Dacomitinib

Dacomitinib is a pan-HER inhibitor: it blocks EGFR (HER1), HER2 and HER4, and it is active against EGFR with exon 19 deletions or the L858R substitution in exon 21, the activating mutations found in a subset of non-small cell lung cancers.

Mechanism of Action

• Pan-HER inhibition: dacomitinib inhibits the tyrosine kinase activity of EGFR/HER1, HER2 and HER4.
• Irreversible binding: it binds selectively and irreversibly to its HER family targets, which gives prolonged inhibition. According to DrugBank the bond is covalent, to cysteine residues in the catalytic domain of the receptors.
• Downstream signalling: HER receptors drive tumour growth through pathways such as Ras–Raf–MAPK and PI3K/AKT (DrugBank); blocking the receptors suppresses this signalling.
• Active metabolite: O-desmethyl dacomitinib showed in vitro pharmacological activity similar to that of dacomitinib.
• Clinical study: in ARCHER 1050, a randomised, open-label phase 3 study, 452 patients with locally advanced or metastatic NSCLC with EGFR-activating mutations received dacomitinib or gefitinib; the primary endpoint was progression-free survival assessed by blinded independent central review. DrugBank reports a significant improvement in progression-free survival with dacomitinib; the SmPC (section 5.1) gives the results.

Pharmacokinetics

• Absorption: mean oral bioavailability is 80% (range 65–100%) compared with intravenous dosing, with peak levels 5–6 hours after a dose. Steady state is reached within 14 days of 45 mg daily. Food does not change bioavailability to a clinically meaningful extent. Dacomitinib is a substrate of P-glycoprotein and BCRP, which are unlikely to affect its absorption.
• Distribution: extensive; the mean steady-state volume of distribution is 27 L/kg (70 kg patient). It binds to plasma proteins, including albumin and acid glycoprotein; the unbound fraction is about 2%.
• Metabolism: oxidation and glutathione conjugation are the major pathways. The main circulating metabolite is O-desmethyl dacomitinib (16% of plasma radioactivity), formed mainly by CYP2D6 and to a lesser extent CYP2C9; CYP3A4 forms other minor oxidative metabolites. Inhibition of CYP2D6 cut exposure to the metabolite by about 90% and raised dacomitinib exposure by about 37%.
• Elimination: plasma half-life is 54 to 80 hours and clearance is 20.0 L/h. After a radiolabelled dose a median of 82% of the radioactivity was recovered within 552 hours: 79% in faeces and 3% in urine, with less than 1% of the dose as unchanged dacomitinib in urine.
• Special populations: age, race, sex and body weight have no clinically relevant effect on exposure. After a single 30 mg dose, exposure was unchanged in mild hepatic impairment, fell by 15% (AUC) and 20% (peak level) in moderate impairment, and in severe impairment AUC was unchanged with a 31% higher peak level. Mild and moderate renal impairment did not change exposure; data in severe renal impairment are limited and haemodialysis has not been studied.

• First-line non-small cell lung cancer with EGFR-activating mutations: as monotherapy, for the first-line treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations.

• Hypersensitivity to dacomitinib or to any of the excipients listed in SmPC section 6.1.

The most common reactions (more than 20% of patients) were diarrhoea (88.6%), rash (79.2%), stomatitis (71.8%), nail disorders (65.5%), dry skin (33.3%), decreased appetite (31.8%), conjunctivitis (24.7%), weight decrease (24.3%), alopecia (23.1%), pruritus (22.4%), increased transaminases (22.0%) and nausea (20.4%). Median treatment duration in the pooled data was 66.7 weeks. Serious reactions occurred in 6.7% of patients, most often (1% or more) diarrhoea (2.0%), interstitial lung disease (1.2%), rash (1.2%) and decreased appetite (1.2%). Reactions led to dose reduction in 52.2% of patients (mainly rash 32.2%, nail disorders 16.5% and diarrhoea 7.5%) and to permanent discontinuation in 6.7% (rash 2.4%, interstitial lung disease 2.0%, diarrhoea 0.8%). The frequencies below come from 255 patients who started on 45 mg once daily.

Very common (≥1/10): metabolism and nutrition (decreased appetite, hypokalaemia); eye (conjunctivitis); gastrointestinal (diarrhoea, stomatitis, vomiting, nausea); skin (rash, palmar-plantar erythrodysaesthesia syndrome, skin fissures, dry skin, pruritus, nail disorders, alopecia); general (fatigue, asthenia); investigations (increased transaminases, weight decrease).

Common (≥1/100 to <1/10): dehydration; dysgeusia; keratitis; interstitial lung disease, including pneumonitis (fatal events have been reported); skin exfoliation; hypertrichosis.

In the SmPC grouping, conjunctivitis includes blepharitis, dry eye and non-infectious conjunctivitis; stomatitis includes mouth ulceration, dry mouth, mucosal inflammation and oral pain; rash includes acne, acneiform dermatitis, erythema and erythema multiforme; nail disorders include paronychia, nail bed inflammation, ingrown nails and onycholysis.

Important serious reactions are interstitial lung disease, severe diarrhoea with dehydration (with or without renal impairment, which could be fatal if untreated), severe rash and exfoliative skin conditions, and hepatotoxicity (isolated reports in 4 patients, 1.6%, and one fatal hepatic failure across the programme).

• Proton pump inhibitors: rabeprazole 40 mg daily for 7 days lowered the peak level of a single 45 mg dose of dacomitinib by about 51%, AUC0-96h by 39% and AUCinf by 29%. PPIs should be avoided during treatment.
• Antacids and H2-receptor antagonists: no apparent effect of local antacids (8 patients) or of H2-receptor antagonists on steady-state trough levels (geometric mean ratio 86%). They may be used if needed. Dacomitinib is taken 2 hours before, or at least 10 hours after, an H2-receptor antagonist.
• CYP2D6 substrates: a single 45 mg dose raised the exposure of a probe CYP2D6 substrate by 855% (AUClast) and 874% (peak level). Medicines mainly metabolised by CYP2D6 should be avoided unless necessary; if they are needed, their own labels are followed for use with strong CYP2D6 inhibitors.
• CYP2D6 inhibitors: inhibition of CYP2D6 raised dacomitinib exposure by about 37%.
• Transporters: in vitro, dacomitinib may inhibit P-glycoprotein in the gut, BCRP (systemically and in the gut) and OCT1 at clinically relevant concentrations.
• Other enzymes: dacomitinib and its metabolite have a low potential to inhibit or induce other CYP enzymes or UGT enzymes at clinically relevant concentrations.
• Food and herbs: DrugBank advises avoiding grapefruit and being cautious with St John’s wort because of CYP3A4. The SmPC names CYP2D6 as the major pathway and CYP3A4 only for minor metabolites, and gives no advice on them. Food does not change bioavailability to a clinically meaningful extent.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicinal products. EGFR mutation status must be established before starting, using a well-validated and robust method to avoid false-negative or false-positive results. The tablets are swallowed with water, with or without meals, at about the same time each day.

Recommended Dose

• 45 mg once daily, until disease progression or unacceptable toxicity.

Dose Modifications

• Dose levels: 45 mg (starting dose), first reduction 30 mg, second reduction 15 mg, all once daily.
• Interstitial lung disease (pneumonitis): withhold during the diagnostic evaluation; stop permanently if confirmed.
• Diarrhoea: grade 1, no change; start an antidiarrhoeal such as loperamide at the first loose stool and encourage oral fluids. Grade 2 not improving to grade 1 or less within 24 hours: withhold; once recovered, resume at the same dose or consider one dose level lower. Grade 3 or higher: withhold, treat with antidiarrhoeals and oral fluids or intravenous fluids and electrolytes; once recovered to grade 1 or less, resume one dose level lower.
• Skin reactions: grade 1 rash, erythematous or exfoliative skin conditions, no change; start treatment (for example antibiotics, topical steroids, emollients). Grade 2, no change, with treatment started or added; if it persists for 72 hours despite treatment, withhold, and once recovered to grade 1 or less resume at the same dose or one level lower. Grade 3 or higher: withhold, treat (for example broad-spectrum oral or intravenous antibiotics and topical steroids) and resume one level lower once recovered to grade 1 or less.
• Other toxicity: grade 1 or 2, no change. Grade 3 or higher: withhold until symptoms fall to grade 2 or less, then resume one dose level lower.

Special Populations

• Hepatic impairment: no starting dose adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. In severe impairment (Child-Pugh C) start at 30 mg once daily; the dose may be raised to 45 mg once daily based on safety and tolerability after at least 4 weeks.
• Renal impairment: no starting dose adjustment in mild or moderate impairment (creatinine clearance of 30 mL/min or more). Data are limited in severe impairment (below 30 mL/min) and absent in patients on haemodialysis, so no dosing recommendation can be made for them.
• Elderly (65 years and over): no starting dose adjustment.
• Children and adolescents: safety and efficacy under 18 years have not been established; no data are available.

Missed or Vomited Dose

Do not take an additional dose. Take the next prescribed dose at the usual time the next day.

EGFR Mutation Testing

A well-validated, robust method must be used to assess EGFR mutation status, to avoid false-negative or false-positive results.

Interstitial Lung Disease

Interstitial lung disease or pneumonitis, which could be fatal, has been reported. Patients with a history of it have not been studied. Anyone with acute or unexplained worsening of lung symptoms (such as breathlessness, cough or fever) should be assessed carefully, and dacomitinib withheld while this is investigated. If the diagnosis is confirmed, dacomitinib is stopped permanently and appropriate treatment given.

Diarrhoea

Severe diarrhoea is very common and can cause dehydration, with or without renal impairment, which could be fatal if not treated. Management starts at the first sign, especially in the first 2 weeks: adequate hydration with antidiarrhoeal medicines such as loperamide, escalated to the highest recommended approved dose if necessary, and continued until loose bowel movements have stopped for 12 hours. Dehydrated patients may need intravenous fluids and electrolytes, and dosing may need to be interrupted or reduced.

Skin Reactions

Rash, erythematous and exfoliative skin conditions have been reported. Moisturisers are started to prevent dry skin; topical antibiotics, emollients and topical steroids are started when a rash develops, and oral antibiotics and topical steroids for exfoliative conditions. Broad-spectrum oral or intravenous antibiotics are considered if any of these worsens to grade 2 or higher. These reactions may appear or worsen in areas exposed to the sun, so protective clothing and sunscreen are advised.

Hepatotoxicity

Raised transaminases have been reported. Periodic liver function tests are recommended, and treatment is interrupted in patients who develop severe elevations.

CYP2D6 Substrates and Acid-Reducing Medicines

Dacomitinib can raise the exposure of other medicines mainly metabolised by CYP2D6, or lower exposure to their active metabolites, so such use is avoided unless necessary. Proton pump inhibitors are avoided (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant and use adequate contraception during therapy and for at least 17 days (5 half-lives) after completing it.
• Pregnancy: there are no data in pregnant women. Animal studies showed limited reproductive toxicity (lower maternal body weight gain and food consumption in rats and rabbits; lower foetal body weight and more unossified metatarsals in rats only). Because of its mechanism of action dacomitinib may cause foetal harm and should not be used during pregnancy.
• Breastfeeding: it is not known whether dacomitinib or its metabolites pass into breast milk; mothers should be advised against breastfeeding during treatment.
• Fertility: no fertility studies have been done. Non-clinical safety studies showed reversible epithelial atrophy in the cervix and vagina of rats.

Lactose and Sodium

Each tablet contains lactose (40 mg, 81 mg or 121 mg in the 15 mg, 30 mg and 45 mg tablets). 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

Dacomitinib has a minor influence on the ability to drive and use machines. Patients with fatigue or eye reactions should take care.

Vizimpro tablets need no special storage conditions. They are supplied in aluminium/aluminium blisters of 10 tablets; each pack holds 30 tablets.

5 years.

Prescription only (Rx). Vizimpro is a medicinal product subject to restricted medical prescription, started and supervised by a physician experienced in anticancer medicinal products. It is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription.