Lazertinib

Lazertinib is an oral, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR). It selectively inhibits the primary activating EGFR mutations (exon 19 deletions and the exon 21 L858R substitution) and the T790M resistance mutation, while having less activity against wild-type EGFR. It is used together with amivantamab, which is given by infusion. The combination was compared with osimertinib alone in the randomised, open-label phase 3 MARIPOSA study in first-line EGFR-mutated advanced non-small cell lung cancer.

Mechanism of Action

• Irreversible EGFR inhibition: lazertinib forms a covalent bond with the Cys797 residue in the ATP-binding site of the EGFR kinase domain.
• Mutation selectivity: it targets single mutations (exon 19 deletion, L858R, T790M) and double mutations (exon 19 deletion or L858R with T790M), and is less potent against wild-type EGFR.
• Downstream signalling: it blocks the phosphorylation of EGFR and the AKT and ERK signalling pathways and promotes apoptosis of EGFR-mutant lung cancer cells.
• With amivantamab: in a mouse xenograft model of human lung cancer with the L858R mutation, the combination increased antitumour activity compared with either agent alone.
• Exposure–response: paraesthesia and stomatitis appeared to become more frequent as lazertinib exposure rose.
• Cardiac electrophysiology: an exposure–response analysis in 243 patients taking 20 to 320 mg daily found no clinically relevant relationship between plasma concentration and QTc change.

Pharmacokinetics

• Absorption: peak concentration and AUC rise roughly in proportion to dose from 20 to 320 mg. The median time to peak is 2 to 4 hours. Steady state is reached by Day 15 of once-daily dosing, with about 2-fold accumulation at 240 mg. Exposure is similar alone or with amivantamab. A high-fat meal (800–1,000 kcal, about 50% fat) did not change exposure meaningfully, so the tablet can be taken with or without food.
• Distribution: extensive; apparent volume of distribution about 4,264 L at 240 mg. About 99.2% is bound to plasma proteins, and covalent binding to blood and plasma proteins was seen.
• Metabolism: mainly glutathione conjugation (enzymatic through glutathione-S-transferase, or non-enzymatic) and, to a lesser extent, CYP3A4. The main metabolites are glutathione catabolites, considered clinically inactive. Exposure is less than 2-fold lower in patients with non-null GSTM1, and no dose adjustment is needed by GSTM1 status.
• Elimination: at 240 mg, apparent clearance about 44.5 L/h and terminal half-life about 64.7 hours. After a radiolabelled dose, about 86% was recovered in faeces (below 5% unchanged) and 4% in urine (below 0.5% unchanged).
• Enzymes and transporters: repeated doses did not raise metformin exposure, so lazertinib does not inhibit OCT1. In vitro it may inhibit UGT1A1, but no clinically relevant interaction is expected because indirect bilirubin was unaffected.
• Special populations: no dose adjustment for mild, moderate or severe renal impairment (population analysis) or for mild or moderate hepatic impairment. The pharmacokinetics in end-stage renal disease and in severe hepatic impairment are unknown.

• Non-small cell lung cancer (first line): in combination with amivantamab, for adults with advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations.
• EGFR mutation status in tumour tissue or plasma must be established with a validated test before treatment starts.

• Hypersensitivity to lazertinib or to any of the excipients.

The data describe lazertinib given with amivantamab in 421 patients in the MARIPOSA study (median lazertinib exposure 18.5 months). Reactions marked (amivantamab) apply to amivantamab only. The most frequent reactions of any grade were rash (89%), nail toxicity (71%), infusion-related reaction (amivantamab, 63%), hypoalbuminaemia (amivantamab, 48%), hepatotoxicity (47%), oedema (amivantamab, 47%), stomatitis (43%), venous thromboembolism (37%), paraesthesia (34%), fatigue (32%), constipation (29%), diarrhoea (29%), dry skin (26%), decreased appetite (24%), pruritus (24%), hypocalcaemia (21%), other eye disorders (21%) and nausea (21%).

Very common (≥1/10): hypoalbuminaemia (amivantamab), decreased appetite, hypocalcaemia, hypokalaemia, paraesthesia, dizziness, other eye disorders, venous thromboembolism, stomatitis, diarrhoea, constipation, nausea, vomiting, abdominal pain, hepatotoxicity, rash, nail toxicity, dry skin, pruritus, muscle spasms, myalgia, oedema (amivantamab), fatigue, pyrexia, infusion-related reaction (amivantamab).

Common (≥1/100 to <1/10): hypomagnesaemia, visual impairment, keratitis, eyelash growth, interstitial lung disease or pneumonitis, haemorrhoids, palmar-plantar erythrodysaesthesia syndrome, urticaria.

Severe (grade 3–4) events were frequent for several reactions: rash 27%, nail toxicity 11%, venous thromboembolism 11%, hepatotoxicity 9%, infusion-related reaction (amivantamab) 6% and hypoalbuminaemia (amivantamab) 5%.

• Serious reactions: the most frequent were venous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), interstitial lung disease or pneumonitis (2.9%), COVID-19 (2.4%), hepatotoxicity (2.4%), pleural effusion (2.1%), infusion-related reaction (2.1%) and respiratory failure (1.4%).
• Reactions leading to any treatment discontinuation: rash (6%), infusion-related reaction (4.5%), nail toxicity (3.6%), interstitial lung disease or pneumonitis (2.9%), venous thromboembolism (2.9%), pneumonia (1.9%) and oedema (1.7%).

• Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St John’s wort): rifampicin lowered lazertinib Cmax by 72% and AUC by 83%. Avoid the combination.
• Moderate CYP3A4 inducers (bosentan, efavirenz, modafinil): may also lower lazertinib levels; use with caution.
• CYP3A4 inhibitors: itraconazole, a strong inhibitor, raised Cmax 1.19-fold and AUC 1.46-fold. No initial dose adjustment is needed.
• Gastric acid-reducing agents: proton pump inhibitors and H2-receptor antagonists caused no clinically relevant change in exposure. No dose adjustment is needed.
• CYP3A4 and BCRP substrates: lazertinib may raise their plasma concentrations. A sensitive CYP3A4 probe substrate showed a 1.39-fold higher Cmax and 1.47-fold higher AUC. Use with caution with narrow-therapeutic-index CYP3A4 substrates such as ciclosporin, everolimus, pimozide, quinidine, sirolimus and tacrolimus.
• OCT1 and UGT1A1 substrates: no increase in metformin exposure; no clinically relevant UGT1A1 interaction is expected.
• Anticoagulants: for preventing venous thromboembolism with amivantamab, vitamin K antagonists are not recommended (see Special Instructions).
• Food: lazertinib can be taken with or without food.

Treatment should be started by a physician experienced in anticancer medicines, after EGFR mutation-positive status has been confirmed in tumour tissue or plasma by a validated test. If no mutation is found in a plasma sample, tumour tissue should be tested if enough is available, because plasma tests can give false-negative results. Tablets are swallowed whole, with or without food, and must not be crushed, split or chewed.

Recommended Dose

• 240 mg once daily, in combination with amivantamab (dose and schedule in the amivantamab SmPC). On days when both are given, lazertinib is taken at any time before amivantamab.
• Duration: until disease progression or unacceptable toxicity.
• Venous thromboembolism prophylaxis: from the start of treatment with amivantamab, give a direct-acting oral anticoagulant or a low molecular weight heparin; vitamin K antagonists are not recommended.
• Skin and nail prophylaxis: oral and topical antibiotics, a non-comedogenic moisturiser on the face and body (except the scalp) and chlorhexidine solution for washing the hands and feet are recommended; sun exposure should be limited during treatment and for 2 months afterwards.

Dose Adjustments for Side Effects

• Reduction steps: 240 mg, then 160 mg once daily, then 80 mg once daily, then discontinue.
• Interstitial lung disease or pneumonitis: withhold lazertinib and amivantamab if suspected; stop both permanently if confirmed.
• Venous thromboembolism: with clinical instability (for example respiratory failure or cardiac dysfunction), withhold both until the patient is stable, then resume at the same doses. If it recurs despite therapeutic anticoagulation, stop amivantamab permanently and continue lazertinib at the same dose.
• Skin and nail reactions: grade 1, supportive care and reassess after 2 weeks. Grade 2, supportive care; if there is no improvement after 2 weeks, reduce the amivantamab dose, and if still no improvement, reduce lazertinib until grade 1 or below. Grade 3, withhold both; resume at the same dose or reduced (amivantamab first) once grade 2 or below; stop both permanently if there is no improvement within 2 weeks. Grade 4 (including severe bullous, blistering or exfoliating conditions such as toxic epidermal necrolysis), stop amivantamab permanently, hold lazertinib until grade 2 or below, then resume lazertinib at the same dose.
• Hepatotoxicity, grade 3–4: withhold both; once grade 1 or below, resume at the same dose or consider a reduction, amivantamab first.
• Paraesthesia, grade 3–4: supportive care and withhold lazertinib until grade 1 or baseline, then resume at the same or a reduced dose; consider stopping permanently if there is no recovery within 4 weeks.
• Diarrhoea: grade 3, withhold both and resume at the same dose or reduced once grade 1 or below. Grade 4, withhold both and reduce the dose on recovery to grade 1 or below, amivantamab first.
• Stomatitis, grade 3–4: withhold both; resume at the same or a reduced dose once grade 2 or below.
• Other grade 3–4 reactions: withhold both until grade 1 or baseline, then resume one or both, lazertinib first at a reduced dose unless the reaction is strongly linked to lazertinib; consider stopping both permanently if there is no recovery within 4 weeks.

Tablets That Cannot Be Swallowed Whole

• Dispersion in water: place all the tablets for the dose in a small cup, add at least 2 teaspoons (10 mL) of non-carbonated water, and swirl gently until the tablets break into small pieces. Swallow the mixture immediately, then rinse the cup with at least 1 teaspoon (5 mL) of non-carbonated water and drink the rinse immediately.
• Nasogastric tube (8 French or larger): place the uncrushed, unsplit tablets in the barrel of a 20 mL syringe, draw non-carbonated water up to 20 mL, close the tip-cap and leave at room temperature for 5 minutes. Rotate the syringe back and forth 15 times, give the contents immediately through the tube, and flush the tube twice with 10 mL of non-carbonated water.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild, moderate or severe impairment (data in severe impairment are limited). Take care in end-stage renal disease, where the pharmacokinetics are unknown.
• Hepatic impairment: no adjustment in mild or moderate impairment. Take care in severe impairment, where the pharmacokinetics are unknown.
• Children and adolescents: there is no relevant use in the paediatric population for non-small cell lung cancer.

Missed or Vomited Dose

• A missed dose can still be taken within 12 hours. After more than 12 hours, skip it and take the next dose at the usual time.
• If vomiting occurs at any time after taking lazertinib, take the next dose the next day.

Interstitial Lung Disease

Interstitial lung disease or ILD-like reactions such as pneumonitis, including fatal events, have been reported with lazertinib and amivantamab. Patients with a history of ILD, drug-induced ILD, radiation pneumonitis needing steroids or active ILD were excluded from the pivotal study. Patients should be monitored for symptoms such as breathlessness, cough and fever. If symptoms develop, lazertinib is interrupted while they are investigated, and it is stopped permanently if ILD is confirmed.

Venous Thromboembolism

Deep vein thrombosis and pulmonary embolism, including fatal cases, were reported with the combination. Prophylactic anticoagulation (a direct-acting oral anticoagulant or a low molecular weight heparin) is given from the start, and vitamin K antagonists are not recommended. Signs and symptoms should be watched for, and events are treated with anticoagulation as clinically indicated. If a clot is accompanied by clinical instability, treatment is withheld until the patient is stable and both medicines can then resume at the same dose.

Skin and Nail Reactions

Rash (including acneiform dermatitis), pruritus and dry skin are very common. Sun exposure should be limited during treatment and for 2 months afterwards, with protective clothing and a broad-spectrum UVA/UVB sunscreen. A preventive approach is recommended:

• an oral antibiotic such as doxycycline or minocycline 100 mg twice daily from Day 1 for the first 12 weeks;
• afterwards, a topical antibiotic lotion such as clindamycin 1% on the scalp for the next 9 months;
• a non-comedogenic moisturiser on the face and body (except the scalp) and chlorhexidine solution to wash the hands and feet, from Day 1 throughout treatment;
• extra topical or oral antibiotics and topical corticosteroids available at the first dose, so that treatment is not delayed if a rash develops.

If a reaction develops, supportive care, topical corticosteroids and topical or oral antibiotics are used. For grade 3 or poorly tolerated grade 2 events, systemic antibiotics and oral steroids are added and dermatological advice considered. The lazertinib dose is reduced, interrupted or stopped according to severity.

Eye Disorders

Eye disorders, including keratitis, occurred with the combination. Patients with worsening eye symptoms should be referred promptly to an ophthalmologist and should stop wearing contact lenses until the symptoms have been assessed.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for up to 3 weeks afterwards. Male patients with female partners of reproductive potential should use effective contraception (for example a condom) and must not donate or store semen during treatment and for 3 weeks after the last dose.
• Pregnancy: there are no human data. Animal studies showed reproductive toxicity (reduced embryo-foetal survival and foetal body weight), and lazertinib may cause foetal harm. It should not be used in pregnancy unless the benefit to the woman outweighs the risk to the foetus. A patient who becomes pregnant should be told of the risk.
• Breastfeeding: it is unknown whether lazertinib or its metabolites pass into human milk. Because a risk to the child cannot be excluded, women should not breastfeed during treatment and for 3 weeks after the last dose.
• Fertility: there are no human data. Animal studies showed effects on the reproductive organs (fewer oestrus cycles and corpora lutea in females, degenerative testis changes in males), so fertility may be impaired.

Sodium

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

Effect on Driving

Lazertinib has a minor influence on the ability to drive and use machines. Patients with treatment-related symptoms such as fatigue that affect concentration and reaction should not drive or use machines until the effect has passed.

Lazcluze tablets need no special storage conditions. They are supplied in blister packs (PVC–PCTFE film with aluminium foil) and in bottles with child-resistant closures. Keep out of the sight and reach of children.

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

Prescription only (Rx), on restricted medical prescription (Annex II B), started by a physician experienced in anticancer medicines. Lazertinib tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription. They are given together with amivantamab, which is administered by infusion by a healthcare professional.