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.

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.

The early assessment of successful treatment response in high-grade glioma is challenging using conventional MRI, due to phenomena such as pseudoprogression which can mimic tumor progression. New methods are needed to evaluate therapeutic efficacy rapidly and accurately. Deuterium Metabolic Imaging (DMI) is a novel, non-invasive technique that can map downstream glucose metabolism in vivo. This study aimed to evaluate the utility of DMI for assessing metabolic response to chemoradiotherapy (ChRT) in glioma patients. In this prospective two-site study, 18 patients with high-grade glioma underwent 3 T DMI before and after ChRT. Following oral administration of [6,6’- 2 H 2 ]glucose, 3D metabolic maps of 2 H-glucose (Gluc), 2 H-lactate (Lac), and 2 H-glutamate+glutamine (Glx) were acquired. Ratios of Lac/Gluc and Glx/Gluc were calculated in the tumor and normal-appearing brain parenchyma to assess glycolytic and oxidative metabolism, respectively. Before treatment, the tumor Glx/Gluc ratio was significantly lower than in the contralateral brain tissue. Following ChRT, a significant decrease in the normalized Lac/Gluc ratio was observed within the tumor volume, indicating a reduction in glycolysis. An important finding was that a lower pre-treatment normalized Glx/Gluc ratio in the tumor was a significant predictor of shorter progression-free survival (median 98 vs. 351 days, p=0.034). DMI identified metabolic changes in high-grade gliomas responding to ChRT. Reduced oxidative metabolism pre-treatment was associated with a poorer prognosis, while post-treatment decreases in glycolysis were demonstrated following therapy. DMI is a promising tool for non-invasively stratifying patients and monitoring treatment efficacy.

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.

Supplementary Figure 1. Efficacy of belzutifan monotherapy for all pancreatic lesions. A, Kaplan-Meier curve of progression-free survival for pancreatic lesions. B, Spider plot showing change from baseline over time in size of target pancreatic lesions.

Supplementary Table 2. Patient-level summary of LGR by best overall response.

PURPOSE:To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. DESIGN:Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS:Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. METHODS:Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES:Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. RESULTS:Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 μm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. CONCLUSIONS:Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, is indicated in the United States for the treatment of certain patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Due to its unique mechanism of action, belzutifan has a distinct safety profile. We characterized the safety profile of belzutifan monotherapy in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) studies and patients with RCC associated with VHL disease in the phase 2 LITESPARK-004 study (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg orally once daily across the 4 studies were included. Severity of adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and were descriptively summarized. Results A total of 576 patients were included (n = 58 [including 3 patients with advanced solid tumors other than RCC], LITESPARK-001; n = 381, LITESPARK-005; n = 76, LITESPARK-013; and n = 61, LITESPARK-004). Overall, 572 patients (99.3%) had ≥1 all-cause AE and 355 patients (61.6%) had ≥1 grade 3-5 AE. AEs led to dose modification (reduction, interruption, or discontinuation) in 288 patients (50.0%), although treatment discontinuation for AEs occurred in 37 patients (6.4%). The most common all-grade AEs were anemia (including patients with decreased hemoglobin; n = 485 [84.2%]; grade 3 or 4, n = 166 [28.8%]), fatigue (n = 246 [42.7%]; grade 3, n = 16 [2.8%]), nausea (n = 139 [24.1%]; grade 3, n = 5 [0.9%]), and dyspnea (n = 123 [21.4%]; grade 3 or 4, n = 10 [1.7%]). Hypoxia was reported in 94 patients (16.3%); grade 3 or 4 hypoxia occurred in 57 patients (9.9%). Summary and time to first onset of adverse drug reactions (AEs considered associated with belzutifan), including anemia and hypoxia, are reported in the table. Among 485 patients with anemia or decreased hemoglobin, 111 (22.9%) were treated with erythropoiesis-stimulating agent (ESA) only, 85 (17.5%) were treated with blood transfusions only, and 62 (12.8%) were treated with ESA and blood transfusions. Among 94 patients with hypoxia, 66 (70.2%) were treated with oxygen therapy. Treatment-related AEs occurred in 526 patients (91.3%) and 217 (37.7%) experienced a grade 3-5 treatment-related AE. One grade 5 adverse event (multiple organ dysfunction syndrome) was considered related to treatment. Conclusions To date, this is the largest pooled safety dataset for belzutifan monotherapy in patients with RCC. The results provide an in-depth characterization of the safety profile for belzutifan and the associated AE management strategies.

BACKGROUND:The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, showed clinically meaningful antitumour activity in von Hippel-Lindau (VHL) disease-associated neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study. We aimed to investigate antitumour activity with an additional 16 months of follow-up and present updated results for the subgroup of patients with CNS haemangioblastomas. METHODS:In the multicentre, single-arm, phase 2 LITESPARK-004 study, adults (aged ≥18 years) from 11 cancer centres or hospitals in the USA, Denmark, France, and the UK, with germline VHL alterations, at least one measurable renal cell carcinoma tumour, no renal cell carcinoma tumour greater than 3 cm requiring immediate surgical intervention, an Eastern Cooperative Oncology Group performance status 0 or 1, and no previous systemic therapy received oral belzutifan 120 mg once daily until unacceptable toxicity, disease progression, or patient decision to withdraw. The primary endpoint, evaluated in patients with CNS haemangioblastomas, was the proportion of patients with an objective response per RECIST version 1.1 by an independent review committee. We assessed response using two approaches. In approach 1, we evaluated all measurable (≥1 cm maximum diameter) or non-measurable lesions at baseline, including both the solid lesion and the associated cystic component if present. In approach 2, we evaluated only baseline lesions with a measurable (≥1 cm maximum diameter) solid lesion. Antitumour activity was assessed in all patients who received at least one dose of belzutifan. This study is no longer recruiting but is ongoing, and is registered with Clinicaltrials.gov, NCT03401788. FINDINGS:Between May 31, 2018, and March 29, 2019, of 67 patients screened, 61 (32 [52%] male and 29 [48%] female) were enrolled; 50 (82%) had at least one CNS haemangioblastoma evaluable at baseline (184 total lesions). Median follow-up for the 50 patients with CNS haemangioblastomas was 38·0 months (IQR 36·7-40·1). In approach 1, 22 of 50 patients (44% [95% CI 30-59]) had an objective response. In approach 2, 19 of 25 patients (76% [55-91] had an objective response. 23 (46%) of 50 patients had a grade 3-5 all-cause adverse event. 19 (38%) patients reported grade 3 adverse events, the most common of which was anaemia (in 6 [12%] patients). Two of 50 patients (4%) reported grade 4 events (retinal vein occlusion and embolism). Two patients died owing to adverse events not considered treatment-related (suicide and toxicity to various agents). INTERPRETATION:Belzutifan showed meaningful antitumour activity in VHL disease-associated CNS haemangioblastomas that was sustained for more than 3 years of treatment. These results continue to support belzutifan as a systemic treatment option for patients with VHL disease-related CNS haemangioblastomas. FUNDING:Merck Sharp & Dohme, National Institutes of Health, and National Cancer Institute.

Purpose: To report the efficacy of the oral hypoxia-inducible factor 2a inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. Design: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. Participants: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. Methods: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. Main Outcome Measures: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. Results: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%e100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 mm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. Conclusions: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Ophthalmology 2024;131:1324-1332 (c) 2024 Published by Elsevier Inc. on behalf of the American Academy of Ophthalmology

Supplementary Table 3. Treatment-related adverse event summary.

Supplementary Table 1. Representativeness of Study Participants.

2008 Background: Patients (pts) with VHL disease are at risk for developing multiorgan tumors and cysts, including CNS HBs. The first-in-class hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan showed clinically meaningful antitumor activity in VHL disease–associated renal cell carcinoma (RCC) and other neoplasms in the ongoing, single-arm, phase 2 LITESPARK-004 study (NCT03401788). We present updated results for the subgroup of pts with CNS HBs. Methods: Adults with a VHL disease diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, no RCC tumor > 3 cm or other VHL tumor requiring immediate surgical intervention, no evidence of metastatic disease, no prior systemic anticancer treatment, and an ECOG PS score of 0 or 1 received belzutifan 120 mg orally once daily. End points evaluated in pts with CNS HBs included objective response rate (ORR), duration of response (DOR), time to response (TTR), and progression-free survival (PFS) per RECIST v1.1 by an independent review committee; linear growth rate (LGR); and safety. CNS HBs were assessed using 2 methodologies: 1) with measurable (≥1 cm) and/or nonmeasurable disease at baseline and with associated cysts, if present; and 2) with measurable disease at baseline, excluding associated cysts, if present, from the lesion measurement. Results: Of 61 enrolled pts, 50 (82%) had ≥1 CNS HB evaluable at baseline, and 22 (59%) pts had undergone ≥1 CNS-related surgery within 4 years prior to starting belzutifan treatment. As of the April 1, 2022 data cutoff date, median study follow-up for pts with CNS HBs was 38.0 mo (range, 36.1-46.1). ORR was 44% (n = 22; 95% CI, 30-59; 4 CRs, 18 PRs), and DCR was 90% (n = 45; 95% CI, 78-97). Median TTR was 5.4 mo (range, 2.3-33.1), and median DOR was not reached (NR; range, 3.7+ to 38.7+ mo). Median PFS was NR (95% CI, 38 mo to NR). After initiating belzutifan, median LGR for all evaluable pts was –1.6 mm/year (range, –7.0 to 3.1). Of all pts, 25/50 (50%) had ≥1 measurable CNS HBs, excluding any associated cysts. For these pts, ORR was 76% (95% CI, 55-91; 1 CR, 18 PRs), and DCR was 96% (n = 24; 95% CI, 80-100). Median TTR was 3.1 mo (range, 2.5-27.8), and median DOR was NR (range, 3.7+ to 38.7+ mo). Median PFS was NR (95% CI, 36 mo to NR). After initiating belzutifan, median LGR was –1.1 mm/year (range, –3.9 to –0.1). Of all pts, 1/50 (2%) underwent a CNS-related surgery after starting belzutifan. Two (3%) pts discontinued treatment due to treatment-related adverse events. Conclusions: With more than 3 years of treatment with belzutifan, consistent and durable antitumor activity was observed in pts with CNS HBs, which is consistent with findings in other VHL disease–associated neoplasms. Using different methodologies of assessing tumors, our data demonstrated that belzutifan induced the shrinkage of VHL disease–related CNS HBs with or without the presence of associated cysts. Clinical trial information: NCT03401788 .

Abstract Previous results of the ongoing single-arm, phase 2 LITESPARK-004 (NCT03401788) study showed clinically meaningful antitumor activity with the HIF-2α inhibitor belzutifan for von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), CNS hemangioblastomas, and other neoplasms. Adults with VHL disease diagnosis based on germline VHL alteration, ≥1 measurable RCC tumor, and no prior systemic anticancer treatment received belzutifan 120 mg orally once daily. End points included ORR, DOR, and PFS per RECIST v1.1; linear growth rate (LGR); and safety. CNS hemangioblastomas were assessed with measurable (≥1 cm) and/or nonmeasurable disease at baseline, which included associated cysts if present, or with measurable disease at baseline excluding associated cysts. Of enrolled patients, 50/61 (82%) had ≥1 CNS hemangioblastoma evaluable at baseline; 22/50 patients (44%) underwent ≥1 CNS-related surgery within 4 years before starting belzutifan treatment. Median follow-up for patients with CNS hemangioblastomas was 38.0 months (range, 36.1-46.1). ORR was 44% and DCR was 90%. Median DOR was not reached (NR; range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 38 months-NR). After initiating belzutifan, median LGR for all evaluable patients was –1.6 mm/year (range, –7.0 to 3.1). A total of 25/50 patients (50%) had ≥1 measurable CNS hemangioblastomas, excluding any associated cysts. For these patients, ORR was 76% and DCR was 96%. Median DOR was NR (range, 3.7+ to 38.7+ months). Median PFS was NR (95% CI, 36 months-NR). After initiating belzutifan, median LGR was –1.1 mm/year (range, –3.9 to –0.1). Of all patients, 1/50 (2%) underwent a CNS-related surgery after starting belzutifan. Two patients (3%) discontinued treatment due to treatment-related adverse events. In summary, consistent and durable antitumor activity was observed in patients with CNS hemangioblastomas. Our data demonstrated that belzutifan induced the shrinkage of VHL disease-related CNS hemangioblastomas with or without the presence of associated cysts.