Rybrevant Faspro Injection
FDA Label NDC 57894-522

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)] .

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)].

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)] .

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.

• 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 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.
• 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.
• 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.

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.

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.

The recommended order of administration and regimen for RYBREVANT FASPRO in combination with carboplatin and pemetrexed are provided in Table 3.

RYBREVANT FASPRO in Combination with Lazertinib or as a Single Agent – 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.

Administer RYBREVANT FASPRO until disease progression or unacceptable toxicity.

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.

Prior to the initial injection of RYBREVANT FASPRO (Week 1 Day 1), administer premedications as described in Table 5 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.

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.

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.

For a 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 notadminister the missed dose and administer the next dose per the usual dosing schedule.

The recommended dose reductions for adverse reactions for RYBREVANT FASPRO are listed in Table 6.

The recommended dosage modifications and management for adverse reactions for RYBREVANT FASPRO are provided in Table 7.

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 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.

• 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 8) 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 NOTexceed 15 mL in each syringe.

The recommended vial selection and dose volume are provided in Table 8.

Table 8: Recommended 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 The entire contents of all vials will not be needed. Discard unused portion.
3,360 mg amivantamab and 42,000 units hyaluronidase	21 mL Divide the 21 mL dose volume approximately equally into two syringes (each syringe should not exceed 15 mL).

NOTE:Preparation of RYBREVANT FASPRO doses of 2,400 mg amivantamab and 30,000 units hyaluronidase and 3,360 mg amivantamab and 42,000 units hyaluronidase will require more than one vial. The entire contents of all vials will not be needed. 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.

Injection

• 1,600 mg amivantamab and 20,000 units hyaluronidase per 10 mL (160 mg and 2,000 units/mL) clear to opalescent and colorless to pale yellow solution in a single-dose vial.
• 2,240 mg amivantamab and 28,000 units hyaluronidase per 14 mL (160 mg and 2,000 units/mL) clear to opalescent and colorless to pale yellow solution in a single-dose vial.

RYBREVANT FASPRO is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients.

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)] .

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)] .

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.

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)] .

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)] .

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)]

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 ²once 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 9 summarizes the adverse reactions (≥ 10%) in PALOMA-3.

Table 9: 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 10 summarizes the laboratory abnormalities in PALOMA-3.

Table 10: 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 11 summarizes the adverse reactions (≥ 10%) in MARIPOSA.

Table 11: 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 12 summarizes the laboratory abnormalities in MARIPOSA.

Table 12: 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 ²once 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 13 summarizes the adverse reactions in MARIPOSA-2.

Table 13: 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 14 summarizes the laboratory abnormalities in MARIPOSA-2.

Table 14: 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 15 summarizes the adverse reactions in PAPILLON.

Table 15: 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 16 summarizes the laboratory abnormalities in PAPILLON.

Table 16: 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 17 summarizes the adverse reactions in CHRYSALIS.

Table 17: 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 18 summarizes the laboratory abnormalities in CHRYSALIS.

Table 18: 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

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.

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.

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.

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

Of the 206 patients with locally advanced or metastatic NSCLC treated with RYBREVANT FASPRO in combination with lazertinib 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.

RYBREVANT FASPRO is a fixed-combination drug product containing amivantamab and hyaluronidase (human recombinant).

• Amivantamab is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa.
• Hyaluronidase (human recombinant) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (human recombinant) has a molecular weight of approximately 61 kDa.

RYBREVANT FASPRO™ (amivantamab and hyaluronidase-lpuj) injection for subcutaneous use is a sterile, preservative free, clear to opalescent and colorless to pale yellow solution supplied in a single-dose vial with a pH of 5.7.

Each RYBREVANT FASPRO 10 mL single-dose vial contains 1,600 mg of amivantamab and 20,000 units of hyaluronidase (human recombinant), edetate disodium (0.18 mg), glacial acetic acid (1.9 mg), methionine (10 mg), polysorbate 80 (6 mg), sodium acetate (22.1 mg), sucrose (710 mg), and Water for Injection, USP.

Each RYBREVANT FASPRO 14 mL single-dose vial contains 2,240 mg of amivantamab and 28,000 units of hyaluronidase (human recombinant), edetate disodium (0.25 mg), glacial acetic acid (2.6 mg), methionine (14 mg), polysorbate 80 (8.4 mg), sodium acetate (30.9 mg), sucrose (994 mg), and Water for Injection, USP.

Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET.

In in vitroand in vivostudies, 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.

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

Amivantamab exposure and accumulation following the approved recommended dosages are provided in Table 19. 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.

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 _troughwas 1.32 (1.23, 1.42).

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 _Cr15 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) 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).

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, 1/378 of patients (0.3%) 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, 37/389 patients (9.5%) who received RYBREVANT FASPRO as a single agent or in combination with lazertinib developed treatment emergent anti-hyaluronidase (recombinant human, rHuPH20) antibodies. There was no identified clinically significant effect of anti-hyaluronidase antibodies on pharmacokinetics, safety, or effectiveness of RYBREVANT FASPRO.

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

Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase. In addition, when hyaluronidase (recombinant human) was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is >300 times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

The effectiveness of RYBREVANT FASPRO has been established based on adequate and well controlled studies of intravenous amivantamab:

• in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic non‑small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see Indications and Usage (1.1)]
• 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 [see Indications and Usage (1.2)]
• 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 [see Indications and Usage (1.3)]
• 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 [see Indications and Usage (1.4)].

MARIPOSA

The efficacy of intravenous amivantamab, in combination with lazertinib, was evaluated in MARIPOSA (NCT04487080), a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.

Patients were randomized (2:2:1) to receive intravenous amivantamab in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:

• Amivantamab administered intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib administered at 240 mg orally once daily.
• Osimertinib administered at a dose of 80 mg orally once daily.

Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR).

A total of 858 patients were randomized between the two study arms, 429 to the intravenous amivantamab in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.

Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the intravenous amivantamab plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.

The trial demonstrated a statistically significant improvement in PFS by BICR assessment and OS for intravenous amivantamab in combination with lazertinib compared to osimertinib (see Table 20and Figures 1and 2).

Efficacy results for intravenous amivantamab in combination with lazertinib are provided in Table 20.

Table 20: Efficacy Results in MARIPOSA by BICR Assessment

	Intravenous amivantamab in combination with lazertinib (N=429)	Osimertinib (N=429)
CI = confidence interval; NR = not reached; NE = not estimable
Progression-free survival (PFS)
Number of events (%)	192 (45)	252 (59)
Median, months (95% CI)	23.7 (19.1, 27.7)	16.6 (14.8, 18.5)
HR Stratified by mutation type (Exon 19del or Exon 21 L858R), prior brain metastases (yes or no), and Asian race (yes or no). , Stratified Cox proportional hazards regression. (95% CI); p-value , Stratified log-rank test.	0.70 (0.58, 0.85); p=0.0002
Overall survival (OS)
Number of events (%)	173 (40)	217 (51)
Median, months (95% CI)	NR (42.9, NE)	36.7 (33.4, 41.0)
HR ,(95% CI); p-value ,	0.75 (0.61, 0.92); p=0.0048
Overall response rate (ORR) Confirmed responses based on the ITT population.
ORR, % (95% CI)	78 (74, 82)	73 (69, 78)
Complete response, %	5.4	3.5
Partial response, %	73	70
Duration of response (DOR) In confirmed responders.
Median (95% CI), months	25.8 (20.1, NE)	16.7 (14.8, 18.5)
Patients with DOR ≥ 6 months Based on observed rates. , %	86	85
Patients with DOR ≥ 12 months , %	68	57

Figure 1: Kaplan-Meier Curves of PFS by BICR Assessment in Patients with Previously Untreated NSCLC



Figure 1 (Rybrevant 01)

Figure 2: Kaplan-Meier Curves of OS in Patients with Previously Untreated NSCLC



Figure 2 (Rybrevant 02)

Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the intravenous amivantamab in combination with lazertinib arm and the osimertinib arm are summarized in Table 21.

Table 21: Exploratory Analysis of Intracranial ORR and DOR by BICR Assessment in Subjects with Intracranial Lesions at Baseline

	Intravenous amivantamab in combination with lazertinib (N=180)	Osimertinib (N=187)
CI = confidence interval
Intracranial tumor response assessment
Intracranial ORR Confirmed responses , % (95% CI)	68 (60, 75)	69 (62, 76)
Complete response %	55	52
Intracranial DOR In confirmed responders
Number of responders	122	129
Patients with DOR ≥ 12 months Based on observed rates , %	66	59
Patients with DOR ≥ 18 months , %	35	23

MARIPOSA-2

The efficacy of intravenous amivantamab in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive intravenous amivantamab in combination with carboplatin and pemetrexed (intravenous amivantamab-CP, N=131), carboplatin and pemetrexed (CP, N=263), or intravenous amivantamab as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between:

• Intravenous amivantamab in combination with carboplatin and pemetrexed.
  Amivantamab was administered intravenously at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity.
• Platinum-based chemotherapy with carboplatin and pemetrexed.

For both arms, carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks and pemetrexed was administered intravenously at 500 mg/m ²once every 3 weeks until disease progression or unacceptable toxicity.

Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every 6 weeks for the first 12 months and every 12 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.

A total of 394 patients were randomized between the two arms, 131 to the intravenous amivantamab-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients ≥ 65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.

The trial demonstrated a statistically significant improvement in PFS by BICR for intravenous amivantamab in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.

Efficacy results are summarized in Table 22.

Table 22: Efficacy Results in MARIPOSA-2

	Intravenous amivantamab with carboplatin and pemetrexed (N=131)	carboplatin and pemetrexed (N=263)
CI = confidence interval; NE = not estimatable
Progression-free survival (PFS) Blinded Independent Central Review by RECIST v1.1.
Number of events	74 (56%)	171 (65%)
Median, months (95% CI)	6.3 (5.6, 8.4)	4.2 (4.0, 4.4)
HR (95% CI) Stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). , Stratified Cox proportional hazards regression. ; p-value , Stratified log-rank test.	0.48 (0.36, 0.64); p<0.0001
Overall response rate , Confirmed responses.
ORR, % (95% CI)	53% (44, 62)	29% (23, 35)
p-value , Stratified logistic regression analysis.	p<0.0001
Complete response	0.8%	0%
Partial response	52%	29%
Duration of response ,(DOR)
Median (95% CI), months	6.9 (5.5, NE)	5.6 (4.2, 9.6)

Figure 3: Kaplan-Meier Curve of PFS in Previously Treated NSCLC Patients by BICR Assessment - MARIPOSA-2



Figure 3 (Rybrevant 03)

At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS. The median OS was 17.7 months (95% CI: 16.0, 22.4) in the ACP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with a hazard ratio of 0.73 (95% CI: 0.54, 0.99).

Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. Baseline disease assessment, including brain magnetic resonance imaging (MRI) was performed at treatment initiation. All patients underwent serial brain MRI during the trial.

Pre-specified secondary analyses of intracranial ORR by BICR in the subset of 91 (23%) patients with baseline intracranial disease were performed. Data were only available for intracranial complete responses and not available for intracranial partial responses. Intracranial ORR was 20% (95% CI: 8, 39) in the 30 patients with baseline intracranial disease in the ACP arm and 7% (95% CI: 1.8, 16) in the 61 patients with baseline intracranial disease in the CP arm.

PAPILLON

The efficacy of intravenous amivantamab was evaluated in PAPILLON (NCT04538664), in a randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, and adequate organ and bone marrow function. Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomization. Patients with a medical history of interstitial lung disease or active ILD were excluded from the clinical study.

A total of 308 patients were randomized 1:1 to receive intravenous amivantamab in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received amivantamab intravenously at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg/m ²on once every 3 weeks until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1) and prior brain metastases (yes or no).

The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Cross-over to single agent intravenous amivantamab was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.

The median age was 62 (range: 27 to 92) years, with 40% of the patients ≥ 65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was 0 (35%) or 1 (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.

PAPILLON demonstrated a statistically significant improvement in progression free survival for patients randomized to intravenous amivantamab in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed.

Efficacy results are summarized in Table 23 and Figure 4.

Figure 4: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – PAPILLON Study

Figure 4 (Rybrevant 04)

While OS results were immature at the current analysis, with 44% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed. Seventy-five (48%) of the treated patients crossed over from the carboplatin and pemetrexed arm after confirmation of disease progression to receive intravenous amivantamab as a single agent.

CHRYSALIS

The efficacy of intravenous amivantamab was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study.

In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360 ^®CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified.

Patients received 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. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.

The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight < 80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was 2 (range: 1 to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.

Efficacy results are summarized in Table 24.

How Supplied

RYBREVANT FASPRO™ (amivantamab and hyaluronidase-lpuj) injection for subcutaneous use is a sterile, preservative free, clear to opalescent and colorless to pale yellow solution supplied as follows:

Storage and Handling

Store RYBREVANT FASPRO vials in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F) in original carton to protect from light. Do not freeze. Do not shake.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypersensitivity and Administration-Related Reactions

Advise patients that RYBREVANT FASPRO can cause hypersensitivity and administration-related reactions, the majority of which may occur with the first injection. Advise patients to alert their healthcare provider immediately for any signs or symptoms of administration-related reactions during treatment with RYBREVANT FASPRO [see Warnings and Precautions (5.1)] .

Interstitial Lung Disease/Pneumonitis

Advise patients that RYBREVANT FASPRO can cause interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms during treatment with RYBREVANT FASPRO [see Warnings and Precautions (5.2)] .

Venous Thromboembolic Events with Concomitant Use with Lazertinib

Advise patients that when RYBREVANT FASPRO is used in combination with lazertinib, it can cause serious and life threatening venous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism. Advise patients that prophylactic anticoagulants are recommended to be used for the first four months of treatment. Advise patients to immediately contact their healthcare provider for signs and symptoms of VTE during treatment with RYBREVANT FASPRO [see Warnings and Precautions (5.3)].

Dermatologic Adverse Reactions

Advise patients that RYBREVANT FASPRO can cause dermatologic adverse reactions. Advise patients that prophylactic oral antibiotics are recommended starting on Day 1 for the first 12 weeks of treatment and, after completion of oral antibiotic treatment, topical antibiotic lotion to the scalp for the next 9 months of treatment. Advise patients to use a non-comedogenic skin moisturizer (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying components) on the face and whole body (except scalp) and 4% chlorhexidine solution to wash hands and feet, while on treatment. Advise patients to limit direct sun exposure during and for 2 months after treatment, to wear protective clothing, and to use broad-spectrum UVA/UVB sunscreen to reduce the risk and severity of dermatologic adverse reactions [see Warnings and Precautions (5.4)] .

Ocular Toxicity

Advise patients that RYBREVANT FASPRO can cause ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Warnings and Precautions (5.5)] .

Paronychia/Nail toxicity

Advise patients that RYBREVANT FASPRO can cause paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with RYBREVANT FASPRO and for 3 months after the last dose, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6)and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with RYBREVANT FASPRO and for 3 months after the last dose [see Use in Specific Populations (8.2)] .

Manufactured by:

Janssen Biotech, Inc.
Horsham, PA 19044, USA
U.S. License Number 1864

Halozyme, Inc.
San Diego, CA 92130, USA
U.S. License Number 2187

For patent information: www.janssenpatents.com
© Johnson & Johnson and its affiliates 2025

NDC 57894-510-01

Rybrevant Faspro™
(amivantamab and
hyaluronidase-lpuj)
Injection

1,600 mg and
20,000 units/10 mL

(160 mg and 2,000 units/mL)

For subcutaneous injection
by a healthcare provider only.

Administer each injection over
approximately 5 minutes.

Single-dose vial
Discard unused portion.

Rx only

One 10 mL Vial

Johnson
& Johnson

Principal Display Panel (10 mL Vial Carton)

NDC 57894-514-01

Rybrevant Faspro™
(amivantamab and
hyaluronidase-lpuj)
Injection

2,240 mg and
28,000 units/14 mL

(160 mg and 2,000 units/mL)

For subcutaneous injection
by a healthcare provider only.

Administer each injection over
approximately 5 minutes.

Single-dose vial
Discard unused portion.

Rx only

One 14 mL Vial

Johnson
& Johnson

Principal Display Panel (14 mL Vial Carton)