Lazertinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh
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Overview
Lazertinib is a kinase inhibitor that is FDA approved for the treatment of LAZCLUZE, in combination with amivantamab, is a kinase inhibitor that is FDA approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) withepidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations.. Common adverse reactions include The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction (amivantamab), musculoskeletal pain,edema, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity..
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Patient Selection
- Select patients for the first-line treatment of NSCLC with LAZCLUZE, in combination with amivantamab, based on the presence of EGFR exon 19 deletions or exon 21 L858R substitution mutations in tumor or plasma specimens.
- If these mutations are not detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests is available.
Recommended Dosage and Administration
- The recommended dosage of LAZCLUZE is 240 mg orally once daily administered in combination with amivantamab with or without food. Swallow LAZCLUZE tablets whole. Do not crush, split, or chew. Continue treatment until disease progression or unacceptable toxicity.
- Administer LAZCLUZE any time prior to amivantamab when given on the same day. Refer to the amivantamab prescribing information for recommended amivantamab dosing information.
Missed Dose
- If a patient misses a dose of LAZCLUZE within 12 hours, instruct patients to take the missed dose. If more than 12 hours has passed since the dose was to be given, instruct the patient to take the next dose at its scheduled time.
Vomiting
- If vomiting occurs any time after taking LAZCLUZE, instruct the patient to take the next dose at its next regularly scheduled time.
Concomitant Medications
- When initiating treatment with LAZCLUZE in combination with amivantamab, administer anticoagulant prophylaxis to prevent venous thromboembolic events (VTE) for the first four months of treatment.
- If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider.
- When initiating treatment with LAZCLUZE in combination with amivantamab, administer alcohol-free emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures to reduce the risk of dermatologic adverse reactions.
Dosage Modifications for Adverse Reactions
- The recommended LAZCLUZE dose reductions for adverse reactions are
- The dose at which the adverse reaction occurred was 240 mg once daily, equivalent to one 240 mg tablet.
- Following this, the first dose reduction was made to 160 mg once daily, which is the same as taking two 80 mg tablets.
- If the adverse reaction persisted, the second dose reduction brought the dosage down to 80 mg once daily, or one 80 mg tablet.
- In cases where the reaction continued, the third and final step would be to discontinue LAZCLUZE altogether.
Recommended Dose Reductions for Adverse Reactions for LAZCLUZE
- The recommended management and dosage modifications of LAZCLUZE for specific adverse reactions are presented
Recommended Management and Dosage Modifications for Adverse Reactions - For venous thromboembolic events (VTE), if the reaction is graded as 2 or 3, both LAZCLUZE and amivantamab should be withheld, and anticoagulant treatment should be administered as clinically indicated. Once anticoagulant treatment is initiated, LAZCLUZE and amivantamab may be resumed at the same dose level at the discretion of the healthcare provider. If the reaction is graded as 4 or there are recurrent Grade 2 or 3 events despite therapeutic anticoagulation, LAZCLUZE should be withheld, and amivantamab should be permanently discontinued. Anticoagulant treatment should continue, and once anticoagulation is achieved, LAZCLUZE may be resumed at the same dose level at the healthcare provider’s discretion.
- In cases of interstitial lung disease (ILD) or pneumonitis, if any grade of ILD/pneumonitis is suspected, both LAZCLUZE and amivantamab should be withheld. If ILD/pneumonitis is confirmed, both medications should be permanently discontinued.
- For dermatologic adverse reactions such as dermatitis acneiform, pruritus, and dry skin, the management depends on the severity. For Grade 1 and Grade 2 reactions, supportive care should be initiated. If there is no improvement within two weeks for Grade 2 reactions, a reduction in the amivantamab dose may be considered, and LAZCLUZE can continue at the same dose. If no improvement occurs, a reduction in LAZCLUZE dose may be necessary until it reaches Grade 1, at which point the healthcare provider can decide whether to resume the previous dose of LAZCLUZE. For Grade 3 reactions, both drugs should be withheld, supportive care should be provided, and upon recovery to Grade 2 or less, LAZCLUZE can be resumed at the same dose or with a dose reduction, while amivantamab may be resumed at a reduced dose. If there is no improvement within two weeks, both medications should be permanently discontinued. For Grade 4 reactions, including severe skin conditions such as bullous, blistering, or exfoliating skin, supportive care should be initiated, amivantamab should be permanently discontinued, and LAZCLUZE should be withheld until recovery to Grade 2 or baseline. Upon recovery, LAZCLUZE can be resumed at a reduced dose at the healthcare provider’s discretion.
- For other Grade 3-4 adverse reactions, both LAZCLUZE and amivantamab should be withheld until the reaction resolves to Grade 1 or baseline. After resolution, both drugs can be resumed at a reduced dose, or LAZCLUZE may be resumed alone. If recovery does not occur within four weeks, permanent discontinuation of both medications should be considered.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lazertinib in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lazertinib in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lazertinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lazertinib in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lazertinib in pediatric patients.
Contraindications
None.
Warnings
Venous Thromboembolic Events
- In combination with amivantamab can cause serious and fatal venous thromboembolic events (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). The majority of these events occurred during the first four months of therapy.
- In MARIPOSA ,VTE occurred in 36% of patients receiving LAZCLUZE in combination with amivantamab, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 7% of patients had VTE leading to dose interruptions of LAZCLUZE, 0.5% of patients had VTE leading to dose reductions of LAZCLUZE, and 1.9% of patients permanently discontinued LAZCLUZE due to VTE. The median time to onset of VTEs was 84 days.
- Administer prophylactic anticoagulation for the first four months of treatment . The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE and treat as medically appropriate.
- Withhold LAZCLUZE and amivantamab based on severity.
- Once anticoagulant treatment has been initiated, resume LAZCLUZE and amivantamab at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue amivantamab. Continue treatment with LAZCLUZE at the same dose level at the discretion of the healthcare provider.
Interstitial Lung Disease (ILD)/Pneumonitis
- LAZCLUZE in combination with amivantamab can cause interstitial lung disease (ILD)/pneumonitis.
- In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with LAZCLUZE in combination with amivantamab, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued LAZCLUZE and amivantamab due to ILD/pneumonitis.
- Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold LAZCLUZE and amivantamab in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed .
Dermatologic Adverse Reactions
- In combination with amivantamab can cause severe rash including dermatitis acneiform, pruritus and dry skin.
- In MARIPOSA , rash occurred in 86% of patients treated with LAZCLUZE in combination with amivantamab, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose reduction of LAZCLUZE occurred in 19% of patients, rash leading to dose interruption of LAZCLUZE occurred in 30% of patients, and LAZCLUZE was permanently discontinued due to rash in 1.7% of patients.
- When initiating treatment with LAZCLUZE in combination with amivantamab, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Instruct patients to limit sun exposure during and for 2 months after treatment with LAZCLUZE in combination with amivantamab. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen.
- Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, administer topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, administer oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose or permanently discontinue LAZCLUZE and amivantamab based on severity.
Ocular Toxicity
- In combination with amivantamab, can cause ocular toxicity, including keratitis.
- In MARIPOSA , ocular toxicity occurred in 16% of patients treated with LAZCLUZE in combination with amivantamab, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose or permanently discontinue amivantamab and continue LAZCLUZE based on severity.
Embryo-Fetal Toxicity
- Based on findings from animal studies and its mechanism of action, LAZCLUZE can cause fetal harm when administered to a pregnant woman .
- In animal reproduction studies, oral administration of lazertinib to pregnant animals during the period of organogenesis resulted in reduced embryo-fetal survival and fetal body weight in rats and malformations in rabbits at exposures approximately 4 and 0.5 times, respectively, the human exposure at the recommended dose of 240 mg/day based on AUC.
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose.
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data described in WARNINGS AND PRECAUTIONS and below reflect exposure to LAZCLUZE in combination with amivantamab in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations in MARIPOSA. Patients received LAZCLUZE 240 mg orally once daily in combination with amivantamab intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5. Among the 421 patients who received LAZCLUZE in combination with amivantamab, 84% were exposed to LAZCLUZE for ≥ 6 months and 73% were exposed to LAZCLUZE for > 1 year.
- The median age of patients who received LAZCLUZE in combination with amivantamab was 64 years (25 to 88); 64% were female; 59% were Asian, 38% were White, 1.7% were American Indian or Alaska Native, 0.7% were Black or African American, 1% were of unknown or other races; 13% were Hispanic or Latino; 67% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, 33% had ECOG PS of 0; 60% had EGFR exon 19 deletions, and 40% had EGFR exon 21 L858R substitution mutations.
- Serious adverse reactions occurred in 49% of patients who received LAZCLUZE in combination with amivantamab. Serious adverse reactions occurring in ≥ 2% of patients included VTE (11%), pneumonia (4%), rash and ILD/pneumonitis (2.9% each), COVID-19 (2.4%), and pleural effusion and infusion-related reaction (amivantamab) (2.1% each). Fatal adverse reactions occurred in 7% of patients who received LAZCLUZE in combination with amivantamab due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).
- Permanent discontinuation of LAZCLUZE due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of LAZCLUZE in ≥ 1% of patients included ILD/pneumonitis, pneumonia, VTE, rash, respiratory failure, and sudden death.
- Dosage interruption of LAZCLUZE due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were rash, nail toxicity, COVID-19, VTE, increased ALT, and increased AST.
- Dose reductions of LAZCLUZE due to an adverse reaction occurred in 42% of patients. Adverse reactions requiring LAZCLUZE dose reductions in ≥ 5% of patients were rash and nail toxicity.
- The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction (amivantamab), musculoskeletal pain, edema, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.
- In a clinical trial comparing LAZCLUZE in combination with amivantamab (N=421) and osimertinib (N=428), various adverse reactions were observed in both treatment groups. Among skin and subcutaneous tissue disorders, rash occurred in 86% of patients receiving LAZCLUZE with amivantamab, with 26% experiencing grade 3 or 4 severity, compared to 48% and 1.2%, respectively, in the osimertinib group. Nail toxicity was more prevalent in the LAZCLUZE group (71%, with 11% grade 3 or 4) versus 34% and 0.7% in the osimertinib group. Dry skin was reported in 25% of the LAZCLUZE group and 18% of the osimertinib group, while pruritus affected 24% and 17%, respectively. Infusion-related reactions were common with LAZCLUZE, occurring in 63% of patients, 6% of which were grade 3 or 4, while no infusion-related reactions were reported with osimertinib. Musculoskeletal pain was experienced by 47% of those on LAZCLUZE, with 2.1% reporting grade 3 or 4 severity, compared to 39% and 1.9% in the osimertinib group.
- Gastrointestinal disorders were also prevalent, with stomatitis occurring in 43% of the LAZCLUZE group (2.4% grade 3 or 4) and 27% of the osimertinib group (0.5% grade 3 or 4). Diarrhea was reported in 31% of the LAZCLUZE group (2.6% grade 3 or 4) and 45% of the osimertinib group (0.9% grade 3 or 4). Other gastrointestinal issues like constipation, nausea, vomiting, abdominal pain, and hemorrhoids were seen in both groups, with higher rates in the LAZCLUZE group for most. For general disorders, edema occurred in 43% of LAZCLUZE-treated patients (2.6% grade 3 or 4) and 8% of the osimertinib group, while fatigue was reported in 32% of the LAZCLUZE group (3.8% grade 3 or 4) and 20% of the osimertinib group (1.9% grade 3 or 4).
- Vascular disorders, including venous thromboembolism and hemorrhage, were more common in the LAZCLUZE group, with venous thromboembolism affecting 36% (11% grade 3 or 4) versus 8% (2.8% grade 3 or 4) in the osimertinib group, and hemorrhage occurring in 25% (1% grade 3 or 4) versus 13% (1.2% grade 3 or 4) in the osimertinib group. Nervous system disorders like paresthesia, dizziness, and headache were reported in both treatment groups, with higher rates of paresthesia and dizziness in the LAZCLUZE group.
- Infections, such as COVID-19, affected 26% of the LAZCLUZE group (1.7% grade 3 or 4) and 24% of the osimertinib group (1.4% grade 3 or 4), while conjunctivitis was more common with LAZCLUZE (11% vs. 1.6% in the osimertinib group). Metabolism and nutrition disorders like decreased appetite were reported by 24% of LAZCLUZE-treated patients (1% grade 3 or 4) and 18% of the osimertinib group (1.4% grade 3 or 4). Respiratory disorders such as cough and dyspnea were common, with more patients on LAZCLUZE experiencing cough (19%) and dyspnea (14%), compared to 23% and 17% of those on osimertinib, respectively. Eye disorders, including ocular toxicity, were noted in 16% of LAZCLUZE patients (0.7% grade 3 or 4) versus 7% of the osimertinib group. Lastly, psychiatric disorders like insomnia were similarly reported in both groups, affecting 10% of the LAZCLUZE group and 11% of the osimertinib group, with no significant difference in grade 3 or 4 severity.
- In the MARIPOSA study, which evaluated select laboratory abnormalities in patients with non-small cell lung cancer (NSCLC) harboring EGFR Exon 19 deletion or Exon 21 L858R substitution mutations, various laboratory abnormalities were observed in both treatment groups, LAZCLUZE in combination with amivantamab (N=421) and osimertinib (N=428). Among chemistry abnormalities, decreased albumin was notably more frequent in the LAZCLUZE group, affecting 89% of patients, with 8% experiencing grade 3 or 4 severity, compared to only 22% and 0.2% in the osimertinib group. Increased ALT was seen in 65% of the LAZCLUZE group (7% grade 3 or 4), versus 29% (2.6% grade 3 or 4) in the osimertinib group. Increased AST was reported in 52% of the LAZCLUZE group (3.8% grade 3 or 4) and 36% (1.9% grade 3 or 4) of the osimertinib group. Increased alkaline phosphatase occurred in 45% of the LAZCLUZE group (0.5% grade 3 or 4), while only 15% (0.5% grade 3 or 4) of the osimertinib group had this abnormality. Decreased calcium was observed in 41% of the LAZCLUZE group (1.4% grade 3 or 4), compared to 27% (0.7% grade 3 or 4) in the osimertinib group. Other abnormalities included increased GGT in 39% of the LAZCLUZE group (2.6% grade 3 or 4) and 24% (1.9% grade 3 or 4) in the osimertinib group, while decreased sodium was noted in 38% (7% grade 3 or 4) of the LAZCLUZE group and 35% (5% grade 3 or 4) of the osimertinib group. Decreased potassium was observed in 30% of the LAZCLUZE group (5% grade 3 or 4) and 15% (1.2% grade 3 or 4) of the osimertinib group. Increased creatinine was noted in 26% (0.7% grade 3 or 4) of the LAZCLUZE group, compared to 35% (0.7% grade 3 or 4) in the osimertinib group. Decreased magnesium was seen in 25% of LAZCLUZE-treated patients (0.7% grade 3 or 4), whereas only 10% (0.2% grade 3 or 4) of the osimertinib group had this abnormality. Increased magnesium was noted in 12% of the LAZCLUZE group (2.6% grade 3 or 4) and 20% (4.8% grade 3 or 4) in the osimertinib group.
- In hematology, decreased platelet count was found in 52% of the LAZCLUZE group (0.7% grade 3 or 4) and 57% (1.4% grade 3 or 4) of the osimertinib group. Decreased hemoglobin was seen in 47% of the LAZCLUZE group (3.8% grade 3 or 4) and 56% (1.9% grade 3 or 4) in the osimertinib group. Decreased white blood cell count was noted in 38% of the LAZCLUZE group (1.0% grade 3 or 4), while 66% (0.7% grade 3 or 4) of patients in the osimertinib group experienced this abnormality. Lastly, decreased neutrophils were seen in 15% of the LAZCLUZE group (1.4% grade 3 or 4), compared to 33% (1.4% grade 3 or 4) in the osimertinib group.
Postmarketing Experience
There is limited information regarding Lazertinib Postmarketing Experience in the drug label.
Drug Interactions
Effect of Other Drugs on LAZCLUZE:
- CYP3A4 Inducers: Avoid concomitant use of LAZCLUZE with strong and moderate CYP3A4 inducers. Consider an alternate concomitant medication with no potential to induce CYP3A4.
- Lazertinib is a CYP3A4 substrate. Concomitant use with a strong or moderate CYP3A4 inducer decreased lazertinib concentrations, which may reduce the efficacy of lazertinib.
Effect of LAZCLUZE on Other Drugs:
- Certain CYP3A4 Substrates: Monitor for adverse reactions associated with a CYP3A4 substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the CYP3A4 substrate.
- Lazertinib is a weak CYP3A4 inhibitor. Concomitant use of LAZCLUZE increased concentrations of CYP3A4 substrates which may increase the risk of adverse reactions related to these substrates.
- Certain BCRP Substrates: Monitor for adverse reactions associated with a BCRP substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the BCRP substrate. Lazertinib is a BCRP inhibitor. Concomitant use of LAZCLUZE increased concentrations of BCRP substrates, which may increase the risk of adverse reactions related to these substrates.
Use in Specific Populations
Pregnancy
- Based on findings from animal studies and its mechanism of action, can cause ====fetal harm==== when administered to a pregnant woman. There are no available data on the use of LAZCLUZE in pregnant women to inform a drug-associated risk. Oral administration of lazertinib to pregnant animals during the period of organogenesis resulted in reduced embryo-fetal survival and fetal body weight in rats and malformations in rabbits at exposures approximately 4 and 0.5 times, respectively, the human exposure at the recommended dose of 240 mg/day based on AUC. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Animal Data:
- In an embryo-fetal development study, pregnant rats received oral doses of 7.5, 30, or 60 mg/kg/day of lazertinib during the period of organogenesis (gestation day 6 to 17). Lazertinib decreased fetal body weights in association with maternal toxicity at 60 mg/kg/day (approximately 4 times the human exposure at the recommended dose of 240 mg/day based on AUC). In a dose range-finding embryo-fetal development study, oral administration of a higher dose of lazertinib (75 mg/kg/day) to pregnant rats during the period of organogenesis resulted in increased post-implantation loss. In an embryo-fetal development study in rabbits, pregnant animals received oral doses of 5, 25, or 45 mg/kg/day of lazertinib during the period of organogenesis (gestation day 7 to 19). Lazertinib caused maternal toxicity (reduced body weight and food consumption leading to moribund condition and early termination) and an increase in the incidence of skeletal malformations in the vertebra and skull (fused maxillary process/zygomatic arch) at 45 mg/kg/day (approximately 0.5 times the human exposure at the recommended dose of 240 mg/day based on AUC).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lazertinib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Lazertinib during labor and delivery.
Nursing Mothers
There are no data on the presence of lazertinib or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LAZCLUZE and for 3 weeks after the last dose. Refer to the amivantamab prescribing information for lactation information during treatment with amivantamab.
Pediatric Use
The safety and effectiveness of LAZCLUZE in pediatric patients have not been established.
Geriatic Use
Of the 421 patients with locally advanced or metastatic NSCLC treated with LAZCLUZE in combination with amivantamab in MARIPOSA, 45% were 65 years and older and 12% were 75 years and older. No overall differences in safety or effectiveness were observed between patients aged 65 and older and younger patients.
Gender
Females
Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose. Refer to the amivantamab prescribing information for recommended duration of contraception during treatment with amivantamab.
Males
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose.
Race
There is no FDA guidance on the use of Lazertinib with respect to specific racial populations.
Renal Impairment
No dose adjustment is recommended in patients with mild or moderate renal impairment (eGFR 30 – 89 mL/min).
LAZCLUZE has not been studied in patients with severe renal impairment or end-stage renal disease (eGFR < 30 mL/min).
Hepatic Impairment
No dose adjustment is recommended in patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin ≤ 1.5×ULN and any AST) or moderate (total bilirubin ≤ 1.5 to 3×ULN and any AST) hepatic impairment
LAZCLUZE has not been studied in patients with severe hepatic impairment (total bilirubin > 3×ULN and any AST).
Females of Reproductive Potential and Males
Based on animal data and its mechanism of action, LAZCLUZE can cause fetal harm when administered to a pregnant woman
Pregnancy Testing:
Verify the pregnancy status of females of reproductive potential prior to initiating LAZCLUZE.
Contraception:
Females: Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose. Refer to the amivantamab prescribing information for recommended duration of contraception during treatment with amivantamab.
Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose.
Infertility
Based on findings in animals, LAZCLUZE may impair fertility in females and males of reproductive potential. The effects on female fertility were reversible. The effects on male testes in animal studies were not reversible within a 2-week recovery period.
Immunocompromised Patients
There is no FDA guidance one the use of Lazertinib in patients who are immunocompromised.
Administration and Monitoring
Administration
Recommended Dosage and Administration
- The recommended dosage of LAZCLUZE is 240 mg orally once daily administered in combination with amivantamab with or without food. Swallow LAZCLUZE tablets whole. Do not crush, split, or chew. Continue treatment until disease progression or unacceptable toxicity.
- Administer LAZCLUZE any time prior to amivantamab when given on the same day. Refer to the amivantamab prescribing information for recommended amivantamab dosing information.
Missed Dose
If a patient misses a dose of LAZCLUZE within 12 hours, instruct patients to take the missed dose. If more than 12 hours has passed since the dose was to be given, instruct the patient to take the next dose at its scheduled time.
Vomiting
If vomiting occurs any time after taking LAZCLUZE, instruct the patient to take the next dose at its next regularly scheduled time.
Monitoring
- When initiating treatment with LAZCLUZE in combination with amivantamab, administer anticoagulant prophylaxis to prevent venous thromboembolic events (VTE) for the first four months of treatment. If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider.
- When initiating treatment with LAZCLUZE in combination with amivantamab, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions.
- If an adverse reaction occurs at the initial dose of 240 mg once daily (one 240 mg tablet), the first dose reduction would be to 160 mg once daily, which can be achieved by taking two 80 mg tablets. If the reaction persists, a second dose reduction to 80 mg once daily (one 80 mg tablet) is recommended. In the event that the adverse reaction continues despite these adjustments, the third and final step is to discontinue LAZCLUZE entirely. These dose adjustments aim to manage adverse reactions while maintaining treatment efficacy.
- The recommended management and dosage modifications for LAZCLUZE in response to ====specific adverse reactions==== are as follows:
- For venous thromboembolic events (VTE), if the severity is Grade 2 or 3, both LAZCLUZE and amivantamab should be withheld, and anticoagulant treatment should be administered as clinically indicated. Once anticoagulant treatment is initiated, both LAZCLUZE and amivantamab can be resumed at the same dose level, at the healthcare provider's discretion. In cases of Grade 4 VTE or recurrent Grade 2 or 3 despite therapeutic anticoagulation, LAZCLUZE should be withheld, and amivantamab should be permanently discontinued. Anticoagulant treatment should continue, and once initiated, LAZCLUZE may be resumed at the same dose level at the healthcare provider's discretion.
- For interstitial lung disease (ILD) or pneumonitis of any grade, both LAZCLUZE and amivantamab should be withheld if ILD or pneumonitis is suspected. If ILD or pneumonitis is confirmed, both drugs should be permanently discontinued.
- Dermatologic adverse reactions, including dermatitis acneiform, pruritus, and dry skin, require supportive care management for Grade 1 and Grade 2 reactions. If there is no improvement after two weeks, the dose of amivantamab should be reduced, and LAZCLUZE should continue at the same dose. If there is no improvement after further reassessment, the dose of LAZCLUZE may be reduced to ≤ Grade 1, with the option to resume the previous dose at the healthcare provider's discretion. For Grade 3 reactions, both LAZCLUZE and amivantamab should be withheld, and supportive care should be initiated. Upon recovery to ≤ Grade 2, LAZCLUZE can be resumed at the same dose or with a dose reduction, and amivantamab can be resumed at a reduced dose. If no improvement occurs within two weeks, both drugs should be permanently discontinued. For Grade 4 dermatologic reactions, including severe bullous, blistering, or exfoliating skin conditions, supportive care should be initiated, and amivantamab should be permanently discontinued. LAZCLUZE should be withheld until recovery to ≤ Grade 2 or baseline, after which it can be resumed at a reduced dose, at the healthcare provider's discretion.
- For other adverse reactions of Grade 3–4 severity, both LAZCLUZE and amivantamab should be withheld until the reaction resolves to ≤ Grade 1 or baseline. Both drugs may then be resumed at a reduced dose or, in some cases, only LAZCLUZE may be resumed. If recovery does not occur within four weeks, consideration should be given to permanently discontinuing both LAZCLUZE and amivantamab. These management strategies are designed to minimize the impact of adverse reactions while maintaining patient safety.
IV Compatibility
There is limited information regarding the compatibility of Lazertinib and IV administrations.
Overdosage
There is limited information regarding Lazertinib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Lazertinib Pharmacology in the drug label.
Mechanism of Action
Lazertinib is a kinase inhibitor of epidermal growth factor receptor (EGFR) that inhibits EGFR exon 19 deletions and exon 21 L858R substitution mutations at lower concentrations than wild-type EGFR. In human NSCLC cells and mouse xenograft models of EGFR exon 19 deletions or EGFR L858R substitution mutations, lazertinib demonstrated anti-tumor activity. Treatment with lazertinib in combination with amivantamab increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.
Structure
Pharmacodynamics
- The exposure-response relationship and time-course of pharmacodynamic response of lazertinib have not been fully characterized.
Cardiac Electrophysiology
- At a dose of 320 mg (1.3 times the approved recommended dosage) once daily, a mean increase in the QTc interval > 20 ms is unlikely.
Pharmacokinetics
- Lazertinib pharmacokinetics are presented as mean (CV%) for descriptive parameters unless otherwise specified.
- Lazertinib maximum plasma concentration (C max) and area under plasma concentration time curve (AUC) increased dose proportionally from 20 mg to 320 mg (0.08 to 1.3 times the approved recommended dosage) following a single administration and once daily administration. Lazertinib steady state plasma exposure was achieved by day 15 with approximately 2-fold accumulation for AUC.
Absorption
The median time to reach C maxis from 2 to 4 hours.
Effect of Food
A high-fat meal (800 to 1000 kcal, approximately 50% fat) did not have a clinically significant effect on lazertinib pharmacokinetics compared to that under fasted conditions.
Distribution
The mean apparent volume of distribution is 2680 L (51%).
Lazertinib is approximately 99.2% bound to human plasma proteins.
Elimination
- The mean terminal half-life is 3.7 days (56%).
- The mean apparent clearance is 36.4 L/h (47%).
- Metabolism
- Lazertinib is primarily metabolized by glutathione conjugation, either enzymatic via glutathione-S-transferase (GST) or non-enzymatic, as well as by CYP3A4.
- Excretion
- Following a single oral dose of radiolabeled lazertinib, approximately 86% of the dose was recovered in feces (< 5% as unchanged) and 4% in urine (< 0.2% as unchanged).
Specific Populations
- No clinically significant differences in pharmacokinetics of lazertinib were observed based on age (21 to 88 years), sex, body weight (28 to 122 kg), race (White, Asian, Black or African American), ethnicity (Hispanic/Latino or not Hispanic/Latino), baseline laboratory assessments (creatinine clearance, albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase), mild or moderate renal impairment (eGFR 30 to 89 mL/min, estimated by CKD-EPI equation), mild [total bilirubin ≤ ULN and AST > ULN or total bilirubin ≤ 1.5 times ULN and any AST] or moderate [total bilirubin ≤ 1.5 to 3×ULN and any AST] hepatic impairment, ECOG performance status, EGFR mutation type, initial diagnosis cancer stage, prior therapies, brain metastasis, and history of smoking.
- The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) or severe hepatic impairment (total bilirubin > 3 times ULN with any AST) on the pharmacokinetics of lazertinib has not been studied.
- GSTM1 Genotype
- Patients with at least one GSTM1 normal function allele have 44% lower systemic levels of lazertinib compared with those with the two GSTM1 no-function alleles (i.e., no enzyme activity). No clinically significant differences in safety or efficacy were observed as a function of GSTM1 genotype in patients receiving LAZCLUZE in combination with amivantamab.
Drug Interactions
Effect of CYP3A4 inducers on lazertinib:
- Concomitant use of rifampin (strong CYP3A4 inducer) with LAZCLUZE decreased lazertinib C maxby 72% and AUC by 83%.
- Concomitant use of efavirenz (moderate CYP3A4 inducer) with LAZCLUZE is predicted to decrease lazertinib steady state C maxby at least 32% and AUC by at least 44%.
- The effect of concomitant use of weak CYP3A4 inducers on lazertinib C maxor AUC is unknown.
Effect of strong CYP3A4 inhibitors on lazertinib:
- Concomitant use of itraconazole (strong CYP3A4 inhibitor) with LAZCLUZE increased lazertinib C maxby 1.2-fold and AUC by 1.5-fold.
Effect of gastric acid reducing agents on lazertinib:
- No clinically significant differences in lazertinib C maxand AUC were observed when used concomitantly with gastric acid reducing agents.
Effect of lazertinib on certain CYP3A4 substrates:
Concomitant use of LAZCLUZE increased midazolam (CYP3A4 substrate) C maxby 1.4-fold and AUC by 1.5-fold.
Effect of lazertinib on BCRP substrates:
- Concomitant use of LAZCLUZE increased rosuvastatin (BCRP substrate) C maxby 2.2-fold and AUC by 2-fold.
- No clinically significant differences in the pharmacokinetics of the following were observed or predicted when used concomitantly with lazertinib: metformin (OCT1 substrate) or raltegravir (UGT1A1 substrate).
In Vitro Studies
- Lazertinib inhibits CYP3A4, UGT1A1, BCRP and OCT1. Lazertinib does not induce CYP1A2, CYP2B6 and CYP3A4.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility:
- Carcinogenicity studies have not been conducted with lazertinib.
- Lazertinib was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration assay, or an in vivo micronucleus assay in rats.
- In a dedicated fertility and early embryonic development study, male and female rats received oral doses of 7.5, 15, or 30 mg/kg/day of lazertinib. Males were dosed for 10 weeks (29 days prior to pairing, during mating period and continuing post-pairing). Females were dosed for 15 days prior to pairing, during mating period and up to Gestation Day 7. Lazertinib did not have clear effects on estrous cyclicity, mating, fertility, or sperm parameters, but induced an increase in post-implantation loss and decreased number of live fetuses at 30 mg/kg/day (approximately 1.2 times the recommended human dose of 240 mg based on body surface area). In repeat-dose oral general toxicology studies up to 13-weeks duration, lazertinib induced histologic tubular degeneration in the testis; cellular lumen debris, degeneration/necrosis, and reduced sperm in the epididymis; decreased corpora lutea in the ovary; and atrophy in the uterus and vagina. These effects were observed at exposures approximately equivalent to the human exposure at the recommended dose of 240 mg in males, and at exposures approximately 2 times the human exposure at the recommended dose of 240 mg dose in females. Findings in female reproductive organs were reversible. The tubular degeneration in the testis observed in rats at exposures approximately 4 times the human exposure at the recommended dose was not reversible within a 2-week recovery period.
Animal Toxicology and/or Pharmacology
- In repeat-dose oral general toxicology studies up to 13-weeks duration in rats and dogs, lazertinib induced multi-organ histologic hyperplasia at exposures approximately equivalent or greater to the human exposure at the recommended dose of 240 mg. Hyperplasia was not reversible in the mandibular lymph node in the 4-week rat study. In rats, lazertinib induced renal toxicity characterized by histologic hyperplasia and inflammation in the kidney at doses ≥ 25 mg/kg (approximately 0.9 times the human exposure at the recommended dose of 240 mg/day based on AUC), along with increased urea nitrogen and histologic papillary necrosis, tubule degeneration/regeneration, and tubule dilatation at exposures approximately 4.4 times the human exposure at the recommended dose of 240 mg/day based on AUC. Increased urea nitrogen, papillary necrosis, and tubule dilatation showed evidence of recovery. In the 13-week toxicology study in dogs, one high dose animal exhibited unilateral tubule cell renal carcinoma at 8 mg/kg/day (approximately 2 times the human exposure at the recommended dose of 240 mg/day based on AUC). Other renal findings in high dose dogs included tubule degeneration/regeneration and infarct, which showed evidence of recovery. In the 4-week toxicology study, lazertinib induced cardiac toxicity in two dogs characterized by histologic findings in the heart (degeneration/necrosis of the myocardium and vessels, fibrosis, hemorrhage, thrombus, mixed cell/vessel inflammation) at 20 mg/kg (approximately 4.8 times the clinical AUC at the 240 mg human dose). One of these dogs also exhibited increased cardiac troponin I and premature ventricular complexes. These cardiac findings were not seen after a 2-week recovery period.
Clinical Studies
- The efficacy of LAZCLUZE, in combination with amivantamab, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.
- Patients were randomized (2:2:1) to receive LAZCLUZE in combination with amivantamab (N=429), osimertinib monotherapy (N=429), or LAZCLUZE monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:
- LAZCLUZE administered at 240 mg orally once daily in combination with amivantamab administered intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5.
- Osimertinib administered at a dose of 80 mg orally once daily.
- Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.
- The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR) and duration of response (DOR).
- A total of 858 patients were randomized between the two study arms, 429 to the LAZCLUZE in combination with amivantamab arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, and 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.
- Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the amivantamab plus LAZCLUZE arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.
- The trial demonstrated a statistically significant improvement in PFS by BICR assessment for LAZCLUZE in combination with amivantamab compared to osimertinib.
How Supplied
The tablet strengths of LAZCLUZE are available in two configurations. The 80 mg tablet is yellow, oval, film-coated, and debossed with "LZ" on one side and "80" on the other side. It is packaged in a 60-count bottle with the NDC number 57894-080-60. The 240 mg tablet is reddish purple, oval, film-coated, and debossed with "LZ" on one side and "240" on the other side. This strength is packaged in a 30-count bottle, with the NDC number 57894-240-30.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Venous Thromboembolic Events
Advise patients of the risks of serious and life threatening venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism. Advise patients that prophylactic anticoagulants are recommended to be used for the first four months of treatment. Advise patients to immediately contact their healthcare provider for signs and symptoms of venous thromboembolism.
Interstitial Lung Disease/Pneumonitis
Advise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms.
Dermatologic Adverse Reactions
Advise patients of the risk of dermatologic adverse reactions. Advise patients to apply alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure during and for 2 months after treatment, to use broad-spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with LAZCLUZE. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions.
Ocular Toxicity
Advise patients of the risk of ocular adverse reactions. Advise patients to contact their ophthalmologist if they develop eye symptoms. Advise discontinuation of contact lenses until symptoms are evaluated.
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose, and to inform their healthcare provider of a known or suspected pregnancy. Refer to the amivantamab prescribing information for recommended duration of contraception during treatment with amivantamab.
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose.
Lactation
Advise women not to breastfeed during treatment with LAZCLUZE and for 3 weeks after the last dose. Refer to the amivantamab prescribing information for lactation information during treatment with amivantamab.
Infertility
Advise males and females of reproductive potential of the potential risk for impaired fertility with LAZCLUZE .
Precautions with Alcohol
Lazertinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
LAZCLUZE
Look-Alike Drug Names
There is limited information regarding Lazertinib Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.