e22659 Background: Belzutifan produces durable volumetric responses in von Hippel–Lindau (VHL)–associated central nervous system (CNS) hemangioblastomas. However, data describing tumor behavior during treatment holidays are limited. Methods: We conducted a retrospective lesion-level volumetric analysis of VHL patients with CNS hemangioblastomas treated with belzutifan at Massachusetts General Brigham Cancer Institute between September 2018 and January 2026 who experienced a treatment interruption (holiday) ≥3 months. Longitudinal MRI data were retrospectively reviewed. Lesions were classified at holiday baseline as measurable (≥10 mm), submeasurable (5–9 mm), or non-measurable ( < 5 mm). The primary endpoint was lesion-level volumetric change during treatment holiday; secondary endpoints included ORR, best overall response, and time to response per RECIST 1.1. Lesion-level volumetric analyses were performed for measurable and submeasurable lesions. Treatment holiday was offered after ≥9 months of sustained maximal response. The study was conducted under an institutional review board–approved protocol. Results: Nine patients were included. At treatment initiation baseline imaging, 16 measurable, 11 submeasurable, and 34 non-measurable lesions were identified. At treatment holiday baseline, 7 measurable, 5 submeasurable, and 9 non-measurable lesions were evaluable. Median duration of belzutifan therapy prior to treatment interruption was 34.4 months (range, 2.9–57.7). Median duration of treatment interruption was 12.7 months (IQR, 9.3–15.3). Seven patients had RECIST-evaluable measurable disease. The ORR was 85.7% (6/7 partial responses; 95% CI, 42.1–99.6), with stable disease observed in 14.3% (1/7). No RECIST-defined progression occurred prior to treatment withholding. Median TTR was 5.9 months (range, 1.8–7.9), and responses were ongoing at the time of treatment interruption in all responding patients. From treatment holiday baseline to last eligible MRI, 10/12 evaluable lesions (83.3%) demonstrated volumetric increase ≥10%, while 2/12 lesions (16.7%) decreased in size by ≥10%. Among lesions that grew during treatment holiday, the median volumetric increase was +116.1% (IQR, 187.1), over a median duration of 8.7 months (IQR, 6.0). Conclusions: During belzutifan treatment holiday, most evaluable CNS lesions demonstrated mild volumetric increase over time, although lesion behavior was heterogeneous and occurred over several months rather than immediately after treatment withholding. These findings provide early, lesion-level insight into CNS hemangioblastoma dynamics during belzutifan holidays and support cautious clinical monitoring during treatment interruption. Ongoing follow-up and expanded analyses will further characterize lesion dynamics during belzutifan treatment holidays.

Iron regulatory protein 1 (IRP1) is a posttranscriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of HIF2α mRNA, which increases renal erythropoietin production. Here, we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscles, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

4550 Background: Belzutifan, a potent and selective hypoxia-inducible factor 2α inhibitor, is indicated for treatment of patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery based on prior results from the open-label phase 2 LITESPARK-004 study (NCT03401788). We report results from LITESPARK-004 after a minimum of 6 years of follow-up. Methods: Participants (pts) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor >3 cm that required immediate surgery, no metastatic disease, no prior anticancer systemic treatment, and an ECOG PS of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. The primary end point was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent review committee (IRC). Secondary end points included safety, ORR in non-RCC neoplasms, duration of response (DOR), and progression-free survival (PFS) per RECIST v1.1 by IRC. Results: Overall, 61 pts received ≥1 dose of belzutifan. Median study follow-up was 73.8 months (range, 72.1-82.1). As of the data cutoff date (April 1, 2025), 34 pts (56%) remained on treatment. ORR was 70% for RCC, 52% for CNS HB, and 91% for pNETs. Additional efficacy results are shown in the Table. Among 14 pts (n = 18 affected eyes by ophthalmic evaluation), retinal HBs in 100% (95% CI, 81-100) of eyes showed improvement. Median DOR in pts with retinal HBs was not reached (NR; 95% CI, 8.5-NR). Within 5 years prior to initiating belzutifan, 46 of 61 pts (75%) had ≥1 VHL-related tumor reduction procedure (surgery or radiation therapy; 43 RCC, 39 CNS HB, 12 retinal HB, 3 pNET, 2 other). Since initiating belzutifan treatment, 22 of 61 pts (36%; 14 during treatment and 8 after discontinuing treatment) underwent 25 VHL-related tumor reduction procedures (16 RCC, 3 CNS HB, 5 retinal HB, 1 pNET). Grade 3 treatment-related adverse events (TRAEs) were reported in 12 pts (20%); the most common grade 3 TRAE was anemia (11%). No grade 4 or 5 TRAEs occurred. No additional pts discontinued belzutifan due to TRAEs since the previous analysis. Conclusions: After 6 years of follow-up, belzutifan continues to show durable antitumor activity and a manageable safety profile in pts with VHL-associated RCC, CNS HB, and pNETs who do not require immediate surgery. These results continue to support the use of belzutifan in this patient population. Clinical trial information: NCT03401788 . RCCn = 61 CNS HBn = 50 pNETsn = 22 ORR (95% CI), % 70 (57-81) 52 (37-66) 91 (71-99) Best overall response, n 8 CR35 PR 17 SD0 PD1 NE 7 CR19 PR20 SD3 PD1 NE 14 CR6 PR2 SD0 PD0 NE DOR, median (range), months NR (5.8+ to 69.1+) NR (0.0+ to 74.3+) NR (11.0+ to 71.8+) 48-month DOR rate 78% 84% 90% PFS, median (95% CI), months NR (71.5-NR) NR (NR-NR) NR (NR-NR) 48-month PFS rate 79% 80% 90%

e22663 Background: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in the tumor suppressor gene FLCN , predisposing affected individuals to tumorigenesis. Clinically, it is characterized by fibrofolliculomas, pulmonary cysts with risk of spontaneous pneumothorax, and an increased risk of renal tumors. Early recognition and genetic confirmation are important to guide surveillance and family screening. Methods: We performed a retrospective review of 59 individuals with suspected or confirmed BHD disease evaluated and managed at Massachusetts General Hospital (Boston, MA) between 2008 and 2025. Demographic data, clinical manifestations, imaging findings, family history, and FLCN genetic testing results were extracted from medical records. Clinical BHD diagnoses were assigned based on the presence of at least two out of three characteristic clinical features when molecular confirmation was negative or unavailable. Results: The cohort included 59 individuals (44% male) with a median age of 55 years (IQR 44-68) at the time of data collection. FLCN genetic testing was performed in 55 of 59 individuals: 45 (82%) had a pathogenic/likely pathogenic FLCN variant, and 10 (18%) had no pathogenic variant identified. The remaining four individuals did not undergo genetic testing but were diagnosed clinically based on clinical manifestations and/or significant family history and were managed with BHD-directed surveillance. Overall, 42 of 59 individuals had clinical manifestations of the disease (71%), with a median age at first symptom or diagnosis of 38 years (IQR 25-50). Among those with clinical disease, 31 had a pathogenic/likely pathogenic FLCN variant (74%), and eight had no pathogenic variant identified (19%). Twenty-four had fibrofolliculomas/angiofibromas (57%), 20 had a history of pneumothorax (48%), and 18 developed renal tumors (43%). A positive family history of BHD or related manifestations was present in 47 of 59 individuals (80%), and 27 of 59 had genetically confirmed affected family members (46%). Consistent with this, the most common reason for referral was family history, followed by targeted or incidental germline detection and clinical suspicion of BHD. Conclusions: In this single-center cohort of individuals with suspected or confirmed BHD disease, renal tumors, pneumothoraces, and fibrofolliculomas were common among those with clinical disease. Most individuals with clinical disease carried a pathogenic/likely pathogenic FLCN variant. Family history was a major driver of diagnosis, emphasizing the value of genetic testing and longitudinal surveillance. Early recognition and coordinated management remain key to reducing BHD-related complications.

Increasing accessibility to genetic screening for cancer risk can lead to earlier surveillance and prevention, but with this comes the caveat of incidental identification of germline pathogenic gene variants. Here, we report a single institution case series of 6 otherwise healthy individuals with "incidental" Von Hippel Lindau (VHL) disease. These patients were found to have pathogenic germline variants in the VHL gene, after undergoing genetic testing for other purposes (5 for familial breast cancer risk and 1 to determine ancestry) but no VHL disease-associated tumors. The penetrance and expressivity of such incidental variants are not currently known, and therefore, no surveillance guidelines exist. Nevertheless, the association of these variants historically with high disease penetrance compels us to currently recommend active surveillance of their carriers with annual imaging of the brain, spine, and abdomen.

Introduction The first-in-class hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan is approved in the United States for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for adult patients with advanced RCC following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Belzutifan has a unique mechanism of action and a distinct adverse event profile that includes anemia and hypoxia. We characterized the safety profile of belzutifan monotherapy and associated adverse events (AE) management strategies in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC who participated in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) trials and patients with VHL disease-associated RCC enrolled in the phase 2 LITESPARK-004 trial (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg by mouth once daily across the 4 trials were included in the pooled population. AE severity was graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and was descriptively summarized. Results Overall, 576 patients were included (LITESPARK-001, n=58 [3 patients had non-RCC advanced solid tumors]; LITESPARK-005, n=381; LITESPARK-013, n=76; and LITESPARK-004, n=61). Of 576 patients, 99.3% experienced ≥1 all-cause AE and 61.6% experienced ≥1 grade 3-5 AE. AEs led to dose modification (reduction/interruption/discontinuation) in 50.0% of patients; 6.4% discontinued treatment due to AEs. The most common AEs were anemia (including decreased hemoglobin; 84.2%; grade 3 or 4, 28.8%) and fatigue (42.7%; grade 3, 2.8%). Hypoxia occurred in 16.3% of patients (grade 3 or 4, 12.2%). Adverse drug reactions (AEs considered associated with belzutifan) are summarized in the table. Among patients with anemia or decreased hemoglobin, 22.9% were treated with erythropoiesis-stimulating agents (ESA) only, 17.5% with blood transfusions only, and 12.8% with ESA and blood transfusions. Among patients with hypoxia, 70.2% received supplemental oxygen. Grade 3-5 treatment-related AEs occurred in 37.7% of patients (grade 5, n=1 [multiple organ dysfunction syndrome]). Conclusions This post hoc pooled analysis showed that belzutifan monotherapy had a generally manageable safety profile in patients with advanced RCC; few patients discontinued treatment due to AEs. Median time to first onset occurred within the first 3 months of treatment. As expected, anemia and hypoxia were among the most frequent AEs and were generally manageable with dose modification and/or treatment with ESA/blood transfusions for anemia and supplemental oxygen for hypoxia. To date, this is the largest pooled safety dataset for a HIF-2α inhibitor.

10621 Background: Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is an autosomal dominant syndrome caused by loss-of-function mutations in the Fumarate Hydratase ( FH ) gene. HLRCC poses an elevated risk for skin leiomyomas, uterine fibroids, pheochromocytomas, paragangliomas, and renal cell cancer (RCC), particularly FH-deficient RCC and potentially clear cell RCC. It is recommended that patients with personal and/or family history of a single skin leiomyoma, multiple FH-deficient (by immunohistochemistry (IHC)) uterine fibroids, pheochromocytoma, paraganglioma, or FH-deficient RCC be tested for, among other genes, germline FH mutations, with yearly surveillance with abdominal imaging being the recommendation if positive. To better describe this patient population, we present our experience with high-volume referrals for HLRCC testing at a single institution. Methods: We performed retrospective chart review (2017-present) of all patients referred for HLRCC testing at the Hereditary Renal Cell Carcinoma & VHL Disease Clinic and the Hemangioblastoma Center at the Massachusetts General Cancer Center. The study was approved by the Massachusetts General Brigham IRB. Results: We herein describe the largest, to our knowledge, series of HLRCC patients (67) at a single institution. While the majority (30, 45%) of cases were referred due to an incidental genetic finding either on prenatal screening or through a comprehensive multi-cancer gene panel sent for hereditary cancer screening, 31% (21) of patients were referred after being found to have an HLRCC-related lesion. Of this subset, the most common first HLRCC-related lesion was a uterine fibroid that was FH-deficient by IHC (13), followed by an equal number of skin leiomyomas (4) and RCCs (4). Importantly, we calculate the rate of patients later confirmed to have an HLRCC diagnosis (pathogenic variant by genetic sequencing) based on referral reason: patients referred for uterine fibroids deficient in FH by IHC, 59.1% (13 of 21); patients referred for RCC either with loss of FH by IHC or papillary RCC, 80% (4 of 5); patients referred with cutaneous leiomyomas deficient in FH by IHC, 66.7% (4 of 6); and patients with family members with known diagnosis of HLRCC, 83.3% (15 of 18). Mutations in positive HLRCC cases either caused premature termination by nonsense or frameshift (18, 26.9%), point mutations by missense (22, 32.8%), or had an AAA duplication at c.1431_1433, causing a lysine duplication at amino acid residue 477 of the fumarate hydratase protein (20, 22.9%), the last of which has ongoing discussion of true association with HLRCC. One patient was indeed seen to have papillary RCC with this mutation, supporting the association of c.1431_1433dupAAA with HLRCC. Conclusions: In sum, we describe populations characteristics, common reasons for referral, and likelihood of genetic testing confirmation for patients with concern for HLRCC.

BACKGROUND:Pheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway. Belzutifan is a HIF-2α inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma. METHODS:We conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication. RESULTS:At a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events. CONCLUSIONS:Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.).

BACKGROUND:Von Hippel-Lindau syndrome (VHL) is a rare hereditary neoplastic disorder caused by mutations in the VHL gene. Treatment options for patients are limited to multiple surgeries dispersed between regular scans, watchful waiting, and treatments that preserve organ function. METHODS:An international, cross-sectional survey comprising patients in the United States (USA), Canada (CA), the United Kingdom (UK), France (FR), and Germany (DE) was conducted. Patients were recruited via the VHL Alliance; data were collected between Dec 2021 and May 2022. For inclusion, patients must have renal cell carcinoma, pancreatic neuroendocrine tumors, and/or central nervous system hemangioblastoma. RESULTS:In all, 220 patients (68.2% female, median age 40.0, median disease duration 15.8 years) in the USA (n = 108), CA (n = 37), the UK (n = 21), FR (n = 3), and DE (n = 51) completed the study. In this sample, n = 205 (93.2%) patients had experienced surgery; n = 171 (77.7%) had experienced multiple surgeries (median number of surgeries, 4.0); 166 (n = 75.5%) patients recorded data on their most recent surgery. Of these, patients reported that their most recent surgery worsened (scored 1-3) their fatigue (51.8%, n = 86), mental health (51.2%, n = 85), and ability to go about daily life (45.2%, n = 75). Approximately, 47.3% (n = 104) of patients selected reducing the number of surgeries as a top treatment goal, whereas 73% (n = 161) of patients indicated they would prefer to take a pill which would possibly delay the time until surgery. CONCLUSION:Surgery negatively impacts the lives of patients, leading to a worsening in their fatigue, mental health, and ability to go about daily life.

BACKGROUND:Hypoxia-inducible factor-2α inhibitor belzutifan is approved for von Hippel-Lindau disease-associated renal cell carcinoma, CNS haemangioblastomas, and pancreatic neuroendocrine tumours, based on previously published initial results from the LITESPARK-004 study. Updated results are presented here after a median follow-up of nearly 50 months. METHODS:In this single-arm, phase 2 study, participants were enrolled at 11 centres in Denmark, France, the UK, and the USA. Oral belzutifan 120 mg once daily was given to eligible adults aged 18 years or older with a diagnosis of von Hippel-Lindau disease (based on germline VHL alterations), at least one measurable renal cell carcinoma tumour, no tumour larger than 3 cm that necessitated immediate surgery, no metastatic disease, no previous systemic anticancer treatment, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. The primary endpoint was the proportion of participants with an objective response in von Hippel-Lindau disease-associated renal cell carcinoma per Response Evaluation Criteria in Solid Tumours, version 1.1, determined by an independent review committee, and assessed in all participants who received at least one dose of belzutifan. This ongoing study is no longer recruiting and is registered at ClinicalTrials.gov, NCT03401788. FINDINGS:Between May 31, 2018, and Mar 29, 2019, 61 participants were enrolled; 36 (59%) were continuing treatment as of April 3, 2023. The median age of all enrolled participants was 41·0 years (IQR 29·0-51·0); 32 (52%) of 61 participants were male and 29 (48%) were female; most were White (n=55; 90%). Median study follow-up was 49·9 months (IQR 48·9-52·2). 41 (67%; 95% CI 54-79) of 61 participants with renal cell carcinoma had an objective response; seven (11%) had a complete response and 34 (56%) a partial response. 13 grade 3 treatment-related adverse events occurred in 11 (18%) participants (anaemia: seven [11%]; fatigue: three [5%]; urinary tract infection: one [2%]; hypoxia: one [2%]; and blister: one [2%]). None of the participants had a grade 4 or 5 treatment-related adverse event. Four (7%) participants had serious treatment-related adverse events (one participant each: anaemia, urinary tract infection, intracranial haemorrhage, and hypoxia). INTERPRETATION:Updated results support the use of belzutifan as systemic treatment for von Hippel-Lindau disease-associated renal cell carcinoma. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA; the Intramural Research Program of the National Institutes of Health, National Cancer Institute Center for Cancer Research; and a grant from the National Cancer Institute.

4507 Background: The HIF-2α inhibitor belzutifan is approved for the treatment of patients with VHL disease–associated renal cell carcinoma (RCC), CNS hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNETs), not requiring immediate surgery based on previously reported results from the ongoing open-label phase 2 LITESPARK-004 study (NCT03401788). Updated results are presented after a minimum of 5 years of follow-up. Methods: Adults with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor > 3 cm that required immediate surgery, no metastatic disease, no prior anticancer systemic treatment, and an ECOG PS of 0 or 1 received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or participant (pt) withdrawal. The primary end point was objective response rate (ORR) in VHL disease–associated RCC per RECIST v1.1 by independent review committee (IRC). Secondary end points included safety, ORR in non-RCC neoplasms, duration of response (DOR), and progression-free survival (PFS) per RECIST v1.1 by IRC. Results: Overall, 61 pts received ≥1 dose of belzutifan. Median study follow-up was 61.8 mo (range, 60.2-70.1). As of the April 1, 2024 data cutoff date, 35 pts (57%) remained on treatment. ORR was 70% for RCC, 50% for CNS HB, and 90% for pNETs. Additional efficacy results are in the Table. Among 14 pts (n = 18 eyes) with retinal HB, 100% (95% CI, 82-100) of eyes showed improvement per ophthalmologic assessment; median DOR for retinal HBs was not reached (NR; range, 8.5-61.0+ mo). At baseline, 59 of 61 pts (97%) had ≥1 prior VHL-related surgery. Within the 5 years before starting belzutifan, 46 of 61 pts (75%) had ≥1 surgery. Since starting belzutifan, 19 of 61 pts (31%) underwent VHL-related surgeries; 4 underwent surgery while on treatment and subsequently discontinued treatment, 8 underwent surgery after discontinuing treatment, and 7 are continuing treatment as of the data cutoff date. Grade 3 treatment-related adverse events (TRAEs) (most commonly anemia [n = 7; 11%]) were reported in 11 pts (18%). No grade 4 or 5 TRAEs occurred. Belzutifan was discontinued in 2 pts (3%) due to TRAEs (grade 1 dizziness and grade 2 intracranial hemorrhage). Conclusions: After 5 years of follow-up, belzutifan continues to demonstrate durable antitumor activity and a manageable safety profile, consistent with prior reports. Most pts remain on treatment after this period. Results continue to support the use of belzutifan in pts with VHL disease–related RCC, CNS HB, and pNETs who do not require immediate surgery. Clinical trial information: NCT03401788 . RCCn = 61 CNS HBn = 50 pNETsn = 20 ORR, % (95% CI) 70 (57-82);7 CRs, 36 PRs 50 (36-64); 6 CRs; 19 PRs 90 (68-99); 13 CRs, 5 PRs DOR, median (range), mo NR (5.8+ to 60.8+) 60.3 (0.0+ to 60.3) NR (11.0+ to 59.6+) 48-mo DOR rate 76% 82% 94% PFS, median (95% CI), mo NR (NR-NR) 63.5 (63.5-NR) NR (NR-NR) 48-mo PFS rate 81% 79% 96%

INTRODUCTION: Hemangioblastomas frequently arise in the nervous system of Von-Hippel Lindau (VHL) patients and are a significant cause of morbidity and mortality. These are benign, highly vascularized lesions that induce symptoms through mass effect. Historically, VHL patients have required frequent surgeries to reduce tumor burden as hemangioblastomas become symptomatic. Belzutifan, an HIF-2α inhibitor, received FDA approval in August 2021 as the first medication for VHL-associated CNS hemangioblastomas. METHODS: VHL patients with CNS hemangioblastomas =3 mm in diameter who received belzutifan were included in this study. Tumor volumes were manually segmented (Elements Smartbrush, Brainlab A/G, Munich, Germany) on all available MRIs from three years before beginning belzutifan treatment through the present day. Lesion location, presence of peritumoral edema, and cystic morphology were determined on each image. RESULTS: We followed 21 VHL patients (13 female, 62%) with 65 tumors. The average age at belzutifan initiation was 40.9±14.7 years, and the average duration of belzutifan treatment at last imaging was 662±477 days. Tumors were in the cerebellar hemispheres (n=40, 62%), vermis (n=14, 22%) and brainstem (n=11, 17%). Mean time to maximum response was 368±320 days and tumors shrank by 72±26%. Twelve tumors had complete resolution (18.5%), while five tumors (8%) grew during belzutifan treatment. All tumors were smaller at last imaging than at treatment initiation. The percentage of all tumors with cyst (34% vs 62% without cyst, p=0.036) and peritumoral edema decreased (74% pre-belzutifan vs 53% post-belzutifan, p=0.0001). CONCLUSIONS: Belzutifan reduces tumor volume in VHL-associated hemangioblastoma. It offers strong therapeutic value as a non-surgical alternative for patients with this disease.

Hemangioblastomas, especially those with von Hippel-Lindau (VHL) disease, exhibit variable clinical trajectories, ranging from prolonged stability to aggressive growth necessitating surgical intervention. We retrospectively identified patients with intracranial hemangioblastomas resected between 2000 and 2022 at a single institution. Patient demographics, VHL status, and symptoms were obtained through chart review. Disease burden and tumor characteristics, including location, peritumoral edema, and cystic morphology, were collected across serial imaging. Tumor volume was determined using 3D contouring software on neuroimaging (Elements SmartBrush, Brainlab AG, Munich) of enhancing tissue only. We analyzed 260 hemangioblastomas (70 sporadic resected, 83 VHL-associated resected, 107 VHL-associated monitored) in 122 patients with 15 years of followup. Similar numbers of hemangioblastomas grew between resected and monitored cohorts (71.2% vs. 65.3% respectively, p = 0.407), Growth patterns were categories as exponential, linear, saltatory, other, or no growth. Analysis of 105 lesions (26 resected, 79 monitored) showed resected tumors primarily grew exponentially (73.1%) compared to linearly (11.5%). Monitored tumors typically remained stable (41.8%) or grew exponentially (34.2%). Tumors undergoing resection were more likely to be edematous (p < 0.001), cystic (p < 0.001), larger (p < 0.001), located in the vermis (p = 0.027), and grow exponentially (p = 0.004). Cervicomedullary lesions underwent surgery more often (33.3% resected, p = 0.046) compared with other locations. Across both VHL and sporadic cohorts, sex, race, and surgical history were not associated with surgical resection (p = 0.169, p = 0.720, p = 0.154, respectively). This study highlights the growth behaviors of sporadic and VHL-associated hemangioblastoma. The decision to pursue surgery is influenced by tumor characteristics such as size, edema, and growth.

Supplementary Figure 2. Efficacy of belzutifan monotherapy for pancreatic neuroendocrine tumors. A, Kaplan-Meier curve of progression-free survival for pancreatic neuroendocrine tumors. B, Spider plot showing change from baseline over time in size of target pancreatic neuroendocrine tumors.

3 Background: The ongoing, open-label, phase 2 LITESPARK-004 study (NCT03401788) showed that belzutifan, a HIF-2α inhibitor, exhibited antitumor activity in patients (pts) with VHL disease associated renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and CNS hemangioblastomas. The most common adverse event (AE) of any grade was anemia and pts could have received erythropoietin-stimulating agents (ESA) and/or blood transfusions for management. This exploratory post-hoc analysis described pattern of ESA use and whether use of ESA impacted antitumor activity to belzutifan in pts with VHL disease. Methods: Pts (≥18 years) with germline VHL alterations, ≥1 measurable nonmetastatic RCC tumor, no tumor of >3 cm requiring immediate surgery, and no prior anticancer systemic treatment received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or pt withdrawal. End points included objective response rate (ORR) and duration of response (DOR) in VHL disease–associated RCC and non-RCC neoplasms per RECIST v1.1 by independent central review, and safety. Efficacy and safety outcomes among pts who received and did not receive ESA were evaluated. Data cutoff was April 1, 2022. Results: Of 61 treated pts, 14 (23%) received ESA and 47 (77%) did not. Median (range) time to onset of ESA use was 151 days (59-886) and median dose per pt was 5 injections (range 1-35). Duration of belzutifan exposure for ≥12 months was achieved in 100% of pts who received ESA vs 92% in pts who did not receive ESA. Median (range) relative dose intensity was 97.4 (51.4-100) and 98.8 (26.4-100) for pts who received and did not receive ESA, respectively. ORR for VHL-associated RCC was 71% (10/14, 95% CI, 42-92) for pts who received ESA and 62% (29/47, 46-76) for those who did not. Median DOR was not reached (NR) for pts who received and who did not receive ESA (NR, range 5.5+ to 33.5+ months and NR, range 5.4+ to 35.8+ months). All pts in both groups had a response for ≥12 months. In pts with CNS hemangioblastomas, ORR was 46% (5/11, 17-77) for pts who received ESA and 44% (17/39, 28-60) for those who did not. In pts with pNETs, ORR was 100% (4/4, 40-100) for pts who received ESA and 89% (16/18, 65-99) for those who did not. Median DOR was not reached for both groups in pts with CNS hemangioblastomas and pNETs. Among pts who received and did not receive ESA, 5 (36%) and 6 (13%) pts had at least 1 dose reduction, respectively. All pts reported at least 1 AE but a larger percentage of pts who received ESA had AEs of grade 3 or higher than those who did not receive ESA (57% and 40%). Conclusions: In this exploratory, post-hoc analysis of LITESPARK-004, data suggests that administration of ESA did not adversely impact overall drug exposure or efficacy of belzutifan in pts with VHL disease associated RCC, CNS hemangioblastomas, and pNETs. Clinical trial information: NCT03401788 .

AbstractPurpose: Primary analysis of the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788) showed clinically meaningful antitumor activity in von Hippel–Lindau (VHL) disease–associated renal cell carcinoma (RCC) and other neoplasms with belzutifan treatment. We describe results of belzutifan treatment for VHL disease–associated pancreatic lesions [pancreatic neuroendocrine tumors (pNET) and serous cystadenomas]. Patients and Methods: Adults with VHL diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no renal tumor >3 cm or other VHL neoplasm requiring immediate surgery, Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior systemic anticancer treatment received belzutifan 120 mg once daily. End points included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and linear growth rate (LGR) in all pancreatic lesions and pNETs per RECIST version 1.1 by independent review committee, and safety. Results: All 61 enrolled patients (100%) had ≥1 pancreatic lesion and 22 (36%) had ≥1 pNET measurable at baseline. Median follow-up was 37.8 months (range, 36.1–46.1). ORR was 84% [51/61; 17 complete responses (CR)] in pancreatic lesions and 91% (20/22; 7 CRs) in pNETs. Median DOR and median PFS were not reached in pancreatic lesions or pNETs. After starting treatment, median LGR for pNETs was –4.2 mm per year (range, –7.9 to –0.8). Eleven patients (18%) had ≥1 grade 3 treatment-related adverse event (AE). No grade 4 or 5 treatment-related AEs occurred. Conclusions: Belzutifan continued to show robust activity and manageable safety in VHL disease–associated pNETs.

Abstract Introduction: Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease-associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery based on initial results from the phase 2 LITESPARK-004 study (NCT03401788). We present results from pts with more than 4 years of follow-up from LITESPARK-004. Methods: Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) in VHL-associated RCC per RECIST v1.1 by independent review. Secondary end points included ORR in CNS HB and pNET; duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) in RCC, CNS HB, and pNET; and safety. Results: As of April 3, 2023, 36 of 61 pts (59%) were continuing treatment. Median follow-up was 49.9 mo (range, 48.2-58.1). Efficacy data are shown in the table. In the 4 years preceding belzutifan treatment, 46 pts (75%) underwent a total of 86 VHL-related tumor reduction procedures (surgery or radiation therapy). Since starting belzutifan, 16 pts (26%) underwent 18 tumor reduction procedures (RCC, n = 13; CNS HB, n = 3; retinal HB, n = 2). Safety profile remained unchanged with long-term follow-up. Conclusions: With a median follow-up of more than 4 years, belzutifan continues to demonstrate clinically meaningful ORR and durable responses in VHL-associated RCC, CNS HBs, and pNET. Fewer tumor reduction procedures were observed after pts started belzutifan treatment. These results support belzutifan as a standard of care for this pt population. Citation Format: Ramaprasad Srinivasan, Othon Iliopoulos, Kathryn E. Beckermann, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Ane B. Iversen, Jerry Cornell, Rodolfo F. Perini, Yanfang Liu, W. Marston Linehan, Eric Jonasch. Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT221.