Amivantamab-Vmjw

1 INDICATIONS AND USAGE RYBREVANT is a 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 a 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 EGFR Exon 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 EGFR Exon 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 EGFR Exon 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 EGFR Exon 20 Insertion Mutations RYBREVANT is indicated as a 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.

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 , 2.4 ) Administer prophylactic and concomitant medications as recommended to reduce the risk of dermatologic adverse reactions. ( 2.6 ) Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. ( 2.10 ) Administer RYBREVANT in combination with lazertinib or RYBREVANT as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7. ( 2.3 ) Administer RYBREVANT in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7. ( 2.4 ) When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment. ( 2.7 ) Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. ( 2.9 , 2.10 ) Body Weight (at Baseline) Dosage Recommended Dose RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Less than 80 kg Weeks 1–5 Week 7 onwards 1,050 mg Greater than or equal to 80 kg Weeks 1–5 Week 7 onwards 1,400 mg RYBREVANT in Combination with Carboplatin and Pemetrexed Less than 80 kg Weeks 1–4 1,400 mg Week 7 onwards 1,750 mg Greater than or equal to 80 kg Weeks 1–4 1,750 mg Week 7 onwards 2,100 mg 2.1 Important Dosage Information To reduce the risk of infusion-related reactions, administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5) ]. To reduce the risk of infusion-related reactions, administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 [see Dosage and Administration (2.10) ]. To reduce the risk and severity of dermatologic adverse reactions with RYBREVANT, prophylactic and concomitant medications are recommended [see Dosage and Administration (2.6) ] . To reduce the risk of venous thromboembolic (VTE) events when administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis for the first four months of treatment [see Dosage and Administration (2.7) ]. Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.10) ]. When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.10) ]. When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.10) ]. 2.2 Patient Selection Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test. Table 1: Patient Selection Indication Treatment Regimen Source for Testing Information 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 lazertinib 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. 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 pemetrexed First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.3) ] RYBREVANT in combination with carboplatin and pemetrexed Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.4) ] RYBREVANT as a single agent 2.3 Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent - Every 2-week dosing The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 2. Administer RYBREVANT until disease progression or unacceptable toxicity. Table 2: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Body weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,050 mg Weekly (total of 5 doses) from Weeks 1 to 5 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 5 - infusion on Day 1 Week 6 – no dose Every 2 weeks starting at Week 7 onwards Greater than or equal to 80 kg 1,400 mg Weekly (total of 5 doses) from Weeks 1 to 5 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 5 - infusion on Day 1 Week 6 – no dose Every 2 weeks starting at Week 7 onwards RYBREVANT in Combination with Lazertinib Order of Administration When 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. 2.4 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 3. Table 3: Recommended Dosage for RYBREVANT in Combination with Carboplatin and Pemetrexed Body weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,400 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 1,750 mg Every 3 weeks starting at Week 7 onwards Greater than or equal to 80 kg 1,750 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 2,100 mg Every 3 weeks starting at Week 7 onwards The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 4. Table 4: Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and Pemetrexed RYBREVANT in Combination with Carboplatin and Pemetrexed Administer the regimen in the following order : pemetrexed first, carboplatin second, and RYBREVANT last. Drug Dose Duration/Timing of Treatment Pemetrexed Pemetrexed 500 mg/m 2 intravenously Refer to the pemetrexed Full Prescribing Information for complete information. Every 3 weeks, continue until disease progression or unacceptable toxicity. Carboplatin Carboplatin AUC 5 intravenously Refer to the carboplatin Full Prescribing Information for complete information. Every 3 weeks for up to 12 weeks. RYBREVANT RYBREVANT intravenously See Table 3 . Every 3 weeks, continue until disease progression or unacceptable toxicity. 2.5 Recommended Premedications to Reduce the Risk of Infusion-Related Reactions Administer premedications as described in Table 5 . After prolonged dose interruptions, restart the following Week 1 Day 1 premedications upon re-initiation: intravenous dexamethasone, diphenhydramine, and acetaminophen. Table 5: Premedications Premedication Schedule Medication and Frequency Route of Administration Dosing Window Prior to RYBREVANT Administration Initial dose as a split infusion Dexamethasone 8 mg (or equivalent) Oral 48 hours Week 1 Day -2 twice daily Initial dose as a split infusion Dexamethasone 8 mg (or equivalent) Oral 24 hours Week 1 Day -1 twice daily Initial dose as a split infusion Dexamethasone 8 mg (or equivalent) Oral One hour Week 1 Day 1 one dose Dexamethasone 20 mg (or equivalent) one dose Intravenous 45 to 60 minutes Diphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes Acetaminophen 650 mg to 1,000 mg one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes Initial dose as a split infusion Dexamethasone 10 mg (or equivalent) Intravenous 45 to 60 minutes Week 1 Day 2 one dose Diphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes Acetaminophen 650 mg to 1,000 mg one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes All subsequent infusions Diphenhydramine 25 mg to 50 mg (or equivalent) one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes Acetaminophen 650 mg to 1,000 mg one dose Oral 30 to 60 minutes Intravenous 15 to 30 minutes Optional: Dexamethasone 10 mg (or equivalent) one dose Intravenous 45 to 60 minutes 2.6 Prophylactic and Concomitant Medications to Reduce the Risk of Dermatologic Adverse Reactions When initiating treatment with RYBREVANT, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions [see Warnings and Precautions (5.4) ]. Administer an oral antibiotic (doxycycline or minocycline, 100 mg orally twice daily) starting on Day 1 for the first 12 weeks of treatment. After completion of oral antibiotic treatment, administer antibiotic lotion to the scalp (clindamycin 1% topical once daily) for the next 9 months of treatment. Administer non-comedogenic skin moisturizer (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents) on the face and whole body (except scalp). Wash hands and feet with 4% chlorhexidine solution once daily. Limit sun exposure during and for 2 months after treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions. 2.7 RYBREVANT in Combination with Lazertinib: Concomitant Medications to Reduce the Risk of Venous Thromboembolic Events When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of 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. 2.8 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 RYBREVANT Dose at which the adverse reaction occurred 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Reduction 1,050 mg 700 mg 350 mg Discontinue RYBREVANT 1,400 mg 1,050 mg 700 mg 1,750 mg 1,400 mg 1,050 mg 2,100 mg 1,750 mg 1,400 mg The 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 RYBREVANT Adverse Reaction Severity Dosage Modifications Infusion-related reactions (IRR) [see Warnings and Precautions (5.1) ] Grade 1 to 2 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 8 and 9 ). Include corticosteroid with premedications for subsequent dose (see Table 5 ). Grade 3 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 8 and 9 ). Include corticosteroid with premedications for subsequent dose (see Table 5 ). For recurrent Grade 3, permanently discontinue RYBREVANT. Grade 4 or any Grade anaphylaxis / anaphylactic reactions Permanently discontinue RYBREVANT. Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2) ] Any Grade Withhold 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 2 or 3 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. Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation 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. Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.4) ] Grade 1 or Grade 2 Initiate supportive care management as clinically indicated. Reassess after 2 weeks; if rash does not improve, consider dose reduction. Grade 3 Withhold RYBREVANT and initiate supportive care management as clinically indicated. Upon recovery to ≤ Grade 2, resume RYBREVANT at reduced dose. If no improvement within 2 weeks, permanently discontinue treatment. Grade 4 or Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN)) Permanently discontinue RYBREVANT. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline. Resume at the same dose if recovery occurs within 1 week. Resume at reduced dose if recovery occurs after 1 week but within 4 weeks. Permanently discontinue if recovery does not occur within 4 weeks. Grade 4 Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline. Resume at reduced dose if recovery occurs within 4 weeks. Permanently discontinue if recovery does not occur within 4 weeks. Permanently discontinue for recurrent Grade 4 reactions. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Lazertinib When 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 Pemetrexed When 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. 2.9 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 patient's baseline weight [see Dosage and Administration (2.3 , 2.4) ] . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw. Withdraw and then discard a 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 7 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 7 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 15°C to 25°C (59°F to 77°F). 2.10 Administration Administer the diluted RYBREVANT solution [see Dosage and Administration (2.9) ] by intravenous infusion using an infusion set fitted with a 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, must be 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 Lazertinib or RYBREVANT as a Single Agent Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8. Administer RYBREVANT via a peripheral line on Week 1 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 8: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent Body Weight Less Than 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 700 mg 50 75 Week 2 1,050 mg 85 Week 3 1,050 mg 125 Week 4 1,050 mg 125 Week 5 1,050 mg 125 Week 6 No dose Week 7 and every 2 weeks thereafter 1,050 mg 125 Body Weight Greater Than or Equal to 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,050 mg 35 50 Week 2 1,400 mg 65 Week 3 1,400 mg 85 Week 4 1,400 mg 125 Week 5 1,400 mg 125 Week 6 No dose Week 7 and every 2 weeks thereafter 1,400 mg 125 RYBREVANT in Combination with Carboplatin and Pemetrexed Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9. Administer RYBREVANT via a peripheral line on Week 1 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. Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last. Table 9: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC Body Weight Less Than 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,050 mg 33 50 Week 2 1,400 mg 65 Week 3 1,400 mg 85 Week 4 1,400 mg 125 Weeks 5 and 6 No dose Week 7 and every 3 weeks thereafter 1,750 mg 125 Body Weight Greater Than or Equal to 80 kg Week Dose (per 250 mL bag) Initial Infusion Rate (mL/hr) Subsequent Infusion Rate (mL/hr) Week 1 (split dose infusion) Week 1 Day 1 350 mg 50 75 Week 1 Day 2 1,400 mg 25 50 Week 2 1,750 mg 65 Week 3 1,750 mg 85 Week 4 1,750 mg 125 Week 5 and 6 No dose Week 7 and every 3 weeks thereafter 2,100 mg 125

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) ] RYBREVANT in Combination with Lazertinib 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. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. ( 6.1 ) RYBREVANT in Combination with Carboplatin and Pemetrexed 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 3 or 4 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 a Single Agent 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 3 or 4 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. RYBREVANT in Combination with Lazertinib The 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 4 weeks, then every 2 weeks thereafter starting at week 5 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 6 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, and nausea. The most common Grade 3 or 4 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 Pemetrexed The 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 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2 once every 3 weeks until disease progression or unacceptable toxicity. Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for 6 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 3 to 4 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. RYBREVANT as a Single Agent The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a 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 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. Among 302 patients who received RYBREVANT as a single agent, 36% were exposed for 6 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 3 to 4 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 mutations The 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 4 weeks, then every 2 weeks thereafter starting at week 5 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 ≥ 6 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 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium. Table 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 MARIPOSA Adverse Reaction RYBREVANT in combination with lazertinib (N=421) Osimertinib (N=428) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped terms 86 26 48 1.2 Nail toxicity 71 11 34 0.7 Dry skin 25 1 18 0.2 Pruritus 24 0.5 17 0.2 Injury, poisoning and procedural complications Infusion-related reaction Applicable for RYBREVANT only 63 6 0 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 47 2.1 39 1.9 Gastrointestinal disorders Stomatitis 43 2.4 27 0.5 Diarrhea 31 2.6 45 0.9 Constipation 29 0 13 0 Nausea 21 1.2 14 0.2 Vomiting 12 0.5 5 0 Abdominal pain 11 0 10 0 Hemorrhoids 10 0.2 2.1 0.2 General disorders and administration site conditions Edema 43 2.6 8 0 Fatigue 32 3.8 20 1.9 Pyrexia 12 0 9 0 Vascular disorders Venous thromboembolism 36 11 8 2.8 Hemorrhage 25 1 13 1.2 Nervous system disorders Paresthesia 35 1.7 10 0.2 Dizziness 14 0 10 0 Headache 13 0.2 13 0 Infections and infestations COVID-19 26 1.7 24 1.4 Conjunctivitis 11 0.2 1.6 0 Metabolism and nutrition disorders Decreased appetite 24 1 18 1.4 Respiratory, thoracic and mediastinal disorders Cough 19 0 23 0 Dyspnea 14 1.7 17 3.5 Eye disorders Ocular toxicity 16 0.7 7 0 Psychiatric disorders Insomnia 10 0 11 0 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with lazertinib included skin ulcer and ILD/pneumonitis. 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 a 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 Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Decreased albumin 89 8 22 0.2 Increased ALT 65 7 29 2.6 Increased AST 52 3.8 36 1.9 Increased alkaline phosphatase 45 0.5 15 0.5 Decreased calcium (corrected) 41 1.4 27 0.7 Increased GGT 39 2.6 24 1.9 Decreased sodium 38 7 35 5 Decreased potassium 30 5 15 1.2 Increased creatinine 26 0.7 35 0.7 Decreased magnesium 25 0.7 10 0.2 Increased magnesium 12 2.6 20 4.8 Hematology Decreased platelet count 52 0.7 57 1.4 Decreased hemoglobin 47 3.8 56 1.9 Decreased white blood cell 38 1 66 0.7 Decreased neutrophils 15 1.4 33 1.4 Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations The 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 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg/m 2 once every 3 weeks until disease progression or unacceptable toxicity. Among patients who received RYBREVANT (n=130), 52% were exposed for 6 months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: 0 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-2 Adverse Reaction RYBREVANT + Carboplatin + Pemetrexed Carboplatin + Pemetrexed (N=130) (N=243) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term 72 11 12 0 Nail toxicity 45 2.3 0.4 0 Pruritus 15 0 7 0 Dry skin 15 0 2.5 0 General disorders and administration site conditions Infusion-related reaction 59 5.4 0.4 0 Fatigue 51 3.8 35 3.7 Edema 36 1.5 11 0.4 Pyrexia 12 0 10 0 Gastrointestinal disorders Nausea 45 0.8 37 0.8 Constipation 39 0.8 30 0 Stomatitis 35 2.3 11 0 Vomiting 25 0.8 17 0.4 Diarrhea 15 1.5 7 0.8 Metabolism and nutrition disorders Decreased appetite 31 0 21 1.2 Musculoskeletal and connective tissue disorders Musculoskeletal pain 30 3.1 19 0.8 Infections and infestations COVID-19 21 1.5 10 0 Eye disorders Ocular toxicity 17 0 3.7 0 Vascular disorders Hemorrhage 14 0.8 4.9 0 Venous Thromboembolism (VTE) 10 2.3 4.5 2.9 Respiratory, thoracic and mediastinal disorders Cough 14 0 16 0.4 Dyspnea 13 1.5 8 1.2 Clinically 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, interstitial lung disease, and skin ulcer. 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-2 RYBREVANT + Carboplatin + Pemetrexed (N=130) Carboplatin + Pemetrexed (N=243) Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Decreased white blood cells 91 42 85 19 Decreased neutrophils 74 49 64 25 Decreased platelets 74 17 58 9 Decreased hemoglobin 71 12 77 9 Decreased lymphocytes 69 28 58 18 Chemistry Decreased albumin 73 3.8 26 0.4 Decreased sodium 49 11 30 6 Increased aspartate aminotransferase 47 0.8 52 0.9 Increased alkaline phosphatase 42 0 29 0.4 Increased alanine aminotransferase 39 3.9 56 6 Decreased magnesium 38 0.8 17 0.4 Decreased potassium 37 11 12 3.4 Increased gamma-glutamyl transferase 30 3.1 41 1.3 Decreased calcium (corrected) 25 0 11 0.9 First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with Exon 20 Insertion Mutations The 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 7 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 3 to 4 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 PAPILLON RYBREVANT 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 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped Term 90 19 19 0 Nail toxicity 62 7 3 0 Dry skin 17 0 6 0 Gastrointestinal disorders Stomatitis 43 4 11 0 Constipation 40 0 30 0.7 Nausea 36 0.7 42 0 Vomiting 21 3.3 19 0.7 Diarrhea 21 3 13 1.3 Hemorrhoids 12 1 1.3 0 Abdominal pain 11 0.7 8 0 General disorders and administration site conditions Infusion-related reaction 42 1.3 1.3 0 Fatigue 42 6 45 3.9 Edema 40 1.3 19 0 Pyrexia 17 0 6 0 Metabolism and nutrition disorders Decreased appetite 36 2.6 28 1.3 Infections and infestations COVID-19 24 2 14 0.6 Pneumonia 13 5 6 1.9 Vascular disorders Hemorrhage 18 0.7 11 1.9 Respiratory, thoracic, and mediastinal disorders Cough 17 0 16 0 Dyspnea 11 1.3 16 3.2 Investigations Weight decreased 14 0.7 8 0 Nervous system disorders Dizziness 11 0 12 0 Psychiatric disorders Insomnia 11 0 13 0 Clinically 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 PAPILLON RYBREVANT 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 a 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 a baseline value and at least one post-treatment value. Laboratory Abnormality Adverse reactions were graded using CTCAE version 5.0 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Decreased white blood cells 89 17 76 10 Decreased hemoglobin 79 11 85 13 Decreased neutrophils 76 36 61 23 Decreased platelets 70 10 54 12 Decreased lymphocytes 61 11 49 13 Chemistry Decreased albumin 87 7 34 1 Increased aspartate aminotransferase 60 1 61 1 Increased alanine aminotransferase 57 4 54 1 Decreased sodium 55 7 39 4 Increased alkaline phosphatase 51 1 28 0 Decreased potassium 44 11 17 1 Decreased magnesium 39 2 30 1 Increased gamma-glutamyl transferase 38 4 43 4 Decreased calcium (corrected) 27 1 18 1 Previously Treated NSCLC Exon 20 Insertion Mutations The 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 6 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 2 patients (1.5%) due to pneumonia and 1 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 3 to 4 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 CHRYSALIS Adverse Reactions RYBREVANT Adverse reactions were graded using CTCAE version 4.03 (N=129) All Grades (%) Grades 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term 84 3.9 Pruritus 18 0 Dry skin 14 0 General disorders and administration site conditions Infusion-related reaction 64 3.1 Fatigue 33 2.3 Edema 27 0.8 Pyrexia 13 0 Infections and infestations Paronychia 50 3.1 Pneumonia 10 0.8 Musculoskeletal and connective tissue disorders Musculoskeletal pain 47 0 Respiratory, thoracic, and mediastinal disorders Dyspnea 37 2.3 Cough 25 0 Gastrointestinal disorders Nausea 36 0 Stomatitis 26 0.8 Constipation 23 0 Vomiting 22 0 Diarrhea 16 3.1 Abdominal Pain 11 0.8 Vascular disorders Hemorrhage 19 0 Metabolism and nutrition disorders Decreased appetite 15 0 Nervous system disorders Peripheral neuropathy 13 0 Dizziness 12 0.8 Headache 10 0.8 Clinically 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 CHRYSALIS Laboratory Abnormality RYBREVANT The denominator used to calculate the rate was 126 based on the number of patients with a baseline value and at least one post-treatment value. (N=129) All Grades (%) Grades 3 or 4 (%) Chemistry Decreased albumin 79 8 Increased glucose 56 4 Increased alkaline phosphatase 53 4.8 Increased creatinine 46 0 Increased alanine aminotransferase 38 1.6 Decreased phosphate 33 8 Increased aspartate aminotransferase 33 0 Decreased magnesium 27 0 Increased gamma-glutamyl transferase 27 4 Decreased sodium 27 4 Decreased potassium 26 6 Hematology Decreased lymphocytes 36 8 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Infusion-related reactions, including anaphylaxis/anaphylactic reactions

12.3 Pharmacokinetics Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1,750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as a 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. Distribution The amivantamab-vmjw mean (%CV) volume of distribution is 5 (24%) L. Elimination The mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%). Specific Populations No 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 Weight Increases 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.