Rybrevant Faspro Drug Information

Important Dosage and Administration Information RYBREVANT FASPRO is for subcutaneous use only. Do not administer RYBREVANT FASPRO intravenously. RYBREVANT FASPRO must be administered by a healthcare professional.

To reduce the risk of medication errors, prior to administration, check the vial labels to ensure that the drug being prepared and administered is subcutaneous RYBREVANT FASPRO and not intravenous amivantamab. RYBREVANT FASPRO has different recommended dosage and administration than intravenous amivantamab products. Do not substitute RYBREVANT FASPRO for or with intravenous amivantamab products.

Adult patients currently receiving intravenous amivantamab at an every 2-week dosing regimen may switch to subcutaneous RYBREVANT FASPRO at an every 2-week dosing regimen or at an every 4-week dosing regimen at their next scheduled dose on or after Week 5. 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).

Administer each injection of RYBREVANT FASPRO subcutaneously in the abdomen over approximately 5 minutes to minimize injection site irritation. Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 2 inches (5 cm) around the periumbilical area. If the total dose requires multiple injections of RYBREVANT FASPRO, administer each injection consecutively in separate quadrants of the abdomen, with each injection taking approximately 5 minutes.

Rotate injection sites at the next scheduled dose. Pause or slow the delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set, 0.9% sodium chloride solution may be utilized to flush remaining drug product through the line. Discard unused portion.

Patient Selection

Select patients for treatment with RYBREVANT FASPRO based on the presence of a mutation as detected by an FDA-approved test as shown in Table 1. Table 1: Patient Selection Indication Treatment Regimen Source for Testing Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations RYBREVANT FASPRO in combination with lazertinib Tumor or plasma specimens.

Previously treated locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (progressive disease on an EGFR tyrosine kinase inhibitor) RYBREVANT FASPRO in combination with carboplatin and pemetrexed First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT FASPRO in combination with carboplatin and pemetrexed Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT FASPRO as a single agent

Recommended Dosage RYBREVANT FASPRO In Combination with Carboplatin and Pemetrexed - Every 3-Week Dosing The recommended dosages of RYBREVANT FASPRO, administered every 3 weeks in combination with carboplatin and pemetrexed, based on baseline body weight are provided in Table 2. Administer RYBREVANT FASPRO until disease progression or unacceptable toxicity. Table 2: Recommended Dosage for The recommended order of administration and regimen for RYBREVANT FASPRO in combination with carboplatin and pemetrexed are provided in Table 3.

Table 3: Order of Administration and Regimen for in Combination with Lazertinib or as a Single Agent – Every 4-Week or Every 2-Week Dosing The recommended dosages of RYBREVANT FASPRO in combination with lazertinib or as a single agent, based on baseline body weight, are provided in Table 4 (every 4-week dosing) and Table 5 (every 2-week dosing). Table 4: Recommended Dosage for RYBREVANT FASPRO in Combination with Lazertinib or for RYBREVANT FASPRO as a Single Agent (Every 4-Week Dosing) as a Single Agent (Every 2-Week Dosing) 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.

Recommended Premedications Prior to the initial injection of RYBREVANT FASPRO (Week 1 Day 1), administer premedications as described in Table 6 to reduce the risk of administration-related reactions. 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, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions.

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.

RYBREVANT FASPRO in Combination with Lazertinib: Concomitant Medications to Reduce the Risk of Venous Thromboembolic Events When initiating treatment with RYBREVANT FASPRO in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment. 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.

Missed Dose For a 4-week or 2-week dosing schedule: If a dose of RYBREVANT FASPRO is missed between Weeks 1 to 4, administer within 24 hours. If a dose of RYBREVANT FASPRO is missed from Week 5 onward, administer within 7 days. If the missed dose is not administered according to this guidance, do not administer the missed dose and administer the next dose per the usual dosing schedule.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions for The recommended dosage modifications and management for adverse reactions for RYBREVANT FASPRO are provided in Table 8. Table 8: Recommended Hypersensitivity and Administration-Related Reactions (ARRs) Interstitial Lung Disease (ILD)/pneumonitis s (including dermatitis acneiform, pruritus, dry skin) 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, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT FASPRO as shown in Table 8. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.

Preparation Instructions

For important information on RYBREVANT FASPRO dosage and administration, see Dosage and Administration. 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". 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 for at least 15 minutes.

Do not warm RYBREVANT FASPRO in any other way. Do not shake. Withdraw the required injection volume of RYBREVANT FASPRO (see Table 9 ) from the vial(s) into a syringe(s) using a transfer needle.

Discard unused portion. RYBREVANT FASPRO is compatible with stainless steel injection needles, polypropylene and polycarbonate syringes, and polyethylene, polyurethane, and polyvinylchloride subcutaneous infusion sets. Use 0.9% Sodium Chloride Injection to flush an infusion set, if needed.

Administer using a 21G to 23G needle or infusion set to ensure ease of administration. If immediate administration is not possible, replace the transfer needle with a syringe closing cap for transport. Divide doses requiring greater than 15 mL into approximately equal volumes in two syringes and administer at separate injection sites.

Do NOT exceed 15 mL in each syringe. The dose volumes are provided in Table 9. 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. RYBREVANT FASPRO in Combination with Lazertinib The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT FASPRO in combination with lazertinib in 206 patients with previously treated locally advanced or metastatic NSCLC whose tumors have either an EGFR exon 19 deletion or an exon 21 L858R substitution mutation in PALOMA-3. 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.

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.

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 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 in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.

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 in 302 patients with locally advanced or metastatic NSCLC. 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.

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. 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. 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.

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). Permanent discontinuations of RYBREVANT FASPRO due to an adverse reaction occurred in 13% of patients.

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 ( %) 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 5 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT FASPRO in combination with lazertinib not included in the table above were abdominal pain, hemorrhoids, ILD/pneumonitis, and skin ulcer. Table 11 summarizes the laboratory abnormalities in PALOMA-3. Table 11: Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations in PALOMA-3 The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test.

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. Serious adverse reactions occurred in 49% of patients who received intravenous amivantamab in combination with lazertinib.

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.

Table 0 Clinically relevant adverse reactions in < 10% of patients who received intravenous amivantamab in combination with lazertinib included skin ulcer and ILD/pneumonitis. Table 13 summarizes the laboratory abnormalities in MARIPOSA. 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.

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. 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.

Serious adverse reactions occurred in 32% of patients who received intravenous amivantamab in combination with carboplatin and pemetrexed. 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. Table 14 summarizes the adverse reactions in MARIPOSA-2. Table 14: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Clinically relevant adverse reactions in < 10% of patients who received intravenous amivantamab in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, interstitial lung disease, and skin ulcer.

Table 15 summarizes the laboratory abnormalities in MARIPOSA-2. 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). 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. Adverse reactions resulting in permanent discontinuation of intravenous amivantamab in ≥ 1% of patients were rash and ILD. 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. Table 16 summarizes the adverse reactions in PAPILLON. Table 17 summarizes the laboratory abnormalities in PAPILLON.

Table 17: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in PAPILLON 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, whose disease had progressed on or after platinum-based chemotherapy. Serious adverse reactions in ≥ 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Adverse reactions requiring dose interruption in ≥ 5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.

Adverse reactions requiring dose reductions in ≥ 2% of patients included rash and paronychia. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium. Table 18 summarizes the adverse reactions in CHRYSALIS.

Table 18: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received Intravenous Amivantamab in CHRYSALIS Clinically relevant adverse reactions in < 10% of patients who received intravenous amivantamab included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN). Table 19 summarizes the laboratory abnormalities in CHRYSALIS.

Pregnancy Risk Summary Based on the mechanism of action 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 respectively.

Data Animal Data RYBREVANT FASPRO for subcutaneous injection contains amivantamab and hyaluronidase. 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.

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

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