Futibatinib

Futibatinib is a tyrosine kinase inhibitor that irreversibly inhibits fibroblast growth factor receptors (FGFR) 1, 2, 3 and 4 by covalent binding. Constitutive FGFR signalling can support the proliferation and survival of malignant cells, and tumours with FGFR2 fusions or rearrangements are the target of the EU indication.

Mechanism of Action

• Covalent FGFR inhibition: futibatinib forms a covalent bond with a cysteine in the ATP-binding pocket of the FGFR kinase domain, blocking receptor phosphorylation and downstream signalling pathways (MAPK, PI3K/Akt/mTOR, PLCγ and JAK/STAT). Its inhibitory concentration against FGFR1–4 is below 4 nM.
• Resistance mutations: in vitro, futibatinib inhibited FGFR2 resistance mutations (N550H, V565I, E566G, K660M).
• Selectivity for FGFR-altered tumours: in mouse and rat xenograft models of human tumours with activating FGFR alterations it suppressed tumour growth in a dose-dependent way; it is not expected to act on cells without FGFR genomic aberrations.
• Effect on phosphate: FGFR inhibition raises serum phosphate, which is why hyperphosphataemia is an expected pharmacodynamic effect.

Pharmacokinetics

• Absorption: median time to peak concentration is 2 hours (range 1.2–22.8). Exposure is linear over 4–24 mg, and steady state is reached after the first dose (accumulation ratio 1.03). At 20 mg once daily the geometric mean steady-state AUC is 790 ng·h/mL and the peak concentration 144 ng/mL. A high-fat, high-calorie meal made no clinically meaningful difference.
• Distribution: about 95% bound to plasma proteins (mainly albumin and α1-acid glycoprotein); apparent volume of distribution about 66 L.
• Metabolism: in vitro, mainly by CYP3A (40–50%) and by glutathione conjugation (50–60%). Unchanged futibatinib was the main drug-related compound in plasma (about 59% of radioactivity), followed by an inactive cysteinylglycine conjugate.
• Elimination: mean half-life about 2.9 hours; apparent clearance about 19.8 L/h. After a radiolabelled dose, about 64% was recovered in faeces and 6% in urine, with negligible unchanged drug in either.
• Enzymes and transporters: futibatinib is a P-gp and BCRP substrate in vitro. In vitro it did not inhibit the main CYP enzymes or induce CYP2B6 or CYP3A4 at relevant concentrations, but it may induce CYP1A2.
• Special populations: no dose adjustment in elderly patients, in mild or moderate renal impairment, or in any degree of hepatic impairment.

• Cholangiocarcinoma: monotherapy for adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy.
• The presence of an FGFR2 gene fusion or rearrangement must be confirmed by an appropriate diagnostic test before treatment starts.

• Hypersensitivity to futibatinib or to any of the excipients.

The SmPC table is based on 145 patients treated in study TAS-120-101 (median exposure 8.87 months). The most common reactions (≥20%) were hyperphosphataemia (89.7%), nail disorders (44.1%), constipation (37.2%), alopecia (35.2%), diarrhoea (33.8%), dry mouth (31.0%), fatigue (31.0%), nausea (28.3%), dry skin (27.6%), increased AST (26.9%), abdominal pain (24.8%), stomatitis (24.8%), vomiting (23.4%), palmar-plantar erythrodysaesthesia syndrome (22.8%), arthralgia (21.4%) and decreased appetite (20.0%). The most common serious reactions were intestinal obstruction and migraine (1.4% each). Treatment was permanently stopped for adverse reactions in 7.6% of patients, most often for stomatitis (1.4%).

Very common (≥1/10): hyperphosphataemia, decreased appetite, hyponatraemia, hypophosphataemia, dysgeusia, dry eye, stomatitis, diarrhoea, nausea, constipation, dry mouth, vomiting, abdominal pain, palmar-plantar erythrodysaesthesia syndrome, nail disorders (including onycholysis, nail discolouration, paronychia and nail infection), dry skin, alopecia, myalgia, arthralgia, fatigue, raised liver transaminases.

Common (≥1/100 to <1/10): migraine, serous retinal detachment (the term also covers retinal pigment epithelial detachment, subretinal fluid, chorioretinopathy, macular oedema and maculopathy), intestinal obstruction.

The SmPC tabulates only these two frequency categories. Reactions needing particular attention are hyperphosphataemia and its consequences (soft tissue mineralisation), serous retinal detachment, dry eye and intestinal obstruction.

• Strong CYP3A inhibitors (for example clarithromycin, itraconazole): itraconazole raised futibatinib peak concentration by 51% and AUC by 41%. Avoid the combination; if it cannot be avoided, consider reducing the futibatinib dose to the next lower level, guided by tolerability.
• Strong or moderate CYP3A inducers (for example carbamazepine, phenytoin, phenobarbital, efavirenz, rifampicin): rifampicin lowered peak concentration by 53% and AUC by 64%. Avoid the combination; if it cannot be avoided, consider increasing the futibatinib dose gradually with careful monitoring of tolerability.
• P-gp inhibitors: quinidine raised peak concentration by 8% and AUC by 17%; no clinically relevant effect is expected.
• Proton pump inhibitors: lansoprazole did not change exposure to a clinically relevant extent.
• CYP3A, P-gp and BCRP substrates: a sensitive CYP3A substrate, digoxin (P-gp) and rosuvastatin (BCRP) showed no clinically relevant change in exposure when given with futibatinib.
• CYP1A2 substrates: futibatinib may induce CYP1A2 in vitro, so sensitive CYP1A2 substrates (for example olanzapine, theophylline) may have lower exposure and reduced activity.
• Hormonal contraceptives: it is not known whether futibatinib reduces their effectiveness. Women using them should add a barrier method during treatment and for at least 1 week after the last dose.
• Food: the tablets can be taken with or without food, at about the same time each day.

Treatment should be started by a physician experienced in the diagnosis and treatment of biliary tract cancer, after an FGFR2 gene fusion or rearrangement has been confirmed by an appropriate diagnostic test. The tablets are swallowed whole, with or without food, at about the same time each day.

Recommended Dose

• 20 mg once daily (five 4 mg tablets), continued until disease progression or unacceptable toxicity.
• Each blister wallet holds a 7-day supply: 35 tablets for the 20 mg daily dose, 28 tablets for 16 mg and 21 tablets for 12 mg.

Phosphate Management

• A diet that limits phosphate intake is recommended in all patients. Phosphate-lowering therapy is started when serum phosphate reaches 5.5 mg/dL or more.
• Serum phosphate 5.5 to 7 mg/dL: start phosphate-lowering therapy, check phosphate weekly, and continue futibatinib at the current dose.
• Above 7 and up to 10 mg/dL: start or intensify phosphate-lowering therapy, check weekly, and reduce futibatinib to the next lower dose. If phosphate is 7.0 mg/dL or lower within 2 weeks, continue at the reduced dose; if not, reduce once more. If phosphate is still above 7.0 mg/dL 2 weeks after the second reduction, withhold futibatinib until it is 7.0 mg/dL or lower and resume at the dose used before suspension.
• Above 10 mg/dL: start or intensify phosphate-lowering therapy, check weekly, suspend futibatinib until phosphate is 7.0 mg/dL or lower, and resume at the next lower dose. Stop permanently if phosphate is not 7.0 mg/dL or lower within 2 weeks after 2 dose reductions.
• If treatment is stopped or serum phosphate falls below the normal range, phosphate-lowering therapy and the diet should be stopped. Severe hypophosphataemia may present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis and haemolytic anaemia.

Dose Reductions for Adverse Reactions

• Dose levels: 20 mg once daily, first reduction to 16 mg once daily, second reduction to 12 mg once daily. Stop permanently if 12 mg once daily is not tolerated.
• Serous retinal detachment: asymptomatic, continue at the current dose with monitoring. With a moderate loss of vision, withhold futibatinib and, if the examination improves, resume at the next lower dose. With a marked loss of vision (worse than 20/40, down to 20/200), withhold until resolution and, if improved, resume two dose levels lower. For visual acuity worse than 20/200, or when symptoms recur, persist or do not improve, permanent discontinuation should be considered.
• Other adverse reactions: grade 3, withhold until the reaction resolves to grade 1 or baseline, then resume (at the previous dose for haematological toxicities resolving within 1 week, otherwise at the next lower dose). Grade 4, stop permanently.
• Interacting medicines: see Drug Interactions for strong CYP3A inhibitors and for strong or moderate CYP3A inducers.

Special Populations

• Elderly (65 years and older): no specific dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment (creatinine clearance 30 to 89 mL/min). No data in severe impairment (below 30 mL/min) or end-stage renal disease on intermittent haemodialysis, so no dosing recommendation can be made.
• Hepatic impairment: no adjustment in mild (Child-Pugh A), moderate (B) or severe (C) impairment, although there are no safety data in severe impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

If a dose is missed by more than 12 hours, or vomiting occurs after a dose, do not take an additional dose; resume with the next scheduled dose.

FGFR2 Alteration Must Be Confirmed

Treatment is only for tumours with an FGFR2 gene fusion or rearrangement, confirmed by an appropriate diagnostic test before the first dose.

Hyperphosphataemia

Hyperphosphataemia is an expected pharmacodynamic effect. Prolonged hyperphosphataemia may cause soft tissue mineralisation, including cutaneous, vascular and myocardial calcification, as well as anaemia, hyperparathyroidism and hypocalcaemia, which may cause muscle cramps, QT interval prolongation and arrhythmias. Management is by dietary phosphate restriction, phosphate-lowering therapy (used by 83.4% of patients in the study) and dose modification as described above.

Serous Retinal Detachment and Dry Eye

Serous retinal detachment may cause blurred vision, visual floaters or photopsia. An ophthalmological examination is advised before starting, 6 weeks later, and urgently at any time for visual symptoms. The study did not routinely screen for asymptomatic detachment (for example with optical coherence tomography), so its true incidence is unknown. Particular care is needed in patients with clinically significant eye disorders, such as central serous retinopathy, macular or retinal degeneration, diabetic retinopathy or earlier retinal detachment. Dry eye can occur; ocular demulcents are used as needed to prevent or treat it.

Strong CYP3A Inhibitors and Inducers

Strong CYP3A inhibitors can raise, and strong or moderate CYP3A inducers can lower, futibatinib levels. Avoid both where possible.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: a pregnancy test is performed before treatment starts. Women of childbearing potential, and men with partners of childbearing potential, must use effective contraception during treatment and for 1 week after the last dose. Because the effect of futibatinib on contraceptives has not been investigated, a barrier method should be used as a second form of contraception.
• Pregnancy: no data in pregnant women; animal studies showed embryo-foetal toxicity and futibatinib can cause foetal harm. It should not be used in pregnancy unless the benefit to the woman justifies the risk to the foetus.
• Breastfeeding: it is unknown whether futibatinib passes into human milk and a risk to the infant cannot be excluded. Breastfeeding should be stopped during treatment and for 1 week after the last dose.
• Fertility: no human data and no animal fertility studies; impairment of male and female fertility cannot be excluded.

Lactose and Sodium

Each tablet contains 5.4 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Futibatinib has a moderate influence on the ability to drive and use machines. Patients should be careful if they feel tired or have visual disturbances.

No special storage conditions are required. The tablets are in PVC/PCTFE laminated blisters with aluminium foil backing, one tablet per cavity; each blister holds a 7-day supply and is sealed inside a folding cardboard wallet. Dose packs: 20 mg daily dose (35 tablets, 5 tablets once daily), 16 mg daily dose (28 tablets, 4 tablets once daily) and 12 mg daily dose (21 tablets, 3 tablets once daily). Not all pack sizes may be marketed. Keep out of the sight and reach of children.

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

Prescription only (Rx). Lytgobi is subject to restricted medical prescription (Annex II B): treatment is started by a physician experienced in the diagnosis and treatment of biliary tract cancer, after the FGFR2 fusion or rearrangement has been confirmed. The tablets are taken at home, so the product is supplied to the patient or to the treating clinic on prescription.