Fruquintinib

Fruquintinib is a selective inhibitor of the tyrosine kinase activity of VEGFR-1, -2 and -3. Signalling through these receptors drives tumour angiogenesis, so blocking it limits the blood supply that tumours need to grow.

Mechanism of Action

• Receptor inhibition: fruquintinib inhibits VEGFR-1, VEGFR-2 and VEGFR-3 with half-maximal inhibitory concentrations of 33, 35 and 0.5 nM respectively in laboratory tests.
• Anti-angiogenic effect: its antitumour effect results from suppressing tumour angiogenesis. In vitro it blocked VEGF-mediated endothelial cell proliferation and tube formation, and in animals it inhibited VEGF-induced VEGFR-2 phosphorylation and slowed tumour growth in a mouse model of colon cancer.
• Cardiac electrophysiology: no prolongation of the heart rate-corrected QT interval (above 10 milliseconds) was seen at the recommended dose, and a concentration-QT analysis (205 patients) found no link between fruquintinib plasma concentrations and QTc change.
• Clinical basis: the authorisation rests on FRESCO-2, a global, randomised, double-blind, placebo-controlled phase III study of fruquintinib plus best supportive care in 691 patients with metastatic colorectal cancer previously treated with standard therapies.

Pharmacokinetics

• Absorption: the median time to peak plasma concentration is about 2 hours, with a second absorption peak about 24 hours after dosing. Exposure (peak level and AUC over 24 hours) rises in proportion to dose across 1 to 6 mg. Steady state is reached after 14 days, with about 4-fold accumulation compared with a single dose; at 5 mg the steady-state peak level is about 300 ng/mL and the AUC over 24 hours about 5,880 ng·h/mL. A high-fat meal had no clinically meaningful effect.
• Distribution: the apparent volume of distribution is about 48.5 L. Plasma protein binding is about 95% in vitro, mainly to human serum albumin.
• Metabolism: several enzymes are involved, both CYP450 (mainly CYP3A4, with minor contributions from CYP2C8, CYP2C9 and CYP2C19) and non-CYP450 pathways such as sulfation and glucuronidation. Unchanged fruquintinib makes up about 72% of total plasma exposure, and the CYP3A4-derived N-demethyl metabolite about 17%. In vitro, fruquintinib is not an inhibitor or inducer of the main CYP enzymes at relevant concentrations, is not a substrate of P-glycoprotein, OATP1B1 or OATP1B3, and inhibits P-glycoprotein and BCRP in a dose-dependent way in vitro.
• Elimination: apparent clearance at steady state is about 14.8 mL/min and the mean half-life about 42 hours. After a single radiolabelled 5 mg dose in healthy subjects, about 60% of the dose was recovered in urine (0.5% as unchanged drug) and about 30% in faeces (5% unchanged).
• Special populations: mild to severe renal impairment (creatinine clearance 15–89 mL/min) and mild or moderate (Child-Pugh B) hepatic impairment had no clinically meaningful effect on pharmacokinetics. Age (18 to 82 years), body weight (48 to 108 kg), sex and race had no clinically relevant effect. Severe hepatic impairment has not been studied, and no studies were done below 18 years.

• Metastatic colorectal cancer (mCRC): as monotherapy in adults previously treated with the available standard therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents, and who have progressed on, or are intolerant to, treatment with either trifluridine-tipiracil or regorafenib.

• Hypersensitivity to fruquintinib or to any of the excipients.

The most common reactions are hypertension (49.3%), anorexia (35.6%), proteinuria (35.5%), palmar-plantar erythrodysaesthesia syndrome (PPES, 34.6%), hypothyroidism (32.4%), dysphonia (28.6%), diarrhoea (26.3%) and asthenia (24.5%). The most common grade 3 or higher reactions are hypertension (19.1%) and PPES (8.3%). The most common serious reactions are gastrointestinal haemorrhage (1.5%), pneumonia (1.5%), hypertension (1.5%) and gastrointestinal perforation (1.3%). Treatment was stopped because of reactions in 7.6% of patients (proteinuria most often, 1.6%) and the dose was reduced in 20.5% (most often for PPES 6.4%, hypertension 3.7% and proteinuria 3.4%). The frequencies below come from pooled data on 911 previously treated patients given 5 mg once daily, 3 weeks on and 1 week off, for a median of 3.68 months.

Very common (≥1/10): thrombocytopenia (including decreased platelet count), hypothyroidism (including raised thyroid-stimulating hormone), anorexia (including decreased appetite and weight loss), hypertension (including raised blood pressure and hypertensive crisis), dysphonia, diarrhoea, stomatitis (including mouth ulcers), raised AST, raised ALT, raised total bilirubin, palmar-plantar erythrodysaesthesia syndrome, musculoskeletal discomfort, arthralgia, proteinuria, asthenia, fatigue.

Common (≥1/100 to <1/10): pneumonia, upper respiratory tract infection, bacterial infections, leukopenia, neutropenia, hypokalaemia, epistaxis, throat pain, gastrointestinal haemorrhage, gastrointestinal perforation, raised pancreatic enzymes (amylase, lipase), oral pain, rash, mucosal inflammation.

Uncommon (≥1/1,000 to <1/100): posterior reversible encephalopathy syndrome, pancreatitis, cholecystitis, impaired wound healing.

Not known: aortic dissection (reported after marketing).

Important serious reactions are hypertension including hypertensive crisis, serious and sometimes fatal bleeding, gastrointestinal perforation including fatal cases, nephrotic syndrome, and posterior reversible encephalopathy syndrome.

• CYP3A inducers: rifampicin, a strong CYP3A inducer, at 600 mg once daily lowered fruquintinib AUC by 65% and peak level by 12%. Strong and moderate CYP3A inducers should be avoided.
• CYP3A inhibitors: itraconazole, a strong CYP3A inhibitor, at 200 mg twice daily caused no clinically meaningful change in fruquintinib AUC or peak level. No dose adjustment is needed.
• Gastric acid-lowering agents: rabeprazole, a proton pump inhibitor, at 40 mg once daily did not change fruquintinib AUC in a clinically meaningful way. No dose adjustment is needed.
• P-glycoprotein substrates: a single dose of dabigatran etexilate 150 mg with a single 5 mg dose of fruquintinib lowered dabigatran AUC by 9%. No dose adjustment is recommended.
• BCRP substrates: a single 10 mg dose of rosuvastatin with a single 5 mg dose of fruquintinib lowered rosuvastatin AUC by 19%. No dose adjustment is recommended.
• Anticoagulants and other medicines that increase bleeding risk: patients at risk of bleeding, including those on anticoagulants, need monitoring of haematological and coagulation profiles.
• Food: the capsules can be taken with or without food; a high-fat meal had no clinically meaningful effect.

Treatment should be started by a physician experienced in anticancer therapy. The capsules are for oral use and are swallowed whole, with or without food, at about the same time each day. They must not be chewed, dissolved or opened, because the effects of doing so are unknown.

Recommended Dose

• 5 mg (one 5 mg capsule) once daily for 21 consecutive days, followed by a 7-day rest period, making a 28-day cycle.
• Duration: until disease progression or unacceptable toxicity.

Dose Reductions

The dose is modified according to safety and tolerability. The first reduction is to 4 mg once daily (four 1 mg capsules) and the second to 3 mg once daily (three 1 mg capsules). Fruquintinib is stopped permanently in patients who cannot tolerate 3 mg once daily. Reactions are graded by the NCI CTCAE version 5.0.

• Hypertension: grade 3 — withhold if it persists despite starting or adjusting antihypertensive treatment; when it recovers to grade 1 or baseline, resume at the next lower dose, and stop permanently if grade 3 persists at 3 mg daily. Grade 4 — stop permanently.
• Haemorrhagic events: grade 2 — withhold until bleeding has fully resolved or recovered to grade 1, then resume at the next lower dose, and stop permanently if grade 2 persists at 3 mg daily. Grade 3 or higher — stop permanently.
• Proteinuria of 2 g/24 hours or more: withhold until it fully resolves or falls below 1 g/24 hours (grade 1), then resume at the next lower dose; stop permanently if it persists at 3 mg daily. Nephrotic syndrome — stop permanently.
• Liver function test abnormalities: grade 2 or 3 — withhold until recovery to grade 1 or baseline, then resume at the next lower dose, and stop permanently if they persist at 3 mg daily. Stop permanently for a grade 2 or higher rise of ALT or AST (above 3 times the upper limit of normal) with a concurrent total bilirubin rise above 2 times the upper limit in the absence of cholestasis, and for grade 4 abnormalities.
• Palmar-plantar erythrodysaesthesia syndrome: grade 2 — give supportive treatment, withhold until grade 1 or baseline, then resume at the same dose. Grade 3 — supportive treatment, withhold until grade 1 or baseline, then resume at the next lower dose; stop permanently if grade 3 persists at 3 mg daily.
• Other adverse reactions: grade 3 — withhold until grade 1 or baseline, then resume at the next lower dose; stop permanently if grade 3 persists at 3 mg daily. Grade 4 — discontinue; resuming at a lower dose may be considered if the toxicity recovers to grade 1 or baseline and the potential benefit outweighs the risks.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no dose adjustment in mild, moderate or severe impairment.
• Hepatic impairment: no dose adjustment in mild or moderate impairment. Fruquintinib is not recommended in severe hepatic impairment because it has not been studied.
• Children and adolescents: there is no relevant use in the paediatric population for metastatic colorectal cancer.

Missed or Vomited Dose

If a dose is missed by less than 12 hours, take it and take the next dose as scheduled. If it is missed by more than 12 hours, skip it and take the next dose as scheduled. After vomiting, do not repeat the dose that day; resume the usual dosing the next day.

Hypertension

Hypertension, including hypertensive crisis, has been reported. Existing hypertension should be monitored and well controlled before starting. New or worsening hypertension is managed with antihypertensive medicines and, if needed, dose adjustment. Fruquintinib is stopped permanently for hypertension that cannot be controlled with treatment and for hypertensive crisis.

Haemorrhagic Events

Bleeding, including gastrointestinal bleeding, has been reported, and serious and sometimes fatal events have occurred. Haematological and coagulation profiles are monitored in patients at risk of bleeding, including those on anticoagulants or other medicines that increase bleeding risk. Fruquintinib is stopped permanently if severe bleeding needs immediate medical intervention.

Gastrointestinal Perforation

Gastrointestinal perforation, including fatal events, has been reported. Symptoms are monitored periodically, and fruquintinib is stopped permanently in patients who develop a perforation.

Proteinuria

Proteinuria is monitored before starting and during treatment. If urine dipstick proteinuria of 2 g/24 hours or more is found, interruption, dose adjustment or discontinuation may be necessary. Fruquintinib is stopped permanently in nephrotic syndrome.

Palmar-Plantar Erythrodysaesthesia Syndrome

PPES is the most frequently reported skin reaction. Grade 2 or higher skin reactions may call for interruption, dose adjustment or discontinuation.

Posterior Reversible Encephalopathy Syndrome

PRES was reported in 1 patient (0.1%) in clinical studies. It is a rare neurological disorder that can present with headache, seizure, lethargy, confusion, altered mental function, blindness and other visual or neurological disturbances, with or without hypertension. The diagnosis needs confirmation by brain imaging, preferably MRI. In affected patients fruquintinib is stopped, hypertension is controlled and other symptoms are managed supportively.

Impaired Wound Healing and Surgery

Impaired wound healing was reported in 1 patient (0.1%) in clinical studies. Fruquintinib should be withheld for at least 2 weeks before surgery and not resumed for at least 2 weeks afterwards, and only once the wound is healing adequately.

Thromboembolic Events

Starting fruquintinib is best avoided in patients with a thromboembolic event (including deep vein thrombosis and pulmonary embolism) in the past 6 months, or a stroke or transient ischaemic attack in the past 12 months. If arterial thrombosis is suspected, fruquintinib is stopped immediately.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use highly effective contraception during treatment and for at least 2 weeks after the last dose.
• Pregnancy: there are no clinical data. Based on its mechanism of action, fruquintinib may cause foetal harm, and animal studies showed reproductive toxicity including foetal malformations. It should not be used in pregnancy unless the woman’s condition requires it; a patient who becomes pregnant on treatment must be told of the potential hazard to the foetus.
• Breastfeeding: its safety during breastfeeding has not been established, and it is not known whether fruquintinib or its metabolites pass into milk. A risk to the infant cannot be excluded, so breastfeeding should stop during treatment and for 2 weeks after the last dose.
• Fertility: there are no human data; animal studies indicate that male and female fertility may be impaired.

Colourants

The 1 mg capsules contain tartrazine (E102) and sunset yellow FCF (E110), and the 5 mg capsules contain Allura red AC (E129). These colourants may cause allergic reactions.

Effect on Driving

Fruquintinib has a minor influence on the ability to drive and use machines. Fatigue may occur after taking it.

Fruquintinib capsules need no special temperature storage. Keep them in the original bottle to protect from moisture, and keep the bottle tightly closed. The bottle has a child-resistant closure and holds 21 capsules with a silica gel desiccant cartridge, which must stay inside. Keep out of the sight and reach of children.

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

Prescription only (Rx), started by a physician experienced in anticancer therapy. Fruquintinib is taken at home as capsules, so it is supplied to the patient or to the treating clinic on prescription.