Amivantamab And Hyaluronidase-Lpuj (Human Recombinant)

1 INDICATIONS AND USAGE RYBREVANT FASPRO is a combination of amivantamab, a bispecific EGF receptor-directed and MET receptor-directed antibody, and hyaluronidase, an endoglycosidase indicated: in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with 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 FASPRO, 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 FASPRO, 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 FASPRO, 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 FASPRO 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 For subcutaneous use only. (2.1) RYBREVANT FASPRO has different recommended dosage and administration than intravenous amivantamab products. ( 2.1 ) Administer each injection of RYBREVANT FASPRO subcutaneously in the abdomen over approximately 5 minutes. ( 2.1 ) The recommended dosage of RYBREVANT FASPRO is based on baseline body weight. ( 2.3 ) Administer premedications as recommended. ( 2.4 ) Recommended dosage for RYBREVANT FASPRO in combination with carboplatin and pemetrexed (every 3-week dosing), see Table 2 . ( 2.3 ) Recommended dosage for RYBREVANT FASPRO in combination with lazertinib or for RYBREVANT FASPRO as a single agent (every 4-week dosing), see Table 4 . ( 2.3 ) Recommended dosage for RYBREVANT FASPRO in combination with lazertinib or for RYBREVANT FASPRO as a single agent (every 2-week dosing), see Table 5 . ( 2.3 ) 2.1 Important Dosage and Administration Information RYBREVANT FASPRO is for subcutaneous use only. Do not administer RYBREVANT FASPRO intravenously. RYBREVANT FASPRO must be administered by a healthcare professional. To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared and administered is subcutaneous RYBREVANT FASPRO and not intravenous amivantamab. RYBREVANT FASPRO has different recommended dosage and administration than intravenous amivantamab products. Do not substitute RYBREVANT FASPRO for or with intravenous amivantamab products. Adult patients currently receiving intravenous amivantamab at an every 2-week dosing regimen may switch to subcutaneous RYBREVANT FASPRO at an every 2-week dosing regimen or at an every 4-week dosing regimen at their next scheduled dose on or after Week 5. Adult patients currently receiving intravenous amivantamab at an every 3-week dosing regimen may switch to subcutaneous RYBREVANT FASPRO at an every 3-week dosing regimen at their next scheduled dose on or after Week 4. Adult patients currently receiving RYBREVANT FASPRO at an every 2-week dosing regimen may switch to an every 4-week dosing regimen at their next scheduled dose on or after Week 5. RYBREVANT FASPRO is not indicated for use in pediatric patients. Administer premedications before each RYBREVANT FASPRO dose as recommended, to reduce the risk of administration-related reactions (ARRs) [see Dosage and Administration (2.4) ] . Administer each injection of RYBREVANT FASPRO subcutaneously in the abdomen over approximately 5 minutes to minimize injection site irritation. Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 2 inches (5 cm) around the periumbilical area. If the total dose requires multiple injections of RYBREVANT FASPRO, administer each injection consecutively in separate quadrants of the abdomen, with each injection taking approximately 5 minutes. Rotate injection sites at the next scheduled dose. Pause or slow the delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose. If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set, 0.9% sodium chloride solution may be utilized to flush remaining drug product through the line. Discard unused portion. 2.2 Patient Selection Select patients for treatment with RYBREVANT FASPRO based on the presence of a mutation as detected by an FDA-approved test as shown in Table 1. 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 FASPRO 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 FASPRO in combination with carboplatin and pemetrexed First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.3) ] RYBREVANT FASPRO in combination with carboplatin and pemetrexed Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.4) ] RYBREVANT FASPRO as a single agent 2.3 Recommended Dosage RYBREVANT FASPRO In Combination with Carboplatin and Pemetrexed - Every 3-Week Dosing The recommended dosages of RYBREVANT FASPRO, administered every 3 weeks in combination with carboplatin and pemetrexed, based on baseline body weight are provided in Table 2. Administer RYBREVANT FASPRO until disease progression or unacceptable toxicity. Table 2: Recommended Dosage for RYBREVANT FASPRO in Combination with Carboplatin and Pemetrexed (Every 3-Week Dosing) Body Weight at Baseline Dose adjustments not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,600 mg amivantamab and 20,000 units hyaluronidase First dose at Week 1 Day 1 2,400 mg amivantamab and 30,000 units hyaluronidase Weekly (total of 2 doses) from Weeks 2 to 3 Weeks 2 to 3 – Injection on Day 1 Every 3 weeks starting at Week 4 onwards Greater than or equal to 80 kg 2,240 mg amivantamab and 28,000 units hyaluronidase First dose at Week 1 Day 1 3,360 mg amivantamab and 42,000 units hyaluronidase Weekly (total of 2 doses) from Weeks 2 to 3 Weeks 2 to 3 – Injection on Day 1 Every 3 weeks starting at Week 4 onwards The recommended order of administration and regimen for RYBREVANT FASPRO in combination with carboplatin and pemetrexed are provided in Table 3. Table 3: Order of Administration and Regimen for RYBREVANT FASPRO in Combination with Carboplatin and Pemetrexed Administer the regimen in the following order : pemetrexed first, carboplatin second, and RYBREVANT FASPRO 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 FASPRO RYBREVANT FASPRO subcutaneously. See Table 2 . Every 3 weeks, continue until disease progression or unacceptable toxicity. RYBREVANT FASPRO in Combination with Lazertinib or as a Single Agent – Every 4-Week or Every 2-Week Dosing The recommended dosages of RYBREVANT FASPRO in combination with lazertinib or as a single agent, based on baseline body weight, are provided in Table 4 (every 4-week dosing) and Table 5 (every 2-week dosing). Administer RYBREVANT FASPRO until disease progression or unacceptable toxicity. Table 4: Recommended Dosage for RYBREVANT FASPRO in Combination with Lazertinib or for RYBREVANT FASPRO as a Single Agent (Every 4-Week Dosing) Body Weight at Baseline Dose adjustments not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,600 mg amivantamab and 20,000 units hyaluronidase Weekly (total of 4 doses) from Weeks 1 to 4 Weeks 1 to 4 – Injection on Day 1 3,520 mg amivantamab and 44,000 units hyaluronidase Every 4 weeks starting at Week 5 onwards Greater than or equal to 80 kg 2,240 mg amivantamab and 28,000 units hyaluronidase Weekly (total of 4 doses) from Weeks 1 to 4 Weeks 1 to 4 – Injection on Day 1 4,640 mg amivantamab and 58,000 units hyaluronidase Every 4 weeks starting at Week 5 onwards Table 5: Recommended Dosage for RYBREVANT FASPRO in Combination with Lazertinib or for RYBREVANT FASPRO as a Single Agent (Every 2-Week Dosing) Body Weight at Baseline Dose adjustments not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,600 mg amivantamab and 20,000 units hyaluronidase Weekly (total of 4 doses) from Weeks 1 to 4 Weeks 1 to 4 – Injection on Day 1 Every 2 weeks starting at Week 5 onwards May switch to RYBREVANT FASPRO every 4-week dosing regimen at their next scheduled dose on or after Week 5. See Table 4 for every 4-week dosing information. Greater than or equal to 80 kg 2,240 mg amivantamab and 28,000 units hyaluronidase Weekly (total of 4 doses) from Weeks 1 to 4 Weeks 1 to 4 – Injection on Day 1 Every 2 weeks starting at Week 5 onwards RYBREVANT FASPRO in Combination with Lazertinib Order of Administration When given in combination with lazertinib, administer RYBREVANT FASPRO any time after lazertinib when given on the same day. Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT FASPRO in combination with lazertinib until disease progression or unacceptable toxicity. 2.4 Recommended Premedications Prior to the initial injection of RYBREVANT FASPRO (Week 1 Day 1), administer premedications as described in Table 6 to reduce the risk of administration-related reactions [see Warnings and Precautions (5.1) ] . Glucocorticoid administration is required at the initial dose at Week 1 Day 1 only, and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent injections. Administer both antihistamine and antipyretic prior to all RYBREVANT FASPRO doses. Table 6: Premedications Medication Dose Route of Administration Dosing Window Prior to RYBREVANT FASPRO Administration Antihistamine Required at all doses. Diphenhydramine (25 mg to 50 mg) or equivalent Intravenous 15 to 30 minutes Oral 30 to 60 minutes Antipyretic Acetaminophen (650 mg to 1,000 mg) or equivalent Intravenous 15 to 30 minutes Oral 30 to 60 minutes Glucocorticoid Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction. Dexamethasone (20 mg) or equivalent Intravenous 45 to 60 minutes Oral At least 60 minutes Glucocorticoid Optional for subsequent doses. Dexamethasone (10 mg) or equivalent Intravenous 45 to 60 minutes Oral 60 to 90 minutes 2.5 Prophylactic and Concomitant Medications to Reduce the Risk of Dermatologic Adverse Reactions When initiating treatment with RYBREVANT FASPRO, 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. 2.6 RYBREVANT FASPRO in Combination with Lazertinib: Concomitant Medications to Reduce the Risk of Venous Thromboembolic Events When initiating treatment with RYBREVANT FASPRO 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. 2.7 Missed Dose For a 4-week or 2-week dosing schedule: If a dose of RYBREVANT FASPRO is missed between Weeks 1 to 4, administer within 24 hours. If a dose of RYBREVANT FASPRO is missed from Week 5 onward, administer within 7 days. For a 3-week dosing schedule: If a dose of RYBREVANT FASPRO is missed between Weeks 1 to 3, administer within 24 hours. If a dose of RYBREVANT FASPRO is missed from Week 4 onward, administer within 7 days. If the missed dose is not administered according to this guidance, do not administer the missed dose and administer the next dose per the usual dosing schedule. 2.8 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions for RYBREVANT FASPRO are listed in Table 7. Table 7: Dose Reductions for Adverse Reactions for RYBREVANT FASPRO Dose at which the adverse reaction occurred 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Reduction 1,600 mg amivantamab and 20,000 units hyaluronidase 1,050 mg amivantamab and 13,200 units hyaluronidase The dose volume should be 6.6 mL for 1,050 mg amivantamab and 13,200 units hyaluronidase dose. 700 mg amivantamab and 8,800 units hyaluronidase The dose volume should be 4.4 mL for 700 mg amivantamab and 8,800 units hyaluronidase dose. Discontinue RYBREVANT FASPRO 2,240 mg amivantamab and 28,000 units hyaluronidase 1,600 mg amivantamab and 20,000 units hyaluronidase The dose volume should be 10 mL for 1,600 mg amivantamab and 20,000 units hyaluronidase dose. 1,050 mg amivantamab and 13,200 units hyaluronidase 2,400 mg amivantamab and 30,000 units hyaluronidase 1,600 mg amivantamab and 20,000 units hyaluronidase 1,050 mg amivantamab and 13,200 units hyaluronidase 3,360 mg amivantamab and 42,000 units hyaluronidase 2,240 mg amivantamab and 28,000 units hyaluronidase The dose volume should be 14 mL for 2,240 mg amivantamab and 28,000 units hyaluronidase dose. 1,600 mg amivantamab and 20,000 units hyaluronidase 3,520 mg amivantamab and 44,000 units hyaluronidase 2,400 mg amivantamab and 30,000 units hyaluronidase The dose volume should be 15 mL for 2,400 mg amivantamab and 30,000 units hyaluronidase dose. 1,600 mg amivantamab and 20,000 units hyaluronidase 4,640 mg amivantamab and 58,000 units hyaluronidase 3,360 mg amivantamab and 42,000 units hyaluronidase The dose volume should be 21 mL for 3,360 mg amivantamab and 42,000 units hyaluronidase dose. 2,240 mg amivantamab and 28,000 units hyaluronidase The recommended dosage modifications and management for adverse reactions for RYBREVANT FASPRO are provided in Table 8. Table 8: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANT FASPRO Adverse Reaction Severity Dosage Modifications Hypersensitivity and Administration-Related Reactions (ARRs) [see Warnings and Precautions (5.1) ] Grade 1 or 2 Interrupt RYBREVANT FASPRO injection if ARR is suspected and monitor patient until reaction symptoms resolve. Resume injection upon resolution of symptoms. Include corticosteroid with premedications for subsequent dose (see Table 6 ). Grade 3 Interrupt RYBREVANT FASPRO injection and administer supportive care medications. Continuously monitor patient until reaction symptoms resolve. Resume injection upon resolution of symptoms. Include corticosteroid with premedications for subsequent dose (see Table 6 ). For recurrent Grade 3, permanently discontinue RYBREVANT FASPRO. Grade 4 Permanently discontinue RYBREVANT FASPRO. Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2) ] Any Grade Withhold RYBREVANT FASPRO if ILD/pneumonitis is suspected. Permanently discontinue RYBREVANT FASPRO 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 FASPRO and lazertinib. Administer anticoagulation treatment as clinically indicated. Once anticoagulant treatment has been initiated, resume RYBREVANT FASPRO and lazertinib at the same dose level, at the discretion of the treating physician. Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation Withhold lazertinib and permanently discontinue RYBREVANT FASPRO. Administer anticoagulation 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 treating physician. Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.4) ] Grade 1 or 2 Initiate supportive care management as clinically indicated. Reassess after 2 weeks; if rash does not improve, consider dose reduction. Grade 3 Withhold RYBREVANT FASPRO and initiate supportive care management as clinically indicated. Upon recovery to Grade ≤ 2, resume RYBREVANT FASPRO 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 FASPRO. Other Adverse Reactions [see Adverse Reactions (6.1) ] Grade 3 Withhold RYBREVANT FASPRO 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 FASPRO 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 FASPRO in Combination with Lazertinib When administering RYBREVANT FASPRO in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT FASPRO first. Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib. Recommended Dosage Modifications for Adverse Reactions for RYBREVANT FASPRO in Combination with Carboplatin and Pemetrexed When administering RYBREVANT FASPRO in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT FASPRO as shown in Table 8. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information. 2.9 Preparation Instructions For important information on RYBREVANT FASPRO dosage and administration, see Dosage and Administration (2.1) . Do not dilute RYBREVANT FASPRO. RYBREVANT FASPRO does not contain an antimicrobial preservative. Administer RYBREVANT FASPRO dose in prepared syringes immediately. If the RYBREVANT FASPRO dose is not administered immediately, refer to "Storage" [see Dosage and Administration (2.9) ] . RYBREVANT FASPRO is a clear to opalescent and colorless to pale yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is discolored, or cloudy, or if foreign particles are present. Remove the appropriate number of RYBREVANT FASPRO vial(s) from refrigeration and equilibrate RYBREVANT FASPRO to room temperature [15 °C to 30 °C (59 °F to 86 °F)] for at least 15 minutes. Do not warm RYBREVANT FASPRO in any other way. Do not shake. Withdraw the required injection volume of RYBREVANT FASPRO (see Table 9 ) from the vial(s) into a syringe(s) using a transfer needle. Discard unused portion. RYBREVANT FASPRO is compatible with stainless steel injection needles, polypropylene and polycarbonate syringes, and polyethylene, polyurethane, and polyvinylchloride subcutaneous infusion sets. Use 0.9% Sodium Chloride Injection to flush an infusion set, if needed. Administer using a 21G to 23G needle or infusion set to ensure ease of administration. If immediate administration is not possible, replace the transfer needle with a syringe closing cap for transport. Divide doses requiring greater than 15 mL into approximately equal volumes in two syringes and administer at separate injection sites. Do NOT exceed 15 mL in each syringe. The dose volumes are provided in Table 9. Table 9: Dosing Volumes for RYBREVANT FASPRO RYBREVANT FASPRO Total Dose Total Dose Volume 1,600 mg amivantamab and 20,000 units hyaluronidase 10 mL 2,240 mg amivantamab and 28,000 units hyaluronidase 14 mL 2,400 mg amivantamab and 30,000 units hyaluronidase 15 mL 3,360 mg amivantamab and 42,000 units hyaluronidase 21 mL For the 21 mL dose volume, the entire contents of the 3,520 mg amivantamab and 44,000 units hyaluronidase/22 mL vial will not be needed. Discard unused portion. Divide the dose volume approximately equally into two syringes (each syringe should not exceed 15 mL). 3,520 mg amivantamab and 44,000 units hyaluronidase 22 mL 4,640 mg amivantamab and 58,000 units hyaluronidase 29 mL For the 29 mL dose volume, use one 2,240 mg amivantamab and 28,000 units hyaluronidase/14 mL vial and one 2,400 mg amivantamab and 30,000 units hyaluronidase/15 mL vial to minimize waste. If a different combination of vials is used, discard unused portion. Storage If immediate administration is not possible, store the prepared syringes of RYBREVANT FASPRO refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for up to 24 hours followed by at room temperature of 15 °C to 30 °C (59 °F to 86 °F) for up to 24 hours. Discard the prepared syringe(s) if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypersensitivity and Administration-Related Reactions [see Warnings and Precautions (5.1) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] Venous Thromboembolic Events with Concomitant Use with Lazertinib [see Warnings and Precautions (5.3) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.4) ] Ocular Toxicity [see Warnings and Precautions (5.5) ] RYBREVANT FASPRO in Combination with Lazertinib The most common adverse reactions (≥ 20%) were rash, nail toxicity, musculoskeletal pain, fatigue, stomatitis, edema, nausea, diarrhea, vomiting, constipation, decreased appetite, and headache. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocyte count, decreased sodium, decreased potassium, decreased albumin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased platelet count, increased gamma-glutamyl transferase, and decreased hemoglobin. (6.1) Intravenous Amivantamab 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 ) Intravenous Amivantamab 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 ) Intravenous Amivantamab as a Single Agent The most common adverse reactions (≥ 20%) were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting, and pruritus. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were increased gamma-glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase. ( 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 FASPRO in Combination with Lazertinib The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT FASPRO in combination with lazertinib in 206 patients with previously treated locally advanced or metastatic NSCLC whose tumors have either an EGFR exon 19 deletion or an exon 21 L858R substitution mutation in PALOMA-3 [see Clinical Pharmacology (12.3) ]. Patients received RYBREVANT FASPRO (N=206) or intravenous amivantamab (N=210), both in combination with lazertinib, at the recommended dosages until disease progression or unacceptable toxicity. Among 206 patients who received RYBREVANT FASPRO in combination with lazertinib, 47% were exposed for 6 months or longer and 12% were exposed for greater than one year. The most common adverse reactions (≥ 20%) were rash, nail toxicity, musculoskeletal pain, fatigue, stomatitis, edema, nausea, diarrhea, vomiting, constipation, decreased appetite, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocyte count, decreased sodium, decreased potassium, decreased albumin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased platelet count, increased gamma-glutamyl transferase, and decreased hemoglobin. Intravenous Amivantamab in Combination with Lazertinib The data described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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, 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. Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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. Intravenous Amivantamab as a Single Agent The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab as a single agent in CHRYSALIS [see Clinical Studies (14.4) ] in 302 patients with locally advanced or metastatic NSCLC. Patients received intravenous amivantamab 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 intravenous amivantamab 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 transferase, decreased sodium, decreased potassium and increased alkaline phosphatase. Subcutaneous RYBREVANT FASPRO Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – RYBREVANT FASPRO In Combination with Lazertinib PALOMA-3 (Every 2-week dosing) The safety of RYBREVANT FASPRO in combination with lazertinib was evaluated in the PALOMA-3 study [see Clinical Pharmacology (12.3) ] . Eligible patients were required to have locally advanced or metastatic NSCLC whose tumors have either an EGFR exon 19 deletion or an exon 21 L858R substitution mutation and whose disease has progressed on prior treatment with osimertinib and platinum-based chemotherapy. Patients were randomized to receive lazertinib 240 mg orally once daily in combination with either RYBREVANT FASPRO (N=206) or intravenous amivantamab (N=210) at the recommended dosages until disease progression or unacceptable toxicity. In total, 164 patients (80%) receiving RYBREVANT FASPRO and 171 patients (81%) receiving intravenous amivantamab received prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin during the first four months of study treatment. Among patients receiving RYBREVANT FASPRO, 47% were exposed for ≥ 6 months and 12% were exposed for ≥ 1 year. The median age of patients who received RYBREVANT FASPRO was 61 years (range: 35–82); 67% were female; 61% Asian, 38% White, 0.5% Black, and 0.5% did not report race; 6% were Hispanic or Latino. Serious adverse reactions occurred in 33% of patients who received RYBREVANT FASPRO in combination with lazertinib. Serious adverse reactions in ≥ 2% of patients who received RYBREVANT FASPRO in combination with lazertinib included ILD/pneumonitis (6%); and pneumonia, VTE and fatigue (2.4% each). Death due to adverse reactions occurred in 5% of patients treated with RYBREVANT FASPRO, including ILD/pneumonitis (1.9%), pneumonia (1.5%), and respiratory failure and sudden death (1% each). Permanent discontinuations of RYBREVANT FASPRO due to an adverse reaction occurred in 13% of patients. Adverse reactions leading to RYBREVANT FASPRO discontinuation in ≥ 1% of patients were ILD/pneumonitis (5%), rash (1.9%) and pneumonia 1%. Dosage interruptions of RYBREVANT FASPRO due to an adverse reaction occurred in 54% of patients. Adverse reactions requiring RYBREVANT FASPRO dose interruption in ≥ 5% of patients were rash (21%) and nail toxicity (13%). Dose reductions of RYBREVANT FASPRO due to an adverse reaction occurred in 20% of patients. Adverse reactions requiring RYBREVANT FASPRO dose reductions in ≥ 5% of patients were rash (11%) and nail toxicity (8%). Table 10 summarizes the adverse reactions (≥ 10%) in PALOMA-3. Table 10: Adverse Reactions (≥ 10%) in Patients with Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Who Received RYBREVANT FASPRO in Combination with Lazertinib in PALOMA-3 Adverse Reaction RYBREVANT FASPRO with lazertinib (N=206) Intravenous amivantamab with lazertinib (N=210) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped terms 80 17 78 13 Nail toxicity 58 3.9 56 2.9 Dry skin 18 0 18 0 Pruritus 17 0 12 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 50 2.4 35 3.8 General disorders and administration site conditions Fatigue 37 3.4 31 2.4 Edema 34 2.9 34 1 Pyrexia 13 0 11 0 Local injection site reactions 11 0 0 0 Gastrointestinal disorders Stomatitis 36 0.5 38 2.9 Nausea 30 0.5 25 1.4 Diarrhea 22 1.5 19 1 Vomiting 22 1 20 0.5 Constipation 22 0 20 0.5 Metabolism and nutrition disorders Decreased appetite 22 0.5 25 1.4 Nervous system disorders Headache 21 0.5 19 0.5 Peripheral neuropathy 19 1.5 23 1.4 Dizziness 12 0 12 0 Injury, poisoning and procedural complications Administration-related reactions 13 0.5 66 3.8 Eye disorders Ocular toxicity 13 0.5 11 0.5 Vascular disorders Venous thromboembolism 11 1.5 18 5 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT FASPRO in combination with lazertinib not included in the table above were abdominal pain, hemorrhoids, ILD/pneumonitis, and skin ulcer. Table 11 summarizes the laboratory abnormalities in PALOMA-3. Table 11: Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations in PALOMA-3 The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test. Laboratory Abnormality RYBREVANT FASPRO with lazertinib (N=206) Intravenous amivantamab with lazertinib (N=210) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Chemistry Decreased Albumin 92 4.9 91 5 Increased Alkaline Phosphatase 47 1.5 37 0 Increased Alanine Aminotransferase 45 3.4 50 5 Decreased Sodium 36 5 43 8 Increased Aspartate Aminotransferase 36 2 40 2.4 Decreased Calcium (Corrected) 33 0 36 0 Decreased Magnesium 27 0 30 1.4 Increased Gamma-Glutamyl Transferase 26 2 27 1.9 Decreased Potassium 22 5 25 4.3 Hematology Decreased Lymphocyte Count 57 6 60 29 Decreased Platelet Count 37 2.4 42 1.9 Decreased White Blood Cell 36 0.5 31 0.5 Decreased Hemoglobin 34 2 36 2.4 Clinical Trials Experience of Amivantamab Intravenous Formulation Below is a description of adverse reactions of intravenous amivantamab in these adequate and well-controlled NSCLC studies. First-line Treatment of NSCLC with Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Lazertinib MARIPOSA The safety data described below reflect exposure to intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab in combination with lazertinib, 73% were exposed to intravenous amivantamab for ≥ 6 months and 59% were exposed to intravenous amivantamab for > 1 year. The median age of patients who received intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 12 summarizes the adverse reactions (≥ 10%) in MARIPOSA. Table 12: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA Adverse Reaction Intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab in combination with lazertinib included skin ulcer and ILD/pneumonitis. Table 13 summarizes the laboratory abnormalities in MARIPOSA. Table 13: 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. Intravenous amivantamab 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 NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed MARIPOSA-2 The safety data described below reflect exposure to intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab (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 intravenous amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each). Permanent discontinuation of intravenous amivantamab due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of intravenous amivantamab in ≥ 5% of patients were infusion-related reactions. Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 14 summarizes the adverse reactions in MARIPOSA-2. Table 14: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Intravenous Amivantamab With Carboplatin and Pemetrexed (N=130) Carboplatin and Pemetrexed (N=243) Adverse Reaction 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 intravenous amivantamab in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, interstitial lung disease, and skin ulcer. Table 15 summarizes the laboratory abnormalities in MARIPOSA-2. Table 15: 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 Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Intravenous Amivantamab with Carboplatin and Pemetrexed (N=130) Carboplatin and 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 NSCLC with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed PAPILLON The safety data described below reflect exposure to intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of intravenous amivantamab in ≥ 1% of patients were rash and ILD. Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 16 summarizes the adverse reactions in PAPILLON. Table 16: Adverse Reactions (≥ 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in PAPILLON Intravenous Amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis, and interstitial lung disease (ILD)/pneumonitis. Table 17 summarizes the laboratory abnormalities in PAPILLON. Table 17: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in PAPILLON Intravenous Amivantamab 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 with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab as a Single Agent CHRYSALIS The safety data described below reflect exposure to intravenous amivantamab 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. Patients received intravenous amivantamab 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 patients who received intravenous amivantamab, 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 intravenous amivantamab. 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 intravenous amivantamab due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of intravenous amivantamab in ≥ 1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash. Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 18 summarizes the adverse reactions in CHRYSALIS. Table 18: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received Intravenous Amivantamab in CHRYSALIS Adverse Reactions Intravenous Amivantamab 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 intravenous amivantamab included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN). Table 19 summarizes the laboratory abnormalities in CHRYSALIS. Table 19: 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 Intravenous Amivantamab in CHRYSALIS Laboratory Abnormality Intravenous Amivantamab 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

12.3 Pharmacokinetics Amivantamab exposure and accumulation following the approved recommended dosages are provided in Table 20. Amivantamab exposure increases dose-proportionally across the recommended dosing regimens. Amivantamab maximum trough concentration is typically observed at the end of the weekly dosing (Cycle 2 Day 1). Amivantamab steady-state concentration is reached by approximately Week 13. Table 20: Amivantamab Exposure and Accumulation Dose Frequency Geometric Mean C trough,max (%CV) Geometric Mean C trough,steady-state (%CV) AUC 1week Accumulation 1,600 mg amivantamab / 20,000 units hyaluronidase to 2,240 mg amivantamab / 28,000 units hyaluronidase every 2-week 335 µg/mL (33%) 206 µg/mL (39%) Increase 3.5-fold 2,400 mg amivantamab / 30,000 units hyaluronidase to 3,360 mg amivantamab / 42,000 units hyaluronidase every 3-week 464 µg/mL (24%) 218 µg/mL (42%) Increase 4.5-fold 3,520 mg amivantamab / 44,000 units hyaluronidase to 4,640 mg amivantamab / 58,000 units hyaluronidase every 4-week 350 µg/mL (31%) 129 µg/mL (52%) Increase 4.8-fold Adult patients with NSCLC were randomized (1:1) to RYBREVANT FASPRO or intravenous amivantamab in combination with lazertinib in PALOMA-3, an open-label, randomized trial. The primary outcome measure was amivantamab steady-state C trough (Cycle 4 Day 1) and Cycle 2 AUC Day 1–15 of RYBREVANT FASPRO as compared to intravenous amivantamab. Additional descriptive efficacy outcome measures were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Amivantamab exposure following administration of RYBREVANT FASPRO and intravenous amivantamab were comparable. At the recommended every 2-week dosage, the observed geometric mean ratios (GMRs) (90% CI) for Cycle 2 AUC Day 1–15 was 1.03 (0.98, 1.09) and for steady-state C trough (Cycle 4 Day 1) was 1.43 (1.27, 1.61). At the recommended every 3-week dosage, the simulated GMRs (90% CI) for average concentration of Cycle 2 Day 1 to Day 21 was 1.20 (1.15, 1.26) and steady-state C trough was 1.32 (1.23, 1.42). At the recommended every 4-week dosage, the simulated GMRs (90% CI) for average concentration of Cycle 2 Day 1 to Day 28 was 1.20 (1.15, 1.26) and steady-state C trough was 1.01 (0.93, 1.09). Absorption Amivantamab bioavailability is 67% (15%) with a median time to reach maximum concentration of 3 days following administration of RYBREVANT FASPRO. Distribution Amivantamab apparent volume of distribution is 5.7 L (24%). Elimination Amivantamab is cleared by parallel linear and nonlinear saturable target mediated clearances after subcutaneous administration. Amivantamab estimated terminal half-life is 19 days (34%) with an associated linear apparent clearance of 0.22 L/day (26%). Specific Populations No clinically significant differences in the pharmacokinetics of amivantamab were observed based on age (range: 28–85 years), baseline albumin level (range: 26–51 g/L), sex, race, ethnicity, mild and moderate renal impairment (creatinine clearance [CL Cr ] 29 to < 90 mL/min estimated by Cockcroft Gault equation), mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)], Eastern Cooperative Oncology Group (ECOG) performance status, history of brain metastases, and EGFR primary mutation type. The effect of severe renal (CL Cr 15 to 29 mL/min) impairment or moderate (total bilirubin 1.5 to 3 times ULN) to severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown. Increases in body weight increased the volume of distribution and clearance of amivantamab. With the recommended dosages, exposures of amivantamab were comparable between patients who weighed < 80 kg and received 1,600 mg amivantamab and 20,000 units hyaluronidase (every 2-week dosing)/2,400 mg amivantamab and 30,000 units hyaluronidase (every 3-week dosing)/3,520 mg amivantamab and 44,000 units hyaluronidase (every 4-week dosing) and patients who weighed ≥ 80 kg and received 2,240 mg amivantamab and 28,000 units hyaluronidase (every 2-week dosing)/3,360 mg amivantamab and 42,000 units hyaluronidase (every 3-week dosing)/4,640 mg amivantamab and 58,000 units hyaluronidase (every 4-week dosing).