Gefitinib

Gefitinib is a selective small-molecule inhibitor of the epidermal growth factor receptor (EGFR, also HER1 or ErbB1) tyrosine kinase. EGF and its receptor are key drivers of cell growth and proliferation in normal and cancer cells. An activating EGFR mutation in a cancer cell promotes tumour growth, blocks apoptosis, increases the production of angiogenic factors and facilitates metastasis.

Mechanism of Action

• Kinase inhibition: gefitinib binds the ATP-binding site of the EGFR tyrosine kinase, which blocks receptor phosphorylation and the downstream signalling (including Ras-dependent pathways) that keeps malignant cells growing and surviving.
• Mutation-dependent activity: it is an effective treatment for tumours with activating mutations of the EGFR tyrosine kinase domain, regardless of line of therapy. No clinically relevant activity has been shown in tumours known to be EGFR mutation-negative.
• Sensitising mutations: the common activating mutations (exon 19 deletions and L858R) have robust response data. Data are sparser for the less common mutations; G719X and L861Q are sensitising, whereas T790M alone or exon 20 insertions alone are resistance mechanisms.
• Acquired resistance: most tumours with sensitising mutations eventually become resistant, with a median time to progression of about 1 year. In about 60% of cases resistance is linked to a secondary T790M mutation, for which T790M-targeted EGFR inhibitors may be considered as the next treatment. Other reported mechanisms include bypass signalling such as HER2 or MET amplification and PIK3CA mutations.

Pharmacokinetics

• Absorption: moderately slow, with peak concentrations 3 to 7 hours after a dose. Mean absolute bioavailability is 59% in cancer patients, and food does not significantly alter exposure. When gastric pH was kept above 5, exposure fell by 47%.
• Distribution: volume of distribution at steady state about 1,400 L, indicating extensive tissue distribution; about 90% bound to plasma proteins (serum albumin and α1-acid glycoprotein). Gefitinib is a P-gp substrate in vitro.
• Metabolism: extensive, mainly through CYP3A4 and CYP2D6. The major metabolite, O-desmethyl gefitinib (formed via CYP2D6), is 14-fold less potent than gefitinib and is unlikely to contribute to its clinical activity. In CYP2D6 poor metabolisers, mean gefitinib exposure was 2-fold higher.
• Elimination: excreted mainly as metabolites in faeces; less than 4% of the dose is eliminated by the kidneys. Total plasma clearance is about 500 mL/min and the mean terminal half-life 41 hours in cancer patients. Once-daily dosing leads to 2- to 8-fold accumulation, with steady state after 7 to 10 doses.
• Special populations: age, body weight, sex, ethnicity and creatinine clearance (above 20 mL/min) did not affect trough concentrations. In cirrhosis with moderate or severe hepatic impairment, exposure rose on average 3.1-fold; in liver impairment due to liver metastases, exposure was similar to that with normal liver function.

• Non-small cell lung cancer: monotherapy for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK.
• When treatment is considered, EGFR mutation assessment of the tumour tissue should be attempted in every patient. If a tumour sample cannot be evaluated, circulating tumour DNA (ctDNA) from a blood (plasma) sample may be used. Only robust, reliable and sensitive tests with demonstrated utility should be used, to avoid false negative or false positive results.

• Hypersensitivity to gefitinib or to any of the excipients.
• Breastfeeding.

In the pooled phase III studies ISEL, INTEREST and IPASS (2,462 gefitinib-treated patients), the reactions reported in more than 20% of patients were diarrhoea and skin reactions (rash, acne, dry skin, pruritus). They usually appear in the first month and are generally reversible. About 8% of patients had a severe reaction (grade 3 or 4) and about 3% stopped treatment because of one. Interstitial lung disease occurred in 1.3% of patients, often severe, and some cases were fatal.

Very common (≥1/10): anorexia (mild or moderate), diarrhoea, vomiting and nausea (mainly mild or moderate), stomatitis (predominantly mild), raised ALT (mainly mild to moderate), skin reactions (mainly mild or moderate pustular rash, sometimes with itching and dry, fissured skin on a reddened base), asthenia (predominantly mild).

Common (≥1/100 to <1/10): conjunctivitis, blepharitis and dry eye (mainly mild), haemorrhage such as epistaxis and haematuria, interstitial lung disease (1.3%, often grade 3–4, with fatal cases), dehydration secondary to diarrhoea, nausea, vomiting or anorexia, dry mouth, raised AST and total bilirubin (mainly mild to moderate), nail disorder, alopecia, allergic reactions (1.1%) including angioedema and urticaria, asymptomatic rises in blood creatinine, proteinuria, cystitis, pyrexia.

Uncommon (≥1/1,000 to <1/100): corneal erosion (reversible, sometimes with aberrant eyelash growth), keratitis (0.12%), pancreatitis, gastrointestinal perforation, hepatitis (including isolated reports of hepatic failure, some fatal), palmar-plantar erythrodysaesthesia syndrome.

Rare (≥1/10,000 to <1/1,000): bullous conditions including toxic epidermal necrolysis, Stevens–Johnson syndrome and erythema multiforme, cutaneous vasculitis, haemorrhagic cystitis.

The most important serious reactions are interstitial lung disease, liver toxicity (including hepatitis and hepatic failure), gastrointestinal perforation, severe bullous skin reactions and keratitis.

Gefitinib is metabolised mainly by CYP3A4 and also by CYP2D6.

• CYP3A4 inducers (phenytoin, carbamazepine, rifampicin, barbiturates, St John’s wort): they lower gefitinib levels and may reduce efficacy; rifampicin reduced mean gefitinib AUC by 83%. Avoid these combinations.
• Potent CYP3A4 inhibitors (ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin): they may raise gefitinib levels, and the rise may be clinically relevant because reactions are dose-related; itraconazole increased mean AUC by 80%. Monitor closely for adverse reactions, especially in CYP2D6 poor metabolisers.
• Potent CYP2D6 inhibitors: there are no data, but they might raise gefitinib levels about 2-fold in extensive metabolisers; monitor closely for adverse reactions.
• Medicines that raise gastric pH (proton pump inhibitors, H2-antagonists, and antacids taken regularly close to gefitinib): they may reduce gefitinib absorption and efficacy. Ranitidine at a dose causing sustained gastric pH of 5 or more reduced mean AUC by 47%.
• Warfarin: raised INR and/or bleeding have been reported; prothrombin time or INR should be monitored regularly.
• CYP2D6 substrates: gefitinib raised metoprolol exposure by 35%. A dose change should be considered for CYP2D6 substrates with a narrow therapeutic window.
• Vinorelbine: gefitinib may worsen its neutropenic effect.
• Transporters: gefitinib inhibits BCRP in vitro; the clinical relevance is unknown.
• Food: tablets can be taken with or without food. Grapefruit products inhibit CYP3A4 and may raise gefitinib levels; use caution.

Treatment should be started and supervised by a physician experienced in the use of anti-cancer therapies. The indication applies to tumours with activating EGFR mutations; see Special Instructions for the testing requirements.

Recommended Dose

• One 250 mg tablet once daily, with or without food, at about the same time each day.

Dose Adjustments for Side Effects

• Diarrhoea or skin reactions that are poorly tolerated can be managed with a short interruption (up to 14 days), then the 250 mg dose is restarted. If treatment still cannot be tolerated after an interruption, gefitinib should be stopped and an alternative treatment considered.
• Interstitial lung disease: interrupt for worsening breathlessness, cough or fever and investigate promptly; stop if the diagnosis is confirmed.
• Liver: periodic liver function tests are recommended; use cautiously in mild to moderate changes and consider stopping if changes are severe.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no dose adjustment when creatinine clearance is above 20 mL/min. Data are limited at lower clearance and caution is advised.
• Hepatic impairment: patients with moderate to severe impairment (Child-Pugh B or C) due to cirrhosis have higher gefitinib levels and should be monitored closely for adverse events. Levels were not raised when AST, alkaline phosphatase or bilirubin were increased because of liver metastases.
• CYP2D6 poor metabolisers: no specific dose adjustment, but close monitoring for adverse events.
• Children and adolescents: safety and efficacy below 18 years have not been established; there is no relevant use of gefitinib in children for NSCLC.

Method of Administration

The tablet is swallowed whole with some water. If whole tablets cannot be taken, they may be dispersed in half a glass of still drinking water, without crushing: swirl the glass occasionally until the tablet has dispersed (up to 20 minutes), drink it immediately (within 60 minutes), then rinse the glass with half a glass of water and drink that too. No other liquids should be used. The dispersion can also be given through a naso-gastric or gastrostomy tube.

Missed Dose

Take it as soon as it is remembered. If it is less than 12 hours to the next dose, skip the missed dose. Never take a double dose to make up for a forgotten one.

EGFR Mutation Testing

Because the indication requires activating EGFR mutations, EGFR mutation assessment of the tumour tissue should be attempted in all patients when gefitinib is considered. Circulating tumour DNA from blood may be used if no tumour sample can be evaluated. Only robust, reliable and sensitive tests should be used.

Interstitial Lung Disease

Interstitial lung disease, which can start acutely, was seen in 1.3% of patients and some cases were fatal. Worsening respiratory symptoms (breathlessness, cough, fever) call for interruption and prompt investigation; if the disease is confirmed, gefitinib is stopped and the patient treated appropriately. In a Japanese case-control study, risk factors for interstitial lung disease with either gefitinib or chemotherapy were smoking, poor performance status, CT evidence of reduced normal lung (50% or less), NSCLC diagnosed within the previous 6 months, pre-existing interstitial lung disease, age 55 or older and concurrent heart disease. The excess risk with gefitinib compared with chemotherapy was seen mostly in the first 4 weeks.

Liver Function

Abnormal liver tests (raised ALT, AST, bilirubin) have been seen, uncommonly as hepatitis, and there have been isolated reports of hepatic failure, some fatal. Liver function should be tested periodically. Cirrhosis raises gefitinib levels.

Diarrhoea, Eyes and Gastrointestinal Perforation

• Patients should seek medical advice at once for severe or persistent diarrhoea, nausea, vomiting or anorexia, which can lead to dehydration.
• Signs of keratitis (acute or worsening eye inflammation, tearing, light sensitivity, blurred vision, eye pain or red eye) need prompt referral to an ophthalmologist. If ulcerative keratitis is confirmed, gefitinib is interrupted, and permanent discontinuation should be considered if symptoms do not resolve or return.
• Gastrointestinal perforation has been reported, mostly with other risk factors such as steroids or NSAIDs, a history of ulceration, age, smoking or bowel metastases at the site of perforation.
• In a trial of gefitinib with radiotherapy in children with brain tumours, central nervous system haemorrhage occurred in 4 of 45 patients (1 fatal). An increased risk of cerebral haemorrhage in adults with NSCLC has not been established.

Interacting Medicines

Avoid CYP3A4 inducers; monitor closely with CYP3A4 or CYP2D6 inhibitors, particularly in CYP2D6 poor metabolisers. Monitor INR in patients taking warfarin. Medicines that sustainably raise gastric pH, such as proton pump inhibitors and H2-antagonists, may reduce efficacy, as may regularly taken antacids close to the gefitinib dose.

Pregnancy and Breastfeeding

• Pregnancy: women of childbearing potential must be advised not to become pregnant during treatment. There are no data in pregnant women and animal studies showed reproductive toxicity; gefitinib should not be used in pregnancy unless clearly necessary.
• Breastfeeding: gefitinib is contraindicated during breastfeeding, which must be stopped during treatment. It is not known whether gefitinib passes into human milk, but it accumulated in the milk of lactating rats.

Lactose and Sodium

Each tablet contains lactose (163.5 mg as 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

Asthenia has been reported. Patients who experience it should be cautious when driving or using machines.

Store in the original package to protect from moisture. No temperature limit is stated. The tablets are in PVC/aluminium blisters (perforated or non-perforated) of 10 tablets; three blisters are combined with an aluminium foil laminate overwrap in a carton of 30 tablets (not all pack sizes may be marketed).

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

Prescription only (Rx). Iressa is subject to restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in the use of anti-cancer therapies. The tablets are taken at home, so the product is supplied to the patient or to the treating clinic on prescription.