Erdafitinib

Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor. FGFRs are cell-surface proteins involved in normal processes such as cell proliferation and migration and the handling of phosphate and vitamin D. Alterations in FGFR genes can drive cancers, including urothelial carcinoma, by promoting tumour-cell growth, migration and blood-vessel formation and by blocking cell death.

Mechanism of Action

• FGFR inhibition: erdafitinib binds to FGFR1, FGFR2, FGFR3 and FGFR4 and blocks their enzymatic activity (in vitro data), reducing receptor phosphorylation and downstream signalling.
• Antitumour activity: it lowered cell viability in cell lines carrying FGFR genetic alterations and was active in xenograft models derived from tumour types including bladder cancer.
• Effect on phosphate: FGFR inhibition raises serum phosphate. This is an expected, transient pharmacodynamic effect and the basis of the phosphate-guided dosing described below.

Pharmacokinetics

• Absorption: oral absorption is near complete; the median time to peak concentration is 2.5 hours (range 2–6 hours). Exposure rises in proportion to dose over 0.5–12 mg, and steady state is reached after 2 weeks of once-daily dosing, with a mean 4-fold accumulation. At 8 mg once daily the mean steady-state Cmax was 1,399 ng/mL and the AUC 29,268 ng·h/mL. A high-fat meal lowered AUC by 6% and Cmax by 14% and delayed the peak by about 1.5 hours, which is not clinically relevant, so tablets can be taken with or without food.
• Distribution: mean apparent volume of distribution 0.411 L/kg in patients with cancer; 99.7% is bound to plasma proteins, preferentially to alpha-1 acid glycoprotein.
• Metabolism: metabolism is the main route of elimination. CYP2C9 and CYP3A4 form an O-demethylated major metabolite and contribute about 39% and 20% of total clearance respectively. Unchanged erdafitinib is the main drug-related compound in plasma, and there are no circulating metabolites.
• Elimination: mean total apparent clearance 0.362 L/h; mean effective half-life about 58.9 hours. After a radiolabelled dose about 69% was recovered in faeces (19% unchanged) and 19% in urine (13% unchanged).
• Special populations: no dose adjustment is needed in mild or moderate renal or hepatic impairment; there are no data in severe renal impairment and limited data in severe hepatic impairment.

• Urothelial carcinoma: as monotherapy for adults with unresectable or metastatic urothelial carcinoma (UC) harbouring susceptible FGFR3 genetic alterations who have previously received at least one line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable or metastatic treatment setting.
• Test before treatment: the physician must have confirmation of the susceptible FGFR3 alteration(s) from a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If no CE-marked IVD is available, an alternative validated test should be used.

• Hypersensitivity to erdafitinib or to any of the excipients.

The safety profile rests on 479 patients with locally advanced unresectable or metastatic urothelial carcinoma treated from a starting dose of 8 mg or 9 mg once daily (median treatment duration 4.8 months). The most common reactions were hyperphosphataemia (78.5%), diarrhoea (55.5%), stomatitis (52.8%), dry mouth (39.9%), decreased appetite (31.7%), anaemia (28.2%), dry skin (28.0%) and central serous retinopathy (28.0%). The most common grade 3 or higher reactions were stomatitis (10.6%), hyponatraemia (8.8%), palmar-plantar erythrodysaesthesia syndrome (7.9%), onycholysis (4.8%) and diarrhoea (4.0%). Reactions led to dose reduction in 59.7% of patients and to discontinuation in 19.4%.

Very common (≥1/10): hyperphosphataemia, hyponatraemia, decreased appetite; dysgeusia; central serous retinopathy (a grouped term that includes retinal pigment epithelial detachment and visual disturbances such as blurred vision), dry eye; epistaxis; diarrhoea, stomatitis (including mouth ulcers), dry mouth, constipation, nausea, vomiting, abdominal pain; paronychia, onycholysis, onychomadesis, nail dystrophy, nail disorder, nail discolouration, palmar-plantar erythrodysaesthesia syndrome, alopecia, dry skin; asthenia, fatigue; anaemia; weight decreased, increased blood creatinine, increased alanine and aspartate aminotransferase.

Common (≥1/100 to <1/10): hyperparathyroidism; hypercalcaemia, hypophosphataemia; ulcerative keratitis, keratitis, conjunctivitis, xerophthalmia, cataract, blepharitis, increased lacrimation; nasal dryness; dyspepsia; onychalgia, onychoclasis, nail ridging, skin fissures, pruritus, skin exfoliation, xeroderma, hyperkeratosis, skin lesion, eczema, rash; acute kidney injury, renal impairment, renal failure; hepatic cytolysis, abnormal liver function, hyperbilirubinaemia.

Uncommon (≥1/1,000 to <1/100): vascular calcification; nail-bed bleeding, nail discomfort, skin atrophy, palmar erythema, skin toxicity; dry mucous membranes.

Central serous retinopathy appears early: most events occurred within the first 90 days of treatment. Hyperphosphataemia was also reported early, mostly within the first 3–4 months, with grade 3 events in the first month. Grade 3 or 4 treatment-related events were reported more often in patients aged 65 and over (47.6% versus 43.5%).

• Moderate CYP2C9 or strong CYP3A4 inhibitors (the SmPC names, among others, itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole, clarithromycin, ritonavir and amiodarone): these raise erdafitinib exposure and may increase toxicity. With fluconazole the AUC was 148% of that with erdafitinib alone, and with itraconazole 134%. Alternatives with no or minimal enzyme inhibition should be considered; if the combination is needed, the dose is reduced to the next lower dose level according to tolerability, and it may be adjusted again as tolerated once the inhibitor is stopped.
• Strong CYP3A4 inducers (apalutamide, enzalutamide, lumacaftor, ivosidenib, mitotane, rifapentine, rifampicin, carbamazepine, phenytoin, St John’s wort): carbamazepine lowered erdafitinib Cmax to 65.4% and AUC to 37.7% of the value without it. Avoid the combination. Moderate CYP3A4 inducers require a dose adjustment (see section 4.5 of the SmPC).
• Grapefruit and Seville oranges: avoid, because of strong CYP3A4 inhibition.
• Hormonal contraceptives: erdafitinib may reduce their effectiveness (see Pregnancy, Breastfeeding and Fertility).
• Medicines that raise serum phosphate: avoid them when serum phosphate is 5.5 mg/dL or higher. Vitamin D supplementation is not recommended during treatment.
• QT-prolonging medicines: see Special Instructions.

The SmPC (section 4.5) holds the complete list of interactions.

Treatment is started and supervised by a physician experienced in anticancer therapy, after the FGFR3 alteration has been confirmed with a suitable test. Tablets are swallowed whole, with or without food, at about the same time each day. Treatment continues until disease progression or unacceptable toxicity. Grapefruit and Seville oranges are avoided.

Starting Dose and Phosphate-Guided Up-Titration

• Starting dose: 8 mg once daily. Serum phosphate is measured before the first dose and then monthly.
• Phosphate check: the 8 mg dose is kept and serum phosphate is assessed 14 to 21 days after starting.
• Up-titration to 9 mg once daily: if serum phosphate is below 9.0 mg/dL (below 2.91 mmol/L) and there is no drug-related toxicity. If the level is 9.0 mg/dL or higher, the dose modifications below apply. After day 21 serum phosphate is no longer used to guide up-titration.

Dose Modifications for Serum Phosphate (after up-titration)

At phosphate concentrations of 5.5 mg/dL (1.75 mmol/L) or higher, dietary phosphate is restricted to 600–800 mg per day. For persistently raised phosphate, a non-calcium-containing phosphate binder (for example sevelamer carbonate) is considered as needed.

• Below 6.99 mg/dL (below 2.24 mmol/L): continue at the current dose.
• 7.00–8.99 mg/dL (2.25–2.90 mmol/L): continue treatment and start a phosphate binder with food until the level is below 7.00 mg/dL. Reduce the dose if phosphate stays at 7.00 mg/dL or above for 2 months, or if additional adverse events or electrolyte disturbances linked to prolonged hyperphosphataemia occur.
• 9.00–10.00 mg/dL (2.91–3.20 mmol/L): withhold treatment until the level returns to below 7.00 mg/dL (weekly testing recommended) and start a binder with food. Restart at the same dose level. Reduce the dose if phosphate stays at 9.00 mg/dL or above for 1 month, or if additional adverse events or electrolyte disturbances linked to prolonged hyperphosphataemia occur.
• Above 10.00 mg/dL (above 3.20 mmol/L): withhold treatment until the level is below 7.00 mg/dL (weekly testing recommended) and restart at the first reduced dose level. If 10.00 mg/dL or higher is sustained for more than 2 weeks, discontinue permanently. Treat symptoms as clinically appropriate.
• Significant change from baseline renal function, or grade 3 hypocalcaemia due to hyperphosphataemia: discontinue permanently and manage medically.

Dose Reduction Steps

• From 9 mg: 8 mg (for example two 4 mg tablets), then 6 mg (two 3 mg tablets), 5 mg (one 5 mg tablet), 4 mg (one 4 mg tablet), then stop. The 9 mg dose can be taken as three 3 mg tablets.
• From 8 mg: 6 mg (two 3 mg tablets), then 5 mg (one 5 mg tablet), 4 mg (one 4 mg tablet), then stop.

Eye Disorders

A baseline eye examination (Amsler grid, fundoscopy, visual acuity and, if available, optical coherence tomography) is done before starting. Examinations are repeated monthly, including an Amsler grid test, for the first 4 months, then every 3 months, and urgently for any visual symptoms.

• Grade 1 (asymptomatic or mild symptoms, or abnormal Amsler grid test only): refer for an ophthalmological examination; if it cannot be done within 7 days, withhold treatment until it can. With no eye toxicity, continue at the same dose. If keratitis or a retinal abnormality (for example central serous retinopathy) is found, withhold until resolution; if reversible within 4 weeks, resume at the next lower dose.
• Grade 2 (moderate, limiting instrumental daily activities): withhold immediately and refer. After resolution or stabilisation without symptoms within 4 weeks, resume at the next lower dose level.
• Grade 3 (severe or medically significant but not immediately sight-threatening, limiting self-care): withhold immediately and refer. If resolved or stable and asymptomatic within 4 weeks, treatment may resume 2 dose levels lower. Consider permanent discontinuation if it recurs.
• Grade 4 (sight-threatening consequences, blindness): discontinue permanently and monitor until resolution or stabilisation.
• After a restart, check for recurrence every 1–2 weeks for a month. When central serous retinopathy occurs, treatment is withheld, and it is discontinued permanently if the event does not resolve within 4 weeks or is grade 4.

Nail, Skin and Mucosal Changes and Other Reactions

• Nail disorder: grade 1, continue; grade 2, withhold and reassess in 1–2 weeks, restarting at the same dose if a first event resolves to grade 1 or baseline within 2 weeks, otherwise at the next lower dose; grade 3, withhold and restart at the next lower dose once grade 1 or baseline; grade 4, discontinue.
• Dry skin and skin toxicity, dry mouth: grades 1 and 2, continue; grade 3, withhold for up to 28 days with weekly reassessment and restart at the next lower dose once grade 1 or baseline; grade 4 skin toxicity, discontinue.
• Oral mucositis: grade 1, continue; grade 2, withhold only if other grade 2 erdafitinib-related reactions are present or symptom management has lasted more than a week, with the same restart rules as for nail disorder; grade 3, withhold and restart at the next lower dose once grade 1 or baseline; grade 4, discontinue.
• Other adverse reactions: grade 3, withhold until grade 1 or baseline, then resume at the next lower dose; grade 4, discontinue permanently.

Special Populations

• Elderly: no specific dose adjustment; data in patients over 85 years are limited. Eye monitoring is closer from age 65 (see Special Instructions).
• Renal impairment: no adjustment in mild or moderate impairment; there are no data in severe impairment, and alternative treatment should be considered.
• Hepatic impairment: no adjustment in mild or moderate impairment; data in severe impairment are limited, and alternative treatment should be considered.
• Children and adolescents: there is no relevant use in urothelial carcinoma; safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

A missed dose can be taken as soon as possible, and the regular daily schedule resumes the next day. Extra tablets are not taken to make up for it. If vomiting occurs after a dose, the next dose is taken the next day.

FGFR3 Test Before Treatment

Treatment starts only once a susceptible FGFR3 genetic alteration has been confirmed with a CE-marked in vitro diagnostic medical device with the corresponding intended purpose, or with another validated test if no CE-marked device is available.

Ocular Disorders

Erdafitinib can cause central serous retinopathy (including retinal pigment epithelial detachment) with visual field defects. Central serous retinopathy was more frequent in patients aged 65 and over (33.3% versus 28.8%), as was retinal pigment epithelial detachment (6.3% versus 2.1%), so closer monitoring is advised in this age group and in patients with retinal disorders, macular or retinal degeneration, diabetic retinopathy or previous retinal detachment. Dry eye occurred in 16.7% of patients (grade 3 or 4 in 0.3%). All patients should use dry eye prophylaxis, with ocular demulcents such as artificial tears or lubricating gels or ointment at least every 2 hours while awake; severe dry eye should be seen by an ophthalmologist. Close ophthalmological follow-up is needed after a restart following an eye event.

Hyperphosphataemia

Prolonged hyperphosphataemia can lead to soft tissue mineralisation, cutaneous calcinosis, non-uraemic calciphylaxis, hypocalcaemia, anaemia, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. It occurs early, mostly within the first 3–4 months. Serum phosphate is monitored throughout treatment. At 5.5 mg/dL or higher, dietary phosphate is restricted (600–800 mg daily) and phosphate-raising agents are avoided; above 7.0 mg/dL an oral phosphate binder is considered. Vitamin D supplements are not recommended because they may add to the rise in phosphate and calcium.

Hypophosphataemia

Serum phosphate can also fall below normal, during treatment and during treatment breaks, so it continues to be monitored. If it falls below normal, phosphate-lowering therapy and dietary restriction are stopped. Severe hypophosphataemia can present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis and haemolytic anaemia; grade 3–4 events occurred in 1.0% of patients.

Nail, Skin, Mucosal Disorders and Photosensitivity

Nail disorders, skin disorders (dry skin, palmar-plantar erythrodysaesthesia syndrome, alopecia, pruritus) and stomatitis or dry mouth are very common. Patients are monitored and given supportive care: good nail hygiene, nail strengthener as needed and watching for infection; regular moisturisers, avoiding perfumed products, excessive soap and bathing; good oral hygiene, baking soda mouthwashes 3 or 4 times a day as needed, and avoiding spicy or acidic food. Because of a potential risk of phototoxicity, protective clothing or sunscreen should be used in the sun.

Laboratory Monitoring

Creatinine increases, hyponatraemia, raised transaminases and anaemia have been reported, so complete blood counts and serum chemistry are checked regularly.

QT-Prolonging Medicines

Caution is advised with medicines known to prolong the QT interval or to cause torsades de pointes, such as class IA (quinidine, disopyramide) and class III (amiodarone, sotalol, ibutilide) antiarrhythmics, macrolide antibiotics, SSRIs (citalopram, escitalopram), methadone, moxifloxacin and antipsychotics (haloperidol, thioridazine).

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential use highly effective contraception before and during treatment and for 1 month after the last dose. Men use effective contraception (for example a condom) and do not donate or store semen during treatment and for 1 month after the last dose.
• Hormonal contraceptives: erdafitinib may reduce their efficacy. Patients should use a method not affected by enzyme inducers (for example a non-hormonal intrauterine device) or add non-hormonal contraception (for example a condom) during treatment and for 1 month after the last dose.
• Pregnancy test: a highly sensitive pregnancy test is recommended before starting in women of reproductive potential.
• Pregnancy: there are no human data; animal studies showed reproductive toxicity, and erdafitinib is embryotoxic and teratogenic. It should not be used in pregnancy unless the woman’s clinical condition requires it. Patients should contact their healthcare professional if pregnancy occurs or is suspected during treatment or up to 1 month afterwards.
• Breastfeeding: a risk to the breast-fed child cannot be excluded; breastfeeding should be stopped during treatment and for 1 month after the last dose.
• Fertility: no human data and no dedicated animal fertility studies; impairment of male and female fertility cannot be excluded.

Sodium

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

Effect on Driving

Erdafitinib has a moderate influence on the ability to drive and use machines. Eye disorders such as central serous retinopathy or keratitis can occur; patients with visual symptoms should not drive or use machines until they subside.

Balversa needs no special storage conditions. The tablets come in high-density polyethylene bottles with a child-resistant closure and an induction seal liner; each carton holds one bottle of 28, 56 or 84 tablets depending on the strength, and not all pack sizes may be marketed.

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

Prescription only (Rx), under restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in anticancer therapy, after the FGFR3 alteration has been confirmed. Balversa tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.