Osimertinib

Osimertinib is a tyrosine kinase inhibitor (TKI) that irreversibly inhibits EGFR carrying sensitising mutations (EGFRm) and the T790M mutation, which makes tumours resistant to earlier EGFR inhibitors. In cell studies it was potent against all clinically relevant sensitising-mutant and T790M-mutant NSCLC cell lines and far less active against wild-type EGFR. Sparing wild-type EGFR is expected to limit toxicity.

Mechanism of Action

• Irreversible inhibition: osimertinib is a third-generation EGFR TKI. It inhibits mutant EGFR, including the T790M gatekeeper mutation, which increases ATP binding by the receptor and is linked to resistance to earlier EGFR inhibitors.
• Selectivity: the apparent IC50 values against phosphorylated EGFR were 6–54 nM in mutant cell lines and 480 nM–1.8 µM in wild-type cell lines, so osimertinib is much less active against wild-type EGFR in vitro.
• Antitumour activity: oral osimertinib shrank tumours in EGFRm and T790M xenograft and transgenic mouse lung tumour models.
• Active metabolites: AZ7550 has a pharmacological profile similar to osimertinib, and AZ5104 is more potent against both mutant and wild-type EGFR. Each circulates at about 10% of the parent drug’s exposure at steady state.
• Cardiac electrophysiology: a pharmacokinetic/pharmacodynamic analysis predicted a concentration-dependent QTc prolongation of 14 ms at 80 mg (upper bound of the 90% confidence interval, 16 ms).

Pharmacokinetics

• Absorption: median time to peak 6 hours (range 3–24), sometimes with several peaks in the first 24 hours. Absolute bioavailability is 70%. Food does not change it to a clinically meaningful extent (AUC up 6%, Cmax down 7%), and omeprazole did not affect exposure. Exposure rises in proportion to dose over 20 to 240 mg; once-daily dosing leads to about 3-fold accumulation, with steady state reached by 15 days.
• Distribution: volume of distribution at steady state is 918 L, indicating extensive tissue distribution. Plasma protein binding in vitro is 94.7%. In a PET study, osimertinib crossed the blood–brain barrier rapidly, and the brain-to-plasma ratio was similar in patients with brain metastases and in healthy volunteers.
• Metabolism: predominantly by CYP3A4 and CYP3A5, mainly through oxidation and dealkylation. The two active metabolites appear slowly (median time to peak 24 hours).
• Elimination: apparent clearance is 14.3 L/h and terminal half-life about 44 hours. After a single 20 mg dose, 67.8% was recovered in faeces and 14.2% in urine; unchanged osimertinib accounted for about 2% of elimination.
• Special populations: age (25–91 years), sex, ethnicity, line of therapy and smoking status have no clinically significant effect on exposure, and the small effects of body weight and serum albumin are not clinically relevant. Mild or moderate hepatic impairment did not raise exposure. In a single-dose study, severe renal impairment (creatinine clearance 15 to under 30 mL/min) raised AUC 1.85-fold, whereas a population analysis found similar exposure across renal function groups. There are no data in severe hepatic impairment.

Osimertinib as monotherapy is indicated for adults with non-small cell lung cancer (NSCLC) as follows:

• Adjuvant treatment: after complete tumour resection in stage IB–IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.
• Locally advanced, unresectable NSCLC: tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, where the disease has not progressed during or following platinum-based chemoradiation therapy.
• First-line treatment: locally advanced or metastatic NSCLC with activating EGFR mutations.
• T790M-positive disease: locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

Osimertinib is also indicated in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adults with advanced NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

• Hypersensitivity to osimertinib or to any of the excipients.
• St John’s wort must not be used together with osimertinib.

Pooled safety data come from 1,956 patients with EGFR mutation-positive NSCLC who took 80 mg daily as monotherapy in phase 1 to 3 studies, and from 276 patients given osimertinib with pemetrexed and platinum-based chemotherapy. Most reactions were grade 1 or 2. With monotherapy the most commonly reported were diarrhoea (46%), rash (45%), paronychia (33%), dry skin (31%) and stomatitis (23%). Grade 3 and grade 4 reactions occurred in 11% and 0.2% of patients; 3.4% needed a dose reduction and 5.5% stopped treatment because of adverse reactions. With chemotherapy the most common were rash (49%), diarrhoea (43%), decreased appetite (31%), stomatitis (31%), paronychia (27%) and dry skin (24%).

Very common (≥1/10): decreased appetite, diarrhoea, stomatitis, rash, paronychia, dry skin, pruritus; and, as laboratory findings, decreased white blood cell, lymphocyte, platelet and neutrophil counts. With pemetrexed and platinum-based chemotherapy, thrombocytopenia, neutropenia, leukopenia and raised blood creatinine are also very common.

Common (≥1/100 to <1/10): thrombocytopenia, neutropenia, leukopenia, lymphopenia, epistaxis, interstitial lung disease, radiation pneumonitis, alopecia, palmar-plantar erythrodysaesthesia syndrome, urticaria, decreased left ventricular ejection fraction, increased blood creatine phosphokinase, QTc interval prolongation, raised blood creatinine. With chemotherapy, heart failure, skin hyperpigmentation and erythema multiforme are also common.

Uncommon (≥1/1,000 to <1/100): keratitis, heart failure, skin hyperpigmentation, erythema multiforme, cutaneous vasculitis, myositis.

Rare (≥1/10,000 to <1/1,000): aplastic anaemia, Stevens-Johnson syndrome.

Not known: hepatitis B reactivation, eosinophilic pneumonia, toxic epidermal necrolysis (reported after marketing).

Interstitial lung disease (ILD) or ILD-like reactions occurred in 4.3% of the 1,956 patients on monotherapy, with eight fatal cases and none in the adjuvant setting; incidence was 10.4% in Japanese patients, and the median time to onset was 85 days. After platinum-based chemoradiation, radiation pneumonitis occurred in 48% of osimertinib patients and 38% of placebo patients, with grade 3 events in 2.1%, all in the osimertinib group. A QTc above 500 ms was found in 1.1% of patients on monotherapy. Diarrhoea was mostly grade 1 or 2, with grade 3 in 1.5%.

Osimertinib is metabolised mainly by CYP3A4 and CYP3A5, and it can raise the exposure of some BCRP and P-glycoprotein substrates.

• Strong CYP3A inducers (phenytoin, rifampicin, carbamazepine): avoid. Rifampicin cut steady-state osimertinib exposure (AUC) by 78%, and that of the AZ5104 metabolite by 82%.
• Moderate CYP3A4 inducers (bosentan, efavirenz, etravirine, modafinil): may also lower exposure; use with caution or avoid when possible. No clinical data are available to recommend a dose adjustment.
• St John’s wort: contraindicated.
• CYP3A4 inhibitors: itraconazole, a strong inhibitor, had no clinically significant effect (AUC up 24%, Cmax down 20%), so CYP3A4 inhibitors are not likely to affect osimertinib exposure.
• Gastric acid-reducing medicines: omeprazole did not cause clinically relevant changes, so these can be used without restriction.
• BCRP substrates: rosuvastatin AUC rose 35% and Cmax 72%. Patients taking BCRP-dependent medicines with a narrow therapeutic index should be monitored for changed tolerability.
• P-gp substrates: fexofenadine AUC and Cmax rose by 56% and 76% after a single dose and by 27% and 25% at steady state. Patients taking P-gp-dependent medicines with a narrow therapeutic index (for example digoxin, dabigatran, aliskiren) should be monitored closely.
• CYP3A4 substrates: simvastatin exposure fell slightly (AUC 9%, Cmax 23%), so clinically relevant interactions are unlikely.
• Hormonal contraceptives: a reduced exposure to hormonal contraceptives cannot be excluded.
• Food: osimertinib can be taken with or without food. St John’s wort should be avoided.

Treatment should be started by a physician experienced in the use of anticancer therapies. EGFR mutation status must be determined with a validated test before treatment (see Special Instructions). The tablet is taken at the same time each day, with or without food.

Recommended Dose

• 80 mg once daily, as monotherapy or together with pemetrexed and platinum-based chemotherapy (pemetrexed, cisplatin and carboplatin are dosed according to their own SmPCs).
• Adjuvant treatment: until disease recurrence or unacceptable toxicity. Treatment for more than 3 years was not studied.
• Locally advanced or metastatic disease: until disease progression or unacceptable toxicity.

Method of Administration

The tablet is swallowed whole with water and is not crushed, split or chewed. If the patient cannot swallow it, the tablet can be dropped without crushing into 50 mL of non-carbonated water, stirred until dispersed and swallowed at once; half a glass of water is then added to rinse out any residue and swallowed as well. No other liquids should be added. The same method can be used for a nasogastric tube, with 15 mL of water for the dispersion and 15 mL for the rinses, and the 30 mL given within 30 minutes of adding the tablets to water.

Dose Adjustments for Side Effects

If a dose reduction is needed, the dose is lowered to 40 mg once daily. The main recommendations in the SmPC are:

• Interstitial lung disease or pneumonitis: stop permanently.
• Radiation pneumonitis after platinum-based chemoradiation: grade 1, consider withholding or continue as clinically indicated; grade 2, withhold until symptoms resolve and then restart, but stop permanently if symptoms do not resolve within 4 weeks or if grade 2 recurs; grade 3 or 4, stop permanently.
• QTc interval above 500 ms on at least 2 separate ECGs: withhold until the QTc is below 481 ms, or back to baseline if the baseline was 481 ms or more, then restart at 40 mg. Stop permanently if QTc prolongation comes with signs or symptoms of serious arrhythmia.
• Stevens-Johnson syndrome, toxic epidermal necrolysis or aplastic anaemia: stop permanently.
• Any other grade 3 or higher adverse reaction: withhold for up to 3 weeks. If it improves to grade 0–2 within that time, restart at 80 mg or 40 mg; if it does not, stop permanently.
• In combination with chemotherapy: each component can be dose-modified as appropriate, and cisplatin and/or carboplatin are used for up to 4 cycles.

Special Populations

• Age, body weight, sex, ethnicity and smoking status: no dose adjustment.
• Hepatic impairment: no adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. Safety and efficacy have not been established in severe impairment, so use is not recommended until more data are available.
• Renal impairment: no adjustment in mild, moderate or severe impairment. Safety and efficacy have not been established in end-stage renal disease (creatinine clearance below 15 mL/min) or on dialysis; use caution in severe and end-stage impairment.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed Dose

A missed dose is made up unless the next dose is due within 12 hours.

EGFR Mutation Testing

EGFR mutation status must be confirmed with a validated test before treatment. Tumour tissue DNA is used for adjuvant treatment and for unresectable locally advanced disease after chemoradiation; tumour tissue or circulating tumour DNA from plasma may be used in locally advanced or metastatic disease. If a plasma test is negative, a tissue test should follow where possible, because plasma tests can give false negative results.

Interstitial Lung Disease

Severe, life-threatening or fatal interstitial lung disease (ILD) or ILD-like reactions such as pneumonitis have occurred, including after definitive platinum-based chemoradiation. Most cases improved or resolved after treatment was interrupted. Any patient with an acute onset or unexplained worsening of breathlessness, cough or fever should be assessed for ILD, and treatment is interrupted during the work-up. If ILD is diagnosed, osimertinib is stopped; restarting should be considered only after careful weighing of benefit and risk. Radiation pneumonitis is usually seen for up to a year after lung radiotherapy. Patients with a history of ILD, drug-induced ILD, radiation pneumonitis needing steroids, or clinically active ILD were excluded from the studies.

QTc Interval Prolongation

QTc prolongation occurs and may raise the risk of ventricular tachyarrhythmias (such as torsade de pointes) or sudden death, although no QTc-related arrhythmias were reported in the studies. Use should be avoided where possible in congenital long QT syndrome. Periodic ECG and electrolyte monitoring should be considered in patients with congestive heart failure, electrolyte abnormalities or medicines known to prolong the QTc interval. Patients with clinically important rhythm or conduction abnormalities (for example a QTc above 470 ms) were excluded from the studies.

Changes in Cardiac Contractility

Left ventricular ejection fraction (LVEF) fell by at least 10 percentage points to below 50% in 4.2% (65 of 1,557) of monotherapy patients with a follow-up assessment, and in 8.0% (21 of 262) of those who also received chemotherapy. Cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered in patients with cardiac risk factors or conditions that can affect LVEF.

Keratitis

Keratitis occurred in 0.6% of patients on monotherapy. Patients with acute or worsening eye inflammation, tearing, light sensitivity, blurred vision, eye pain or a red eye should be referred promptly to an ophthalmology specialist.

Severe Skin Reactions

Stevens-Johnson syndrome (rare) and toxic epidermal necrolysis (frequency not known) have been reported. Patients should be told the signs before starting; treatment is interrupted if they appear and stopped at once if either condition is diagnosed.

Aplastic Anaemia

Rare cases of aplastic anaemia, including fatal ones, have been reported. Patients should know the warning signs (persistent fever, bruising, bleeding, pallor, infection, fatigue). If they develop, close monitoring and interruption or discontinuation should be considered, and osimertinib is stopped in confirmed aplastic anaemia.

Skeletal Muscle Toxicity

Myositis has been reported, and rhabdomyolysis after marketing. Patients should report unexplained muscle pain, tenderness or weakness, trouble moving the arms or legs, dark tea-coloured urine or reduced urination.

Elderly Patients and Low Body Weight

Patients over 65 years of age or under 50 kg may be at higher risk of grade 3 or higher adverse events and should be monitored closely.

Hepatitis B Reactivation

Hepatitis B virus can reactivate, sometimes causing fulminant hepatitis, liver failure and death. Patients with positive hepatitis B serology should be monitored for clinical and laboratory signs of reactivation. If it occurs, osimertinib is withheld and the patient is managed according to local guidelines.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant. Effective contraception should be used for at least 2 months after the last dose by women and 4 months by men. A reduced effect of hormonal contraceptives cannot be excluded.
• Pregnancy: there are few or no data in pregnant women. Animal studies showed reproductive toxicity (embryo lethality, reduced foetal growth and neonatal death), and osimertinib may cause foetal harm. It should not be used in pregnancy unless the woman’s clinical condition requires treatment.
• Breastfeeding: it is unknown whether osimertinib or its metabolites pass into human milk. They were found in suckling rat pups, which grew poorly and survived less well, so a risk to the suckling child cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: there are no human data. Animal studies show effects on male and female reproductive organs, and fertility could be impaired.

Sodium

Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Osimertinib has no or negligible influence on the ability to drive and use machines.

Tagrisso tablets do not require any special storage conditions. They are supplied in aluminium/aluminium perforated unit-dose blisters, in cartons of 30 × 1 tablets (3 blisters) or 28 × 1 tablets (4 blisters); not all pack sizes may be marketed. Keep out of the sight and reach of children.

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

Prescription only (Rx), subject to restricted medical prescription: treatment is started by a physician experienced in the use of anticancer therapies. Osimertinib is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.