LAZCLUZE

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of LAZCLUZE is 240 mg orally once daily with or without food, given in combination with amivantamab. ( 2.2 ) Continue treatment until disease progression or unacceptable toxicity. ( 2.2 ) Administer LAZCLUZE any time prior to amivantamab when given on the same day. ( 2.2 ) Refer to the amivantamab prescribing information for recommended amivantamab dosing information. ( 2.2 ) Administer prophylactic and concomitant medications to reduce the risk of dermatologic adverse reactions. ( 2.3 ) Administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic events (VTE) for the first four months of treatment. ( 2.3 ) 2.1 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 [see Clinical Studies (14) ] . If these mutations are not detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage and 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. 2.3 Prophylactic and Concomitant Medications Venous Thromboembolic Events When initiating treatment with LAZCLUZE in combination with amivantamab, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic events (VTE) for the first four months of treatment [see Warnings and Precautions (5.1) ]. 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. Dermatologic Adverse Reactions 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 Warnings and Precautions (5.3) ] . Administer an oral antibiotic (doxycycline or minocycline, 100 mg orally twice daily) starting on Day 1 for the first 12 weeks of treatment. After completion of oral antibiotic treatment, administer antibiotic lotion to the scalp (clindamycin 1% topical once daily) for the next 9 months of treatment. Administer non-comedogenic skin moisturizer (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents) on the face and whole body (except scalp). Wash hands and feet with 4% chlorhexidine solution once daily. Limit sun exposure during and for 2 months after treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions. 2.4 Dosage Modifications for Adverse Reactions The recommended LAZCLUZE dose reductions for adverse reactions are presented in Table 1. Table 1: Recommended Dose Reductions for Adverse Reactions for LAZCLUZE Dose at which the adverse reaction occurred 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Reduction 240 mg once daily (one 240 mg tablet) 160 mg once daily (two 80 mg tablets) 80 mg once daily (one 80 mg tablet) Discontinue LAZCLUZ…

5 WARNINGS AND PRECAUTIONS 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 [s…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 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.

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).

6 ADVERSE REACTIONS 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 reacti…