Lazertinib

12.1 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.

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 LAZCLUZE The recommended management and dosage modifications of LAZCLUZE for specific adverse reactions are presented in Table 2. Refer to the amivantamab prescribing information for information about dosage modifications for amivantamab. Table 2: Recommended Management and Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Venous Thromboembolic Events (VTE) [see Warnings and Precautions (5.1) ] Grade 2 or 3 Withhold LAZCLUZE and amivantamab. Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, resume LAZCLUZE and amivantamab at the same dose level, at the discretion of the healthcare provider. Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation Withhold LAZCLUZE and permanently discontinue amivantamab. Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, treatment can continue with LAZCLUZE at the same dose level at the

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) ] Ocular Toxicity [see Warnings and Precautions (5.4) ] 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

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.