Purpose:

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.

This article is featured in Highlights of This Issue, p. 1703

Translational Relevance

Management for patients with von Hippel–Lindau (VHL) disease includes observation followed by surgery. Hypoxia-inducible factor 2α (HIF-2α) plays an important role in manifestations of VHL disease, including clear cell renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors (pNET), by inactivating the VHL gene and inducing upregulation of genes associated with cancer growth and survival. Most patients with VHL disease will develop pancreatic lesions and require multiple surgeries throughout their lifetime. Results of the phase 2 LITESPARK-004 trial demonstrated that treatment with the first-in-class HIF-2α inhibitor belzutifan had durable antitumor activity in VHL-associated pancreatic lesions, which included both pNETs and serous cystadenomas. Changes in growth rate after initiating belzutifan treatment indicate changes in tumor behavior and may indicate longer time to surgical intervention. No patients underwent a pancreas-related surgery after starting belzutifan treatment. Results from this trial further support the use of belzutifan in this patient population.

Von Hippel–Lindau (VHL) disease is a genetic disorder characterized by the inactivation of the VHL tumor-suppressor gene and the formation of multiple multisystemic benign and malignant tumors (1, 2). The VHL protein is part of an E3 ubiquitin ligase that regulates the activity of hypoxia-inducible factor (HIF) by targeting the alpha subunit for ubiquitylation and proteasomal degradation under normal conditions (2, 3). Loss of VHL expression results in constitutive activation and stabilization of HIF-2α. This accumulation drives the transcriptional activity and upregulation of genes involved in the tumorigenesis of renal cell carcinoma (RCC; refs. 4, 5). RCC will subsequently develop in approximately 70% of patients with VHL disease (6). Individuals with VHL disease are also at risk for developing other neoplasms, including hemangioblastomas of the retina and central nervous system (CNS), pancreatic serous cystadenomas, and pancreatic neuroendocrine tumors (pNET; refs. 7, 8). Approximately 70% of patients with VHL disease will develop pancreatic lesions of solid or cystic nature (3, 9). Although VHL disease–associated pancreatic cystic lesions are benign, they can be associated with symptoms such as abdominal pain, vomiting, jaundice, weight loss, or diarrhea, or very rarely, biliary tract compression, which may require intervention (3, 10, 11). Furthermore, 9% to 17% of patients with VHL disease will develop pNETs (3, 12). The prognosis for VHL disease–associated pNETs is generally favorable because pNETs are always nonfunctional and mostly asymptomatic (13–15). However, larger tumors have metastatic potential (16).

Pancreatic serous cystadenomas should be evaluated and monitored by anatomic imaging techniques such as CT, MRI, or, in certain circumstances, endoscopic ultrasonography (10, 14). Management of serous cystadenomas is generally conservative, and surgical intervention recommendations are reserved for patients who are truly symptomatic or for those in whom a diagnosis is not attainable with other methods (10).

The management strategy for pNETs is determined by prognostic factors, including tumor size (surgical resection is typically recommended for pNETs ≥3 cm in the body and tail and ≥2 cm in the head of the pancreas) and tumor growth kinetics/doubling time (4, 10, 14, 17, 18). Active surveillance is generally recommended for smaller tumors with no malignant characteristics (4, 10). A partial pancreatectomy may be performed for small, low-grade tumors (10, 19). Symptomatic, advanced pNETs may require more aggressive surgical management (19).

Although systemic treatments are available for sporadic advanced pNETs (20, 21), historically no nonsurgical treatment was specifically available for patients with VHL disease–associated pNETs (17). On the basis of the initial results of the single-arm phase 2 LITESPARK-004 (NCT03401788) trial, the small-molecule HIF-2α inhibitor belzutifan was approved by the FDA, UK Medicines and Healthcare products Regulatory Agency, Australian Therapeutic Goods Association and Health Products, and Food Branch of Health Canada for adults with VHL disease–associated RCC, CNS hemangioblastomas, or pNETs (22–26). In LITESPARK-004, belzutifan provided an objective response rate (ORR) of 49% [95% confidence interval (CI), 36–62] for patients with RCC after a median follow-up of 21.8 months (range, 20.2–30.1; ref. 23). ORR for patients with pancreatic lesions was 77%, including 6 complete responses (CR; ref. 23). Among patients with pNETs, ORR was 91% with 3 CRs (23). Responses were also observed in other VHL disease–associated neoplasms. A manageable safety profile was observed with belzutifan treatment, and most treatment-related adverse events (AE) were grade 1 or 2 (23). Here, we describe the updated antitumor and safety results after ≥3 years of median follow-up in the pancreatic tumor cohort from the phase 2 LITESPARK-004 study of belzutifan for the treatment of VHL disease–associated neoplasms.

Trial design and patients

LITESPARK-004 is a multicenter, open-label, phase 2 study evaluating belzutifan in patients with VHL disease–associated RCC and other neoplasms. Detailed study design and methods have been previously published (23). Eligible patients were aged ≥18 years and had a VHL disease diagnosis based on a germline VHL alteration, at least 1 measurable RCC tumor, no RCC tumor of ≥3 cm or other VHL tumors that required immediate surgery, no evidence of metastatic disease, no prior systemic anticancer treatment, and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients received oral belzutifan 120 mg once daily until unacceptable treatment-related toxicity, disease progression, or patient withdrawal. Dose adjustments could be made to 80 mg, then 40 mg, once daily to manage toxic effects.

Outcomes and assessments

The primary end point was ORR [defined as a CR or partial response (PR)] in VHL disease–associated RCC according to RECIST v1.1, assessed by independent review committee (IRC). Secondary end points included duration of response (DOR), time to response (TTR), and progression-free survival (PFS) in RCC; efficacy in pancreatic and other VHL disease–associated neoplasms; and safety. End points evaluated in patients with pancreatic lesions and pNETs included ORR, DOR, TTR, PFS, and linear growth rate (LGR).

For patients with neoplasms other than RCC VHL documented at screening, radiographic imaging was performed at baseline and continued every 12 weeks for a minimum of 3 years, then every 24 weeks thereafter. Tumor assessments of solid lesions were evaluated for individual organ systems by IRC according to RECIST v1.1. A maximum of 5 target lesions could be identified in each VHL-affected organ system.

In assessments of pancreatic lesions, both pNETs and serous cystadenomas were measured; simple cysts were excluded. pNETs were radiologically defined as solid parenchymal lesions that do not communicate with the pancreatic duct. Two approaches were used to determine the number of patients with pNETs at baseline. The IRC standard approach consisted of scan review by 2 primary blinded and independent radiologists, with a third radiologist as an adjudicator when adjudication parameters per imaging charter were met. A second exploratory ad hoc approach of determining pNETs required agreement from at least 2 blinded radiologists, who could be the 2 primary radiologists or 1 primary radiologist and the adjudicator.

Safety assessments were conducted throughout the trial and included physical examinations, vital sign measurements, laboratory assessments, and monitoring of AEs. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Statistical analysis

Details of this statistical analysis have been previously reported (23). Efficacy was assessed in all patients with radiographically measurable disease by IRC and in those who received at least 1 dose of belzutifan. Safety was assessed in all patients who received at least 1 dose of belzutifan. The two-sided Clopper–Pearson method was used to calculate CIs for objective responses. The Kaplan–Meier method was used to estimate the distribution of DOR and PFS. TTR was evaluated using descriptive summary statistics. LGR before and after study treatment was calculated for patients with at least 3 scans at either time point. A linear regression model was applied to determine LGR by regressing tumor size with time as a continuous variable and individual tumor as categorical variable. The LGR was derived as the coefficient of time.

Ethics statement

The protocol and its amendments were approved by the appropriate ethics committee or institutional review board at each center, and the trial was conducted as per Good Clinical Practice guidelines and in accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent.

Data availability

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data-sharing website (available at http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that might prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject-matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker co-variates and add them to a file with clinical data that are uploaded to an analysis portal so that the requestor can perform the proposed analyses.

Study population and clinical characteristics

Sixty-one patients were enrolled in this trial. Median age was 41 years (range, 19–66), 52% (n = 32) were male, and 82% (n = 50) had an ECOG PS score of 0 (Table 1; Supplementary Table S1). All patients had ≥1 pancreatic lesion. Per IRC approach, 22 patients (36%) had ≥1 solid pNET measurable at baseline. Twelve patients (20%) had ≥1 solid pNET at baseline determined from at least 2 blinded radiologists. As of April 1, 2022, median follow-up, defined as the time from the first dose to database cutoff date, was 37.8 months (range, 36.1–46.1 months). Median duration of treatment was 37.3 months (range, 1.9–46.1 months). Thirty-eight patients (62%) were continuing treatment with belzutifan as of the data cutoff date. The most common reason for discontinuing belzutifan treatment was patient decision (n = 11; 18%). Most of these patients withdrew from treatment because of trial fatigue, switch to standard-of-care belzutifan, family planning, and change in insurance coverage. Other reasons for discontinuing treatment were disease progression in VHL disease–associated RCC neoplasms (n = 6; 10%), AEs (n = 2; 3%), death (n = 2; 3%; not treatment-related), and other (n = 1; 2%).

Table 1.

Baseline characteristics.

Pancreatic lesionspNETs
CharacteristicN = 61N = 22
Age, median (range; y) 41 (19–66) 42 (19–66) 
Sex, n (%) 
 Male 32 (52) 11 (50) 
 Female 29 (48) 11 (50) 
ECOG PS, n (%) 
 0 50 (82) 20 (91) 
 1 10 (16) 2 (9) 
 2 1 (2) 
VHL disease subtype, n (%) 
 1 51 (84) 17 (77) 
 2A 2 (3) 1 (5) 
 2B 6 (10) 3 (14) 
 2C 
 Missing 2 (3) 1 (5) 
Prior surgeriesa, n (%) 
 Total number of patients who had ≥1 prior surgery 59 (97) 22 (100) 
 Pancreatic lesionsb 9 (15) 2 (9) 
Size of target lesions, median (range; mm) 19 (10–61)c 19 (10–52)d 
Pancreatic lesionspNETs
CharacteristicN = 61N = 22
Age, median (range; y) 41 (19–66) 42 (19–66) 
Sex, n (%) 
 Male 32 (52) 11 (50) 
 Female 29 (48) 11 (50) 
ECOG PS, n (%) 
 0 50 (82) 20 (91) 
 1 10 (16) 2 (9) 
 2 1 (2) 
VHL disease subtype, n (%) 
 1 51 (84) 17 (77) 
 2A 2 (3) 1 (5) 
 2B 6 (10) 3 (14) 
 2C 
 Missing 2 (3) 1 (5) 
Prior surgeriesa, n (%) 
 Total number of patients who had ≥1 prior surgery 59 (97) 22 (100) 
 Pancreatic lesionsb 9 (15) 2 (9) 
Size of target lesions, median (range; mm) 19 (10–61)c 19 (10–52)d 

Note: Percentages may not equal 100 because of rounding.

aPatients may have undergone surgery to multiple organ systems.

bPancreatic lesions include pNETs and serous cystadenomas.

cOn the basis of 91 target pancreatic lesions.

dOn the basis of 27 target pNET lesions.

ORR was 84% (n = 51; 17 CRs, 34 PRs; Table 2) in patients with pancreatic lesions (consisting of pNETs and serous cystadenomas). Median TTR was 8.3 months (range, 2.5–32.9 months) and median DOR was not reached (NR; range, 2.6+ to 37.3+ months; Fig. 1A). By Kaplan–Meier estimate, 95% of responders remained in response for at least 36 months. Median PFS was NR (95% CI, NR–NR; Supplementary Fig. S1A); no patient's disease progressed in pancreatic lesions. Most patients had growing tumors before initiation of belzutifan treatment and had a decrease in the total sum of target lesion after starting belzutifan initiation (Supplementary Fig. S1B). A total of 92% (n = 56) of patients experienced a reduction from baseline in the total sum of pancreatic target lesion diameter (Fig. 1B).

Table 2.

Response in VHL disease–associated pancreatic neoplasms.

Pancreatic lesionspNETs
N = 61N = 22
ORR, n (%; 95% CI) 51 (84) 20 (91) 
 (71.9–91.8) (70.8–98.9) 
Best overall response, n (%) 
 CR 17 (28) 7 (32) 
 PR 34 (56) 13 (59) 
 Stable disease 9 (15) 2 (9) 
 Progressive disease 
 Not evaluable 1 (2) 
TTR, median (range; mo) 8.3 (2.5–32.9) 8.2 (2.5–16.4) 
DOR, median (range; mo) NR (2.6+ to 37.3+) NR (11.0+ to 37.3+) 
Pancreatic lesionspNETs
N = 61N = 22
ORR, n (%; 95% CI) 51 (84) 20 (91) 
 (71.9–91.8) (70.8–98.9) 
Best overall response, n (%) 
 CR 17 (28) 7 (32) 
 PR 34 (56) 13 (59) 
 Stable disease 9 (15) 2 (9) 
 Progressive disease 
 Not evaluable 1 (2) 
TTR, median (range; mo) 8.3 (2.5–32.9) 8.2 (2.5–16.4) 
DOR, median (range; mo) NR (2.6+ to 37.3+) NR (11.0+ to 37.3+) 

Note: “+” indicates response is ongoing.

Figure 1.

Best overall response of patients with pancreatic lesions. A, Swimmer plot showing duration of treatment and best response. Each line represents a patient. B, Waterfall plot showing the best percentage change from baseline in total sum of pancreatic lesions.

Figure 1.

Best overall response of patients with pancreatic lesions. A, Swimmer plot showing duration of treatment and best response. Each line represents a patient. B, Waterfall plot showing the best percentage change from baseline in total sum of pancreatic lesions.

Close modal

In the 22 patients with pNETs, ORR was 91% with 7 CRs and 13 PRs. Representative images of patients with CRs are displayed in Fig. 2A and B: a patient with pNET who had a 21-mm lesion at baseline and showed PR by week 43 and CR at week 202 (Fig. 2A) and a patient with a serous cystadenoma who had a 52-mm lesion at baseline and showed PR by week 63 and CR at week 159 (Fig. 2B). Median TTR was 8.2 months (range, 2.5–16.4 months) and median DOR was NR (range, 11.0+ to 37.3+ months; Fig. 3A). By Kaplan–Meier estimate, 100% of responders remained in response for at least 36 months. Median PFS was NR in patients with pNETs (95% CI, NR–NR; Supplementary Fig. S2A); no patient experienced disease progression in pNETs. The proportion of patients with pNETs who experienced any reduction from baseline in the total sum of pNET target lesion diameters was 100% (n = 22; Fig. 3B; Supplementary Fig. S2B). In the 12 patients with pNETs per agreement of 2 blinded radiologists (ad hoc analysis), ORR was 83% (n = 10; 95% CI, 51.6–97.9) with 5 CRs and 5 PRs. Median DOR was NR (range, NR–NR).

Figure 2.

Representative images from patients who achieved CRs. A, Scan of a patient with pNET who had a CR at week 202. B, Scan of a patient with non-pNET (serous cystadenoma) who had a CR at week 159.

Figure 2.

Representative images from patients who achieved CRs. A, Scan of a patient with pNET who had a CR at week 202. B, Scan of a patient with non-pNET (serous cystadenoma) who had a CR at week 159.

Close modal
Figure 3.

Best overall response of patients with pNETs. A, Swimmer plot showing duration of treatment and best response. Each line represents a patient. B, Waterfall plot showing the best percentage of change from baseline in total sum of pNET target lesions.

Figure 3.

Best overall response of patients with pNETs. A, Swimmer plot showing duration of treatment and best response. Each line represents a patient. B, Waterfall plot showing the best percentage of change from baseline in total sum of pNET target lesions.

Close modal

Median LGR at the lesion level for pancreatic lesions was 1.6 mm per year (range, –14.7 to 21.3 mm) before belzutifan treatment and −4.5 mm per year (range, –15.3 to 0.3 mm) after starting belzutifan (Table 3). Median LGR at the lesion level for pNETs was 1.3 mm per year (range, –14.7 to 21.3 mm) before belzutifan treatment and −4.2 mm per year (range, –7.9 to –0.8 mm) after starting belzutifan. At the patient level, the median LGR for pancreatic lesions was 1.9 mm per year (range, –7.4 to 10.6 mm) before belzutifan treatment and −4.8 mm per year (range, –14.6 to 0.0 mm) after starting belzutifan. Median LGR after treatment was –4.7 mm per year (range, −9.2 to −2.6) for the patients who achieved CRs (n = 17), –5.3 mm per year (range, –14.6 to –0.5) for patients who achieved PRs (n = 34), and −1.2 mm per year (range, –10.9 to 0.0) for patients with stable disease (n = 6; Supplementary Table S2). At the patient level, median LGR for pNETs was 1.2 mm per year (range, –7.4 to 7.7 mm) before belzutifan treatment and –4.4 mm per year (range, –7.6 to –0.8 mm) after starting belzutifan. Median LGR after treatment was −5.1 mm per year (range, –7.4 to –3.0) for the patients who achieved CRs (n = 7), –5.1 mm per year (range, –11.0 to –1.4) for patients who achieved PRs (n = 13), and –1.2 mm per year (range, –1.5 to –0.8) for patients with stable disease (n = 2).

Table 3.

Lesion level summary of LGR by quartiles of before treatment LGRa.

OverallLGR, median (range), mm/y before treatmentLGR, median (range), mm/y after treatment initiation
Pancreatic lesions, mm/y 
 –14.7 to 0.5 –0.2 (–14.7 to 0.5) –3.9 (–7.9 to –0.5) 
 0.5–1.6 1.2 (–2.4 to 4.4) –4.7 (–9.2 to 0.3) 
 1.6–3.5 3.0 (–10.6 to 14.6) –5.2 (–15.3 to –0.6) 
 3.5–21.3 4.8 (–1.5 to 21.3) –4.1 (–14.6 to –1.5) 
pNETs, mm/y 
 –14.7 to 0.04 –2.4 (–14.7 to 0.0) –2.8 (–7.9 to –0.8) 
 0.04–1.3 0.7 (0.1–1.4) –3.9 (–6.7 to –3.1) 
 1.3–3.5 2.9 (1.2–3.6) –4.7 (–6.9 to –2.7) 
 3.5–21.3 5.1 (–1.5 to 21.3) –5.5 (–7.4 to –1.5) 
OverallLGR, median (range), mm/y before treatmentLGR, median (range), mm/y after treatment initiation
Pancreatic lesions, mm/y 
 –14.7 to 0.5 –0.2 (–14.7 to 0.5) –3.9 (–7.9 to –0.5) 
 0.5–1.6 1.2 (–2.4 to 4.4) –4.7 (–9.2 to 0.3) 
 1.6–3.5 3.0 (–10.6 to 14.6) –5.2 (–15.3 to –0.6) 
 3.5–21.3 4.8 (–1.5 to 21.3) –4.1 (–14.6 to –1.5) 
pNETs, mm/y 
 –14.7 to 0.04 –2.4 (–14.7 to 0.0) –2.8 (–7.9 to –0.8) 
 0.04–1.3 0.7 (0.1–1.4) –3.9 (–6.7 to –3.1) 
 1.3–3.5 2.9 (1.2–3.6) –4.7 (–6.9 to –2.7) 
 3.5–21.3 5.1 (–1.5 to 21.3) –5.5 (–7.4 to –1.5) 

aLesions with <3 scans before treatment are not included in the table.

Fifteen percent (n = 9) of patients underwent ≥1 pancreatic-related surgery [pancreatectomy (n = 50), pancreatic lesion excision (n = 10), and pancreaticoduodenectomy (n = 3)] before starting belzutifan treatment. Of those 9 patients, 33% (n = 3) underwent pancreatic-related surgery [partial pancreatectomy (n = 1), distal pancreatectomy (n = 1), and Whipple resection (n = 1)] within 4 years before starting belzutifan treatment. After starting belzutifan, no patients underwent pancreatic-related surgery as of the data cutoff date.

Safety was consistent with the primary analysis. Treatment-related AEs of any grade occurred in all patients (100%; Supplementary Table S3). The most common (≥25% of patients) treatment-related AEs were anemia (n = 54; 89%), fatigue (n = 39; 64%), dizziness (n = 15; 25%), and nausea (n = 15; 25%). Grade 3 treatment-related AEs occurred in 18% of patients (n = 11), most commonly anemia (n = 7; 11%). No grade 4 or 5 treatment-related AEs were reported. Treatment was discontinued in 3% of patients (n = 2) due to a treatment-related AE (grade 1 dizziness and grade 2 intracranial hemorrhage).

Patients with VHL disease are at lifelong risk for developing recurrent benign and malignant neoplasms in multiple organs, and pancreatic lesions are among the most common neoplasms. Pancreatic cystadenomas have a benign course but may be associated with bile duct compression and related symptoms (10). Cystadenomas are managed on the basis of symptomology and cross-sectional imaging and rarely require surgical intervention (10, 14). pNETs, however, may be malignant and may cause abdominal pain, jaundice, pancreatitis, gastrointestinal bleeding, or metastasize if left untreated (11, 19). Patients therefore require lifelong monitoring and management, which often includes multiple surgeries throughout their lives. Patients who undergo pancreatic surgery are at risk for several complications, including perioperative infections, development of diabetes mellitus, loss of exocrine function, and pancreatic fistulas (13).

Treatment with the HIF-2α inhibitor belzutifan has previously shown responses in VHL disease–associated neoplasms, and belzutifan is currently the only systemic treatment approved in the United States for patients with VHL disease–associated pNETs (22, 23). In the current analysis, belzutifan continued to show durable antitumor activity in patients with any VHL disease–associated pancreatic lesion, including those with pNETs. ORR was 84% for pNETs and serous cystadenomas and 91% for pNETs only. These responses were durable, with most patients remaining in response for at least 36 months and more patients achieving CRs compared with earlier analysis (23). Regardless of pretreatment LGR, the LGR of pancreatic lesions and pNETs on belzutifan treatment remained comparable across quartiles of pretreatment LGR, suggesting that belzutifan induces tumor reduction in both slow- and fast-growing tumors. VHL-associated tumors have a variable growth rate, with some displaying aggressive growth over time, and the only treatment is surgery (7, 27, 28). The decrease in growth rate observed in this study may indicate changes in tumor biology, which may delay the need for surgery. No patients in this study underwent pancreatic-related surgery since starting belzutifan treatment, which suggests the potential of belzutifan to reduce and/or delay the need for surgical interventions.

There have been few studies evaluating systemic treatments for VHL disease. A retrospective analysis of tyrosine kinase inhibitors, including sunitinib, sorafenib, axitinib, and pazopanib for the treatment in VHL disease, showed an ORR of 27% in pancreatic tumors or cysts across all treatments (29). The observed AEs were consistent with previous reports of sunitinib side effects (29). A phase 1 pilot study of sunitinib for the treatment of VHL disease reported a best response of stable disease in all 5 evaluable pNETs, and pNETs had grown by week 48 follow-up (30). A phase 2 trial of 31 evaluable patients with VHL disease reported that 9 (53%) of 17 pancreatic lesions showed a PR after treatment with pazopanib (31).

The safety profile of belzutifan in the current analysis was consistent with previous reports (23). Mostly, grades 1 and 2 treatment-related AEs occurred in all patients with VHL disease; no grade 4 or 5 treatment-related AEs occurred. Anemia was the most common treatment-related AE of any grade. As of the data cutoff date, 62% of patients remain on treatment, suggesting long-term tolerability of belzutifan. Further follow-up is important to better identify the safety profile in patients with VHL disease and to define the long-term effects of belzutifan on tumor biology.

This study is limited by its single-arm design and the small number of patients with pNETs. Belzutifan was shown to have durable antitumor activity and a manageable safety profile in VHL disease–associated pNETs and non-pNET lesions such as serous cystadenomas. Results from the LITESPARK-004 trial provide support for treatment with belzutifan in VHL disease–associated pNETs.

T. Else reports support from MSD during the conduct of the study, as well as personal fees from MSD, Lantheus, and HRA Pharma outside the submitted work. E. Jonasch reports grants from MSD during the conduct of the study. E. Jonasch also reports grants from Aveo, Arrowhead, Corvus, MSD, NiKang, and Telix, as well as honoraria from Aveo, DAVA, Eisai, Exelixis, Ipsen, MSD, NiKang, and Novartis outside the submitted work. O. lliopoulos received consultancy fees from Merck. K.E. Beckermann reports support from MSD during the conduct of the study. K.E. Beckermann also reports grants from BMS-LCFA-IASLC, Arsenal Biosciences, Pionyr, Aravive, and the US Department of Defense, as well as consulting fees from Aravive, Aveo, Alpine Bioscience, BMS, Exelixis, Merck, Nimbus, Arcus, Xencor, Sanofi, AstraZeneca, and Seagen. V. Narayan reports grants from Merck during the conduct of the study. V. Narayan also reports consulting fees from AstraZeneca, Exelixis, Janssen, Merck & Co., Inc., Myovant Sciences, Pfizer Regeneron, and Sanofi, as well as research support (to institution) from Bristol Myers Squibb, Janssen, Merck & Co., Inc., Pfizer, Regeneron, and TMunity Therapeutics outside the submitted work. B.L. Maughan reports personal fees from AbbVie, Pfizer, Aveo Oncology, Janssen, Astellas, Tempus, MSD, Bayer Oncology, Lilly, Sanofi, Telix, and Peloton Therapeutics; grants and personal fees from Bristol Myers Squibb, Clovis, and Exelixis; and grants from Bavarian-Nordic and Genentech during the conduct of the study. B.L Maughan also reports working for Xencor as a consultant/advisor. S. Oudard reports honoraria from Astellas, Bayer, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche/Genentech, and Sanofi; consulting to Astellas, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and SD Oncology; research funding from Ipsen and Sanofi; and travel, accommodation, and expense reimbursements from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, MSD, Novartis, and Roche. J.K. Maranchie reports personal fees from Elsevier; grants from NCI; and other support from Janssen, LUGPA, and MSD during the conduct of the study. J.K. Maranchie also reports other support from SUO outside the submitted work. C.M. Goldberg is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. and has stock ownership in Merck & Co. W. Fu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. R.F. Perini is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., and has stock ownership in Merck & Co., Inc. Y. Liu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. R. Srinivasan reports research funding (to institution) from MSD during the conduct of the study. No disclosures were reported by the other authors.

T. Else: Investigation, writing–review and editing. E. Jonasch: Conceptualization, writing–review and editing. O. lliopoulos: Conceptualization, resources, investigation, writing–review and editing. K.E. Beckermann: Resources, data curation, investigation, writing–review and editing. V. Narayan: Formal analysis, investigation, writing–review and editing. B.L. Maughan: Resources, data curation, investigation, writing–review and editing. S. Oudard: Formal analysis, investigation, writing–review and editing. J.K. Maranchie: Investigation, writing–review and editing. A.B. Iversen: Validation, investigation, writing–review and editing. C.M. Goldberg: Investigation, writing–review and editing. W. Fu: Conceptualization, formal analysis, investigation, writing–review and editing. R.F. Perini: Formal analysis, validation, investigation, writing–review and editing. Y. Liu: Investigation, writing–review and editing. W.M. Linehan: Conceptualization, investigation, writing–review and editing. R. Srinivasan: Conceptualization, resources, formal analysis, supervision, funding acquisition, validation, investigation, writing–review and editing.

We thank the patients and their families and caregivers for participating in the study. Medical writing and/or editorial assistance was provided by Mallory Campbell, PhD, and Robert Steger, PhD, of ApotheCom. This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. and the Intramural Research Program of the National Institutes of Health, National Cancer Institute (NCI) Center for Cancer Research, and a grant (UO1 CA236489) from the NCI.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

1.
Chittiboina
P
,
Lonser
RR
.
Von Hippel–Lindau disease
.
Handb Clin Neurol
2015
;
132
:
139
56
.
2.
Haase
VH
.
The VHL tumor suppressor: master regulator of HIF
.
Curr Pharm Des
2009
;
15
:
3895
903
.
3.
van Asselt
SJ
,
de Vries
EG
,
van Dullemen
HM
,
Brouwers
AH
,
Walenkamp
AM
,
Giles
RH
, et al
.
Pancreatic cyst development: insights from von Hippel–Lindau disease
.
Cilia
2013
;
2
:
3
.
4.
Ganeshan
D
,
Menias
CO
,
Pickhardt
PJ
,
Sandrasegaran
K
,
Lubner
MG
,
Ramalingam
P
, et al
.
Tumors in von Hippel–Lindau syndrome: from head to toe-comprehensive state-of-the-art review
.
Radiographics
2018
;
38
:
849
66
.
5.
Choueiri
TK
,
Kaelin
WG
.
Targeting the HIF2–VEGF axis in renal cell carcinoma
.
Nat Med
2020
;
26
:
1519
30
.
6.
Maher
ER
,
Neumann
HP
,
Richard
S
.
von Hippel–Lindau disease: a clinical and scientific review
.
Eur J Hum Genet
2011
;
19
:
617
23
.
7.
Schuhmacher
P
,
Kim
E
,
Hahn
F
,
Sekula
P
,
Jilg
CA
,
Leiber
C
, et al
.
Growth characteristics and therapeutic decision markers in von Hippel–Lindau disease patients with renal cell carcinoma
.
Orphanet J Rare Dis
2019
;
14
:
235
.
8.
Couch
V
,
Lindor
NM
,
Karnes
PS
,
Michels
VV
.
von Hippel–Lindau disease
.
Mayo Clin Proc
2000
;
75
:
265
72
.
9.
Flores-Martínez
A
,
García-Núñez
A
,
Rojas
A
,
Cano
DA
.
Stabilization of HIF-2α impacts pancreas growth
.
Sci Rep
2018
;
8
:
13713
.
10.
Keutgen
XM
,
Hammel
P
,
Choyke
PL
,
Libutti
SK
,
Jonasch
E
,
Kebebew
E
.
Evaluation and management of pancreatic lesions in patients with von Hippel–Lindau disease
.
Nat Rev Clin Oncol
2016
;
13
:
537
49
.
11.
Hammel
PR
,
Vilgrain
V
,
Terris
B
,
Penfornis
A
,
Sauvanet
A
,
Correas
JM
, et al
.
Pancreatic involvement in von Hippel–Lindau disease. The groupe francophone d'etude de la maladie de von Hippel–Lindau
.
Gastroenterology
2000
;
119
:
1087
95
.
12.
Tirosh
A
,
Sadowski
SM
,
Linehan
WM
,
Libutti
SK
,
Patel
D
,
Nilubol
N
, et al
.
Association of VHL genotype with pancreatic neuroendocrine tumor phenotype in patients with von Hippel–Lindau disease
.
JAMA Oncol
2018
;
4
:
124
6
.
13.
Zwolak
A
,
Świrska
J
,
Tywanek
E
,
Dudzińska
M
,
Tarach
JS
,
Matyjaszek-Matuszek
B
.
Pancreatic neuroendocrine tumours in patients with von Hippel–Lindau disease
.
Endokrynol Pol
2020
;
71
:
256
9
.
14.
Ayloo
S
,
Molinari
M
.
Pancreatic manifestations in von Hippel–Lindau disease: a case report
.
Int J Surg Case Rep
2016
;
21
:
70
2
.
15.
Ahmad
S
,
Naber
MR
,
Giles
RH
,
Valk
GD
,
van Leeuwaarde
RS
.
Diagnostic and management strategies for pNETs in von Hippel–Lindau: a systematic review
.
Endocr Relat Cancer
2021
;
28
:
151
60
.
16.
Krauss
T
,
Ferrara
AM
,
Links
TP
,
Wellner
U
,
Bancos
I
,
Kvachenyuk
A
, et al
.
Preventive medicine of von Hippel–Lindau disease-associated pancreatic neuroendocrine tumors
.
Endocr Relat Cancer
2018
;
25
:
783
93
.
17.
Laks
S
,
van Leeuwaarde
R
,
Patel
D
,
Keutgen
XM
,
Hammel
P
,
Nilubol
N
, et al
.
Management recommendations for pancreatic manifestations of von Hippel–Lindau disease
.
Cancer
2022
;
128
:
435
46
.
18.
Blansfield
JA
,
Choyke
L
,
Morita
SY
,
Choyke
PL
,
Pingpank
JF
,
Alexander
HR
, et al
.
Clinical, genetic and radiographic analysis of 108 patients with von Hippel–Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs)
.
Surgery
2007
;
142
:
814
8
.
19.
Kanthan
R
,
Senger
J
,
Ahmed
S
,
Kanthan
S
.
Pancreatic neuroendocrine tumors in the 21st century—an update
.
J Can Ther
2017
;
8
:
1194
233
.
20.
Blumenthal
GM
,
Cortazar
P
,
Zhang
JJ
,
Tang
S
,
Sridhara
R
,
Murgo
A
, et al
.
FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors
.
Oncologist
2012
;
17
:
1108
13
.
21.
Megdanova-Chipeva
VG
,
Lamarca
A
,
Backen
A
,
McNamara
MG
,
Barriuso
J
,
Sergieva
S
, et al
.
Systemic treatment selection for patients with advanced pancreatic neuroendocrine tumours (PanNETs)
.
Cancers
2020
;
12
:
1988
.
22.
WELIREG (belzutifan) tablets, for oral use. 05/2022
.
Merck & Co., Inc.
,
Rahway, NJ
;
2022
.
Available from:
https://www.merck.com/product/usa/pi_circulars/w/welireg/welireg_pi.pdf.
23.
Jonasch
E
,
Donskov
F
,
Iliopoulos
O
,
Rathmell
WK
,
Narayan
VK
,
Maughan
BL
, et al
.
Belzutifan for renal cell carcinoma in von Hippel–Lindau disease
.
N Engl J Med
2021
;
385
:
2036
46
.
24.
Medicines and Healthcare products Regulatory Agency (MHRA)
.
First Innovation Passport awarded to help support development and access to cutting-edge medicines
.
London, UK
:
MHRA
;
2022
.
Available from
: https://www.gov.uk/government/news/first-innovation-passport-awarded-to-help-support-development-and-access-to-cutting-edge-medicines.
25.
Commonwealth of Australia
.
Welireg Australian Therapeutic Goods Administration approval
. In
Commonwealth of Australia. MSD (Australia) Pty Limited
2023. Available from:
https://www.tga.gov.au/resources/auspmd/welireg.
26.
WELIREG belzutifan tablets, 40 mg, oral
.
(Monograph). 07/11/2022
.
Merck Canada Inc.
:
Kirkland QC Canada
;
2022
. p.
26
.
27.
Li
Z
,
Zhang
J
,
Zhang
L
,
Yao
L
,
Zhang
C
,
He
Z
, et al
.
Natural history and growth kinetics of clear cell renal cell carcinoma in sporadic and von Hippel–Lindau disease
.
Transl Androl Urol
2021
;
10
:
1064
.
28.
Weisbrod
AB
,
Kitano
M
,
Thomas
F
,
Williams
D
,
Gulati
N
,
Gesuwan
K
, et al
.
Assessment of tumor growth in pancreatic neuroendocrine tumors in von Hippel–Lindau syndrome
.
J Am Coll Surg
2014
;
218
:
163
9
.
29.
Ma
K
,
Hong
B
,
Zhou
J
,
Gong
Y
,
Wang
J
,
Liu
S
, et al
.
The efficacy and safety of tyrosine kinase inhibitors for von Hippel–Lindau disease: a retrospective study of 32 patients
.
Front Oncol
2019
;
9
:
1122
.
30.
Jonasch
E
,
McCutcheon
IE
,
Waguespack
SG
,
Wen
S
,
Davis
DW
,
Smith
LA
, et al
.
Pilot trial of sunitinib therapy in patients with von Hippel–Lindau disease
.
Ann Oncol
2011
;
22
:
2661
6
.
31.
Jonasch
E
,
McCutcheon
IE
,
Gombos
DS
,
Ahrar
K
,
Perrier
ND
,
Liu
D
, et al
.
Pazopanib in patients with von Hippel–Lindau disease: a single-arm, single-centre, phase 2 trial
.
Lancet Oncol
2018
;
19
:
1351
9
.
This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.