan in combination with immunotherapy and/or with immune and targeted agents (NCT05030506, NCT04627064, NCT04626479, NCT04626518, NCT05468697). It will be interesting to see whether the clinical effect of HIF-2α blockade is synergistic, additive, or antagonistic when combined with other agents [7,19]. As previously discussed, the VEGF pathway contributes to tumor-associated angiogenesis via the growth, migration and proliferation of vascular endothelial cells and is recognized as a major contributor to RCC pathogenesis. The HIF–VEGF axis can therefore be targeted by combination strategies with belzutifan upstream, reducing the transcription of VEGF by HIF inhibition, then downstream via direct inhibition of VEGFR and other growth factor receptors using TKIs [61]. This might help to overcome the known upregulation of HIF-2α activity as a resistance mechanism for anti-VEGF therapy [61]. Additionally, HIF-2α inhibitors may not provide sufficient VEGF expression regulation, as HIF-1α also activates VEGF in acute hypoxia [16]. Belzutifan does not inhibit HIF-1α, and therefore, VEGF TKIs may manage the downstream activity of unregulated HIF-1α. Several hypotheses exist supporting the combination of HIF inhibition with immunotherapy. HIF-2α appears to be critically important for modulating the immune microenvironment. Indeed, targeting the HIF–VEGF axis inhibits suppressive immune elements (e.g., myeloid-derived suppressor cells and regulatory T cells), allowing for immune activation via effector T cells and antigen presentation, theoretically amplifying the effects of ICIs [69]. Similarly, hypoxia upregulates PD-L1 expression on suppressive immune cells; HIF inhibition therefore results in a decrease of PD-L1, again enhancing the effects of ICI [70]. Lastly, preclinical studies in ccRCC have shown a synergistic effect between HIF-2α inhibition and inhibitors of the cell cycle regulators CDK4 and CDK6, causing synthetic lethality. Two ongoing studies are evaluating the combination of belzutifan with palbociclib and abemaciclib, respectively, in advanced RCC (NCT05468697, NCT04627064) [71].

Remaining questions

Evidence to date suggests that belzutifan is well tolerated, with a predictable and manageable safety profile. There are several phase I/II trials underway to further assess the safety and efficacy of belzutifan at variable doses. The maximum tolerated dose was not identified in LITESPARK-001 so it is possible that dose escalation may further enhance the efficacy of belzutifan [7]. Currently accruing phase I and II trials are evaluating the safety and efficacy of escalating belzutifan dosing in advanced RCC, and in end-stage renal disease and moderate hepatic impairment (NCT04489771, NCT04846920, NCT04994522, NCT04995484) [37,38,72,73].

Our understanding of belzutifan’s side effects continues to improve from real-world experience in the treatment of patients with VHL disease, resulting in new, practical questions being raised in clinical practice. This experience is being collected through large multicenter datasets, including those recognized by the VHL Alliance. These data should help to provide valuable insight into the natural history of the disease; the clinical impact of belzutifan treatment; toxicity and tolerance; and health-related quality-of-life measures [19]. These patient-centered measures have not been addressed in the published LITESPARK trials thus far, although many have included them as secondary end points going forward. Remaining questions include the potential utility of intermittent versus long-term treatment strategies, belzutifan efficacy according to specific VHL disease genotype and phenotype, the exploration of use in the younger patient population, and for prophylactic purposes in those with known germline diagnosis but prior to disease manifestation [19]. A key unmet need in VHL disease is the prevention of lesion development, so a trial demonstrating that belzutifan stops new lesion formation could be practice-changing [7]. There is also interest in exploring larger health system issues with belzutifan use, including access and cost–effectiveness [19].

Outside of VHL disease, biomarkers predicting treatment response in RCC are lacking. Two meta-analyses found no correlation between the presence or absence of VHL alterations and the prognosis or pathological features of ccRCC [74,75]. Although the HIF–VEGF axis is often dysregulated in RCC, levels of HIF expression might not affect response to targeted therapy. Whether HIF-2α or other potential biomarkers are associated with response to belzutifan remains a topic of interest, and further studies are required.

Another important clinical question is that of treatment resistance. The resistance mechanism for belzutifan is currently under investigation. Following prolonged exposure to first-generation HIF-2α inhibitor PT-2385, whole-exome studies observed resistance mechanisms including acquired gatekeeper mutations of HIF-2α (i.e., G323E) and HIF-1β (i.e., F446L) [7]. G323E is a mutation of the HIF-2α protein that prevents HIF-2α inhibitor binding, and F446L is a mutation in HIFβ that increases the affinity of protein binding [7]. Treatment resistance could be quite concerning for the VHL population who are expected to take belzutifan for a prolonged period of time. As discussed, combining belzutifan with other antitumor agents with different molecular targets could help to avoid resistance and increase responsiveness [28]. Aside from allosteric inhibition, there also may be alternative mechanisms for inhibiting HIF-2α, which could help combat resistance [18].

Conclusion

The identification of the VHL gene and its role in regulation of the HIF signaling pathway has helped to revolutionize the treatment of RCC. Over the years, this understanding has led to the development of novel therapeutics, which have improved the OS of patients significantly, first with the development of targeted therapies and then with the addition of immunotherapy. Yet again, we see a paradigm shift on the horizon, certainly for patients with VHL disease and likely also for RCC. While many questions remain unanswered, belzutifan represents a novel therapeutic strategy for VHL disease, RCC and beyond.

Financial disclosure

M Soleimani has received consulting and medical advisory fees from Bayer, Pfizer, Ipsen and Novartis as well as institutional academic funding from AbbVie, Astellas Pharma, Inc. and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.