ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Infusion-Related Reactions [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] Venous Thromboembolic Events [see Warnings and Precautions (5.3)] Dermatologic Adverse Reactions [see Warnings and Precautions (5.4)] Ocular Toxicity [see Warnings and Precautions (5.5)] Infusion-Related Reactions [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] Venous Thromboembolic Events [see Warnings and Precautions (5.3)] Dermatologic Adverse Reactions [see Warnings and Precautions (5.4)] Ocular Toxicity [see Warnings and Precautions (5.5)] RYBREVANT in Combination with LazertinibThe most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. 6.1) RYBREVANT in Combination with Carboplatin and PemetrexedThe most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma glutamyl transferase, and decreased albumin. 6.1) RYBREVANT as Single AgentThe most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. 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. The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. 6.1) The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma glutamyl transferase, and decreased albumin. 6.1) The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. 6.1) The most common Grade or laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. 6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. RYBREVANT in Combination with LazertinibThe data described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT in combination with lazertinib in the MARIPOSA study in 421 patients with previously untreated locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations [see Clinical Studies (14.1)] Patients received RYBREVANT intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib, 240 mg orally once daily, until disease progression or unacceptable toxicity. Among 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed for months or longer and 59% were exposed for greater than one year. The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, dry skin, hemorrhage, decreased appetite, pruritus, nausea, and ocular toxicity. The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium. RYBREVANT in Combination with Carboplatin and PemetrexedThe pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies:MARIPOSA-2 [see Clinical Studies (14.2)] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib. PAPILLON [see Clinical Studies (14.3)] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Patients received RYBREVANT intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC once every weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2once every weeks until disease progression or unacceptable toxicity. Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for months or longer and 24% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade to laboratory abnormalities (>= 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin. MARIPOSA-2 [see Clinical Studies (14.2)] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib. PAPILLON [see Clinical Studies (14.3)] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. RYBREVANT as Single AgentThe data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as single agent in CHRYSALIS [see Clinical Studies (14.4)] in 302 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT at 1,050 mg (for patient baseline body weight 80 kg) or 1,400 mg (for patient baseline body weight >= 80 kg) once weekly for weeks, then every weeks thereafter until disease progression or unacceptable toxicity. Among 302 patients who received RYBREVANT as single agent, 36% were exposed for months or longer and 12% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade to laboratory abnormalities (>= 2%) were increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase. First-line Treatment of NSCLC with Exon 19 deletions or Exon 21 L858R substitution mutationsThe safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutation in the MARIPOSA [see Clinical Studies (14.1)]. Patients received RYBREVANT intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib, 240 mg orally once daily. Among the 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed to RYBREVANT for >= months and 59% were exposed to RYBREVANT for 1 year. The median age of patients who received RYBREVANT in combination with lazertinib was 64 years (range: 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; and 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 RYBREVANT in combination with lazertinib. Serious adverse reactions occurring in >= 2% of patients included VTE (11%), pneumonia (4%), rash, and ILD/pneumonitis (2.9% each), COVID-19 (2.4%), pleural effusion and infusion-related reaction (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib 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 RYBREVANT due to an adverse reaction occurred in 34% of patients. Adverse reactions which resulted in permanent discontinuation in >= 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea.Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in >=5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in >= 5% of patients were rash and nail toxicity.The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, and nausea. The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.Table 10 summarizes the adverse reactions (>= 10%) in MARIPOSA.Table 10: Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSAAdverse ReactionRYBREVANT in combination with lazertinib (N=421) Osimertinib (N=428) All Grades (%) Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disorders Rash Grouped terms 8626481.2 Nail toxicity 7111340.7 Dry skin 251180.2 Pruritus240.5170.2Injury, poisoning and procedural complications Infusion-related reaction Applicable for RYBREVANT only 63600Musculoskeletal and connective tissue disorders Musculoskeletal pain 472.1391.9Gastrointestinal disorders Stomatitis 432.4270.5 Diarrhea 312.6450.9 Constipation290130 Nausea211.2140.2 Vomiting120.550 Abdominal pain 110100 Hemorrhoids100.22.10.2General disorders and administration site conditions Edema 432.680 Fatigue 323.8201.9 Pyrexia12090Vascular disorders Venous thromboembolism 361182.8 Hemorrhage 251131.2Nervous system disorders Paresthesia 351.7100.2 Dizziness 140100 Headache 130.2130Infections and infestations COVID-19261.7241.4 Conjunctivitis110.21.60Metabolism and nutrition disorders Decreased appetite241181.4Respiratory, thoracic and mediastinal disorders Cough 190230 Dyspnea 141.7173.5Eye disorders Ocular toxicity 160.770Psychiatric disorders Insomnia100110Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with lazertinib included ILD/pneumonitis (3.1%).Table 11 summarizes the laboratory abnormalities in MARIPOSA.Table 11: 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 baseline value and at least one post-treatment value for the specific lab test. RYBREVANT in combination with lazertinib (N=421) Osimertinib (N=428) Laboratory AbnormalityAll Grades (%) Grade or (%) All Grades (%) Grade or (%) Chemistry Decreased albumin898220.2 Increased ALT657292.6 Increased AST523.8361.9 Increased alkaline phosphatase450.5150.5 Decreased calcium (corrected)411.4270.7 Increased GGT392.6241.9 Decreased sodium387355 Decreased potassium305151.2 Increased creatinine260.7350.7 Decreased magnesium250.7100.2 Increased magnesium122.6204.8Hematology Decreased platelet count520.7571.4 Decreased hemoglobin473.8561.9 Decreased white blood cell381660.7 Decreased neutrophils151.4331.4. Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution MutationsThe safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 [see Clinical Studies (14.2)]. Eligible patients had locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations with progressive disease on or after treatment with osimertinib .Patients with asymptomatic or previously treated and stable intracranial metastases were eligible. Patients received RYBREVANT intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC once every weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2once every weeks until disease progression or unacceptable toxicity. Among patients who received RYBREVANT (n=130), 52% were exposed for months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: to 14.7 months). The median age was 62 years (range: 36 to 84 years); 62% were female; 48% were Asian, 46% were White, 2.3% Black or African American, 1.5% race not reported, 1.5% race unknown, 0.8% Alaska native; 7% were Hispanic or Latino; and 87% had baseline body weight 80 kg.Serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in 2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of RYBREVANT in >= 5% of patients were infusion-related reactions.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included infusion-related reaction, rash and fatigue.Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash.The most common adverse reactions >= 20% were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19.Table 12 summarizes the adverse reactions in MARIPOSA-2.Table 12: Adverse Reactions (>= 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2Adverse ReactionRYBREVANT Carboplatin PemetrexedCarboplatin Pemetrexed(N=130)(N=243)All Grades (%)Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disordersRash Grouped term 7211120Nail toxicity 452.30.40Pruritus15070Dry skin 1502.50General disorders and administration site conditionsInfusion-related reaction595.40.40Fatigue 513.8353.7Edema 361.5110.4Pyrexia120100Gastrointestinal disordersNausea450.8370.8Constipation390.8300Stomatitis 352.3110Vomiting250.8170.4Diarrhea 151.570.8Metabolism and nutrition disordersDecreased appetite310211.2Musculoskeletal and connective tissue disordersMusculoskeletal pain 303.1190.8Infections and infestationsCOVID-19211.5100Eye disordersOcular toxicity 1703.70Vascular disordersHemorrhage 140.84.90Venous Thromboembolism (VTE) 102.34.52.9Respiratory, thoracic and mediastinal disordersCough 140160.4Dyspnea 131.581.2Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, and interstitial lung disease.Table 13 summarizes the laboratory abnormalities in MARIPOSA-2.Table 13: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2RYBREVANT Carboplatin Pemetrexed (N=130) Carboplatin Pemetrexed (N=243) Laboratory AbnormalityAll Grades (%) Grade or (%) All Grades (%) Grade or (%) HematologyDecreased white blood cells91428519Decreased neutrophils74496425Decreased platelets7417589Decreased hemoglobin7112779Decreased lymphocytes69285818ChemistryDecreased albumin733.8260.4Decreased sodium4911306Increased aspartate aminotransferase470.8520.9Increased alkaline phosphatase420290.4Increased alanine aminotransferase393.9566Decreased magnesium380.8170.4Decreased potassium3711123.4Increased gamma-glutamyl transferase303.1411.3Decreased calcium (corrected)250110.9. First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with Exon 20 Insertion MutationsThe safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Clinical Studies (14.3)] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months). In patients that received carboplatin and pemetrexed alone, the median exposure was 6.7 months (range 0.0 to 25.3). The median age was 61 years (range: 27 to 86 years); 56% were female; 64% were Asian, 32% were White, 1.3% were Black or African American, race was not reported in 1.3% of patients; 89% were not Hispanic or Latino; 86% had baseline body weight 80 kg.Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in >= 2% of patients included rash, pneumonia, interstitial lung disease (ILD), pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >= 1% of patients were rash and ILD.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 64% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 38% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included rash and nail toxicity.Dose reductions of RYBREVANT due to an adverse reaction occurred in 36% of patients. Adverse reactions requiring dose reductions in >= 5% of patients included rash and nail toxicity.The most common adverse reactions (>= 20%) were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.Table 14 summarizes the adverse reactions in PAPILLON.Table 14: Adverse Reactions (>= 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLONRYBREVANT in Combination with Carboplatin and Pemetrexed (n=151) Carboplatin and Pemetrexed (n=155) Adverse Reaction Adverse reactions were graded using CTCAE version 5.0. All Grades (%) Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disorders Rash Grouped Term 9019190 Nail toxicity 62730 Dry skin 17060Gastrointestinal disorders Stomatitis 434110 Constipation400300.7 Nausea360.7420 Vomiting213.3190.7 Diarrhea213131.3 Hemorrhoids1211.30 Abdominal pain 110.780General disorders and administration site conditions Infusion-related reaction421.31.30 Fatigue 426453.9 Edema 401.3190 Pyrexia 17060Metabolism and nutrition disorders Decreased appetite362.6281.3Infections and infestations COVID-19242140.6 Pneumonia 13561.9Vascular disorders Hemorrhage 180.7111.9Respiratory, thoracic, and mediastinal disorders Cough 170160 Dyspnea 111.3163.2Investigations Weight decreased140.780Nervous system disorders Dizziness 110120Psychiatric disorders Insomnia110130Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis, and interstitial lung disease (ILD)/pneumonitis.Table 15 summarizes the laboratory abnormalities in PAPILLON.Table 15: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLONRYBREVANT in Combination with Carboplatin and Pemetrexed The denominator used to calculate the rate varied from 113 to 150 based on the number of patients with baseline value and at least one post-treatment value. Carboplatin in Combination with Pemetrexed The denominator used to calculate the rate varied from 119 to 154 based on the number of patients with baseline value and at least one post-treatment value. Laboratory Abnormality Adverse reactions were graded using CTCAE version 5.0 All Grades (%) Grade or (%) All Grades (%) Grade or (%) Hematology Decreased white blood cells89177610 Decreased hemoglobin79118513 Decreased neutrophils76366123 Decreased platelets70105412 Decreased lymphocytes61114913Chemistry Decreased albumin877341 Increased aspartate aminotransferase601611 Increased alanine aminotransferase574541 Decreased sodium557394 Increased alkaline phosphatase511280 Decreased potassium4411171 Decreased magnesium392301 Increased gamma-glutamyl transferase384434 Decreased calcium (corrected)271181. Previously Treated NSCLC Exon 20 Insertion MutationsThe safety data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial [see Clinical Studies (14.4)], whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for months or longer and 12% were exposed for greater than one year. The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight 80 kg.Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in >= 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in patients (1.5%) due to pneumonia and patient (0.8%) due to sudden death.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >= 1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash and paronychia.The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.Table 16 summarizes the adverse reactions in CHRYSALIS.Table 16: Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALISAdverse ReactionsRYBREVANT Adverse reactions were graded using CTCAE version 4.03 (N=129) All Grades (%)Grades or (%)Skin and subcutaneous tissue disorders Rash Grouped term 843.9 Pruritus180 Dry skin140General disorders and administration site conditions Infusion-related reaction643.1 Fatigue 332.3 Edema 270.8 Pyrexia130Infections and infestations Paronychia503.1 Pneumonia 100.8Musculoskeletal and connective tissue disorders Musculoskeletal pain 470Respiratory, thoracic, and mediastinal disorders Dyspnea 372.3 Cough 250Gastrointestinal disorders Nausea360 Stomatitis 260.8 Constipation230 Vomiting220 Diarrhea163.1 Abdominal Pain 110.8Vascular disorders Hemorrhage 190Metabolism and nutrition disorders Decreased appetite150Nervous system disorders Peripheral neuropathy 130 Dizziness120.8 Headache 100.8Clinically relevant adverse reactions in 10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).Table 17 summarizes the laboratory abnormalities in CHRYSALIS.Table 17: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALISLaboratory AbnormalityRYBREVANT The denominator used to calculate the rate was 126 based on the number of patients with baseline value and at least one post-treatment value. (N=129) All Grades (%) Grades or (%) Chemistry Decreased albumin798 Increased glucose564 Increased alkaline phosphatase534.8 Increased creatinine460 Increased alanine aminotransferase381.6 Decreased phosphate338 Increased aspartate aminotransferase330 Decreased magnesium270 Increased gamma-glutamyl transferase274 Decreased sodium274 Decreased potassium266Hematology Decreased lymphocytes368. 6.2 Postmarketing Experience. The following adverse reactions associated with the use of RYBREVANT were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune system disorders:Infusion-related reactions, including anaphylaxis/anaphylactic reactions.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Amivantamab-vmjw is bispecific antibody that binds to the extracellular domains of EGFR and MET.In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in mouse xenograft model of human NSCLC with an EGFR L858R mutation.. 12.2 Pharmacodynamics. The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.. 12.3 Pharmacokinetics. Amivantamab-vmjw exposures increased proportionally over dosage range from 350 to 1,750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as single agent. Steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.. DistributionThe amivantamab-vmjw mean (%CV) volume of distribution is (24%) L.. EliminationThe mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%).. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 21-88 years), body weight (31 to 140 kg), sex, race (White, Asian or Black or African American) and ethnicity (Hispanic/Latino or not Hispanic/Latino), mild or moderate renal impairment (eGFR 30 to 89 mL/min) or mild hepatic impairment [(total bilirubin <= ULN and AST ULN) or (ULN total bilirubin <= 1.5 times ULN)]. The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR 15 mL/min) or moderate to severe hepatic impairment (total bilirubin 1.5 times ULN and any AST) on amivantamab-vmjw pharmacokinetics has not been studied.. Body WeightIncreases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30 to 40% lower in patients who weighed >= 80 kg compared to patients with body weight 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed 80 kg and received 1,050 mg dose and patients who weighed >= 80 kg and received 1,400 mg dose.. 12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), of the 1,862 (0.2%) patients who received RYBREVANT as single agent or in combination developed treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 First Line Treatment of NSCLC with Exon 19 deletion or Exon 21 L858R Substitution Mutation MARIPOSA. The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], 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 RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib 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:RYBREVANT administered intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib administered at 240 mg orally once daily.Osimertinib administered at 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 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 RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25-88) years; 61% were female; 58% were Asian, 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 (34%) or (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 RYBREVANT plus lazertinib 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 statistically significant improvement in PFS by BICR assessment and OS for RYBREVANT in combination with lazertinib compared to osimertinib (see Table 18and Figures 1and 2). Efficacy results for RYBREVANT in combination with lazertinib are provided in Table 18.Table 18: Efficacy Results in MARIPOSA by BICR AssessmentRYBREVANT in combination with lazertinib (N=429) Osimertinib (N=429) CI confidence interval; NR not reached; NE not estimableProgression-free survival (PFS) Number of events (%)192 (45)252 (59) Median, months (95% CI)23.7 (19.1, 27.7)16.6 (14.8, 18.5) HR Stratified by mutation type (Exon 19del or Exon 21 L858R), prior brain metastases (yes or no), and Asian race (yes or no). Stratified Cox proportional hazards regression.(95% CI); p-value Stratified log-rank test. 0.70 (0.58, 0.85); p=0.0002Overall survival (OS) Number of events (%)173 (40)217 (51) Median, months (95% CI)NR (42.9, NE)36.7 (33.4, 41.0) HR (95% CI); p-value 0.75 (0.61, 0.92); p=0.0048Overall response rate (ORR)Confirmed responses based on the ITT population. ORR, (95% CI)78 (74, 82)73 (69, 78) Complete response, %5.43.5 Partial response, %7370Duration of response (DOR)In confirmed responders. Median (95% CI), months25.8 (20.1, NE)16.7 (14.8, 18.5) Patients with DOR >= months Based on observed rates., 8685 Patients with DOR >= 12 months % 6857Figure 1: Kaplan-Meier Curves of PFS by BICR Assessment in Patients with Previously Untreated NSCLCFigure 2: Kaplan-Meier Curves of OS in Patients with Previously Untreated NSCLCOut of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the RYBREVANT in combination with lazertinib arm and the osimertinib arm are summarized in Table 19.Table 19: Exploratory Analysis of Intracranial ORR and DOR by BICR Assessment in Subjects with Intracranial Lesions at BaselineRYBREVANT in combination with lazertinib (N=180) Osimertinib (N=187) CI confidence intervalIntracranial tumor response assessment Intracranial ORR Confirmed responses, (95% CI) 68 (60, 75)69 (62, 76) Complete response %5552Intracranial DORIn confirmed responders Number of responders122129 Patients with DOR >= 12 months Based on observed rates, 6659 Patients with DOR >= 18 months % 3523. RYBREVANT administered intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib administered at 240 mg orally once daily.. Osimertinib administered at dose of 80 mg orally once daily.. Figure 1. Figure 2. 14.2 Previously Treated NSCLC Patients with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations MARIPOSA-2. The efficacy of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131), carboplatin and pemetrexed (CP, N=263), or RYBREVANT as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between:RYBREVANT in combination with carboplatin and pemetrexed. RYBREVANT was administered intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity. Platinum-based chemotherapy with carboplatin and pemetrexed.For both arms, carboplatin was administered intravenously at area under the concentration-time curve mg/mL per minute (AUC 5) once every weeks, for up to 12 weeks and pemetrexed was administered intravenously at 500 mg/m 2once every weeks until disease progression or unacceptable toxicity. Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every weeks for the first 12 months and every 12 weeks thereafter.The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.A total of 394 patients were randomized between the two arms, 131 to the RYBREVANT-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients >= 65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was (40%) or (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.The trial demonstrated statistically significant improvement in PFS by BICR for RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.Efficacy results are summarized in Table 20.Table 20: Efficacy results in MARIPOSA-2RYBREVANT carboplatin+ pemetrexed (N=131) carboplatin+ pemetrexed (N=263) CI confidence interval; NE not estimableProgression-free survival (PFS)Blinded Independent Central Review by RECIST v1.1 Number of events74 (56%)171 (65%) Median, months (95% CI)6.3 (5.6, 8.4)4.2 (4.0, 4.4) HR (95% CI) Stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Stratified Cox proportional hazards regression.; p-value Stratified log-rank test. 0.48 (0.36, 0.64); p<0.0001Overall response rate,Confirmed responses. ORR, (95% CI)53% (44, 62)29% (23, 35) p-value Stratified logistic regression analysis. p<0.0001 Complete response0.8%0% Partial response52%29%Duration of response,(DOR) Median (95% CI), months6.9 (5.5, NE)5.6 (4.2, 9.6)Figure 3: Kaplan-Meier curve of PFS in Previously Treated NSCLC Patients by BICR assessment- MARIPOSA-2At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS. The median OS was 17.7 months (95% CI: 16.0, 22.4) in the ACP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with hazard ratio of 0.73 (95% CI: 0.54, 0.99).Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. Baseline disease assessment, including brain magnetic resonance imaging (MRI) was performed at treatment initiation. All patients underwent serial brain MRI during the trial.Pre-specified secondary analyses of intracranial ORR by BICR in the subset of 91 (23%) patients with baseline intracranial disease were performed. Data were only available for intracranial complete responses and not available for intracranial partial responses. Intracranial ORR was 20% (95% CI: 8, 39) in the 30 patients with baseline intracranial disease in the ACP arm and 7% (95% CI: 1.8, 16) in the 61 patients with baseline intracranial disease in the CP arm.. RYBREVANT in combination with carboplatin and pemetrexed. RYBREVANT was administered intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity. Platinum-based chemotherapy with carboplatin and pemetrexed.. Figure 3. 14.3 First Line Treatment of NSCLC with Exon 20 Insertion Mutations PAPILLON. The efficacy of RYBREVANT was evaluated in PAPILLON (NCT04538664), in randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 1, and adequate organ and bone marrow function. Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least weeks prior to randomization. Patients with medical history of interstitial lung disease or active ILD were excluded from the clinical study.A total of 308 patients were randomized 1:1 to receive RYBREVANT in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received RYBREVANT intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve mg/mL per minute (AUC 5) once every weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg/m 2on once every weeks until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1) and prior brain metastases (yes or no). The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Cross-over to single agent RYBREVANT was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.The median age was 62 (range: 27 to 92) years, with 40% of the patients >= 65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was (35%) or (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.PAPILLON demonstrated statistically significant improvement in progression free survival for patients randomized to RYBREVANT in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed.Efficacy results are summarized in Table 21 and Figure 4.Table 21: Efficacy Results in PAPILLONRYBREVANT+ carboplatin+ pemetrexed (N=153) carboplatin+ pemetrexed (N=155) CI confidence intervalProgression-free survival (PFS) Number of events (%)84 (55)132 (85) Median, months (95% CI)11.4 (9.8, 13.7)6.7 (5.6, 7.3) HR (95% CI)0.40 (0.30, 0.53) p-valuep<0.0001Overall response rate (ORR)Confirmed responses. ORR, (95% CI)67 (59, 75)36 (29, 44) Complete response, %41 Partial response, %6336Duration of response (DOR)In confirmed responders. Median (95% CI), months10.1 (8.5, 13.9)5.6 (4.4, 6.9)Figure 4: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment PAPILLON StudyWhile OS results were immature at the current analysis, with 44% of pre-specified deaths for the final analysis reported, no trend towards detriment was observed. Seventy-five (48%) of the treated patients crossed over from the carboplatin and pemetrexed arm after confirmation of disease progression to receive RYBREVANT as single agent.. Figure 3. 14.4 Previously Treated NSCLC with Exon 20 Insertion Mutations CHRYSALIS. The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last years were not eligible for the study.In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360 (R)CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified. Patients received RYBREVANT at 1,050 mg (for patient baseline body weight 80 kg) or 1,400 mg (for patient baseline body weight >= 80 kg) once weekly for weeks, then every weeks thereafter until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight 80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was (range: to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.Efficacy results are summarized in Table 22.Table 22: Efficacy Results for CHRYSALISPrior Platinum-based Chemotherapy Treated (N=81) Based on Kaplan-Meier estimates. NE=Not Estimable; CI=confidence interval. Overall response rate(95% CI) 40% (29%, 51%) Complete response (CR)3.7% Partial response (PR)36%Duration of response (DOR) Median, months (95% CI), months11.1 (6.9, NE) Patients with DOR >= months63%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. RYBREVANT in Combination with LazertinibThe data described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT in combination with lazertinib in the MARIPOSA study in 421 patients with previously untreated locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations [see Clinical Studies (14.1)] Patients received RYBREVANT intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib, 240 mg orally once daily, until disease progression or unacceptable toxicity. Among 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed for months or longer and 59% were exposed for greater than one year. The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, dry skin, hemorrhage, decreased appetite, pruritus, nausea, and ocular toxicity. The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium. RYBREVANT in Combination with Carboplatin and PemetrexedThe pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies:MARIPOSA-2 [see Clinical Studies (14.2)] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib. PAPILLON [see Clinical Studies (14.3)] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Patients received RYBREVANT intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC once every weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2once every weeks until disease progression or unacceptable toxicity. Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for months or longer and 24% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade to laboratory abnormalities (>= 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin. MARIPOSA-2 [see Clinical Studies (14.2)] in 130 patients with previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib. PAPILLON [see Clinical Studies (14.3)] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. RYBREVANT as Single AgentThe data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as single agent in CHRYSALIS [see Clinical Studies (14.4)] in 302 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT at 1,050 mg (for patient baseline body weight 80 kg) or 1,400 mg (for patient baseline body weight >= 80 kg) once weekly for weeks, then every weeks thereafter until disease progression or unacceptable toxicity. Among 302 patients who received RYBREVANT as single agent, 36% were exposed for months or longer and 12% were exposed for greater than one year. In the safety population, the most common (>= 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade to laboratory abnormalities (>= 2%) were increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase. First-line Treatment of NSCLC with Exon 19 deletions or Exon 21 L858R substitution mutationsThe safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutation in the MARIPOSA [see Clinical Studies (14.1)]. Patients received RYBREVANT intravenously at 1,050 mg (for patients 80 kg) or 1,400 mg (for patients >= 80 kg) once weekly for weeks, then every weeks thereafter starting at week in combination with lazertinib, 240 mg orally once daily. Among the 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed to RYBREVANT for >= months and 59% were exposed to RYBREVANT for 1 year. The median age of patients who received RYBREVANT in combination with lazertinib was 64 years (range: 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; and 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 RYBREVANT in combination with lazertinib. Serious adverse reactions occurring in >= 2% of patients included VTE (11%), pneumonia (4%), rash, and ILD/pneumonitis (2.9% each), COVID-19 (2.4%), pleural effusion and infusion-related reaction (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib 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 RYBREVANT due to an adverse reaction occurred in 34% of patients. Adverse reactions which resulted in permanent discontinuation in >= 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea.Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in >=5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in >= 5% of patients were rash and nail toxicity.The most common adverse reactions (>= 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, and nausea. The most common Grade or laboratory abnormalities (>= 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.Table 10 summarizes the adverse reactions (>= 10%) in MARIPOSA.Table 10: Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSAAdverse ReactionRYBREVANT in combination with lazertinib (N=421) Osimertinib (N=428) All Grades (%) Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disorders Rash Grouped terms 8626481.2 Nail toxicity 7111340.7 Dry skin 251180.2 Pruritus240.5170.2Injury, poisoning and procedural complications Infusion-related reaction Applicable for RYBREVANT only 63600Musculoskeletal and connective tissue disorders Musculoskeletal pain 472.1391.9Gastrointestinal disorders Stomatitis 432.4270.5 Diarrhea 312.6450.9 Constipation290130 Nausea211.2140.2 Vomiting120.550 Abdominal pain 110100 Hemorrhoids100.22.10.2General disorders and administration site conditions Edema 432.680 Fatigue 323.8201.9 Pyrexia12090Vascular disorders Venous thromboembolism 361182.8 Hemorrhage 251131.2Nervous system disorders Paresthesia 351.7100.2 Dizziness 140100 Headache 130.2130Infections and infestations COVID-19261.7241.4 Conjunctivitis110.21.60Metabolism and nutrition disorders Decreased appetite241181.4Respiratory, thoracic and mediastinal disorders Cough 190230 Dyspnea 141.7173.5Eye disorders Ocular toxicity 160.770Psychiatric disorders Insomnia100110Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with lazertinib included ILD/pneumonitis (3.1%).Table 11 summarizes the laboratory abnormalities in MARIPOSA.Table 11: 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 baseline value and at least one post-treatment value for the specific lab test. RYBREVANT in combination with lazertinib (N=421) Osimertinib (N=428) Laboratory AbnormalityAll Grades (%) Grade or (%) All Grades (%) Grade or (%) Chemistry Decreased albumin898220.2 Increased ALT657292.6 Increased AST523.8361.9 Increased alkaline phosphatase450.5150.5 Decreased calcium (corrected)411.4270.7 Increased GGT392.6241.9 Decreased sodium387355 Decreased potassium305151.2 Increased creatinine260.7350.7 Decreased magnesium250.7100.2 Increased magnesium122.6204.8Hematology Decreased platelet count520.7571.4 Decreased hemoglobin473.8561.9 Decreased white blood cell381660.7 Decreased neutrophils151.4331.4. Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution MutationsThe safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 [see Clinical Studies (14.2)]. Eligible patients had locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations with progressive disease on or after treatment with osimertinib .Patients with asymptomatic or previously treated and stable intracranial metastases were eligible. Patients received RYBREVANT intravenously at 1,400 mg (for patients 80 kg) or 1,750 mg (for patients >= 80 kg) once weekly through weeks, then every weeks with dose of 1,750 mg (for patients 80 kg) or 2,100 mg (for patients >= 80 kg) starting at Week until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC once every weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2once every weeks until disease progression or unacceptable toxicity. Among patients who received RYBREVANT (n=130), 52% were exposed for months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: to 14.7 months). The median age was 62 years (range: 36 to 84 years); 62% were female; 48% were Asian, 46% were White, 2.3% Black or African American, 1.5% race not reported, 1.5% race unknown, 0.8% Alaska native; 7% were Hispanic or Latino; and 87% had baseline body weight 80 kg.Serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in 2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of RYBREVANT in >= 5% of patients were infusion-related reactions.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included infusion-related reaction, rash and fatigue.Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash.The most common adverse reactions >= 20% were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19.Table 12 summarizes the adverse reactions in MARIPOSA-2.Table 12: Adverse Reactions (>= 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2Adverse ReactionRYBREVANT Carboplatin PemetrexedCarboplatin Pemetrexed(N=130)(N=243)All Grades (%)Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disordersRash Grouped term 7211120Nail toxicity 452.30.40Pruritus15070Dry skin 1502.50General disorders and administration site conditionsInfusion-related reaction595.40.40Fatigue 513.8353.7Edema 361.5110.4Pyrexia120100Gastrointestinal disordersNausea450.8370.8Constipation390.8300Stomatitis 352.3110Vomiting250.8170.4Diarrhea 151.570.8Metabolism and nutrition disordersDecreased appetite310211.2Musculoskeletal and connective tissue disordersMusculoskeletal pain 303.1190.8Infections and infestationsCOVID-19211.5100Eye disordersOcular toxicity 1703.70Vascular disordersHemorrhage 140.84.90Venous Thromboembolism (VTE) 102.34.52.9Respiratory, thoracic and mediastinal disordersCough 140160.4Dyspnea 131.581.2Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, and interstitial lung disease.Table 13 summarizes the laboratory abnormalities in MARIPOSA-2.Table 13: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2RYBREVANT Carboplatin Pemetrexed (N=130) Carboplatin Pemetrexed (N=243) Laboratory AbnormalityAll Grades (%) Grade or (%) All Grades (%) Grade or (%) HematologyDecreased white blood cells91428519Decreased neutrophils74496425Decreased platelets7417589Decreased hemoglobin7112779Decreased lymphocytes69285818ChemistryDecreased albumin733.8260.4Decreased sodium4911306Increased aspartate aminotransferase470.8520.9Increased alkaline phosphatase420290.4Increased alanine aminotransferase393.9566Decreased magnesium380.8170.4Decreased potassium3711123.4Increased gamma-glutamyl transferase303.1411.3Decreased calcium (corrected)250110.9. First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with Exon 20 Insertion MutationsThe safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Clinical Studies (14.3)] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months). In patients that received carboplatin and pemetrexed alone, the median exposure was 6.7 months (range 0.0 to 25.3). The median age was 61 years (range: 27 to 86 years); 56% were female; 64% were Asian, 32% were White, 1.3% were Black or African American, race was not reported in 1.3% of patients; 89% were not Hispanic or Latino; 86% had baseline body weight 80 kg.Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in >= 2% of patients included rash, pneumonia, interstitial lung disease (ILD), pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >= 1% of patients were rash and ILD.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 64% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 38% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included rash and nail toxicity.Dose reductions of RYBREVANT due to an adverse reaction occurred in 36% of patients. Adverse reactions requiring dose reductions in >= 5% of patients included rash and nail toxicity.The most common adverse reactions (>= 20%) were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.Table 14 summarizes the adverse reactions in PAPILLON.Table 14: Adverse Reactions (>= 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLONRYBREVANT in Combination with Carboplatin and Pemetrexed (n=151) Carboplatin and Pemetrexed (n=155) Adverse Reaction Adverse reactions were graded using CTCAE version 5.0. All Grades (%) Grade or (%) All Grades (%) Grade or (%) Skin and subcutaneous tissue disorders Rash Grouped Term 9019190 Nail toxicity 62730 Dry skin 17060Gastrointestinal disorders Stomatitis 434110 Constipation400300.7 Nausea360.7420 Vomiting213.3190.7 Diarrhea213131.3 Hemorrhoids1211.30 Abdominal pain 110.780General disorders and administration site conditions Infusion-related reaction421.31.30 Fatigue 426453.9 Edema 401.3190 Pyrexia 17060Metabolism and nutrition disorders Decreased appetite362.6281.3Infections and infestations COVID-19242140.6 Pneumonia 13561.9Vascular disorders Hemorrhage 180.7111.9Respiratory, thoracic, and mediastinal disorders Cough 170160 Dyspnea 111.3163.2Investigations Weight decreased140.780Nervous system disorders Dizziness 110120Psychiatric disorders Insomnia110130Clinically relevant adverse reactions in 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis, and interstitial lung disease (ILD)/pneumonitis.Table 15 summarizes the laboratory abnormalities in PAPILLON.Table 15: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLONRYBREVANT in Combination with Carboplatin and Pemetrexed The denominator used to calculate the rate varied from 113 to 150 based on the number of patients with baseline value and at least one post-treatment value. Carboplatin in Combination with Pemetrexed The denominator used to calculate the rate varied from 119 to 154 based on the number of patients with baseline value and at least one post-treatment value. Laboratory Abnormality Adverse reactions were graded using CTCAE version 5.0 All Grades (%) Grade or (%) All Grades (%) Grade or (%) Hematology Decreased white blood cells89177610 Decreased hemoglobin79118513 Decreased neutrophils76366123 Decreased platelets70105412 Decreased lymphocytes61114913Chemistry Decreased albumin877341 Increased aspartate aminotransferase601611 Increased alanine aminotransferase574541 Decreased sodium557394 Increased alkaline phosphatase511280 Decreased potassium4411171 Decreased magnesium392301 Increased gamma-glutamyl transferase384434 Decreased calcium (corrected)271181. Previously Treated NSCLC Exon 20 Insertion MutationsThe safety data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial [see Clinical Studies (14.4)], whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for months or longer and 12% were exposed for greater than one year. The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight 80 kg.Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in >= 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in patients (1.5%) due to pneumonia and patient (0.8%) due to sudden death.Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in >= 1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in >= 5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in >= 2% of patients included rash and paronychia.The most common adverse reactions (>= 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade to laboratory abnormalities (>= 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.Table 16 summarizes the adverse reactions in CHRYSALIS.Table 16: Adverse Reactions (>= 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALISAdverse ReactionsRYBREVANT Adverse reactions were graded using CTCAE version 4.03 (N=129) All Grades (%)Grades or (%)Skin and subcutaneous tissue disorders Rash Grouped term 843.9 Pruritus180 Dry skin140General disorders and administration site conditions Infusion-related reaction643.1 Fatigue 332.3 Edema 270.8 Pyrexia130Infections and infestations Paronychia503.1 Pneumonia 100.8Musculoskeletal and connective tissue disorders Musculoskeletal pain 470Respiratory, thoracic, and mediastinal disorders Dyspnea 372.3 Cough 250Gastrointestinal disorders Nausea360 Stomatitis 260.8 Constipation230 Vomiting220 Diarrhea163.1 Abdominal Pain 110.8Vascular disorders Hemorrhage 190Metabolism and nutrition disorders Decreased appetite150Nervous system disorders Peripheral neuropathy 130 Dizziness120.8 Headache 100.8Clinically relevant adverse reactions in 10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).Table 17 summarizes the laboratory abnormalities in CHRYSALIS.Table 17: Select Laboratory Abnormalities (>= 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALISLaboratory AbnormalityRYBREVANT The denominator used to calculate the rate was 126 based on the number of patients with baseline value and at least one post-treatment value. (N=129) All Grades (%) Grades or (%) Chemistry Decreased albumin798 Increased glucose564 Increased alkaline phosphatase534.8 Increased creatinine460 Increased alanine aminotransferase381.6 Decreased phosphate338 Increased aspartate aminotransferase330 Decreased magnesium270 Increased gamma-glutamyl transferase274 Decreased sodium274 Decreased potassium266Hematology Decreased lymphocytes368.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Amivantamab-vmjw is low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has molecular weight of approximately 148 kDa. RYBREVANT (R)(amivantamab-vmjw) injection for intravenous infusion is sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7. Each RYBREVANT vial contains 350 mg (50 mg/mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. 2.3, 2.5, 2.6, 2.7) Administer premedications as recommended. 2.5) Administer via peripheral line on Week and Week to reduce the risk of infusion-related reactions. 2.8) Administer RYBREVANT in combination with chemotherapy weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 7. 2.3) Administer RYBREVANT in combination with lazertinib or RYBREVANT as single agent weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 7. 2.4) When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment. 2.4) Administer diluted RYBREVANT intravenously according to the infusion rates in Tables and 9. 2.8) Body Weight (at Baseline)DosageRecommended DoseRYBREVANT in Combination with Carboplatin and PemetrexedLess than 80 kgWeeks 1-41,400 mgWeek onwards1,750 mgGreater than or equal to 80 kgWeeks 1-41,750 mgWeek onwards2,100 mgRYBREVANT in Combination with Lazertinib or RYBREVANT as Single AgentLess than 80 kgWeeks 1-5 Week onwards 1,050 mgGreater than or equal to 80 kgWeeks 1-5 Week onwards 1,400 mg. The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. 2.3, 2.5, 2.6, 2.7) Administer premedications as recommended. 2.5) Administer via peripheral line on Week and Week to reduce the risk of infusion-related reactions. 2.8) Administer RYBREVANT in combination with chemotherapy weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 7. 2.3) Administer RYBREVANT in combination with lazertinib or RYBREVANT as single agent weekly for weeks, with the initial dose as split infusion in Week on Day and Day 2, then administer every weeks starting at Week 7. 2.4) When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment. 2.4) Administer diluted RYBREVANT intravenously according to the infusion rates in Tables and 9. 2.8) 2.1 Important Dosage Information. Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)]. Administer diluted RYBREVANT intravenously according to the infusion rates in Tables and 9, with the initial dose as split infusion on Week on Day and Day [see Dosage and Administration (2.8)]. Administer RYBREVANT via peripheral line for Week Day and and Week to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Dosage and Administration (2.4)]. Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)]. Administer diluted RYBREVANT intravenously according to the infusion rates in Tables and 9, with the initial dose as split infusion on Week on Day and Day [see Dosage and Administration (2.8)]. Administer RYBREVANT via peripheral line for Week Day and and Week to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.8)]. When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Dosage and Administration (2.4)]. 2.2 Patient Selection. Select patients for treatment with RYBREVANT based on the presence of mutation as detected by an FDA-approved test.Table 1: Patient SelectionIndicationTreatment RegimenSource for TestingInformation on FDA approved tests is available at: http://www.fda.gov/CompanionDiagnostics.First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations [see Indications and Usage (1.1)] RYBREVANT in combination with lazertinibTumor or plasma specimens.Testing may be performed at any time from initial diagnosis.Testing does not need to be repeated once EGFR mutation status has been established.Previously treated locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (progressive disease on an EGFR tyrosine kinase inhibitor) [see Indications and Usage (1.2)] RYBREVANT in combination with carboplatin and pemetrexedFirst-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.3)] RYBREVANT in combination with carboplatin and pemetrexedPreviously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.4)] RYBREVANT as single agent. Tumor or plasma specimens.. Testing may be performed at any time from initial diagnosis.. Testing does not need to be repeated once EGFR mutation status has been established.. 2.3 Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the Treatment of NSCLC Every 3-week dosing. The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 2.Table 2: Recommended Dosage for RYBREVANT in Combination with Carboplatin and PemetrexedBody weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended DoseDosing ScheduleLess than 80 kg1,400 mgWeekly (total of doses) from Weeks to Week - split infusion on Day and Day 2Weeks to - infusion on Day 1Weeks and - no dose 1,750 mgEvery weeks starting at Week onwardsGreater than or equal to 80 kg1,750 mgWeekly (total of doses) from Weeks to Week - split infusion on Day and Day 2Weeks to - infusion on Day 1Weeks and - no dose 2,100 mgEvery weeks starting at Week onwardsThe recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 3.Table 3: Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and PemetrexedRYBREVANT in Combination with Carboplatin and PemetrexedAdminister the regimen in the following order: pemetrexed first, carboplatin second, and RYBREVANT last. DrugDoseDuration/Timing of TreatmentPemetrexedPemetrexed 500 mg/m 2intravenously Refer to the pemetrexed Full Prescribing Information for complete information. Every weeks, continue until disease progression or unacceptable toxicity.CarboplatinCarboplatin AUC intravenously Refer to the carboplatin Full Prescribing Information for complete information. Every weeks for up to 12 weeks.RYBREVANTRYBREVANT intravenously See Table 2. Every weeks, continue until disease progression or unacceptable toxicity.. Week - split infusion on Day and Day 2. Weeks to - infusion on Day 1. Weeks and - no dose. Week - split infusion on Day and Day 2. Weeks to - infusion on Day 1. Weeks and - no dose. 2.4 Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent Every 2-week dosing. The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as single agent, based on baseline body weight, are provided in Table 4. Administer RYBREVANT until disease progression or unacceptable toxicity.Table 4: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as Single AgentBody weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended DoseDosing ScheduleLess than 80 kg1,050 mgWeekly (total of doses) from Weeks to Week - split infusion on Day and Day 2Weeks to - infusion on Day 1Week - no dose Every weeks starting at Week onwardsGreater than or equal to 80 kg1,400 mgWeekly (total of doses) from Weeks to Week - split infusion on Day and Day 2Weeks to - infusion on Day 1Week - no dose Every weeks starting at Week onwards. Week - split infusion on Day and Day 2. Weeks to - infusion on Day 1. Week - no dose. Week - split infusion on Day and Day 2. Weeks to - infusion on Day 1. Week - no dose. RYBREVANT in Combination with Lazertinib. Order of AdministrationWhen given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day. Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT in combination with lazertinib until disease progression or unacceptable toxicity.. Concomitant MedicationsWhen initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (5.3)]. 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. Refer to the lazertinib prescribing information for information about concomitant medications. When initiating treatment with RYBREVANT in combination with lazertinib, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions [see Warnings and Precautions (5.4)]. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Refer to the lazertinib prescribing information for information about concomitant medications. 2.5 Recommended Premedications. Administer premedications as described in Table . After prolonged dose interruptions, restart the following Week Day premedications upon re-initiation: intravenous dexamethasone, diphenhydramine, and acetaminophen.Table 5: PremedicationsPremedication ScheduleMedication and FrequencyRoute of AdministrationDosing Window Prior to RYBREVANT AdministrationInitial dose as split infusionDexamethasone mg (or equivalent) Oral48 hoursWeek Day -2twice dailyInitial dose as split infusionDexamethasone mg (or equivalent) Oral24 hoursWeek Day -1twice dailyInitial dose as split infusionDexamethasone mg (or equivalent) OralOne hourWeek Day 1one doseDexamethasone 20 mg (or equivalent) one dose Intravenous45 to 60 minutesDiphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral30 to 60 minutesIntravenous15 to 30 minutesAcetaminophen 650 mg to 1,000 mg one dose Oral30 to 60 minutesIntravenous15 to 30 minutesInitial dose as split infusionDexamethasone 10 mg (or equivalent) Intravenous45 to 60 minutesWeek Day 2one doseDiphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral30 to 60 minutesIntravenous15 to 30 minutesAcetaminophen 650 mg to 1,000 mg one dose Oral30 to 60 minutesIntravenous15 to 30 minutesAll subsequent infusionsDiphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral30 to 60 minutesIntravenous15 to 30 minutesAcetaminophen 650 mg to 1,000 mg one dose Oral30 to 60 minutesIntravenous15 to 30 minutesOptional: Dexamethasone 10 mg (or equivalent) one dose Intravenous45 to 60 minutes. 2.6 Dosage Modifications for Adverse Reactions. The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.Table 6: Dose Reductions for Adverse Reactions for RYBREVANTDose at which the adverse reaction occurred1 stDose Reduction ndDose Reduction rdDose Reduction 1,050 mg700 mg350 mgDiscontinue RYBREVANT1,400 mg1,050 mg700 mg1,750 mg1,400 mg1,050 mg2,100 mg1,750 mg1,400 mgThe recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.Table 7: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANTAdverse ReactionSeverityDosage ModificationsInfusion-related reactions (IRR) [see Warnings and Precautions (5.1)] Grade to 2Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve.Resume the infusion at 50% of the infusion rate at which the reaction occurred.If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8and 9). Include corticosteroid with premedications for subsequent dose (see Table 5). Grade 3Interrupt RYBREVANT infusion and administer supportive care medications. Continuously monitor patient until reaction symptoms resolve.Resume the infusion at 50% of the infusion rate at which the reaction occurred.If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8and 9). Include corticosteroid with premedications for subsequent dose (see Table 5). For recurrent Grade 3, permanently discontinue RYBREVANT. Grade or any Grade anaphylaxis anaphylactic reactionsPermanently discontinue RYBREVANT.Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] Any GradeWithhold RYBREVANT if ILD/pneumonitis is suspected.Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed.Venous Thromboembolic (VTE) Events [Applies to the combination with lazertinib, see Warnings and Precautions (5.3)] Grade or 3Withhold RYBREVANT and lazertinib.Administer anticoagulant treatment as clinically indicated.Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level, at the discretion of the healthcare provider.Grade or recurrent Grade or despite therapeutic level anticoagulationWithhold lazertinib and permanently discontinue RYBREVANT.Administer anticoagulant treatment as clinically indicated.Once anticoagulant treatment has been initiated, treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider.Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.4)] Grade or Grade 2Initiate supportive care management.Reassess after weeks; if rash does not improve, consider dose reduction.Grade 3Withhold RYBREVANT and initiate supportive care management.Upon recovery to <= Grade 2, resume RYBREVANT at reduced dose.If no improvement within weeks, permanently discontinue treatment.Grade 4Permanently discontinue RYBREVANT.Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN))Permanently discontinue RYBREVANT.Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3Withhold RYBREVANT until recovery to <= Grade or baseline.Resume at the same dose if recovery occurs within week.Resume at reduced dose if recovery occurs after week but within weeks.Permanently discontinue if recovery does not occur within weeks.Grade 4Withhold RYBREVANT until recovery to <= Grade or baseline.Resume at reduced dose if recovery occurs within weeks.Permanently discontinue if recovery does not occur within weeks.Permanently discontinue for recurrent Grade reactions.. Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve.. Resume the infusion at 50% of the infusion rate at which the reaction occurred.. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8and 9). Include corticosteroid with premedications for subsequent dose (see Table 5). Interrupt RYBREVANT infusion and administer supportive care medications. Continuously monitor patient until reaction symptoms resolve.. Resume the infusion at 50% of the infusion rate at which the reaction occurred.. If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8and 9). Include corticosteroid with premedications for subsequent dose (see Table 5). For recurrent Grade 3, permanently discontinue RYBREVANT. Permanently discontinue RYBREVANT.. Withhold RYBREVANT if ILD/pneumonitis is suspected.. Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed.. Withhold RYBREVANT and lazertinib.. Administer anticoagulant treatment as clinically indicated.. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level, at the discretion of the healthcare provider.. Withhold lazertinib and permanently discontinue RYBREVANT.. Administer anticoagulant treatment as clinically indicated.. Once anticoagulant treatment has been initiated, treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider.. Initiate supportive care management.. Reassess after weeks; if rash does not improve, consider dose reduction.. Withhold RYBREVANT and initiate supportive care management.. Upon recovery to <= Grade 2, resume RYBREVANT at reduced dose.. If no improvement within weeks, permanently discontinue treatment.. Permanently discontinue RYBREVANT.. Permanently discontinue RYBREVANT.. Withhold RYBREVANT until recovery to <= Grade or baseline.. Resume at the same dose if recovery occurs within week.. Resume at reduced dose if recovery occurs after week but within weeks.. Permanently discontinue if recovery does not occur within weeks.. Withhold RYBREVANT until recovery to <= Grade or baseline.. Resume at reduced dose if recovery occurs within weeks.. Permanently discontinue if recovery does not occur within weeks.. Permanently discontinue for recurrent Grade reactions.. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with LazertinibWhen administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first.Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib.. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and PemetrexedWhen administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.. 2.7 Preparation. Dilute and prepare RYBREVANT for intravenous infusion before administration.Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.Determine the dose required and number of RYBREVANT vials needed based on patients baseline weight [see Dosage and Administration (2.3)] Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw. Withdraw and then discard volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).Withdraw mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.Gently invert the bag to mix the solution. Do not shake.Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15C to 25C (59F to 77F).. Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.. Determine the dose required and number of RYBREVANT vials needed based on patients baseline weight [see Dosage and Administration (2.3)] Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw. Withdraw and then discard volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).. Withdraw mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.. Gently invert the bag to mix the solution. Do not shake.. Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15C to 25C (59F to 77F).. 2.8 Administration. Administer the diluted RYBREVANT solution [see Dosage and Administration (2.7)] by intravenous infusion using an infusion set fitted with flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.The administration set with filter, mustbe primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion. Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.. Administer the diluted RYBREVANT solution [see Dosage and Administration (2.7)] by intravenous infusion using an infusion set fitted with flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.. The administration set with filter, mustbe primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion. Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.. RYBREVANT in Combination with Carboplatin and PemetrexedAdminister RYBREVANT in combination with carboplatin and pemetrexed infusions every weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.Administer RYBREVANT via peripheral line on Week and Week to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. RYBREVANT may be administered via central line for subsequent weeks.For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.Table 8: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLCBody Weight Less Than 80 kgWeekDose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion RateIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day and 6-8 hours for day 2. Subsequent infusion time is approximately hours.(mL/hr)Week (split dose infusion) Week Day 350 mg5075 Week Day 1,050 mg3350Week 21,400 mg65Week 31,400 mg85Week 41,400 mg125Weeks and 6No doseWeek and every weeks thereafter1,750 mg125Body Weight Greater Than or Equal to 80 kgWeekDose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week (split dose infusion) Week Day 350 mg5075 Week Day 1,400 mg2550Week 21,750 mg65Week 31,750 mg85Week 41,750 mg125Week and 6No doseWeek and every weeks thereafter2,100 mg125. Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.. Administer RYBREVANT via peripheral line on Week and Week to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. RYBREVANT may be administered via central line for subsequent weeks.. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.. Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.. RYBREVANT in Combination with Lazertinib or RYBREVANT as Single AgentAdminister RYBREVANT as single agent infusion every weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.Administer RYBREVANT via peripheral line on Week and Week 2, to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. RYBREVANT may be administered via central line for subsequent weeks.For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.Table 9: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single AgentBody Weight Less Than 80 kgWeekDose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion RateIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day and 6-8 hours for day 2. Subsequent infusion time is approximately hours.(mL/hr)Week (split dose infusion) Week Day 350 mg5075 Week Day 700 mg5075Week 21,050 mg85Week 31,050 mg125Week 41,050 mg125Week 51,050 mg125Week 6No doseWeek and every weeks thereafter1,050 mg125Body Weight Greater Than or Equal to 80 kgWeekDose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week (split dose infusion) Week Day 350 mg5075 Week Day 1,050 mg3550Week 21,400 mg65Week 31,400 mg85Week 41,400 mg125Week 51,400 mg125Week 6No doseWeek and every weeks thereafter1,400 mg125. Administer RYBREVANT as single agent infusion every weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.. Administer RYBREVANT via peripheral line on Week and Week 2, to reduce the risk of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)]. RYBREVANT may be administered via central line for subsequent weeks.. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.. When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in single-dose vial.. Injection: 350 mg/7 mL (50 mg/mL) solution in single-dose vial 3).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. RYBREVANT can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months after the last dose of RYBREVANT.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were >= 65 years of age and 12% were >= 75 years of age.Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were >= 65 years of age and 10% were >= 75 years of age.Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were >= 65 years of age and 8% were >= 75 years of age.Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as single agent in the CHRYSALIS study, 39% were >= 65 years of age and 11% were >= 75 years of age.No clinically important differences in safety or efficacy were observed between patients who were >= 65 years of age and younger patients.. Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were >= 65 years of age and 12% were >= 75 years of age.. Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were >= 65 years of age and 10% were >= 75 years of age.. Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were >= 65 years of age and 8% were >= 75 years of age.. Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as single agent in the CHRYSALIS study, 39% were >= 65 years of age and 11% were >= 75 years of age.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedRYBREVANT (R)(amivantamab-vmjw) injection is sterile, preservative-free, colorless to pale yellow solution for intravenous infusion. Each single-dose vial contains 350 mg/7 mL (50 mg/mL) RYBREVANT. Each vial is individually packed in single carton. (NDC 57894-501-01). Storage and HandlingStore in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

IMMUNOGENICITY.

12.6 Immunogenicity. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), of the 1,862 (0.2%) patients who received RYBREVANT as single agent or in combination developed treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RYBREVANT is bispecific EGF receptor-directed and MET receptor-directed antibody indicated:in combination with lazertinib 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, 2.2) in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. 1, 2.2) in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. 1, 2.2) as single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. 1, 2.2) in combination with lazertinib 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, 2.2) in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. 1, 2.2) in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. 1, 2.2) as single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. 1, 2.2) 1.1 First-Line Treatment of NSCLC with EGFRExon 19 Deletions or Exon 21 L858R Substitution Mutations. RYBREVANT, in combination with lazertinib, 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 (2.2)] . 1.2 Previously Treated NSCLC with EGFRExon 19 Deletions or Exon 21 L858R Substitution Mutations. RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2)] . 1.3 First-Line Treatment of NSCLC with EGFRExon 20 Insertion Mutations. RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] . 1.4 Previously Treated NSCLC with EGFRExon 20 Insertion Mutations. RYBREVANT is indicated as single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] whose disease has progressed on or after platinum-based chemotherapy.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. Infusion-Related ReactionsAdvise patients that RYBREVANT can cause infusion-related reactions (IRR), including anaphylaxis. Instruct patients to take glucocorticoids 48 hours prior to the first RYBREVANT infusion to reduce the risk of IRR [see Dosage and Administration (2.5)]. The majority of infusion-related reactions occurred with the first infusion. Advise patients to alert their healthcare provider immediately for any signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)] . Interstitial Lung Disease/PneumonitisAdvise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)] . Venous Thromboembolic Events with Concomitant Use with LazertinibWhen RYBREVANT is used in combination with lazertinib, advise patients of the risks of serious and life threatening venous thromboembolic (VTE) events, 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 [see Warnings and Precautions (5.3)] . Dermatologic Adverse ReactionsAdvise 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 skin reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure during and for months after treatment, to use broad-spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Warnings and Precautions (5.4)] . Ocular ToxicityAdvise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Warnings and Precautions (5.5)] . Paronychia/Nail ToxicityAdvise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)]. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus, to use effective contraception during treatment with RYBREVANT and for months after the last dose, and to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)]. LactationAdvise women not to breastfeed during treatment with RYBREVANT and for months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for months after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Amivantamab-vmjw is bispecific antibody that binds to the extracellular domains of EGFR and MET.In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in mouse xenograft model of human NSCLC with an EGFR L858R mutation.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 7 mL Vial Carton. NDC 57894-501-01Rybrevant (R) (amivantamab-vmjw) Injection 350 mg/7 mL (50 mg/mL) For Intravenous Infusion Only Dilute Before Use Rx only mL Vial janssenSingle-dose vial. Discard unused portion. Rybrevant 350mg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of RYBREVANT have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Amivantamab-vmjw exposures increased proportionally over dosage range from 350 to 1,750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as single agent. Steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.. DistributionThe amivantamab-vmjw mean (%CV) volume of distribution is (24%) L.. EliminationThe mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%).. Specific PopulationsNo clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 21-88 years), body weight (31 to 140 kg), sex, race (White, Asian or Black or African American) and ethnicity (Hispanic/Latino or not Hispanic/Latino), mild or moderate renal impairment (eGFR 30 to 89 mL/min) or mild hepatic impairment [(total bilirubin <= ULN and AST ULN) or (ULN total bilirubin <= 1.5 times ULN)]. The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR 15 mL/min) or moderate to severe hepatic impairment (total bilirubin 1.5 times ULN and any AST) on amivantamab-vmjw pharmacokinetics has not been studied.. Body WeightIncreases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30 to 40% lower in patients who weighed >= 80 kg compared to patients with body weight 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed 80 kg and received 1,050 mg dose and patients who weighed >= 80 kg and received 1,400 mg dose.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions associated with the use of RYBREVANT were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune system disorders:Infusion-related reactions, including anaphylaxis/anaphylactic reactions.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data). Advise pregnant women of the potential risk to 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 DataNo animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.

RECENT MAJOR CHANGES SECTION.

Indications and Usage 1) 09/2024Dosage and Administration 2) 09/2025Warnings and Precautions 5) 02/2025.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION RYBREVANT (R)(RYE-breh-vant) (amivantamab-vmjw) injection, for intravenous use This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 02/2025What is RYBREVANTRYBREVANT is prescription medicine used to treat adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic) or cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor (EGFR) gene(s): in combination with lazertinib as first-line treatment for non-small cell lung cancer (NSCLC)in combination with carboplatin and pemetrexed as second-line treatment for NSCLC in patients whose disease has worsened on or after treatment with an EGFR tyrosine kinase inhibitor (TKI)in combination with carboplatin and pemetrexed as first-line treatment for NSCLCalone for the treatment of NSCLC whose disease has worsened on or after platinum-based chemotherapy.Your healthcare provider will perform test to make sure that RYBREVANT is right for you. It is not known if RYBREVANT is safe and effective in children. Before you receive RYBREVANT, tell your healthcare provider about all of your medical conditions, including if you:have history of lung or breathing problemsare pregnant or plan to become pregnant. RYBREVANT can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.You should use effective birth control (contraception) during treatment and for months after your last dose of RYBREVANT.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT. are breastfeeding or plan to breastfeed. It is not known if RYBREVANT passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of RYBREVANT.Tell your healthcare provider about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will receive RYBREVANTRYBREVANT will be given to you by your healthcare provider by intravenous infusion into your vein.Your healthcare provider will decide the time between doses as well as how many treatments you will receive.Your healthcare provider will give you medicines before each dose of RYBREVANT to help reduce the risk of infusion-related reactions.RYBREVANT may be given in combination with the medicines carboplatin and pemetrexed. If you have any questions about these medicines, ask your healthcare provider.If your treatment with RYBREVANT is given in combination with the medicine lazertinib, you should take your dose of lazertinib by mouth anytime before your infusion with RYBREVANT.If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.What should avoid while receiving RYBREVANTRYBREVANT can cause skin reactions. You should limit your time in the sun during and for months after your treatment with RYBREVANT. Wear protective clothing, and use sunscreen during treatment with RYBREVANT. What are the possible side effects of RYBREVANT RYBREVANT may cause serious side effects, including: infusion-related reactions. Infusion-related reactions are common but can be severe or serious and can include life-threatening (anaphylaxis) allergic reaction. Tell your healthcare provider right away if you get any of the following symptoms during your infusion of RYBREVANT: shortness of breath, difficulty breathing, or wheezingchest discomfortswelling of your eyes, lips, or tonguefeverchillsnumbness of the tongue, lips, cheeks, or gumsflushingskin rash, hives, or itchingnausea or vomitingstomach crampslightheadedness, dizziness, or faintingheadachelung problems. RYBREVANT may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including shortness of breath, cough, or fever. blood clot problems. Blood clots are serious, but common side effect of RYBREVANT, when given together with another drug called lazertinib, may cause blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism) that may lead to death. Your healthcare provider will start you on medicine to prevent blood clots for the first months of treatment. Tell your healthcare provider right away if you have any signs and symptoms of blood clots, including swelling, pain or tenderness in the leg, sudden unexplained chest pain, or shortness of breath. skin problems. RYBREVANT can cause severe rash; including blisters, peeling, skin pain and sores, redness, raised acne-like bumps, itching, and dry skin. You may use alcohol-free (such as isopropanol-free, ethanol-free) moisturizing cream to reduce the risk of skin problems. Tell your healthcare provider right away if you get any skin reactions. Your healthcare provider may treat you with medicine(s) or send you to see skin specialist (dermatologist) if you get skin reactions during treatment with RYBREVANT. See What should avoid while receiving RYBREVANT eye problems. RYBREVANT may cause eye problems. Tell your healthcare provider right away if you get symptoms of eye problems which may include: eye paininflammation of eye lidsdry eyeseye rednessblurred visionchanges in visionitchy eyesexcessive tearingsensitivity to lightYour healthcare provider may send you to see an eye specialist (ophthalmologist) if you get new or worsening eye problems during treatment with RYBREVANT. You should not use contact lenses until your eye symptoms are checked by healthcare provider.The most common side effects of RYBREVANT when given in combination with lazertinib include:rashinfected skin around the nailmuscle and joint painsores in the mouthswelling of hands, ankles, feet, face, or all of your bodyunusual feeling in the skin (such as tingling or crawling feeling)feeling very tireddiarrheaconstipationCOVID-19dry skinbleedingdecreased appetiteitchy skinnauseachanges in certain blood testsThe most common side effects of RYBREVANT when given in combination with carboplatin and pemetrexed include:rashinfected skin around the nailfeeling very tirednauseasores in the mouthconstipationswelling of hands, ankles, feet, face, or all of your bodydecreased appetitemuscle and joint painvomitingCOVID-19changes in certain blood testsThe most common side effects of RYBREVANT when given alone:rashinfected skin around the nailmuscle and joint painshortness of breathnauseafeeling very tiredswelling of hands, ankles, feet, face, or all of your bodysores in the mouthcoughconstipationvomitingchanges in certain blood testsYour healthcare provider may temporarily stop, decrease your dose, or completely stop your treatment with RYBREVANT if you have serious side effects. These are not all of the possible side effects of RYBREVANT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about safe and effective use of RYBREVANTMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about RYBREVANT that is written for health professionals. What are the ingredients of RYBREVANTActive ingredient: amivantamab-vmjw Inactive ingredients: EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection. Product of Ireland Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, USA. U.S. License Number 1864 For patent information: www.janssenpatents.com (C) Johnson Johnson and its affiliates 2021 2025 For more information, call 1-800-526-7736 or go to www.RYBREVANT.com. in combination with lazertinib as first-line treatment for non-small cell lung cancer (NSCLC). in combination with carboplatin and pemetrexed as second-line treatment for NSCLC in patients whose disease has worsened on or after treatment with an EGFR tyrosine kinase inhibitor (TKI). in combination with carboplatin and pemetrexed as first-line treatment for NSCLC. alone for the treatment of NSCLC whose disease has worsened on or after platinum-based chemotherapy.. have history of lung or breathing problems. are pregnant or plan to become pregnant. RYBREVANT can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.You should use effective birth control (contraception) during treatment and for months after your last dose of RYBREVANT.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT. Your healthcare provider should do pregnancy test before you start treatment with RYBREVANT.. You should use effective birth control (contraception) during treatment and for months after your last dose of RYBREVANT.. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with RYBREVANT.. are breastfeeding or plan to breastfeed. It is not known if RYBREVANT passes into your breast milk. Do not breastfeed during treatment and for months after your last dose of RYBREVANT.. RYBREVANT will be given to you by your healthcare provider by intravenous infusion into your vein.. Your healthcare provider will decide the time between doses as well as how many treatments you will receive.. Your healthcare provider will give you medicines before each dose of RYBREVANT to help reduce the risk of infusion-related reactions.. RYBREVANT may be given in combination with the medicines carboplatin and pemetrexed. If you have any questions about these medicines, ask your healthcare provider.. If your treatment with RYBREVANT is given in combination with the medicine lazertinib, you should take your dose of lazertinib by mouth anytime before your infusion with RYBREVANT.. If you miss any appointments, call your healthcare provider as soon as possible to reschedule your appointment.. infusion-related reactions. Infusion-related reactions are common but can be severe or serious and can include life-threatening (anaphylaxis) allergic reaction. Tell your healthcare provider right away if you get any of the following symptoms during your infusion of RYBREVANT: shortness of breath, difficulty breathing, or wheezing. chest discomfort. swelling of your eyes, lips, or tongue. fever. chills. numbness of the tongue, lips, cheeks, or gums. flushing. skin rash, hives, or itching. nausea or vomiting. stomach cramps. lightheadedness, dizziness, or fainting. headache. lung problems. RYBREVANT may cause lung problems that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your healthcare provider right away if you get any new or worsening lung symptoms, including shortness of breath, cough, or fever. blood clot problems. Blood clots are serious, but common side effect of RYBREVANT, when given together with another drug called lazertinib, may cause blood clots in the veins of your legs (deep vein thrombosis) or lungs (pulmonary embolism) that may lead to death. Your healthcare provider will start you on medicine to prevent blood clots for the first months of treatment. Tell your healthcare provider right away if you have any signs and symptoms of blood clots, including swelling, pain or tenderness in the leg, sudden unexplained chest pain, or shortness of breath. skin problems. RYBREVANT can cause severe rash; including blisters, peeling, skin pain and sores, redness, raised acne-like bumps, itching, and dry skin. You may use alcohol-free (such as isopropanol-free, ethanol-free) moisturizing cream to reduce the risk of skin problems. Tell your healthcare provider right away if you get any skin reactions. Your healthcare provider may treat you with medicine(s) or send you to see skin specialist (dermatologist) if you get skin reactions during treatment with RYBREVANT. See What should avoid while receiving RYBREVANT eye problems. RYBREVANT may cause eye problems. Tell your healthcare provider right away if you get symptoms of eye problems which may include: eye pain. inflammation of eye lids. dry eyes. eye redness. blurred vision. changes in vision. itchy eyes. excessive tearing. sensitivity to light. rash. infected skin around the nail. muscle and joint pain. sores in the mouth. swelling of hands, ankles, feet, face, or all of your body. unusual feeling in the skin (such as tingling or crawling feeling). feeling very tired. diarrhea. constipation. COVID-19. dry skin. bleeding. decreased appetite. itchy skin. nausea. changes in certain blood tests. rash. infected skin around the nail. feeling very tired. nausea. sores in the mouth. constipation. swelling of hands, ankles, feet, face, or all of your body. decreased appetite. muscle and joint pain. vomiting. COVID-19. changes in certain blood tests. rash. infected skin around the nail. muscle and joint pain. shortness of breath. nausea. feeling very tired. swelling of hands, ankles, feet, face, or all of your body. sores in the mouth. cough. constipation. vomiting. changes in certain blood tests.

SPL UNCLASSIFIED SECTION.

1.1 First-Line Treatment of NSCLC with EGFRExon 19 Deletions or Exon 21 L858R Substitution Mutations. RYBREVANT, in combination with lazertinib, 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 (2.2)].

STORAGE AND HANDLING SECTION.

Storage and HandlingStore in refrigerator at 2C to 8C (36F to 46F) in original carton to protect from light. Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) 8.1 Pregnancy. Risk SummaryBased on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data). Advise pregnant women of the potential risk to 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 DataNo animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.. 8.2 Lactation. Risk SummaryThere are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for months after the last dose.. 8.3 Females and Males of Reproductive Potential. RYBREVANT can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment and for months after the last dose of RYBREVANT.. 8.4 Pediatric Use. The safety and efficacy of RYBREVANT have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were >= 65 years of age and 12% were >= 75 years of age.Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were >= 65 years of age and 10% were >= 75 years of age.Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were >= 65 years of age and 8% were >= 75 years of age.Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as single agent in the CHRYSALIS study, 39% were >= 65 years of age and 11% were >= 75 years of age.No clinically important differences in safety or efficacy were observed between patients who were >= 65 years of age and younger patients.. Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were >= 65 years of age and 12% were >= 75 years of age.. Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were >= 65 years of age and 10% were >= 75 years of age.. Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were >= 65 years of age and 8% were >= 75 years of age.. Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as single agent in the CHRYSALIS study, 39% were >= 65 years of age and 11% were >= 75 years of age.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. 2.6, 5.1) Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. 2.6, 5.2) Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib:Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. 2.6, 5.3) Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. 2.6, 5.4) Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. 2.6, 5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. 5.6, 8.1, 8.3) Infusion-Related Reactions (IRR): Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. 2.6, 5.1) Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. 2.6, 5.2) Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib:Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. 2.6, 5.3) Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. 2.6, 5.4) Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. 2.6, 5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. 5.6, 8.1, 8.3) 5.1 Infusion-Related Reactions. RYBREVANT can cause infusion-related reactions (IRR) including anaphylaxis; signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately hour.. RYBREVANT with LazertinibRYBREVANT in combination with lazertinib can cause infusion-related reactions. In MARIPOSA, [see Adverse Reactions (6.1)] IRRs occurred in 63% of patients treated with RYBREVANT in combination with lazertinib, including Grade in 5% and Grade in 1% of patients. The incidence of infusion modifications due to IRR was 54%, and IRRs leading to dose reduction of RYBREVANT occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT occurred in 4.5% of patients receiving RYBREVANT in combination with lazertinib. RYBREVANT with Carboplatin and PemetrexedBased on the pooled safety population [see Adverse Reactions (6.1)] IRR occurred in 50% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR. RYBREVANT as Single AgentIn CHRYSALIS, [see Adverse Reactions (6.1)], IRR occurred in 66% of patients treated with RYBREVANT as single agent. Among patients receiving treatment on Week Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day infusion, 0.4% with the Week infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR. Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Dosage and Administration (2.5)] Administer RYBREVANT via peripheral line on Week and Week to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)] Monitor patients for signs and symptoms of infusion reactions during RYBREVANT infusion in setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)]. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT. 5.2 Interstitial Lung Disease/Pneumonitis. RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.. RYBREVANT with LazertinibIn MARIPOSA [see Adverse Reactions (6.1)] ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with lazertinib, including Grade in 1% and Grade in 0.2% of patients. There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT and lazertinib due to ILD/pneumonitis [see Adverse Reactions (6.1)]. RYBREVANT with Carboplatin and PemetrexedBased on the pooled safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 2.1% treated with RYBREVANT in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade ILD/pneumonitis. 2.1% discontinued RYBREVANT due to ILD/pneumonitis. RYBREVANT as Single AgentIn CHRYSALIS, [see Adverse Reactions (6.1)] ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT as single agent, with 0.7% of patients experiencing Grade ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.6)] . 5.3 Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib. RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. 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)], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, including Grade in 10% and Grade 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%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, 1% of patients had VTE leading to dose reductions of RYBREVANT, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: to 777). Administer prophylactic anticoagulation for the first four months of treatment [see Dosage and Administration (2.4)]. The use of Vitamin antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity [see Dosage and Administration (2.6)] Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.4)]. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.6)]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification. 5.4 Dermatologic Adverse Reactions. RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.. RYBREVANT with LazertinibIn MARIPOSA, [see Adverse Reactions (6.1)] rash occurred in 86% of patients treated with RYBREVANT in combination with lazertinib, including Grade in 26% of patients. The median time to onset of rash was 14 days (range: to 556 days). Rash leading to dose interruptions of RYBREVANT occurred in 37% of patients, rash leading to dose reductions of RYBREVANT occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT occurred in 5% of patients. RYBREVANT with Carboplatin and PemetrexedBased on the pooled safety population [see Adverse Reactions (6.1)] rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT and 3.1% discontinued pemetrexed. RYBREVANT as Single AgentIn CHRYSALIS, [see Adverse Reactions (6.1)] rash occurred in 74% of patients treated with RYBREVANT as single agent, including Grade rash in 3.3% of patients. The median time to onset of rash was 14 days (range: to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)]. Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT as single agent.Instruct patients to limit sun exposure during and for months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream 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 skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within weeks to dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)] . 5.5 Ocular Toxicity. RYBREVANT can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.. RYBREVANT with LazertinibIn MARIPOSA [see Adverse Reactions (6.1)] ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with lazertinib, including Grade or ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue lazertinib based on severity [see Dosage and Administration (2.4)] . RYBREVANT with Carboplatin and PemetrexedBased on the pooled safety population [see Adverse Reactions (6.1)], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade or 2. RYBREVANT as Single AgentIn CHRYSALIS, [see Adverse Reactions (6.1)] keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)] . 5.6 Embryo-Fetal Toxicity. Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for months after the last dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)].