Rybrevant Drug Information

Patient Selection

Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test. Table 1: Patient Selection Indication Treatment Regimen Source for Testing Information on FDA approved tests is available at: http://www.fda.gov/CompanionDiagnostics. First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations RYBREVANT 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 in combination with carboplatin and pemetrexed First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT in combination with carboplatin and pemetrexed Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations - Every 2-week dosing The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 2. Administer RYBREVANT until disease progression or unacceptable toxicity. Table 2: Recommended in Combination with Lazertinib Order of Administration When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.

Refer to the lazertinib prescribing information for recommended lazertinib dosing information.

Recommended Premedications to Reduce the Risk of Infusion-Related Reactions Administer premedications as described in Table 5. After prolonged dose interruptions, restart the following Week 1 Day 1 premedications upon re-initiation: intravenous dexamethasone, diphenhydramine, and acetaminophen. Table 5: Premedications

Prophylactic and Concomitant Medications to Reduce the Risk of Dermatologic Adverse Reactions When initiating treatment with RYBREVANT, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions. 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 in Combination with Lazertinib: Concomitant Medications to Reduce the Risk of Venous Thromboembolic Events When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment. 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.

Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions for The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7. Table 7: Recommended Interstitial Lung Disease (ILD)/pneumonitis s (including dermatitis acneiform, pruritus, dry skin) in Combination with Lazertinib When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first. Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib.

Recommended, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.

Preparation Dilute and prepare RYBREVANT for intravenous infusion before administration. Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use if discoloration or visible particles are present. Determine the dose required and number of RYBREVANT vials needed based on patient's baseline weight. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.

Withdraw and then discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard 7 mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag.

The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial. Gently invert the bag to mix the solution.

Do not shake. Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15°C to 25°C (59°F to 77°F).

Administration Administer the diluted

RYBREVANT solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE. The administration set with filter, must be primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion.

Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents. Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk of infusion-related reactions during initial treatment. RYBREVANT may be administered via central line for subsequent weeks.

For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction. Table 8: Infusion Rates of infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9. Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.

Table 9: Infusion Rates of

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. RYBREVANT in Combination with Lazertinib The data described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT in combination with lazertinib in the MARIPOSA study in 421 patients with previously untreated locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations. The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, dry skin, hemorrhage, decreased appetite, pruritus, and nausea.

The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium. RYBREVANT in Combination with Carboplatin and Pemetrexed The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies: MARIPOSA-2 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.

In the safety population, the most common (≥ 20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin. RYBREVANT as a Single Agent The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a single agent in CHRYSALIS 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. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase. First-line Treatment of NSCLC with Exon 19 deletions or Exon 21 L858R substitution mutations The safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutation in the MARIPOSA.

Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with lazertinib. Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each). Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 34% of patients.

Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea. Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.

Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients were rash and nail toxicity. Table 0 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with lazertinib included skin ulcer and ILD/pneumonitis.

Table 11 summarizes the laboratory abnormalities in MARIPOSA. Table 11: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test. Previously Treated Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations The safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2.

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 RYBREVANT (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 RYBREVANT in combination with carboplatin and pemetrexed. Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each). Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients.

The most frequent adverse reactions leading to discontinuation of RYBREVANT in ≥ 5% of patients were infusion-related reactions. Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients.

Adverse reactions requiring dose interruption in ≥ 5% of patients included infusion-related reaction, rash and fatigue. Adverse reactions requiring dose reductions in ≥ 2% of patients included rash. Table 12 summarizes the adverse reactions in MARIPOSA-2.

Table 12: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, interstitial lung disease, and skin ulcer. Table 13 summarizes the laboratory abnormalities in MARIPOSA-2. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months).

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 RYBREVANT in ≥ 1% of patients were rash and ILD.

Adverse reactions requiring dose interruption in ≥ 5% of patients included rash and nail toxicity. Table 14 summarizes the adverse reactions in PAPILLON. Table 15 summarizes the laboratory abnormalities in PAPILLON.

Table 15: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON Insertion Mutations The safety data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial, whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for 6 months or longer and 12% were exposed for greater than one year. 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. Table 16 summarizes the adverse reactions in CHRYSALIS. Table 16: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALIS Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).

Table 17 summarizes the laboratory abnormalities in CHRYSALIS.

Postmarketing Experience

The following adverse reactions associated with the use of RYBREVANT were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Infusion-related reactions, including anaphylaxis/anaphylactic reactions

Pregnancy Risk Summary Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT 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 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 No animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT 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-vmjw has the potential to be transmitted from the mother to the developing fetus.

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