Pemigatinib

Pemigatinib is a kinase inhibitor of fibroblast growth factor receptors (FGFR) 1, 2 and 3. FGFRs are not constitutively active in normal cells, but in some tumours alterations of the FGFR genes keep the signalling pathway switched on and support the growth and survival of malignant cells. FGFR2 fusions or rearrangements are strong oncogenic drivers; they occur, almost exclusively, in about 10–16 % of intrahepatic cholangiocarcinoma (cancer of the bile ducts inside the liver).

Mechanism of Action

• FGFR inhibition: pemigatinib inhibits the phosphorylation and signalling of FGFR1, FGFR2 and FGFR3 and lowers the viability of cells that express FGFR alterations, including point mutations, amplifications, and fusions or rearrangements. In laboratory tests it was a potent inhibitor of all three receptors (IC50 below 2 nM).
• Normal and abnormal signalling: when a fibroblast growth factor binds an FGFR, the receptor dimerises and activates downstream pathways (PI3K-AKT, RAS/MAPK and phospholipase Cγ) that promote cell growth, survival, migration and new blood-vessel formation. In tumours with FGFR fusions or amplifications this activation is constitutive, and pemigatinib blocks it.
• Why testing is required: FGFR gene alterations occur in selected patients and do not always drive tumour development, so an FGFR2 fusion or rearrangement must be demonstrated by a diagnostic test before treatment starts.
• FGFR4: in the laboratory pemigatinib also inhibited FGFR4, but only at concentrations about 100 times higher than those that inhibit FGFR1–3.
• Serum phosphate: FGFR inhibition raises serum phosphate, so hyperphosphataemia is an expected pharmacodynamic effect of treatment.

Pharmacokinetics

• Absorption: the median time to peak plasma concentration is 1 to 2 hours. Pharmacokinetics are linear between 1 and 20 mg. At 13.5 mg once daily, steady state is reached by day 4, with an accumulation ratio of about 1.6, a steady-state AUC0–24h of 2,620 nM·h and a Cmax of 236 nM (geometric means). A high-fat, high-calorie meal made no clinically meaningful difference.
• Distribution: 90.6 % bound to human plasma proteins, mainly albumin; apparent volume of distribution about 235 L in patients with cancer.
• Metabolism: predominantly by CYP3A4 in vitro. After a radiolabelled dose, unchanged pemigatinib was the main drug-related compound in plasma and no metabolite exceeded 10 % of the total circulating radioactivity.
• Elimination: geometric mean half-life 15.4 hours and apparent clearance 10.6 L/h. After a radiolabelled dose, 82.4 % was recovered in the faeces (1.4 % as unchanged drug) and 12.6 % in the urine (1 % as unchanged drug).
• Special populations: in severe renal impairment the geometric mean AUC0–∞ was 159 % of the value in subjects with normal renal function (Cmax 64.6 %), whereas in end-stage renal disease on haemodialysis exposure was not higher than normal. Doses are reduced in severe renal or hepatic impairment (see Administration and Dosage).

Pemigatinib is used as monotherapy.

• Cholangiocarcinoma (bile duct cancer): adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that has progressed after at least one prior line of systemic therapy.
• Testing first: the FGFR2 fusion status must be known before treatment starts, using an appropriate diagnostic test on a tumour specimen.
• Evidence: the efficacy data in the SmPC come from one open-label, single-arm study (FIGHT-202) in 108 previously treated patients whose FGFR2 fusion or rearrangement was confirmed at a central laboratory.

• Hypersensitivity to pemigatinib or to any of the excipients (microcrystalline cellulose, sodium starch glycolate, magnesium stearate).
• Concomitant use with St John’s wort.

The most common side effects are hyperphosphataemia (60.5 %), alopecia (49.7 %), diarrhoea (47.6 %), nail toxicity (44.9 %), fatigue (43.5 %), nausea (41.5 %), stomatitis (38.1 %), constipation (36.7 %), dysgeusia (36.1 %), dry mouth (34.0 %), arthralgia (29.9 %), dry eye (27.9 %), hypophosphataemia (23.8 %), dry skin (21.8 %) and palmar-plantar erythrodysaesthesia syndrome (16.3 %). The most common serious reactions were hyponatraemia (2.0 %) and increased blood creatinine (1.4 %).

Very common (≥1/10): hyponatraemia, hyperphosphataemia, hypophosphataemia, dysgeusia, dry eye, nausea, stomatitis, diarrhoea, constipation, dry mouth, palmar-plantar erythrodysaesthesia syndrome, nail toxicity, alopecia, dry skin, arthralgia, fatigue, increased blood creatinine.

Common (≥1/100 to <1/10): serous retinal detachment, punctate keratitis, blurred vision, trichiasis, abnormal hair growth.

Uncommon (≥1/1,000 to <1/100): cutaneous calcification.

Serious eye reactions were retinal detachment, non-arteritic optic ischaemic neuropathy and retinal artery occlusion (0.7 % each). Prolonged hyperphosphataemia can cause soft tissue mineralisation, including cutaneous calcification, calcinosis and non-uraemic calciphylaxis. No serious reaction led to a dose reduction; one serious hyponatraemia (0.7 %) led to a dose interruption and one serious increase in blood creatinine (0.7 %) to discontinuation.

Pemigatinib is metabolised mainly by CYP3A4, so strong modulators of this enzyme change its exposure.

• Strong CYP3A4 inhibitors: itraconazole 200 mg once daily raised the pemigatinib AUC by 88 % (geometric mean), which may increase the frequency and severity of side effects. Avoid the combination, including grapefruit juice; if a strong inhibitor is necessary, reduce the dose from 13.5 mg to 9 mg or from 9 mg to 4.5 mg once daily.
• CYP3A4 inducers: rifampicin 600 mg once daily lowered the AUC by 85 %, which may reduce efficacy. Strong inducers (for example carbamazepine, phenytoin, phenobarbital, rifampicin) should be avoided, and strong or moderate inducers are not recommended. St John’s wort is contraindicated. Other enzyme inducers (for example efavirenz) should be used only under close surveillance.
• Proton pump inhibitors: with esomeprazole in healthy subjects, Cmax was 65.3 % and AUC 92.1 % of the values with pemigatinib alone, which is not a clinically important change; however, a significant fall in exposure was seen in more than one third of patients given proton pump inhibitors, so they should be avoided.
• H2-receptor antagonists: ranitidine produced no clinically important change in pemigatinib exposure.
• CYP2B6 substrates: pemigatinib induces CYP2B6 in vitro and may lower the exposure of substrates such as cyclophosphamide, ifosfamide, methadone and efavirenz. Close clinical surveillance is recommended, particularly for any substrate with a narrow therapeutic index.
• P-glycoprotein substrates: pemigatinib inhibits P-glycoprotein in vitro and may raise the exposure and toxicity of substrates such as digoxin, dabigatran and colchicine. For a substrate with a narrow therapeutic index, pemigatinib should be given at least 6 hours before or after it.
• Food: grapefruit and grapefruit juice must be avoided. Pemigatinib can be taken with or without food, and a high-fat meal has no clinically significant effect.

Treatment should be started by a physician experienced in the diagnosis and treatment of biliary tract cancer, and the FGFR2 fusion status must be known first. The tablets are taken by mouth at about the same time every day, with or without food, and must not be crushed, chewed, split or dissolved.

Recommended Dose

• 13.5 mg once daily for 14 days, followed by 7 days off therapy (a 21-day cycle).
• Treatment continues as long as there is no evidence of disease progression or unacceptable toxicity.

Phosphate Management

• A low-phosphate diet should be started when serum phosphate is above 5.5 mg/dL, and phosphate-lowering therapy considered when it is above 7 mg/dL; that therapy is adjusted until the level returns below 7 mg/dL.
• Phosphate-lowering therapy and diet should be reconsidered during treatment breaks or if serum phosphate falls below the normal range.
• Above 5.5 and up to 7 mg/dL: continue at the current dose.
• Above 7 and up to 10 mg/dL: continue at the current dose, start phosphate-lowering therapy and monitor serum phosphate weekly. Withhold pemigatinib if the level has not returned below 7 mg/dL within 2 weeks of starting phosphate-lowering therapy, and restart both at the same dose once it is below 7 mg/dL. If it rises above 7 mg/dL again despite phosphate-lowering therapy, reduce by one dose level.
• Above 10 mg/dL: continue at the current dose, start phosphate-lowering therapy and monitor weekly. Withhold if the level stays above 10 mg/dL for 1 week, and restart one dose level lower when it is below 7 mg/dL. If it rises above 10 mg/dL again after 2 dose reductions, stop pemigatinib permanently.

Dose Reduction Levels

• First reduction: 9 mg once daily for 14 days, then 7 days off. Second reduction: 4.5 mg once daily for 14 days, then 7 days off. Treatment is stopped permanently if 4.5 mg is not tolerated.
• Serous retinal detachment, no symptoms: continue at the current dose with the eye monitoring described under Special Instructions.
• Serous retinal detachment, moderate decrease in visual acuity (best corrected acuity 20/40 or better, or a loss of up to 3 lines from baseline, limiting instrumental activities of daily living): withhold until resolution and, if it improves, resume one dose level lower.
• Serous retinal detachment, marked decrease (acuity worse than 20/40, or more than 3 lines lost from baseline, down to 20/200, or worse than 20/200, limiting activities of daily living): withhold until resolution and, if it improves, resume 2 dose levels lower.
• If the retinal event recurs, symptoms persist or the examination does not improve, permanent discontinuation should be considered based on clinical status.

With Strong CYP3A4 Inhibitors

If a strong CYP3A4 inhibitor cannot be avoided, patients taking 13.5 mg are reduced to 9 mg once daily and patients taking 9 mg to 4.5 mg once daily. Grapefruit juice is included in this advice.

Special Populations

• Elderly: the dose is the same as in younger adults.
• Renal impairment: no adjustment in mild or moderate impairment or in end-stage renal disease on haemodialysis. In severe impairment, reduce 13.5 mg to 9 mg once daily, or 9 mg to 4.5 mg once daily.
• Hepatic impairment: no adjustment in mild or moderate impairment. In severe impairment, the same reductions apply.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

If a dose is missed by 4 hours or more, or vomiting occurs after a dose, do not take an extra dose. Take the next scheduled dose as usual.

FGFR2 Fusion Testing

Pemigatinib is for tumours with an FGFR2 fusion or rearrangement, shown by an appropriate diagnostic test on a tumour specimen before treatment starts.

Hyperphosphataemia and Hypophosphataemia

• Hyperphosphataemia is an expected pharmacodynamic effect. If prolonged, calcium-phosphate crystals can precipitate and cause hypocalcaemia, soft tissue mineralisation, anaemia, secondary hyperparathyroidism, muscle cramps, seizure activity, QT interval prolongation and arrhythmias. Management is dietary phosphate restriction, phosphate-lowering therapy and dose modification; 19 % of patients used phosphate-lowering therapy.
• Hypophosphataemia: severe cases can present with confusion, seizures, focal neurological findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis and haemolytic anaemia. Reactions of grade 3 or higher occurred in 14.3 % of participants; none was serious or led to discontinuation or dose reduction, and dose interruption occurred in 1.4 %.
• Patients with hyperphosphataemia or hypophosphataemia need additional close monitoring and follow-up for dysregulation of bone mineralisation.

Serous Retinal Detachment and Dry Eye

• Serous retinal detachment may present with blurred vision, visual floaters or photopsia.
• An ophthalmological examination, including optical coherence tomography (OCT), should be performed before treatment starts, every 2 months for the first 6 months, every 3 months afterwards, and urgently at any time if visual symptoms appear. Dose changes follow the guidance above.
• The study did not use routine OCT monitoring, so the frequency of asymptomatic detachment is unknown.
• Take particular care in patients with clinically significant eye disorders, such as retinal disorders, central serous retinopathy, macular or retinal degeneration, diabetic retinopathy and previous retinal detachment.
• Dry eye: patients should use ocular demulcents as needed to prevent or treat it.

Blood Creatinine Increase

Pemigatinib can raise serum creatinine by reducing the renal tubular secretion of creatinine (through inhibition of the transporters OCT2 and MATE1), without necessarily affecting glomerular function. In the first cycle serum creatinine rose by a mean of 0.2 mg/dL, reached steady state by day 8 and fell during the 7 days off therapy. If elevations persist, alternative markers of renal function should be considered.

CNS Metastases

Patients with untreated or progressing brain or CNS metastases were not allowed in the study, so efficacy in this group has not been evaluated and no dose recommendation can be made. Blood-brain barrier penetration is expected to be low.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test: a pregnancy test should be performed before treatment starts.
• Contraception: women of childbearing potential, and men with partners of childbearing potential, should use effective contraception during treatment and for 1 week after the last dose. The effect of pemigatinib on the metabolism and efficacy of contraceptives has not been investigated, so barrier methods should be added as a second form of contraception. Women should be advised not to become pregnant and men not to father a child during treatment.
• Pregnancy: no data in pregnant women; animal studies showed reproductive toxicity and foetal harm is possible. It should not be used in pregnancy unless the woman’s clinical condition requires treatment.
• Breastfeeding: it is unknown whether pemigatinib passes into human milk and a risk to the infant cannot be excluded. Breastfeeding should stop during treatment and for 1 week after the last dose.
• Fertility: there are no human data and no animal fertility studies; impairment of male and female fertility cannot be excluded.

Effect on Driving

Pemigatinib has a moderate influence on the ability to drive and use machines. Fatigue and visual disturbances can occur, so caution is advised.

Pemazyre tablets do not require any special storage conditions. They are supplied in PVC/aluminium blisters of 14 tablets, in cartons of 14 or 28 tablets; not all pack sizes may be marketed.

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

Prescription only (Rx): a medicinal product subject to restricted medical prescription. Treatment is started by a physician experienced in the diagnosis and treatment of biliary tract cancer, after the tumour has been shown to have an FGFR2 fusion or rearrangement; serum phosphate and eye examinations, including OCT, continue as described in the SmPC. Pemigatinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.