Belzutifan

Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α). When oxygen levels are normal, the VHL protein targets HIF-2α for destruction. If VHL protein function is impaired, as in VHL disease, HIF-2α accumulates and switches on genes that promote cell proliferation, angiogenesis and tumour growth. Belzutifan blocks this step.

Mechanism of Action

• Normal regulation: under normal oxygen levels, HIF-2α is targeted for degradation by the VHL protein.
• Loss of VHL function: when VHL protein function is impaired, HIF-2α accumulates, moves into the cell nucleus and regulates the expression of genes associated with cell proliferation, angiogenesis and tumour growth.
• Inhibition: belzutifan binds to HIF-2α. In conditions of hypoxia or impaired VHL function it blocks the interaction between HIF-2α and HIF-1β, which reduces transcription and expression of HIF-2α target genes.
• Erythropoietin as a marker: circulating erythropoietin was followed as a marker of HIF-2α inhibition. It fell in a dose- and exposure-dependent way, with the greatest suppression (a mean decrease of about 60% from baseline) after 2 weeks of daily dosing, and mean levels gradually returned to baseline after 12 weeks of treatment.
• Cardiac electrophysiology: at the recommended dose of 120 mg once daily there were no clinically relevant effects on the QTc interval.

Pharmacokinetics

• Absorption: the median time to peak concentration is 1 to 2 hours after a single 120 mg dose, and steady state is reached after about 3 days. At 120 mg daily the simulated geometric mean steady-state Cmax is 1.5 µg/mL and the AUC0–24h is 20.8 µg·h/mL. Cmax and AUC rise in proportion to dose between 40 mg and 120 mg. A high-fat, high-calorie meal delayed the peak by about 2 hours and lowered Cmax by 24% but did not change AUC, so the tablets can be taken with or without food.
• Distribution: mean volume of distribution about 120 L; about 45% bound to plasma proteins; blood-to-plasma concentration ratio 0.88.
• Metabolism: mainly by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4. Both UGT2B17 and CYP2C19 show genetic polymorphisms. Active transport is not an important determinant of its disposition.
• Elimination: mean clearance about 5.89 L/h and mean elimination half-life about 14 hours. After a radiolabelled dose in healthy subjects, about 49.6% was excreted in urine and 51.7% in faeces, mostly as inactive metabolites; about 6% of the dose was recovered as unchanged drug in urine.
• Special populations: no dose adjustment is recommended in older patients, in renal impairment (including end-stage renal disease), or in mild or moderate hepatic impairment. Belzutifan has not been studied in severe hepatic impairment. In patients who are poor metabolisers for both UGT2B17 and CYP2C19, the CYP3A4-inducing effect may be more pronounced (see Drug Interactions).

Belzutifan is used as monotherapy in adults.

• Advanced clear cell renal cell carcinoma (RCC): disease that progressed following two or more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF-targeted therapies.
• von Hippel-Lindau (VHL) disease-associated tumours: patients with VHL disease who require therapy for associated, localised RCC, central nervous system (CNS) haemangioblastomas or pancreatic neuroendocrine tumours (pNET), and for whom localised procedures are unsuitable.

• Hypersensitivity to belzutifan or to any of the excipients.
• Pregnancy in patients with VHL disease-associated tumours. (For advanced RCC, belzutifan should not be used in pregnancy unless the woman’s clinical condition requires treatment; see Special Instructions.)

The safety of belzutifan 120 mg once daily was evaluated in 576 patients with advanced solid tumours and VHL disease-associated localised tumours (median exposure 9.2 months). The most common reactions were anaemia (84.2%), fatigue (42.7%), nausea (24.1%), dyspnoea (21.4%), dizziness (17.9%) and hypoxia (16.3%). The most common Grade 3 or 4 reactions were anaemia (28.8%) and hypoxia (12.2%), and the most common serious reactions were hypoxia (7.1%), anaemia (4.7%) and dyspnoea (1.2%). Dose interruption was most often needed for anaemia (7.1%) and hypoxia (5.4%), dose reduction for hypoxia (6.3%), anaemia (3.8%) and fatigue (1.7%), and discontinuation for hypoxia (1.4%). The frequencies may include contributions from the underlying disease.

Very common (≥1/10): anaemia (including decreased haemoglobin), dizziness, haemorrhage, dyspnoea, hypoxia, nausea, fatigue.

Common (≥1/100 to <1/10): weight increased.

Anaemia and hypoxia are also very common at Grade 3 or 4; haemorrhage, dyspnoea and fatigue are common at Grade 3 or 4, and nausea is uncommon at that severity. The bleeding terms reported in 5 or more patients were haematuria, haemoptysis, contusion and epistaxis. Haemorrhage includes CNS haemorrhage, with one fatal case observed.

Belzutifan is metabolised by UGT2B17 and CYP2C19 and induces CYP3A4 in a concentration-dependent way.

• Hormonal contraceptives: belzutifan lowers the concentration of CYP3A4 substrates, including hormonal contraceptives. This may lead to contraceptive failure or increased breakthrough bleeding. Patients using hormonal contraceptives should be advised to use an alternative non-hormonal method, or to have their male partner use a condom, during treatment.
• Sensitive CYP3A4 substrates: repeated daily doses of 120 mg reduced the exposure (AUC) of a CYP3A4 probe substrate by 40%, consistent with a weak inducer, and the effect may be moderate in patients with higher belzutifan exposure or who are poor metabolisers for both UGT2B17 and CYP2C19. Avoid giving belzutifan with sensitive CYP3A4 substrates for which a small fall in concentration could cause treatment failure; if the combination cannot be avoided, increase the substrate dose as set out in its own SmPC.
• CYP2B6 and CYP2C8 substrates: belzutifan induces CYP2B6 and CYP2C8 in vitro (not yet studied in patients). Concentrations of sensitive substrates of these enzymes may fall to a clinically relevant extent.
• MATE transporters: inhibition of MATE2-K is expected at clinically relevant exposures, and inhibition of MATE1 cannot be excluded.
• Inhibitors of UGT2B17 or CYP2C19: these raise belzutifan exposure and may increase the frequency and severity of its side effects. CYP3A4 inhibitors are expected to do the same in patients with reduced activity of both UGT2B17 and CYP2C19; such patients should be monitored for anaemia and hypoxia and the belzutifan dose reduced as recommended.
• Strong CYP2C19 inducers: their effect on belzutifan exposure has not been studied.
• Food: the tablets can be taken with or without food.

Therapy must be started and supervised by specialist physicians experienced in the treatment of cancer. The tablets are swallowed whole at the same time every day, with or without food. They must not be split, crushed or chewed, because it is not known whether this affects absorption.

Recommended Dose

• 120 mg (three 40 mg tablets) once daily.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Adjustments for Side Effects

Severity is graded by NCI CTCAE version 5.0, and each dose reduction is by 40 mg (one tablet).

• Anaemia, Grade 3 (haemoglobin below 8 g/dL, 4.9 mmol/L or 80 g/L; transfusion indicated): withhold until resolved to Grade 2 or lower, then resume at the same or a reduced dose; consider discontinuing, depending on the severity and persistence of the anaemia.
• Anaemia, Grade 4 (life-threatening consequences or urgent intervention indicated): withhold until resolved to Grade 2 or lower, then resume at a reduced dose, or permanently discontinue upon recurrence of Grade 4.
• Hypoxia, Grade 3 without symptoms (resting oxygen saturation below 88% by pulse oximeter, or PaO2 of 55 mmHg or lower): continue or withhold until resolved to Grade 2 or lower; resume at a reduced dose or discontinue, depending on severity and persistence.
• Hypoxia, Grade 3 with symptoms: withhold until resolved to Grade 2 or lower; resume at a reduced dose or discontinue, depending on severity and persistence.
• Hypoxia, Grade 4 (life-threatening airway compromise; urgent intervention such as tracheotomy or intubation needed): permanently discontinue.
• Other reactions, Grade 3: withhold until resolved to Grade 2 or lower; consider resuming at a reduced dose, depending on severity and persistence; permanently discontinue upon recurrence of Grade 3.
• Other reactions, Grade 4: permanently discontinue.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment, including in end-stage renal disease.
• Hepatic impairment: no dose adjustment in mild impairment (total bilirubin up to the upper limit of normal with raised AST, or total bilirubin above 1 to 1.5 times the upper limit with any AST) or moderate impairment (total bilirubin above 1.5 and up to 3 times the upper limit with any AST, or Child-Pugh B). Belzutifan has not been studied in severe hepatic impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

• A missed dose can be taken as soon as possible on the same day. The regular daily dose is resumed the next day. Do not take extra tablets to make up for it.
• If vomiting occurs at any time after taking Welireg, do not take another dose; take the next dose the following day.

Pregnancy Status and Contraception (Required)

Belzutifan may cause embryo-foetal harm, including foetal loss. The SmPC sets these conditions.

• Before treatment: the pregnancy status of women of childbearing potential must be verified before treatment starts, and they should be told of the potential risk to a foetus.
• During treatment: women of childbearing potential must use highly effective contraception during treatment and for at least 1 week after the last dose.
• Hormonal contraceptives may fail: belzutifan can reduce the efficacy of hormonal contraceptives and may increase breakthrough bleeding. Patients using hormonal contraceptives should be advised to use an alternative non-hormonal method, or to have their male partner use a condom, during treatment.
• VHL disease-associated tumours: belzutifan is contraindicated in pregnancy. If pregnancy occurs during treatment, treatment should be discontinued.
• Renal cell carcinoma: belzutifan should not be used in pregnancy unless the woman’s clinical condition requires treatment. There are no or limited data from pregnant women, and animal studies have shown reproductive toxicity.

Anaemia

Anaemia is very common. Patients should be monitored for anaemia before treatment and periodically during it. For Grade 3 anaemia, belzutifan is withheld and the anaemia treated according to standard medical practice, which includes giving an erythropoiesis-stimulating agent, until it resolves to Grade 2 or lower. For recurrent Grade 3 anaemia, belzutifan should be discontinued. For Grade 4 anaemia it is withheld and permanently discontinued if Grade 4 anaemia recurs.

Hypoxia

Oxygen saturation should be monitored by pulse oximetry before treatment and periodically during it. For Grade 3 hypoxia without symptoms, supplemental oxygen and either continuing or withholding belzutifan should be considered; if it is withheld it is resumed at a reduced dose. For Grade 3 hypoxia with symptoms, belzutifan is withheld, the hypoxia treated and the drug resumed at a reduced dose; if symptomatic hypoxia keeps recurring, treatment is discontinued. For Grade 4 hypoxia, treatment is permanently discontinued.

CNS Haemorrhage in VHL Disease

CNS haemorrhage, including with a fatal outcome, has been observed in patients with VHL disease-associated CNS haemangioblastomas. Physicians should be alert for symptoms or signs of CNS haemorrhage in these patients.

Breastfeeding and Fertility

• Breastfeeding: there are no data on belzutifan in human milk. Because of the potential for serious reactions in breastfed children, women should not breastfeed during treatment and for at least 1 week after the last dose.
• Fertility: from animal findings, belzutifan may impair fertility in males and females of reproductive potential. Patients should be told of this risk; whether the effect is reversible is unknown.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Belzutifan has a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur. Patients should not drive or use machines until they are reasonably certain that belzutifan does not affect them adversely.

Welireg tablets do not require any special storage conditions. They are supplied in aluminium/aluminium blisters, in packs of 90 tablets (3 cartons of 30).

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation). Therapy must be started and supervised by specialist physicians experienced in the treatment of cancer. Welireg is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription. Because belzutifan can harm an unborn child, the pregnancy status of a woman of childbearing potential must be verified before treatment starts, and she must use highly effective contraception during treatment and for at least 1 week after the last dose; as belzutifan can make hormonal contraceptives less effective, a non-hormonal method is advised. In VHL disease-associated tumours belzutifan is contraindicated in pregnancy.