Lazertinib

LAZCLUZE, in combination with amivantamab, is indicated for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1) ] . LAZCLUZE is a kinase inhibitor indicated in combination with amivantamab for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. ( 1 )

Tablets : 80 mg and 240 mg. ( 3 ) Tablets 80 mg tablets: yellow, oval film-coated tablet, debossed with "LZ" on one side and "80" on the other side. Each tablet contains 80 mg of lazertinib. 240 mg tablets: reddish purple, oval film-coated tablet, debossed with "LZ" on one side and "240" on the other side. Each tablet contains 240 mg of lazertinib.

None. None. ( 4 )

Venous Thromboembolic Events (VTE) : Prophylactic anticoagulation is recommended for the first four months of treatment. 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 at the discretion of the healthcare provider. Permanently discontinue amivantamab and continue LAZCLUZE for recurrent VTE despite therapeutic anticoagulation. ( 2.3 , 2.4 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening symptoms indicative of ILD/pneumonitis. Withhold LAZCLUZE and amivantamab in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 2.4 , 5.2 ) Dermatologic Adverse Reactions : Can cause severe rash including acneiform dermatitis. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, reduce the dose or permanently discontinue LAZCLUZE and amivantamab based on severity. ( 2.3 , 2.4 , 5.3 ) Hepatotoxicity : Can cause severe hepatotoxicity (including increased ALT and AST). Withhold, reduce the dose, or permanently discontinue LAZCLUZE and amivantamab based on severity. ( 2.4 , 5.4 ) Ocular Adverse Reactions : Promptly refer patients with new or worsening signs and symptoms of ocular adverse reactions, including keratitis, to an ophthalmologist for evaluation. Withhold, reduce the dose, or permanently discontinue amivantamab and continue LAZCLUZE based on severity. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1 Venous Thromboembolic Events LAZCLUZE 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 [see Adverse Reactions (6.1) ] . In MARIPOSA [see Adverse Reactions (6.1) ] , 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 (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.3) ] . 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 [see Dosage and Administration (2.4) ]. 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 [see Dosage and Administration (2.4) ] . Refer to the amivantamab prescribing information for recommended amivantamab dosage modification.

5.2 Interstitial Lung Disease (ILD)/Pneumonitis LAZCLUZE in combination with amivantamab can cause interstitial lung disease (ILD)/pneumonitis. In MARIPOSA [see Adverse Reactions (6.1) ], 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 [see Adverse Reactions (6.1) ]. 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 [see Dosage and Administration (2.4) ].

5.3 Dermatologic Adverse Reactions LAZCLUZE in combination with amivantamab can cause severe rash including dermatitis acneiform, pruritus and dry skin. In MARIPOSA [see Adverse Reactions (6.1) ] , 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 [see Adverse Reactions (6.1) ]. When initiating treatment with LAZCLUZE in combination with amivantamab, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions [see Dosage and Administration (2.3) ]. 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. If skin reactions develop, administer supportive care including 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 [see Dosage and Administration (2.4) ] .

5.4 Hepatotoxicity LAZCLUZE in combination with amivantamab can cause severe hepatotoxicity (including increased ALT and AST). In MARIPOSA [see Adverse Reactions (6.1) ], based on adverse reaction data, hepatotoxicity occurred in 49% of patients treated with LAZCLUZE, including Grade 3 in 9.3% of patients and Grade 4 in 0.5%. LAZCLUZE was interrupted for an adverse reaction of hepatotoxicity in 8% of patients, the dose was reduced in 1.4% and permanently discontinued in 0.2%. Perform liver function tests (including ALT, AST, and total bilirubin) before initiation of LAZCLUZE and during treatment, as clinically indicated. Withhold, reduce the dose, or permanently discontinue LAZCLUZE and amivantamab based on severity [see Dosage and Administration (2.4) ].

5.5 Ocular Toxicity LAZCLUZE, in combination with amivantamab, can cause ocular toxicity, including keratitis. In MARIPOSA [see Adverse Reactions (6.1) ] , 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 [see Dosage and Administration (2.4) ] .

5.6 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. […]

The following adverse reactions are discussed elsewhere in the labeling: Venous Thromboembolic Events [see Warnings and Precautions (5.1) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Ocular Toxicity [see Warnings and Precautions (5.5) ] LAZCLUZE in Combination with Amivantamab 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, and nausea. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 [see Clinical Studies (14) ] . 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, and nausea. 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. Table 3 summarizes the adverse reactions (≥ 10%) in MARIPOSA. Table 3: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA Adverse Reaction LAZCLUZE in combination with amivantamab (N=421) Osimertinib (N=428) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped terms 86 26 48

1.2 Nail toxicity 71 11 34

0.7 Dry skin 25 1 18

0.2 Pruritus 24 0.5 17

0.2 Injury, poisoning and procedural complications Infusion-related reaction Applicable only to amivantamab 63 6 0 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 47 2.1 39

1.9 Gastrointestinal disorders Stomatitis 43 2.4 27

0.5 Diarrhea 31 2.6 45

0.9 Constipation 29 0 13 0 Nausea 21 1.2 14

0.2 Vomiting 12 0.5 5 0 Abdominal pain 11 0 10 0 Hemorrhoids 10 0.2 2.1

0.2 General disorders and administration site conditions Edema 43 2.6 8 0 Fatigue 32 3.8 20

1.9 Pyrexia 12 0 9 0 Vascular disorders Venous thromboembolism 36 11 8

2.8 Hemorrhage 25 1 13

1.2 Nervous system disorders Paresthesia 35 1.7 10

0.2 Dizziness 14 0 10 0 Headache 13 0.2 13 0 Infections and infestations COVID-19 26 1.7 24

1.4 Conjunctivitis 11 0.2 1.6 0 Metabolism and nutrition disorders Decreased appetite 24 1 18

1.4 Respiratory, thoracic and mediastinal disorders Cough 19 0 23 0 Dyspnea 14 1.7 17

3.5 Eye disorders Ocular toxicity 16 0.7 7 0 Psychiatric disorders Insomnia 10 0 11 0 Clinically relevant adverse reactions occurring in < 10% of patients who received LAZCLUZE in combination with amivantamab included skin ulcer (applicable to amivantamab) and ILD/pneumonitis. Table 4 summarizes the laboratory abnormalities in MARIPOSA. Table 4: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test. Laboratory Abnormality LAZCLUZE in combination with amivantamab (N=421) Osimertinib (N=428) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Decreased albumin 89 8 22

0.2 Increased ALT 65 7 29

2.6 Increased AST 52 3.8 36

1.9 Increased alkaline phosphatase 45 0.5 15

0.5 Decreased calcium (corrected) 41 1.4 27

0.7 Increased GGT 39 2.6 24

1.9 Decreased sodium 38 7 35 5 Decreased potassium 30 5 15

1.2 Increased creatinine 26 0.7 35

0.7 Decreased magnesium 25 0.7 10

0.2 Increased magnesium 12 2.6 20

4.8 Hematology Decreased platelet count 52 0.7 57

1.4 Decreased hemoglobin 47 3.8 56

1.9 Decreased white blood cell 38 1.0 66

0.7 Decreased neutrophils 15 1.4 33 1.4

Strong and moderate CYP3A4 inducers: Avoid concomitant use. ( 7.1 )

7.1 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 [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of lazertinib.

7.2 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 [see Clinical Pharmacology (12.3) ] , 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 [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions related to these substrates.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , LAZCLUZE 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 (see Data ) . 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. Data 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).

8.2 Lactation Risk Summary 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.

8.3 Females and Males of Reproductive Potential Based on animal data and its mechanism of action, LAZCLUZE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . 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 [see Nonclinical Toxicology (13.1) ].

8.4 Pediatric Use The safety and effectiveness of LAZCLUZE in pediatric patients have not been established.

8.5 Geriatric 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.

8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment (eGFR 30 – 89 mL/min) [see Clinical Pharmacology (12.3) ] . LAZCLUZE has not been studied in patients with severe renal impairment or end-stage renal disease (eGFR < 30 mL/min).

8.7 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 [see Clinical Pharmacology (12.3) ] . LAZCLUZE has not been studied in patients with severe hepatic impairment (total bilirubin > 3×ULN and any AST).

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.