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Efficacy

WELIREG (belzutifan) achieved objective response across 3 VHL-associated tumor types

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

WELIREG reduced tumor size in VHL-associated RCC

NEARLY HALF OF PATIENTS HAD AN OBJECTIVE RESPONSE (n=30/61)a

49
%
ORRa
(95% CI, 36–62)
All responses were partial responses (complete response, 0%)

ORR per RECIST v1.1:

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

Median DOR was not reached:

Median DOR could not be estimatedb since 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.2

Median DOR was not reached, with ongoing responses ranging from 2.8 to 22 months

56%
of patients who responded (n=17/30) maintained a response that lasted ≥12 months
Median TTR was 8 months

(range: 2.7 to 19 months)

See study design.
document icon

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer

(confirmed hereditary VHL-associated RCC)

Belzutifan (WELIREG) is the only preferred systemic therapy option (category 2A) for patients with VHL-associated RCC not requiring immediate surgery.3

a
All patients with a response were followed for a minimum of 18 months from the start of treatment.
b
By Kaplan-Meier method.
Category 2A = Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
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.
VHL = von Hippel-Lindau; CI = confidence interval; ORR = overall response rate; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; DOR = duration of response; TTR = time to response; NCCN = National Comprehensive Cancer Network.

Patient subgroup: WELIREG reduced tumor size in VHL-associated CNS hemangioblastomas

NEARLY TWO-THIRDS OF PATIENTS HAD AN OBJECTIVE RESPONSE (n=15/24)a

63
%
ORR
(95% CI, 41–81)
Complete response, 4%; partial response, 58%

ORR per RECIST v1.1:

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

Median DOR was not reached:

Median DOR could not be estimatedb since 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.2

Median DOR was not reached, with ongoing responses ranging from 3.7 to 22 months

73%
of patients who responded (n=11/15) maintained a response that lasted ≥12 months
Median TTR was 3.1 months

(range: 2.5 to 11 months)

See study design.
document icon

NCCN Guidelines® for CNS Cancers

(VHL-associated CNS hemangioblastomas)

Belzutifan (WELIREG) is the only recommended systemic therapy option (category 2A) for patients with VHL-associated CNS hemangioblastomas not requiring immediate surgery.4

a
Number of patients with measurable solid lesions, based on IRC assessment.
b
By Kaplan-Meier method.
Category 2A = Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
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.
VHL = von Hippel-Lindau; CI = confidence interval; CNS = central nervous system; ORR = overall response rate; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; DOR = duration of response; TTR = time to response; IRC = independent review committee; NCCN = National Comprehensive Cancer Network.

Patient subgroup: WELIREG reduced tumor size in VHL-associated pNET

THE MAJORITY OF PATIENTS HAD AN OBJECTIVE RESPONSE (n=10/12)a

83
%
ORR
(95% CI, 52–98)
Complete response, 17%; partial response, 67%

ORR per RECIST v1.1:

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

Median DOR was not reached:

Median DOR could not be estimatedb since 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.2

Median DOR was not reached, with ongoing responses ranging from 11 to 19 months

50%
of patients who responded (n=5/10) maintained a response that lasted ≥12 months
Median TTR was 8.1 months

(range: 2.7 to 11 months)

See study design.
a
Number of patients with measurable solid lesions, based on IRC assessment.
b
By Kaplan-Meier method.
VHL = von Hippel-Lindau; CI = confidence interval; ORR = overall response rate; pNET = pancreatic neuroendocrine tumors; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1; DOR = duration of response; TTR = time to response; IRC = independent review committee.

Study design

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

Patients
  • VHL-associated RCC (N=61)
    • ≥1 measurable solid tumor localized to the kidneya
  • Enrolled patients had other VHL-associated tumorsa,b:
    • CNS hemangioblastomas (n=24)
    • pNET (n=12)

Exclusion criteria

  • Any evidence of metastatic disease

Study population characteristics

  • Median age: 41 years (range 19 to 66 years)
  • 3.3% age 65 years or older
  • 53% male
  • 90% White, 3.3% Black or African-American, 1.6% Asian, and 1.6% Native Hawaiian or other Pacific Islander
Treatment
40 mg40 mg40 mg
WELIREG 120 mg once daily

Study population characteristics (continued)

  • Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 82%; ECOG PS of 1, 16%; and ECOG PS of 2, 1.6%
  • Prior RCC surgical procedures: 77%
  • Median time from initial radiographic diagnosis of VHL-associated RCC tumors that led to enrollment to the time of treatment with WELIREG was 17.9 months (range: 2.8 to 96.7 months)
Assessment
Treatment was continued until progression of disease or unacceptable toxicity.

Major efficacy end point for RCC

  • Overall response rate (ORR)
    • Measured by radiology assessment using RECIST v1.1 as assessed by IRCc

Additional efficacy end points for RCC

  • Duration of response (DOR)
  • Time to response (TTR)

Additional efficacy end points for CNS hemangioblastomas and pNETd

  • ORR
  • DOR
  • TTR
a
As defined by RECIST v1.1.
b
Based on central independent review committee (IRC).
c
RECIST v1.1 response defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.1
d
Assessed by IRC using RECIST v1.1.
VHL = von Hippel-Lindau; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors v1.1.
See Adverse Reaction Profile
References: 1. 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. 2. Delgado A, Guddati AK. Clinical endpoints in oncology - a primer. Am J Cancer Res. 2021;11(4):1121–1131. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2023. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed June 21, 2022. To view the most recent and complete version of the guidelines, go to NCCN.org. 4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Central Nervous System Cancers V.1.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed June 8, 2022. To view the most recent and complete version of the guidelines, go to NCCN.org. 
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.
Indication

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.

Indication

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.

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. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, anemia occurred in 76% of patients and 28% had Grade 3 anemia.
  • Monitor for anemia before initiation of and periodically throughout treatment. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.
  • Transfuse patients as clinically indicated. For patients with hemoglobin (Hb) <9 g/dL, withhold WELIREG until Hb ≥9 g/dL, then resume at reduced dose or permanently discontinue depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until Hb ≥9 g/dL, then resume at a reduced dose or permanently discontinue.
  • The use of erythropoiesis stimulating agents (ESAs) for treatment of anemia is not recommended in patients treated with WELIREG.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. In Study 004, hypoxia occurred in 1.6% of patients. In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, hypoxia occurred in 29% of patients; 16% were Grade 3 hypoxia.
  • 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.
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 Study 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%) were decreased hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
  • In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, the following additional adverse reactions have been reported: edema, cough, musculoskeletal pain, vomiting, diarrhea, and dehydration.
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.

Indication

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.

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. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months). In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, anemia occurred in 76% of patients and 28% had Grade 3 anemia.
  • Monitor for anemia before initiation of and periodically throughout treatment. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers due to potential increases in exposure that may increase the incidence or severity of anemia.
  • Transfuse patients as clinically indicated. For patients with hemoglobin (Hb) <9 g/dL, withhold WELIREG until Hb ≥9 g/dL, then resume at reduced dose or permanently discontinue depending on the severity of anemia. For life-threatening anemia or when urgent intervention is indicated, withhold WELIREG until Hb ≥9 g/dL, then resume at a reduced dose or permanently discontinue.
  • The use of erythropoiesis stimulating agents (ESAs) for treatment of anemia is not recommended in patients treated with WELIREG.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization. In Study 004, hypoxia occurred in 1.6% of patients. In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, hypoxia occurred in 29% of patients; 16% were Grade 3 hypoxia.
  • 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.
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 Study 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%) were decreased hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
  • In Study 001, a clinical trial in patients with advanced solid tumors (n=58) treated at the recommended dose, the following additional adverse reactions have been reported: edema, cough, musculoskeletal pain, vomiting, diarrhea, and dehydration.
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.