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Indications
WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Indications

WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Selected Safety Information
WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Selected Safety Information

WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.
Anemia
  • WELIREG can cause severe anemia that can require blood transfusion.
    • Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG.
  • In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).
  • The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.
  • In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received erythropoiesis-stimulating agents (ESAs) only, and 12% received both transfusion and ESAs.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
  • Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a health care provider.
  • In LITESPARK-004, hypoxia occurred in 1.6% of patients.
  • In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).
Embryo-Fetal Toxicity
  • Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Adverse Reactions
  • In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
  • WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.
  • Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
  • In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).
  • WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).
  • Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).
Drug Interactions
  • Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.
  • Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Lactation
  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.
Females and Males of Reproductive Potential
  • WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.
  • Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
  • Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.
Pediatric Use
  • Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.
Before prescribing WELIREG, please read the accompanying Prescribing Information, including the Boxed Warning about embryo-fetal toxicity. The Medication Guide also is available.

Efficacy Data for WELIREG™ (belzutifan)

On this page:
Primary Analysis
Extended Analysis
Study Design
On this page:
Primary Analysis
Extended Analysis
Study Design

Reimagine your approach to the management of certain VHL disease–associated tumors

When surgery is not immediately required, consider the only approved systemic option1,2

In LITESPARK-004, an open-label clinical trial for adult patients with VHL disease–associated RCC (N=61),

Nearly half of patients achieved tumor reduction in VHL disease–associated RCC with WELIREGa

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated RCC in the Primary Analysis

Objective response rate (ORR) per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

with ongoing responses ranging from 2.8+ to 22+ months
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5

56 %

of patients who responded (n=17/30) continued to respond at ≥12 months.
Time to response (TTR) as early as 2.7 months
  • Median time to response was 8 months (range: 2.7 to 19 months).
See study design

NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer (confirmed hereditary VHL disease–associated RCC)

Belzutifan (WELIREG) is the only preferred systemic therapy option (NCCN category 2A) for patients with VHL disease–associated RCC not requiring immediate surgery.6
 
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
a
All patients with a response were followed for a minimum of 18 months from the start of treatment.
+ Denotes ongoing response.
Category 2A = Based upon lower-level evidence, there is uniform National Comprehensive Cancer Network® (NCCN®) consensus (≥85% support of the Panel) that the intervention is appropriate.6
CI = confidence interval; DOR = duration of response; NCCN = National Comprehensive Cancer Network; NCCN Guidelines = NCCN Clinical Practice Guidelines in Oncology; RCC = renal cell carcinoma; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; VHL = von Hippel-Lindau.

PATIENT SUBGROUP: VHL disease–associated CNS hemangioblastomas

In LITESPARK-004, an open-label clinical trial for adult patients with VHL disease–associated RCC (N=61),

Nearly two-thirds of patients with VHL disease–associated CNS hemangioblastomas achieved tumor reduction with WELIREGa

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated CNS Hemangioblastomas in the Primary Analysis

ORR per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

with ongoing responses ranging from 3.7+ to 22+ months
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5

73 %

of patients who responded (n=11/15) continued to respond at ≥12 months.
Time to response (TTR) as early as 2.5 months 
  • Median time to response was 3.1 months (range: 2.5 to 11 months).
See study design

NCCN Guidelines® for CNS Cancers (VHL disease–associated CNS hemangioblastomas)

Belzutifan (WELIREG) is the only systemic therapy option identified as useful in certain circumstances (NCCN category 2A) for patients with VHL disease–associated CNS hemangioblastomas not requiring immediate surgery or those for whom surgery is contraindicated due to location or prior surgeries or comorbidities, growing or symptomatic.7
 
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
a
Number of patients with measurable solid lesions, based on IRC assessment.
Category 2A = Based upon lower-level evidence, there is uniform NCCN consensus (≥85% support of the Panel) that the intervention is appropriate.7
CI = confidence interval; CNS = central nervous system; DOR = duration of response; IRC = independent review committee; NCCN = National Comprehensive Cancer Network; NCCN Guidelines = NCCN Clinical Practice Guidelines in Oncology; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; VHL = von Hippel-Lindau.

PATIENT SUBGROUP: VHL disease–associated pNET

In LITESPARK-004, an open-label clinical trial for adult patients with VHL disease–associated RCC (N=61),

Most patients with VHL disease–associated pNET achieved tumor reduction with WELIREGa

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated pNET in the Primary Analysis

ORR per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

with ongoing responses ranging from 11+ to 19+ months
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5

50 %

of patients who responded (n=5/10) continued to respond at ≥12 months.
Time to response (TTR) as early as 2.7 months 
  • Median time to response was 8.1 months (range: 2.7 to 11 months).
a
Number of patients with measurable solid lesions, based on IRC assessment.
CI = confidence interval; DOR = duration of response; IRC = independent review committee; pNET = pancreatic neuroendocrine tumors; RECIST v1.1 = Response Evaluation In Solid Tumors; VHL = von Hippel-Lindau.
See study design

Objective response rate (ORR) data at 49.9 months in adult patients with VHL disease–associated RCC8

LIMITATIONS: Statistical analysis performed for the extended follow-up is consistent with the previous interim analysis. Approval of WELIREG is not based on the extended follow-up analysis; therefore, these data are for informational purposes only.

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated RCC in the Extended Follow-Up Analysis

ORR per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

(range: 8.6+ to 44.4+ months)
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5
Median time to response was 11.1 months (range: 2.7 to 41.2 months)

59% of patients remained on WELIREG at the data cutoff date in the 49.9-month analysis4

+ Denotes ongoing response.
CI = confidence interval; DOR = duration of response; RCC = renal cell carcinoma; RECIST v1.1 = Response Evaluation In Solid Tumors; VHL = von Hippel-Lindau.

Objective response rate (ORR) data at 49.9 months in adult patients with VHL disease–associated CNS hemangioblastomas8

LIMITATIONS: Statistical analysis performed for the extended follow-up is consistent with the previous interim analysis. Approval of WELIREG is not based on the extended follow-up analysis; therefore, these data are for informational purposes only.

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated CNS Hemangioblastomas in the Extended Follow-Up Analysis

ORR per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

(range: 0+ to 47.5+ months)
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5
Median time to response was 5.5 months (range: 2.3 to 38.7 months)

In the extended analysis, the number of patients with CNS hemangioblastomas is from a prespecified data set that included solid lesions and the associated cystic component, if present. Other post hoc data that specifically assessed only solid lesions are not included here.9

CI = confidence interval; CNS = central nervous system; DOR = duration of response; RECIST v1.1 = Response Evaluation In Solid Tumors; VHL = von Hippel-Lindau.

Objective response rate (ORR) data at 49.9 months in adult patients with VHL disease–associated pNET8

LIMITATIONS: Statistical analysis performed for the extended follow-up is consistent with the previous interim analysis. Approval of WELIREG is not based on the extended follow-up analysis; therefore, these data are for informational purposes only.

Percentage of Patients Who Achieved an Objective Response (Objective Response Rate, ORR) for VHL Disease-Associated pNET in the Extended Follow-Up Analysis

ORR per RECIST v1.1: Complete response was defined as disappearance of all target and nontarget lesions. Partial response was defined as ≥30% decrease in the sum of the longest diameters of target lesions compared with baseline.4

MEDIAN DURATION OF RESPONSE WAS NOT REACHED

(range: 11.0+ to 48.3+ months)
  • Median DOR could not be estimated (by Kaplan-Meier method), as the majority of patients who responded to treatment maintained their response (did not experience disease progression per RECIST v1.1) at the time of data cutoff.5
Median time to response was 8.2 months (range: 2.5 to 16.4 months)

In the extended analysis, pNET was assessed by 2 different review committee approaches. The data set shown is by an IRC approach consisting of scan review by 2 primary blinded, independent radiologists, with a third radiologist as an adjudicator when needed. Other post hoc data that required the presence of pNET were confirmed by at least 2 of the 3 blinded radiologists' reviews and are not included here.10

CI = confidence interval; DOR = duration of response; IRC = independent review committee; pNET = pancreatic neuroendocrine tumors; RECIST v1.1 = Response Evaluation In Solid Tumors; VHL = von Hippel-Lindau.

Study design

WELIREG was evaluated in LITESPARK-004, an open-label clinical trial

See Study Design of WELIREG™ (belzutifan) Evaluated in LITESPARK-004, Including Exclusion Criteria, Major and Additional Efficacy End Points for RCC and CNS Hemangioblastomas and pNET, and Study Population CharacteristicsSee Study Design of WELIREG™ (belzutifan) Evaluated in LITESPARK-004, Including Exclusion Criteria, Major and Additional Efficacy End Points for RCC and CNS Hemangioblastomas and pNET, and Study Population Characteristics

Prior to enrollment in LITESPARK-004, 77% of study participants had previous surgical procedures for RCC

aAs defined by RECIST v1.1.

bAssessed by IRC using RECIST v1.1.

cCNS hemangioblastomas and pNET in these patients were diagnosed based on the presence of at least 1 measurable solid tumor in the brain/spine or pancreas, respectively, as defined by RECIST v1.1 and identified by IRC.

dRECIST v1.1 response defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.5

CNS = central nervous system; IRC = independent review committee; pNET = pancreatic neuroendocrine tumors; RCC = renal cell carcinoma; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; VHL = von Hippel-Lindau.

References: 1. Narayan V, Jonasch E. Systemic therapy development in von Hippel-Lindau disease: an outsized contribution from an orphan disease. Cancers (Basel). 2022;14(21):5313. 2. Center for Drug Evaluation and Research. Advancing Health Through Innovation: New Drug Therapy Approvals 2021. https://www.fda.gov/media/155227/download. Published January 2022. Accessed February 6, 2024. 3. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N Engl J Med. 2021;385(22):2036–2046. 4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. 5. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11(4):1121–1131. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.2.2025. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed September 9, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 3, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 8. Srinivasan R, Iliopoulos O, Beckermann KE, et al. Belzutifan, a hypoxia-inducible factor-2α inhibitor, for von Hippel-Lindau disease–associated neoplasms: long-term results of the phase 2 LITESPARK-004 study. Poster presented at: the American Association for Cancer Research (AACR) Annual Meeting; April 5–10, 2024; San Diego, CA. 9. Iliopoulos O, Iversen AB, Narayan V, et al. Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024;25(10):1325–1336. 10. Else T, Jonasch E, Iliopoulos O, et al. Belzutifan for von Hippel-Lindau disease: pancreatic lesion population of the phase 2 LITESPARK-004 study. Clin Cancer Res. 2024;30(9):1750–1757.

References: 1. Narayan V, Jonasch E. Systemic therapy development in von Hippel-Lindau disease: an outsized contribution from an orphan disease. Cancers (Basel). 2022;14(21):5313. 2. Center for Drug Evaluation and Research. Advancing Health Through Innovation: New Drug Therapy Approvals 2021. https://www.fda.gov/media/155227/download. Published January 2022. Accessed February 6, 2024. 3. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel–Lindau disease. N Engl J Med. 2021;385(22):2036–2046. 4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–247. 5. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11(4):1121–1131. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.2.2025. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed September 9, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 3, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. 8. Srinivasan R, Iliopoulos O, Beckermann KE, et al. Belzutifan, a hypoxia-inducible factor-2α inhibitor, for von Hippel-Lindau disease–associated neoplasms: long-term results of the phase 2 LITESPARK-004 study. Poster presented at: the American Association for Cancer Research (AACR) Annual Meeting; April 5–10, 2024; San Diego, CA. 9. Iliopoulos O, Iversen AB, Narayan V, et al. Belzutifan for patients with von Hippel-Lindau disease-associated CNS haemangioblastomas (LITESPARK-004): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2024;25(10):1325–1336. 10. Else T, Jonasch E, Iliopoulos O, et al. Belzutifan for von Hippel-Lindau disease: pancreatic lesion population of the phase 2 LITESPARK-004 study. Clin Cancer Res. 2024;30(9):1750–1757.

Learn more about WELIREG:

Mechanism of ActionGuidelinesSafety

Indications

WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Selected Safety Information

WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.
Anemia
  • WELIREG can cause severe anemia that can require blood transfusion.
    • Monitor for anemia before initiation of, and periodically throughout, treatment. Transfuse patients as clinically indicated. For patients with hemoglobin <8 g/dL, withhold WELIREG until ≥8 g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8 g/dL, then resume at a reduced dose or permanently discontinue WELIREG.
  • In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).
  • The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.
  • In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced RCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received erythropoiesis-stimulating agents (ESAs) only, and 12% received both transfusion and ESAs.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
  • Monitor oxygen saturation before initiation of, and periodically throughout, treatment. For decreased oxygen saturation with exercise (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a health care provider.
  • In LITESPARK-004, hypoxia occurred in 1.6% of patients.
  • In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).
Embryo-Fetal Toxicity
  • Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Adverse Reactions
  • In LITESPARK-004, serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
  • WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.
  • Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
  • In LITESPARK-005, serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).
  • WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).
  • Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1.0%) were hypoxia (5%) and anemia (3.2%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).
Drug Interactions
  • Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.
  • Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Lactation
  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.
Females and Males of Reproductive Potential
  • WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.
  • Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
  • Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.
Pediatric Use
  • Safety and effectiveness of WELIREG in pediatric patients under 18 years of age have not been established.
Before prescribing WELIREG, please read the accompanying Prescribing Information, including the Boxed Warning about embryo-fetal toxicity. The Medication Guide also is available.