Amivantamab and Hyaluronidase-Lpuj (Human Recombinant)

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.

5 WARNINGS AND PRECAUTIONS Hypersensitivity and Administration-Related Reactions (ARR) : Premedicate with antihistamines, antipyretics, and glucocorticoids. Monitor patients for any signs and symptoms of ARRs. Resume treatment upon resolution of symptoms or permanently discontinue RYBREVANT FASPRO based on severity. ( 2.8 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening symptoms indicative of ILD/pneumonitis. Immediately withhold RYBREVANT FASPRO in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 2.8 , 5.2 ) Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT FASPRO and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT FASPRO and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT FASPRO and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. ( 2.8 , 5.3 ) Dermatologic Adverse Reactions : Can cause severe rash including toxic epidermal necrolysis (TEN) and dermatitis acneiform. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, dose reduce or permanently discontinue RYBREVANT FASPRO based on severity. ( 2.5 , 2.8 , 5.4 ) Ocular Toxicity : Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT FASPRO based on severity. ( 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1 Hypersensitivity and Administration-Related Reactions RYBREVANT FASPRO can cause hypersensitivity and administration-related reactions (ARR); signs and symptoms of ARR include dyspnea, flushing, fever, chills, chest discomfort, hypotension, and vomiting. The median time to ARR onset is approximately 2 hours. Local injection site reactions are described separately in Section 6.1. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 [see Adverse Reactions (6.1) ] , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade ARR occurred in 13%, including 0.5% Grade 3. Of the patients who experienced ARR, 89% occurred with the initial dose (Week 1, Day 1). Premedicate with antihistamines, antipyretics, and glucocorticoids and administer RYBREVANT FASPRO as recommended [see Dosage and Administration (2.4) ] . Monitor patients for any signs and symptoms of administration-related reactions during injection in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt RYBREVANT FASPRO injection, if ARR is suspected. Resume treatment upon resolution of symptoms or permanently discontinue RYBREVANT FASPRO based on severity [see Dosage and Administration (2.8) ] .

5.2 Interstitial Lung Disease/Pneumonitis RYBREVANT FASPRO can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 [see Adverse Reactions (6.1) ] , in 206 patients who received RYBREVANT FASPRO in combination with lazertinib, ILD/pneumonitis occurred in 6%, including Grade 3 in 1%, Grade 4 in 1.5%, and fatal cases in 1.9%. In total, 5% of patients permanently discontinued RYBREVANT FASPRO and lazertinib due to ILD/pneumonitis. Intravenous Amivantamab with Lazertinib In MARIPOSA [see Adverse Reactions (6.1) ] , in 421 patients who received intravenous amivantamab in combination with lazertinib, ILD/pneumonitis occurred in 3.1%, including Grade 3 in 1% and Grade 4 in 0.2% of patients. There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued intravenous amivantamab and lazertinib due to ILD/pneumonitis. Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population [see Adverse Reactions (6.1) ] , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, ILD/pneumonitis occurred in 2.1%, including 1.8% Grade 3 ILD/pneumonitis. Of these, 2.1% of patients permanently discontinued intravenous amivantamab due to ILD/pneumonitis. Intravenous Amivantamab as a Single Agent In CHRYSALIS [see Adverse Reactions (6.1) ] , in 302 patients who received intravenous amivantamab as a single agent, ILD/pneumonitis occurred in 3.3%, including 0.7% Grade 3. Three patients (1%) permanently discontinued intravenous amivantamab due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT FASPRO in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.8) ] .

5.3 Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib RYBREVANT FASPRO in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. Without prophylactic anticoagulation, the majority of these events occurred during the first four months of therapy [see Adverse Reactions (6.1) ] . RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 [see Adverse Reactions (6.1) ] , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade VTE occurred in 11% and 1.5% were Grade 3. Of the 206 patients treated with RYBREVANT FASPRO in combination with lazertinib, 80% received prophylactic anticoagulation at study entry. In the 164 patients treated with RYBREVANT FASPRO in combination with lazertinib who received prophylactic anticoagulation, all Grade VTE occurred in 7%. In the 42 patients treated with RYBREVANT FASPRO in combination with lazertinib who did not receive prophylactic anticoagulation, all Grade VTE occurred in 17%. In total, 0.5% of patients had VTE leading to dose reductions of RYBREVANT FASPRO and no patients required permanent discontinuation. The median time to onset of VTEs was 95 days (range: 17 to 390). Intravenous Amivantamab with Lazertinib In MARIPOSA [see Adverse Reactions (6.1) ] , in 421 patients who received intravenous amivantamab in combination with lazertinib, VTEs occurred in 36%, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of intravenous amivantamab, 1% of patients had VTE leading to dose reductions of intravenous amivantamab, and 3.1% of patients had VTE leading to permanent discontinuation of intravenous amivantamab. The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate. Withhold RYBREVANT FASPRO and lazertinib based on severity [see Dosage and Administration (2.8) ] . Once anticoagulant treatment has been initiated, resume RYBREVANT FASPRO and lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.8) ] . In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT FASPRO. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.8) ] . Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.

5.4 Dermatologic Adverse Reactions RYBREVANT FASPRO can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus and dry skin. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 [see Adverse Reactions (6.1) ] , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, rash occurred in 80% of patients, including Grade 3 in 17% and Grade 4 in 0.5%. Rash leading to dose reduction occurred in 11% of patients, and RYBREVANT FASPRO was permanently discontinued due to rash in 1.5% of patients. Intravenous Amivantamab with Lazertinib In MARIPOSA [see Adverse Reactions (6.1) ] , in 421 patients who received intravenous amivantamab in combination with lazertinib, rash occurred in 86%, including 26% Grade 3. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions of intravenous amivantamab occurred in 37% of patients, rash leading to dose reductions of intravenous amivantamab occurred in 23% of patients, and rash leading to permanent discontinuation of intravenous amivantamab occurred in 5% of patients. Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population [see Adverse Reactions (6.1) ] , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, rash occurred in 82%, including 15% Grade 3. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued intravenous amivantamab and 3.1% discontinued pemetrexed. Intravenous Amivantamab as a Single Agent In CHRYSALIS [see Adverse Reactions (6.1) ] , in 302 patients who received intravenous amivantamab as a single agent, rash occurred in 74%, including 3.3% Grade 3. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and intravenous amivantamab was permanently discontinued due to rash in 0.7% of patients. Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with intravenous amivantamab as a single agent. When initiating treatment with RYBREVANT FASPRO, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions [see Dosage and Administration (2.5) ] . Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT FASPRO. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. If skin reactions develop, administer supportive care including topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT FASPRO based on severity [see Dosage and Administration (2.8) ] .

5.5 Ocular Toxicity RYBREVANT FASPRO can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus and uveitis. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 [see Adverse Reactions (6.1) ] , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade ocular toxicity occurred in 13%, including 0.5% Grade 3. Intravenous Amivantamab with Lazertinib In MARIPOSA [see Adverse Reactions (6.1) ] , in 421 patients treated with intravenous amivantamab in combination with lazertinib, ocular toxicity occurred in 16%, including 0.7% Grade 3 or 4 ocular toxicity. Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population [see Adverse Reactions (6.1) ] , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, ocular toxicity occurred in 16%. All events were Grade 1 or 2. Intravenous Amivantamab as a Single Agent In CHRYSALIS [see Adverse Reactions (6.1) ] , in 302 patients treated with intravenous amivantamab, keratitis occurred in 0.7% and uveitis occurred in 0.3%. All events were Grade 1– 2. Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT FASPRO based on severity [see Dosage and Administration (2.8) ] .

5.6 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal models, RYBREVANT FASPRO can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT FASPRO. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT FASPRO [see Use in Specific Populations (8.1 , 8.3) ] .

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 …

Lactation : Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animal models, RYBREVANT FASPRO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT FASPRO in pregnant women or animal data to assess the risk of RYBREVANT FASPRO in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data RYBREVANT FASPRO for subcutaneous injection contains amivantamab and hyaluronidase [see Description (11) ]. Amivantamab: No animal studies have been conducted to evaluate the effects of amivantamab on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT FASPRO can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing fetus. Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 3600 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 600 times higher than the human dose. In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1800 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

8.2 Lactation Risk Summary There are no data on the presence of amivantamab or hyaluronidase in human milk or its effects on the breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to RYBREVANT FASPRO are unknown. Because of the potential for serious adverse reactions from RYBREVANT FASPRO in breastfed children, advise women not to breastfeed during treatment with RYBREVANT FASPRO and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential RYBREVANT FASPRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT FASPRO [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1) ] . Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT FASPRO.

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

8.5 Geriatric Use Of the 206 patients with locally advanced or metastatic NSCLC treated with RYBREVANT FASPRO in combination with lazertinib (every 2-week dosing) in the PALOMA-3 study, 35% were ≥ 65 years of age, and 9% were ≥ 75 years of age. The safety of RYBREVANT FASPRO in combination with other antineoplastic drugs or as a single agent for its approved indications [see Indications and Usage (1.1 , 1.2 , 1.3 , 1.4) ] has been established in adequate and well-controlled studies of intravenous amivantamab in combination with other antineoplastic drugs and as a single agent. Of the 421 patients with locally advanced or metastatic NSCLC treated with intravenous amivantamab in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age. Of the 130 patients with locally advanced or metastatic NSCLC treated with intravenous amivantamab in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were ≥ 65 years of age and 10% were ≥ 75 years of age. Of the 151 patients with locally advanced or metastatic NSCLC treated with intravenous amivantamab in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥ 65 years of age and 8% were ≥ 75 years of age. Of the 302 patients with locally advanced or metastatic NSCLC treated with intravenous amivantamab as a single agent in the CHRYSALIS study, 39% were ≥ 65 years of age and 11% were ≥ 75 years of age. No clinically important differences in safety or efficacy were observed between patients who were ≥ 65 years of age and younger patients.

12.1 Mechanism of Action Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET. In in vitro and in vivo studies, amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively. Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in RYBREVANT FASPRO acts transiently and locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.

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

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).

12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of RYBREVANT FASPRO or other amivantamab products or other hyaluronidase products. During the treatment period of up to 30 months across PALOMA, PALOMA-2, and PALOMA-3, 3/729 of patients (0.4%) who received RYBREVANT FASPRO as a single agent or in combination with lazertinib developed treatment emergent anti-amivantamab antibodies. Because of the low occurrence of anti-amivantamab antibodies, the effect of these antibodies on the pharmacokinetics, safety, and/or effectiveness of amivantamab products is unknown. During the treatment period of up to 30 months across PALOMA, PALOMA-2 and PALOMA-3, 66/741 patients (9%) who received RYBREVANT FASPRO as a single agent or in combination with lazertinib developed treatment emergent anti-hyaluronidase (recombinant human, rHuPH20) antibodies and 2/66 patients (3%) tested positive for neutralizing antibodies. There was no identified clinically significant effect of anti-hyaluronidase antibodies on pharmacokinetics, safety, or effectiveness of RYBREVANT FASPRO.