Prescribing Information Medication Guide

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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:

On this page:

Primary analysis of LITESPARK-005: 18.4-month median follow-up

WELIREG demonstrated superior PFS vs everolimus in patients with advanced RCC following treatment with both anti⁠–⁠PD⁠-⁠1⁠/⁠L1 and VEGF⁠-⁠TKI therapies

25% reduced risk of disease progression or death shown with WELIREG vs everolimus (HR=0.75^a; 95% CI, 0.63–0.90; P=0.0008)^b
Events observed: 257/374 (69%) with WELIREG vs 262/372 (70%) with everolimus
Median PFS^c: 5.6 months (95% CI, 3.9–7.0) with WELIREG vs 5.6 months (95% CI, 4.8–5.8) with everolimus
OS results were immature. At the time of the subsequent prespecified analysis, 59% of the patients had died in the randomized population

Kaplan-Meier Estimates of PFS in LITESPARK-005

Kaplan-Meier Estimates of PFS in LITESPARK-005

a

Based on the stratified Cox proportional hazard model.

b

One-sided P-value based on stratified log-rank test compared with the significance boundary of 0.0021.

c

From product-limit (Kaplan-Meier) method for censored data.

CI = confidence interval; HR = hazard ratio; OS = overall survival; PD⁠-⁠1/L1 = programmed death receptor-1 (PD⁠-⁠1)/programmed death-ligand 1 (PD⁠-⁠L1); PFS = progression-free survival; VEGF-TKI = vascular endothelial growth factor tyrosine kinase inhibitor.

WELIREG demonstrated superior ORR vs everolimus in advanced RCC following treatment with both anti⁠–⁠PD⁠-⁠1⁠/⁠L1 and VEGF⁠-⁠TKI therapies

Patients who received WELIREG achieved an ORR of 22% vs 4% of patients who received everolimus (P<0.0001)^d

Patients With Advanced RCC Who Received WELIREG™ (belzutifan) Achieved an Objective Response Rate of 22% While Patients With Advanced RCC Who Received Everolimus Achieved an Objective Response Rate of 4%

30^%

of patients who responded (25/82) with WELIREG had a duration of response that lasted ≥12 months.

d

One-sided P-value based on stratified Miettinen and Nurminen (M&N) method.

e

ORR measured by blinded independent central review using RECIST v1.1.

ORR = objective response rate; CR = complete response; PR = partial response.

WELIREG is the only approved therapy studied in a phase 3 trial in advanced RCC that included patients who had disease progression following treatment with both anti–PD⁠-⁠1/L1 and VEGF-TKI therapies

WELIREG was studied in an open-label, randomized, phase 3 trial vs everolimus

LITESPARK-005 Study Design: Information on Key Eligibility Criteria

LITESPARK-005 Study Design: Information on Key Eligibility Criteria

Distribution of prior anti–PD-1/L1 and VEGF-TKI therapies that patients received in LITESPARK-005

Distribution of Prior Anti-PD-1/L1 and VEGF-TKI Therapies in LITESPARK-005

Distribution of Prior Anti-PD-1/L1 and VEGF-TKI Therapies in LITESPARK-005

Of all evaluated patients, 49% received 2 to 3 prior VEGF receptor–targeted therapies

Additional study design and study population details

1L = first line; 2L = second line; 3L = third line; ECOG PS = Eastern Cooperative Oncology Group performance status; IMDC = International Metastatic Database Consortium; PD⁠-⁠1/L1 = programmed death receptor⁠-⁠1 (PD⁠-⁠1)/programmed death⁠-⁠ligand 1 (PD⁠-⁠L1); RCC = renal cell carcinoma; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors; VEGF = vascular endothelial growth factor; VEGF⁠-⁠TKI = vascular endothelial growth factor tyrosine kinase inhibitor.

Watch a video to learn more about the efficacy of WELIREG in LITESPARK-005

Extended analysis of LITESPARK-005:

PFS at 25.7-month median follow-up in adult patients with advanced RCC¹

LIMITATIONS: No statistical testing was performed for PFS at the extended analysis. No conclusions can be drawn.

Kaplan-Meier Estimates of PFS in LITESPARK-005 Extended Analysis

Kaplan-Meier Estimates of PFS in LITESPARK-005 Extended Analysis

From N Engl J Med. Choueiri TK, Powles T, Peltola K, et al. Supplementary appendix to: Belzutifan versus everolimus for advanced renal-cell carcinoma. 391(8),710-721. © 2024 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

PFS events observed: 289/374 (77.3%) with WELIREG vs 276/372 (74.2%) with everolimus.
Median PFS: 5.6 months (95% CI, 3.8–6.5) with WELIREG vs 5.6 months (95% CI, 4.8–5.8) with everolimus.

ORR and duration of response at 25.7-month median follow-up in adult patients with advanced RCC¹

LIMITATIONS: No statistical testing was performed for ORR, DOR, or TTR at the extended analysis. No conclusions can be drawn.

ORR: 22.7% (95% CI, 18.6–27.3; n=85/374) with WELIREG vs 3.5% (95% CI, 1.9–5.9; n=13/372) with everolimus.

CR was 3.5% (n=13/374) and PR was 19.3% (n=72/374) with WELIREG; CR was 0% (n=0/372) and PR was 3.5% (n=13/372) with everolimus.

Kaplan-Meier Estimates of DOR in LITESPARK-005 Extended Analysis

Kaplan-Meier Estimates of DOR in LITESPARK-005 Extended Analysis

From N Engl J Med. Choueiri TK, Powles T, Peltola K, et al. Supplementary appendix to: Belzutifan versus everolimus for advanced renal-cell carcinoma, 391(8),710-721. © 2024 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Median DOR: 19.5 months (range: 1.9+ to 31.6+ months) with WELIREG vs 13.7 months (range: 3.8 to 21.2+ months) with everolimus.
Median TTR: 3.8 months (range: 1.7 to 22.0 months) with WELIREG vs 3.7 months (range: 1.8 to 5.4 months) with everolimus.

+ Denotes ongoing response.
TTR = time to response.

Reference: 1. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710–721.

Additional videos and resources

WELIREG may be considered as early as the second line for your appropriate patients with advanced RCC following treatment with both anti⁠–⁠PD⁠-⁠1⁠/⁠L1 and VEGF⁠-⁠TKI therapies

Patient Identification Safety Guidelines

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.