Leaflet LAZCLUZE 240mg film-coated tablets
Indicated for: non-small cell lung cancer
Route of administration: oral
Substance: lazertinib (antineoplastic agent)
ATC: L01EB09 (Antineoplastic and immunomodulating agents | Protein kinase inhibitors | Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors)
This medicine may affect fertility.
Dose adjustment may be needed in liver disease.
Handle with special care.
Effective contraception is required during treatment.
Do not use this medicine while breastfeeding.
Do not use this medicine during pregnancy.
This medicine may affect the liver.
This medicine may have important interactions with other medicines.
This medicine may lower blood cell counts.
This medicine is subject to additional monitoring.
Periodic laboratory tests may be required during treatment.
Stop taking the medicine and seek urgent medical help if a severe rash occurs.
Lazertinib is an anticancer medicine used for locally advanced or metastatic non-small cell lung cancer with specific EGFR mutations, such as exon 19 deletion or the exon 21 L858R mutation. It is commonly given together with amivantamab as part of a targeted treatment plan.
The medicine is an EGFR inhibitor and blocks signals that help tumour cells grow. For patients, genetic testing of the cancer is essential before treatment starts. The choice of therapy also depends on overall health, previous treatments and the expected risk of side effects.
Lazertinib is taken by mouth once daily, exactly as prescribed. Because use with amivantamab can increase the risk of blood clots, your doctor may recommend preventive measures and close monitoring. Do not start new medicines, including supplements, without telling your oncology team.
Side effects may include rash, itching, dry skin, nail problems, diarrhoea, mouth inflammation, tiredness, swelling, muscle pain and abnormal liver tests. Seek urgent medical help for chest pain, shortness of breath, a new or worsening cough, swelling in one leg, or sudden neurological symptoms.
General data about LAZCLUZE 240mg
- Substance: lazertinib
- Date of latest medicines list: 01-11-2025
- Product code: W71423001
- Concentration: 240mg
- Pharmaceutical form: film-coated tablets
- Quantity: 14
- Product type: Original
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Concentrations available for lazertinib
- 240mg
- 80mg
Leaflet LAZCLUZE 240mg
Contents of the package leaflet for the medicine LAZCLUZE 240mg film-coated tablets
1. NAME OF THE MEDICINAL PRODUCT
Lazcluze 80 mg film-coated tablets
Lazcluze 240 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Lazcluze 80 mg film-coated tablets
Each film-coated tablet contains 80 mg lazertinib (as mesylate monohydrate).
Lazcluze 240 mg film-coated tablets
Each film-coated tablet contains 240 mg lazertinib (as mesylate monohydrate).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Lazcluze 80 mg film-coated tablets
Yellow, 14 mm, oval tablet, debossed with “LZ” on one side and “80” on the other side.
Lazcluze 240 mg film-coated tablets
Reddish purple, 20 mm, oval tablet, debossed with “LZ” on one side and “240” on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Lazcluze in combination with amivantamab is indicated for the first-line treatment of adult patientswith advanced non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858Rsubstitution mutations.
4.2 Posology and method of administration
Treatment with Lazcluze should be initiated by a physician experienced in the use of anticancermedicinal products.
Before initiation of Lazcluze, EGFR mutation-positive status in tumour tissue or plasma specimensmust be established using a validated test method. If no mutation is detected in a plasma specimen,tumour tissue should be tested if available in sufficient amount and quality due to the potential forfalse negative results using a plasma test.
PosologyThe recommended dose of Lazcluze is 240 mg once daily in combination with amivantamab.
It is recommended to administer Lazcluze any time prior to amivantamab when given on the sameday. Refer to section 4.2 of the amivantamab Summary of Product Characteristics for recommendedamivantamab dosing information.
Venous thromboembolic (VTE) events with concomitant use with amivantamab
At the initiation of treatment, prophylactic anticoagulants should be administered to prevent venousthromboembolic (VTE) events in patients receiving Lazcluze in combination with amivantamab.
Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct actingoral anticoagulant (DOAC) or a low molecular weight heparin (LMWH). Use of Vitamin Kantagonists is not recommended.
Skin and nail reactions
Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severityof skin and nail reactions in patients receiving Lazcluze in combination with amivantamab. Non-comedogenic skin moisturiser (ceramide-based or other formulations that provide long-lasting skinhydration and exclude drying agents are preferred) on the face and whole body (except scalp) andchlorhexidine solution to wash hands and feet is also recommended. Patients should be instructed tolimit sun exposure during and for 2 months after Lazcluze combination therapy. For furtherinformation about prophylaxis for skin and nail reactions, see section 4.4.
Duration of treatmentTreatment should continue until disease progression or unacceptable toxicity.
Missed doseIf a planned dose of Lazcluze is missed, it can be administered within 12 hours. If more than 12 hourshave passed since the dose was to be given, the missed dose should not be administered and the nextdose should be administered per the usual dosing schedule.
Dose modificationsThe recommended dose reductions for adverse reactions are presented in Table 1.
Table 1: Recommended Lazcluze dose reductions for adverse reactions
Dose reduction Recommended dose
Initial dose 240 mg once daily1st dose reduction 160 mg once daily2nd dose reduction 80 mg once daily3rd dose reduction Discontinue Lazcluze
Dose modifications for specific adverse reactions are presented in Table 2.
Refer to section 4.2 of the amivantamab Summary of Product Characteristics for information aboutdose modifications for amivantamab.
Table 2: Recommended Lazcluze and amivantamab dose modifications for adversereactions*
Adverse reaction Severity Dose modification
Interstitial lung disease Any grade - Withhold Lazcluze and(ILD)/pneumonitis amivantamab if ILD/pneumonitis issuspected.
- Permanently discontinue Lazcluzeand amivantamab if
ILD/pneumonitis is confirmed.
Venous thromboembolic Events with clinical - Withhold Lazcluze and(VTE) events (see instability (e.g., amivantamab until the patient issection 4.4) respiratory failure or clinically stable. Thereafter, bothcardiac dysfunction) medicinal products can be resumedat the same dose.
Recurrent VTE event - Permanently discontinuedespite therapeutic level amivantamab. Treatment cananticoagulation continue with Lazcluze at the samedose.
Skin and nail reactions Grade 1 - Supportive care should be initiated(see section 4.4) as clinically indicated.
- Reassess after 2 weeks.
Grade 2 - Supportive care should be initiatedas clinically indicated.
- If there is no improvement after2 weeks, reduce amivantamab doseand continue Lazcluze.
- Reassess every 2 weeks, if noimprovement, reduce Lazcluze doseuntil ≤ Grade 1 (Table 1).
Grade 3 - Supportive care should be initiatedas clinically indicated.
- Withhold Lazcluze andamivantamab.
- Upon recovery to ≤ Grade 2, resumeboth medicinal products at the samedose or consider dose reduction,preferentially reducing the dose ofamivantamab first.
- If there is no improvement within2 weeks, permanently discontinueboth Lazcluze and amivantamab.
Grade 4 (including severe - Permanently discontinuebullous, blistering or amivantamab and hold Lazcluze.exfoliating skin - Withhold Lazcluze until ≤ Grade 2conditions, e.g., Toxic or baseline.epidermal necrolysis) - Upon recovery to ≤ Grade 2, resume
Lazcluze at the same dose.
Hepatotoxicity Grade 3-4 - Withhold Lazcluze andamivantamab.
- Upon recovery to ≤ Grade 1, resumeboth medicinal products at the samedose or consider dose reduction,preferentially reducing the dose ofamivantamab first.
Paraesthesia Grade 3-4 - Supportive care should be initiated.
- Withhold Lazcluze until ≤ Grade 1or baseline. Resume Lazcluze at thesame dose or consider dosereduction.
- Consider permanently discontinuing
Lazcluze if recovery does not occurwithin 4 weeks.
Diarrhoea Grade 3 - Supportive care should be initiated.
- Withhold Lazcluze andamivantamab.
- Upon recovery to ≤ Grade 1, resumeboth medicinal products at the samedose or consider dose reduction,preferentially reducing the dose ofamivantamab first.
Grade 4 - Supportive care should be initiated.
- Withhold Lazcluze andamivantamab.
- Upon recovery to ≤ Grade 1, reducethe dose, preferentially reducing thedose of amivantamab first.
Stomatitis Grade 3-4 - Withhold Lazcluze andamivantamab.
- Upon recovery to ≤ Grade 2, resumeboth medicinal products at the samedose or consider dose reduction,preferentially reducing the dose ofamivantamab first.
Other adverse reactions Grade 3-4 - Withhold Lazcluze andamivantamab until the adversereaction resolves to ≤ Grade 1 orbaseline.
- Resume one or both medicinalproducts, preferentially resuming
Lazcluze first at a reduced dose,unless the adverse reaction isstrongly suspected to be related to
Lazcluze.
- Consider permanently discontinuingboth Lazcluze and amivantamab ifrecovery does not occur within4 weeks.
* Refer to section 4.2 of the amivantamab Summary of Product Characteristics for recommended amivantamab dosinginformation.
Special populationsElderly
No dose adjustment is required (see sections 4.8, 5.1 and 5.2).
Renal impairmentBased on population pharmacokinetics (PK) analysis, no dose adjustment is required for patients withmild, moderate or severe renal impairment. Data in patients with severe renal impairment are limited.
The PK of lazertinib in patients with end stage renal disease is unknown. Caution is required inpatients with end-stage renal disease (see section 5.2).
Hepatic impairmentNo dose adjustment is required for patients with mild or moderate hepatic impairment. The PK oflazertinib in patients with severe hepatic impairment is unknown. Caution is required in patients withsevere hepatic impairment (see section 5.2).
Paediatric populationThere is no relevant use of lazertinib in the paediatric population for the treatment of non-small celllung cancer.
Method of administrationLazcluze is for oral use. The tablets should be swallowed whole with or without food. Tablets shouldnot be crushed, split, or chewed.
If vomiting occurs any time after taking Lazcluze, the next dose should be taken the next day.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Interstitial lung disease/pneumonitis
Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis), including fatal events,have been reported in patients treated with lazertinib and amivantamab (see section 4.8). Patients witha medical history of ILD, drug‑induced ILD, radiation pneumonitis that required steroid treatment, orany evidence of clinically active ILD were excluded from the pivotal clinical study.
Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough,fever). If symptoms develop, treatment with Lazcluze should be interrupted pending investigation ofthese symptoms. Suspected ILD or ILD-like adverse reactions should be evaluated and appropriatetreatment should be initiated as necessary. Lazcluze should be permanently discontinued in patientswith confirmed ILD or ILD-like adverse reactions (see section 4.2).
Venous thromboembolic (VTE) events
In patients receiving Lazcluze in combination with amivantamab, venous thromboembolic (VTE)events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events,were reported (see section 4.8). Consistent with clinical guidelines, patients should receiveprophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weightheparin (LMWH). Use of Vitamin K antagonists is not recommended.
Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treatedwith anticoagulation as clinically indicated. For VTE events associated with clinical instability,treatment should be withheld until the patient is clinically stable. Thereafter, both medicinal productscan be resumed at the same dose.
In the event of recurrence despite appropriate anticoagulation, amivantamab should be discontinued.
Treatment can continue with Lazcluze at the same dose (see section 4.2).
Skin and nail reactions
Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with lazertinibin combination with amivantamab (see section 4.8). Patients should be instructed to limit sun exposureduring and for 2 months after Lazcluze combination therapy. Protective clothing and use ofbroad-spectrum UVA/UVB sunscreen are advisable. A prophylactic approach to rash prevention isrecommended. This includes prophylactic therapy, at treatment initiation, with an oral antibiotic (e.g.,doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatmentand after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin1%) for the next 9 months of treatment. Non-comedogenic skin moisturiser (ceramide-based or otherformulations that provide long-lasting skin hydration and exclude drying agents are preferred) on theface and whole body (except scalp) and chlorhexidine solution to wash hands and feet isrecommended beginning on Day 1 and continued for the duration of treatment.
Prescriptions for additional topical and/or oral antibiotics and topical corticosteroids are recommendedto be available at the time of initial dosing to minimise any delay in reactive management should rashdevelop despite prophylactic treatment. If skin or nail reactions develop, supportive care, topicalcorticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 orpoorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered anddermatologic consultation should be considered. Lazcluze should be dose reduced, interrupted, orpermanently discontinued based on severity (see section 4.2).
Eye disordersEye disorders, including keratitis, occurred in patients treated with lazertinib in combination withamivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly bereferred to an ophthalmologist and should discontinue use of contact lenses until symptoms areevaluated.
ExcipientsThis medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.
4.5 Interaction with other medicinal products and other forms of interaction
Strong CYP3A4 inducers can decrease lazertinib plasma concentrations. Lazertinib may increase theplasma concentrations of CYP3A4 and BCRP substrates.
Agents that may alter lazertinib plasma concentrations
CYP3A4 inducersThe co-administration of multiple doses of rifampicin (strong CYP3A4 inducer) decreased lazertinib
Cmax by 72% and AUC by 83% in healthy subjects. The co-administration of Lazcluze with strong
CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin, St. John’s wort) should be avoided. Theco-administration of Lazcluze with moderate CYP3A4 inducers may also decrease lazertinib plasmaconcentrations and hence moderate CYP3A4 inducers (e.g. bosentan, efavirenz, modafinil) should beused with caution.
CYP3A4 inhibitorsThe co-administration of multiple doses of itraconazole (strong CYP3A4 inhibitor) increasedlazertinib Cmax by 1.19-fold and AUC by 1.46-fold in healthy subjects. No initial dose adjustment isrequired when Lazcluze is co-administered with CYP3A4 inhibitors.
Gastric acid reducing agents
No clinically relevant differences in lazertinib pharmacokinetics were observed when co-administeredwith gastric acid reducing agents (proton pump inhibitors and H2-receptor antagonists). No doseadjustments are required when Lazcluze is used with gastric acid reducing agents.
Agents that may have their plasma concentrations altered by Lazcluze
CYP3A4 substratesThe co-administration of multiple doses of 160 mg Lazcluze once daily increased midazolam(CYP3A4 substrate) Cmax by 1.39-fold and AUC by 1.47-fold. Narrow therapeutic index medicinalproducts that are CYP3A4 substrates (e.g., cyclosporine, everolimus, pimozide, quinidine, sirolimus,tacrolimus) should be used with caution, as lazertinib may increase the plasma concentrations of thesemedicinal products.
BCRP substratesThe co-administration of multiple doses of 160 mg Lazcluze once daily increased rosuvastatin (BCRPsubstrate) Cmax by 2.24-fold and AUC by 2.02-fold. Narrow therapeutic index medicinal products thatare BCRP substrates (e.g., sunitinib) should be used with caution, as lazertinib may increase theplasma concentrations of these medicinal products.
CYP1A2 substrates
Induction of CYP1A2 cannot be excluded. Therefore, caution is advised when co-administering withsubstrates of CYP1A2 (e.g., tizanidine).
4.6 Fertility, pregnancy and lactation
Women of childbearing potential should be advised to use effective contraception during treatmentand up to 3 weeks after treatment.
Male patients with female partners of reproductive potential should be advised to use effectivecontraception (e.g., condom) and not donate or store semen during treatment and for 3 weeks after thelast dose of lazertinib.
PregnancyThere are no data from the use of lazertinib in pregnant women. Studies in animals have shownreproductive toxicity (reduced embryo-foetal survival and foetal body weight) (see section 5.3). Basedon its mechanism of action and animal data, lazertinib may cause foetal harm when administered to apregnant woman. Lazertinib should not be used during pregnancy unless the benefit of treatment of thewoman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant whiletaking this medicinal product the patient should be informed of the potential risk to the foetus.
Breast-feedingIt is unknown whether lazertinib or its metabolites are excreted in human milk or affects milkproduction. Because the risk to the breast-feeding child cannot be excluded, female patients should beadvised not to breast-feed during treatment and for 3 weeks after the last dose of lazertinib.
FertilityThere are no data on the effect of Lazcluze on human fertility. Studies in animals have shown thatlazertinib has effects on reproductive organs in females (decreased numbers of oestrus cycles andcorpora lutea) and males (degenerative changes in the testis) and may impair female and male fertility(see section 5.3).
4.7 Effects on ability to drive and use machines
Lazcluze has minor influence on the ability to drive and use machines. If patients experiencetreatment-related symptoms (such as fatigue) affecting their ability to concentrate and react, it isrecommended that they do not drive or use machines until the effect subsides.
4.8 Undesirable effects
The most frequent adverse reactions in all grades 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%) andnausea (21%).
The most frequent serious adverse reactions included venous thromboembolism (11%), pneumonia(4.0%), rash (3.1%), interstitial lung disease/pneumonitis (2.9%), COVID-19 (2.4%), hepatotoxicity(2.4%), pleural effusion (2.1%), infusion-related reaction (amivantamab) (2.1%), respiratory failure(1.4%), fatigue (1.2%), oedema (amivantamab) (1.2%), hypoalbuminaemia (amivantamab) (1.2%),and hyponatraemia (1.2%).
The most frequent adverse reactions leading to any treatment discontinuation in patients receiving
Lazcluze in combination with amivantamab were rash (6%), infusion-related reaction (amivantamab)(4.5%), nail toxicity (3.6%), interstitial lung disease/pneumonitis (2.9%), venous thromboembolism(2.9%), pneumonia (1.9%) and oedema (amivantamab) (1.7%).
Tabulated list of adverse reactionsTable 3 summarises the adverse reactions that occurred in patients receiving lazertinib in combinationwith amivantamab.
The data reflects exposure to lazertinib in 421 patients who received lazertinib in combination withamivantamab in MARIPOSA. The median exposure to lazertinib was 18.5 months (range: 0.2 to31.4 months).
Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon(≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known(frequency cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in the order of decreasing seriousness.
Table 3: Adverse reactions in patients receiving lazertinib in combination withamivantamab
System organ class Frequency Any grade Grade 3-4
Adverse reaction category (%) (%)
Metabolism and nutrition disordersHypoalbuminaemiaa, b Very common 48 5
Decreased appetite 24 1.0
Hypocalcaemia 21 2.1
Hypokalaemia 14 3.1
Hypomagnesaemia Common 5 0
Nervous system disordersParaesthesiaa Very common 34 1.7
Dizzinessa 13 0
Eye disordersOther eye disordersa Very common 21 0.5
Visual impairmenta Common 4.5 0
Keratitis 2.6 0.5
Growth of eyelashesa 1.9 0
Vascular disordersVenous thromboembolisma Very common 37 11
Respiratory, thoracic and mediastinal disordersInterstitial lung disease/pneumonitisa Common 3.1 1.2
Gastrointestinal disordersStomatitisa Very common 43 2.4
Diarrhoea 29 2.1
Constipation 29 0
Nausea 21 1.2
Vomiting 12 0.5
Abdominal paina 11 0
Haemorrhoids Common 10 0.2
Hepatobiliary disordersHepatotoxicitya Very common 47 9
Skin and subcutaneous tissue disordersRasha Very common 89 27
Nail toxicitya 71 11
Dry skina 26 1.0
Pruritus 24 0.5
Palmar-plantar erythrodysaesthesia syndrome Common 6 0.2
Urticaria 1.2 0
Musculoskeletal and connective tissue disordersMuscle spasms Very common 17 0.5
Myalgia 13 0.7
General disorders and administration site conditionsOedemaa, b Very common 47 2.9
Fatiguea 32 3.8
Pyrexia 12 0
Injury, poisoning and procedural complicationsInfusion-related reactionb Very common 63 6a grouped termsb applicable only to amivantamab.
Description of selected adverse reactionsVenous thromboembolism
Venous thromboembolic (VTE) events, including deep vein thrombosis (14.5%) and pulmonaryembolism (PE) (17.3%), were reported in 37% of patients receiving lazertinib in combination withamivantamab. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 11% and deathsoccurring in 0.5% of patients receiving lazertinib in combination with amivantamab. For informationon prophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4.
In patients receiving lazertinib in combination with amivantamab, the median time to first onset of a
VTE event was 84 days. VTE events led to any treatment discontinuation in 2.9% of patients.
Interstitial lung disease (ILD)/pneumonitisInterstitial lung disease or ILD-like adverse reactions (e.g., pneumonitis) have been reported with theuse of lazertinib in combination with amivantamab as well as with other EGFR inhibitors. ILD orpneumonitis was reported in 3.1% of patients treated with lazertinib in combination withamivantamab, including 0.2% fatal cases. Patients with a medical history of ILD, drug-induced ILD,radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD wereexcluded from the clinical study (see section 4.4).
Skin and nail reactions
Rash (including dermatitis acneiform), pruritus and dry skin has occurred. Rash occurred in 89% ofpatients treated with lazertinib in combination with amivantamab. Most cases were Grade 1 or 2, with
Grade 3 events occurring in 27% of patients. Rash leading to any treatment discontinuation occurredin 6% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time toonset of 14 days. Nail toxicity occurred in patients treated with lazertinib in combination withamivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients(see section 4.4).
A Phase 2 study in patients treated with Lazcluze in combination with amivantamab was conducted toassess the use of prophylactic therapy with an oral antibiotic, a topical antibiotic on the scalp, amoisturiser on the face and whole body (except scalp), and an antiseptic on hands and feet (seesections 4.2 and 4.4). A reduction in the incidence of ≥ Grade 2 dermatologic adverse events duringthe first 12 weeks of treatment was demonstrated, compared with the standard dermatologicmanagement used in clinical practice (38.6% vs. 76.5%, p<0.0001). In addition, there was a reductionin ≥ Grade 2 adverse events involving the scalp in the first 12 weeks of treatment (8.6% vs. 29.4%)along with lower incidence of dose reductions (7.1% vs. 19.1%), interruptions (15.7% vs. 33.8%), andtreatment discontinuations (1.4% vs. 4.4%) due to dermatological adverse events.
Eye disordersEye disorders, including keratitis (2.6%), occurred in patients treated with lazertinib in combinationwith amivantamab. Other reported adverse reactions included growth of eyelashes, visual impairment,and other eye disorders. Most events were Grade 1-2 (see section 4.4).
HepatotoxicityHepatotoxicity-related reactions occurred in 47% of patients treated with lazertinib in combinationwith amivantamab. Most events were Grade 1-2, with Grade 3-4 hepatotoxicity occurring in 9% ofpatients. Most events were related to elevations of serum transaminases (36% alanineaminotransferase increased and 29% aspartate aminotransferase increased). Most patients withelevations of transaminases were able to continue study treatment without modification of studytreatment while a small number were managed with a dose interruption or with a dose reduction.
There were no cases of liver failure or fatal cases of hepatotoxicity in clinical studies with lazertinib incombination with amivantamab.
Isolated reports of alkaline phosphatase increased and prolonged elevated bilirubin have beenidentified with lazertinib monotherapy.
Paraesthesia
Paraesthesia occurred in 34% of patients treated with lazertinib in combination with amivantamab.
Most events were Grade 1-2, with Grade 3 paraesthesia occurring in 1.7% of patients. Most patientswith paraesthesia had resolution with dose interruption or dose reduction.
Stomatitis
Stomatitis occurred in 43% of patients treated with lazertinib in combination with amivantamab. Mostevents were Grade 1-2, with Grade 3 stomatitis occurring in 2.4% of patients.
DiarrhoeaDiarrhoea occurred in 29% of patients treated with lazertinib in combination with amivantamab. Mostevents were Grade 1-2, with Grade 3 diarrhoea occurring in 2.1% of patients.
Special populationsElderly
There are limited clinical data with lazertinib in patients 75 years of age or over (see section 5.1).
Older patients (≥ 65 years of age) reported more Grade 3 or higher adverse events compared topatients < 65 years of age (81% vs. 70%). While the rates of drug interruptions and dose reductionswere similar, the rate of adverse events leading to any treatment discontinuation was higher in patients≥ 65 years of age compared to patients < 65 years of age (47% vs. 25%).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no known specific antidote for Lazcluze overdose. In the event of an overdose, stop Lazcluzeand undertake general supportive measures. Patients should be closely monitored for signs orsymptoms of adverse reactions.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EB09.
Mechanism of actionLazertinib is an irreversible EGFR tyrosine kinase inhibitor (TKI). It selectively inhibits both primaryactivating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) and the
EGFR T790M resistance mutation, while having less activity against wild-type EGFR.
Pharmacodynamic effectsBased on the exposure-response analyses for safety, paraesthesia and stomatitis appeared to show atrend of increasing occurrence with increase in lazertinib exposure.
Cardiac electrophysiologyThe QTc interval prolongation potential of lazertinib was evaluated by exposure-response (E-R)analysis conducted with clinical data from 243 NSCLC patients who received 20, 40, 80, 120, 160,240 or 320 mg lazertinib once daily in a phase 1/II study. The E-R analysis revealed no clinicallyrelevant relationship between lazertinib plasma concentration and change in QTc interval.
Clinical efficacy and safetyMARIPOSA is a randomised, open-label, active-controlled, multicentre phase 3 study assessing theefficacy and safety of Lazcluze in combination with amivantamab as compared to osimertinibmonotherapy in the first-line treatment of patients with EGFR-mutated locally advanced or metastatic
NSCLC not amenable to curative therapy. Patient samples were required to have one of the twocommon EGFR mutations (exon 19 deletion or exon 21 L858R substitution mutation), as identified bylocal testing. Tumour tissue (94%) and/or plasma (6%) samples for all patients were tested locally todetermine EGFR exon 19 deletion and/or exon 21 L858R substitution mutation status usingpolymerase chain reaction (PCR) in 65% and next generation sequencing (NGS) in 35% of patients.
A total of 1074 patients were randomised (2:2:1) to receive Lazcluze in combination withamivantamab, osimertinib monotherapy, or Lazcluze monotherapy until disease progression orunacceptable toxicity. Lazcluze was administered at 240 mg orally once daily. Amivantamab wasadministered intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) onceweekly for 4 weeks, then every 2 weeks thereafter starting at week 5. Osimertinib was administered ata dose of 80 mg orally once daily. Randomisation was stratified by EGFR mutation type (exon 19deletion or exon 21 L858R substitution mutation), race (Asian or non-Asian), and history of brainmetastasis (yes or no).
Baseline demographics and disease characteristics were balanced across the treatment arms. Themedian age was 63 (range: 25-88) years with 45% of patients ≥ 65 years and 11% ≥ 75 years; 62%were female; and 59% were Asian, and 38% were White. Baseline Eastern Cooperative Oncology
Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brainmetastases; and 90% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status,60% were exon 19 deletions and 40% were exon 21 L858R substitution mutations.
Lazcluze in combination with amivantamab demonstrated a statistically significant improvement inprogression-free survival (PFS) by BICR assessment.
The final analysis of OS demonstrated a statistically significant improvement in OS for Lazcluze incombination with amivantamab compared to osimertinib (see Table 4 and Figure 2).
Table 4, Figure 1 and Figure 2 summarise efficacy results for Lazcluze in combination withamivantamab.
Table 4: Efficacy results in MARIPOSA
Lazcluze + amivantamab Osimertinib(N=429) (N=429)
Progression-free survival (PFS)a
Number of events 192 (45%) 252 (59%)
Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5)
HR (95% CI); p-value 0.70 (0.58, 0.85); p=0.0002
Overall survival (OS)
Number of events 173 (40%) 217 (51%)
Median, months (95% CI) NE (42.9, NE) 36.7 (33.4, 41.0)
HR (95% CI); p-value 0.75 (0.61, 0.92); p=0.0048
Objective response rate (ORR)a, b
ORR % (95% CI) 80% (76%, 84%) 77% (72%, 81%)
Duration of response (DOR)a, b
Median, months (95% CI) 25.8 (20.3, 33.9) 18.1 (14.8, 20.1)
BICR = blinded independent central review; CI = confidence interval; NE = not estimable.
PFS results are from data cut-off 11 August 2023 with median follow-up of 22.0 months. ORR and DOR results are fromdata cut-off 13 May 2024 with median follow-up of 31.3 months. OS results are from data cut-off 04 December 2024 witha median follow-up of 37.8 months.a BICR by RECIST v1.1.b Based on confirmed responders.
Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICRassessment
Figure 2: Kaplan-Meier curve of OS in previously untreated NSCLC patients
Intracranial ORR and DOR by BICR were pre-specified endpoints in MARIPOSA. In the subset ofpatients with intracranial lesions at baseline, the combination of Lazcluze and amivantamabdemonstrated similar intracranial ORR to the control. Per protocol, all patients in MARIPOSA hadserial brain MRIs to assess intracranial response and duration. Results are summarised in Table 5.
Table 5: Intracranial ORR and DOR by BICR assessment in subjects with intracraniallesions at baseline
Lazcluze + amivantamab Osimertinib(N=180) (N=186)
Intracranial tumour response assessment
Intracranial ORR (CR+PR), % 78% 77%(95% CI) (71%, 84%) (71%, 83%)
Complete response 64% 59%
Intracranial DOR
Median, months (95% CI) 35.0 (20.4, NE) 25.1 (22.1, 31.2)
CI = confidence interval; NE = not estimable
Intracranial ORR and DOR results are from data cut-off 04 December 2024 with median follow-up of 37.8 months.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with
Lazcluze in all subsets of the paediatric population in non-small cell lung cancer.
5.2 Pharmacokinetic properties
Following single and multiple once daily oral administration, lazertinib maximum plasmaconcentration (Cmax) and area under plasma concentration time curve (AUC) increased approximatelydose proportionally across 20 to 320 mg dose range.
The steady state plasma exposure was achieved by day 15 of once daily administration andapproximately 2-fold accumulation was observed at steady state with 240 mg once daily dose.
The lazertinib plasma exposure was comparable when lazertinib was administered either incombination with amivantamab or as a monotherapy.
AbsorptionThe median time to reach single dose and steady state Cmax was comparable and ranged from 2 to4 hours.
Following administration of 240 mg lazertinib with a high-fat meal (800~1000 kcal, fat contentapproximately 50%), the Cmax and AUC of lazertinib were comparable to that under fasting conditionssuggesting lazertinib can be taken with or without food.
DistributionLazertinib was extensively distributed, with mean (CV%) apparent volume of distribution of 4264(43.2%) L at 240 mg dose. Lazertinib mean (CV%) plasma protein binding was approximately 99.2%(0.13%) in humans. Lazertinib demonstrated covalent binding to human blood and plasma proteinsafter oral dosing, and during in vitro incubations.
MetabolismLazertinib is primarily metabolised by glutathione conjugation, either enzymatic viaglutathione-S-transferase (GST) or non-enzymatic, as well as by CYP3A4. The most abundantmetabolites are glutathione catabolites and considered clinically inactive. The plasma exposure oflazertinib was affected by GSTM1 mediated metabolism, leading to lower exposure (less than 2-folddifference) in Non-null GSTM1 patients. No dose adjustment is required based on GSTM1 status.
EliminationThe mean (CV%) apparent clearance and terminal half-life of lazertinib at 240 mg dose were 44.5(29.5%) L/h and 64.7 (32.8%) hours, respectively.
Excretion
Following a single oral dose of radiolabelled lazertinib, approximately 86% of the dose was recoveredin faeces (< 5% as unchanged) and 4% in urine (< 0.5% as unchanged).
Co-administration with OCT1 and UGT1A1 substrates
The co-administration of multiple doses of Lazcluze did not increase metformin (OCT1 substrate) Cmaxand AUC. Lazcluze does not inhibit OCT1.
Based on in vitro studies, Lazcluze may inhibit UGT1A1. However, due to lack of effect on indirectbilirubin levels in clinical study, no clinically relevant interaction is expected with UGT1A1substrates.
Special populationsElderly
Based on population PK analysis, no clinically meaningful age-based differences in pharmacokineticsof lazertinib were observed.
Renal impairmentBased on population PK analysis, no dose adjustment is required for patients with mild, moderate orsevere renal impairment with estimated glomerular filtration rate (eGFR) of 15 to 89 mL/min. Data inpatients with severe renal impairment (eGFR of 15 to 29 mL/min) are limited (n=3), but there is noevidence to suggest that dose adjustment is required in these patients. No data are available in patientswith end stage renal disease (eGFR < 15 mL/min).
Hepatic impairmentBased on findings from clinical pharmacology study, moderate hepatic impairment (Child-Pugh Class
B) had no clinically meaningful effect on lazertinib single dose PK. Based on population PK analysis,no dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or ULN< total bilirubin ≤ 1.5×ULN and any AST) or moderate (1.5×ULN < total bilirubin ≤ 3×ULN and any
AST) hepatic impairment. No data are available in patients with severe hepatic impairment (totalbilirubin > 3×ULN and any AST).
Paediatric populationThe pharmacokinetics of lazertinib in paediatric patients have not been investigated.
Other populations
No clinically meaningful differences in lazertinib PK were observed based on sex, body weight, race,ethnicity, baseline laboratory assessments (creatinine clearance, albumin, alanine aminotransferase,alkaline phosphatase, aspartate aminotransferase), ECOG performance status, EGFR mutation type,initial diagnosis cancer stage, prior therapies, brain metastasis, and history of smoking.
5.3 Preclinical safety data
The main findings observed in repeat-dose toxicity studies with lazertinib in rats and dogs comprisedmild epithelial atrophy to degenerative erosions, inflammation, and necrosis affecting the eye (cornealatrophy) skin (thin and rough hair coat, hair follicle degeneration, alopecia, ulcer), liver (increasedliver enzymes, Kupffer cell hypertrophy and hepatocellular necrosis), lungs (alveolar macrophageinfiltrate, lung inflammation and hyperplasia of alveolar type II cells), kidney (tubular dilatation,papillary necrosis, higher urea nitrogen, creatinine (females only), inorganic phosphorus, andpotassium), GI (oesophageal epithelial atrophy, villus blunting/fusion in duodenum, and jejunum,liquid faeces), reproductive system (testis tubular degeneration, hypospermia, decreased oestrouscycles and corpora lutea, atrophy in uterus and vagina) These findings were observed in animals inexposures ranges of 0.9-3.4x than estimated exposures of patients administered with the recommendeddose (240 mg) and were fully or partially resolved during the recovery phases. The heart wasconsidered a target organ in dog alone and occurred at exposure levels 7x to that of exposure levelsexpected at the human recommended dose.
Carcinogenicity and mutagenicityNo evidence of genotoxicity for lazertinib was observed in in vitro bacterial mutagenicity, in vitrochromosomal aberration, and in vivo micronucleus tests in rats. Long-term animal studies have notbeen conducted to evaluate the carcinogenic potential of lazertinib.
Reproductive toxicologyBased on studies in animals, male and female fertility may be impaired by treatment with lazertinib.
Degenerative changes were present in the testes of rats and dogs resulting in reduced luminal sperm indogs following exposure to lazertinib for 1 month at clinically relevant exposure levels. Decreasednumbers of corpora lutea were noted in the ovaries of rats exposed to lazertinib for ≥ 1 month atclinically relevant exposure levels. In a fertility and early embryonic development study in male andfemale rats, lazertinib induced a decrease in the number of oestrus cycles, an increase inpost-implantation loss and decreased live litter size at or below the dose level that approximated thehuman clinical exposure at the recommended dose of 240 mg.
Developmental toxicity was observed in embryo-foetal development studies in rats and rabbits. In rats,decreases in foetal body weights in association with maternal toxicity were observed at a maternalexposure approximately 4 times higher than the human clinical exposure at 240 mg. In rabbits, anincreased incidence of a foetal skull bone fusion (zygomatic arch fused to the maxillary process) wasobserved at maternal exposures well below the human clinical exposure at 240 mg.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Silica, hydrophobic colloidal
Croscarmellose sodium (E468)
Cellulose, microcrystalline (E460 (i))
Mannitol (E421)
Magnesium stearate (E572)
Film coatingLazcluze 80 mg film-coated tablets
Macrogol poly(vinyl alcohol) grafted copolymer (E1209)
Polyvinyl alcohol (E1203)
Glycerol monocaprylocaprate type I (E471)
Titanium dioxide (E171)
Talc (E553b)
Yellow iron oxide (E172)
Lazcluze 240 mg film-coated tablets
Macrogol poly(vinyl alcohol) grafted copolymer (E1209)
Polyvinyl alcohol (E1203)
Glycerol monocaprylocaprate type I (E471)
Titanium dioxide (E171)
Talc (E553b)
Red iron oxide (E172)
Black iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Lazcluze 80 mg film-coated tablets
Blister pack
Polyvinyl chloride - polychlorotrifluoroethylene (PVC-PCTFE) film and aluminium push-throughfoil.
- One carton contains 56 film-coated tablets (2 wallet packs containing 28 tablets each).
BottleWhite opaque high-density polyethylene (HDPE) bottle with polypropylene child-resistant closurecontaining either 60 or 90 tablets. Each carton contains one bottle.
Lazcluze 240 mg film-coated tablets
Blister pack
Polyvinyl chloride - polychlorotrifluoroethylene (PVC-PCTFE) film and aluminium push-throughfoil.
- One carton contains 14 film-coated tablets (1 wallet pack containing 14 tablets).
- One carton contains 28 film-coated tablets (2 wallet packs containing 14 tablets each).
BottleWhite opaque high-density polyethylene (HDPE) bottle with polypropylene child-resistant closurecontaining 30 film-coated tablets. Each carton contains one bottle.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.