Rybrevant SC Product Monograph

Recent Major Label Changes

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Table of Contents

Recent Major Label Changes ................................................................................................... 4

Table of Contents ................................................................................................................... 4

Part 1: Healthcare Professional Information ........................................................................... 7

1. 1.

   Indications ....................................................................................................................... 7

   1.1. Pediatrics .................................................................................................................. 7

   1.2. Geriatrics .................................................................................................................. 7

2. 2. Contraindications ............................................................................................................ 7
3. 4.

   Dosage and Administration ............................................................................................. 8

   4.1. Dosing Considerations .............................................................................................. 8

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 8

   4.4. Administration ........................................................................................................ 14

   4.5. Missed Dose ........................................................................................................... 15

4. 5. Overdose ....................................................................................................................... 15
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................. 16
6. 7.

   Warnings and Precautions ............................................................................................. 16

   Carcinogenesis and Genotoxicity ........................................................................................ 16

   Cardiovascular .................................................................................................................... 16

   Driving and Operating Machinery ....................................................................................... 17

   Immune .............................................................................................................................. 17

   Monitoring and Laboratory Tests ....................................................................................... 17

   Ophthalmologic .................................................................................................................. 18

   Reproductive Health ........................................................................................................... 18

   Respiratory ......................................................................................................................... 18

   Skin ..................................................................................................................................... 18

   7.1. Special Populations ................................................................................................ 19

   7.1.1. Pregnancy ...................................................................................................... 19

   7.1.2. Breastfeeding ................................................................................................ 19

   7.1.3. Pediatrics ....................................................................................................... 19

   7.1.4. Geriatrics ....................................................................................................... 19

7. 8.

   Adverse Reactions ......................................................................................................... 20

   8.1. Adverse Reaction Overview .................................................................................... 20

   8.2. Clinical Trial Adverse Reactions .............................................................................. 22

   Select Adverse Reactions .................................................................................................... 35

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 38

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 39

   8.5. Post Market Adverse Reactions .............................................................................. 43

8. 9. Drug Interactions ........................................................................................................... 43
9. 10.

   Clinical Pharmacology ................................................................................................... 44

   10.1. Mechanism of Action .............................................................................................. 44

   10.2. Pharmacodynamics ................................................................................................ 44

   10.3. Pharmacokinetics ................................................................................................... 44

   10.4. Immunogenicity ...................................................................................................... 46

10. 11. Storage, Stability, and Disposal ...................................................................................... 46

Part 2: Scientific Information ................................................................................................ 47

1. 13. Pharmaceutical Information .......................................................................................... 47
2. 14.

   Clinical Trials .................................................................................................................. 47

   14.1. Clinical Trials by Indication ..................................................................................... 47

   RYBREVANT SC (Subcutaneous Formulation) ..................................................................... 47

   Previously treated patients with Locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations ........................................ 47

   RYBREVANT (Intravenous Formulation) .............................................................................. 49

   First-line Treatment of Adult Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations. ............................. 49

   Previously Treated Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations ................................................ 53

   First-Line Treatment of Patients with Locally Advanced or Metastatic NSCLC with activating EGFR Exon 20 insertion mutations. ............................................................... 56

   Previously Treated NSCLC with EGFR Exon 20 insertion Mutations .............................. 58

3. 15. Microbiology ................................................................................................................. 60
4. 16. Non-Clinical Toxicology .................................................................................................. 60
5. 17. Supporting Product Monographs ................................................................................... 60

Patient Medication Information ........................................................................................... 61

Part 1: Healthcare Professional Information

This Product Monograph for RYBREVANT® SC (amivantamab injection) includes information based on RYBREVANT® (amivantamab for injection) which is the intravenous formulation.

1. Indications

RYBREVANT SC (amivantamab injection) is indicated:

• in combination with lazertinib for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 19 deletions or Exon 21 L858R substitution mutations.
• in combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with epidermal-growth factor receptor (EGFR) Exon 19 deletions or Exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with osimertinib.
• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic NSCLC with activating EGFR Exon 20 insertion mutations.

• as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

  Clinical effectiveness of RYBREVANT SC monotherapy is based on overall response rate (ORR) and duration of response (DOR) from a single-arm trial in patients with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations.

1.1. Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of RYBREVANT SC in pediatric patients (<18 years of age) has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥65 years of age): Among all patients treated with RYBREVANT SC, no overall differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.

No clinically relevant differences in efficacy were observed between elderly patients (≥65 years of age) and younger patients when treated with RYBREVANT as a monotherapy or in combination with carboplatin and pemetrexed. Evidence from the clinical studies suggests that the use of RYBREVANT in the geriatric population is associated with differences in safety (see 7.1.4 Geriatrics).

Evidence from clinical studies suggests that use of RYBREVANT in combination with lazertinib in the geriatric population is associated with differences in safety. Differences were seen in subgroup analyses for efficacy in geriatrics patients, however no formal statistical testing of efficacy was planned for subgroup analyses by age and interpretation of these differences is non-conclusive (see 7.1.4 Geriatrics, 10.3 Pharmacokinetics, 14.1 Clinical Trials by Indication).

2. Contraindications

• RYBREVANT® SC is contraindicated in patients who are hypersensitive to this drug or to any

  • ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

4. Dosage and Administration

4.1. Dosing Considerations

• RYBREVANT SC is for subcutaneous use only. RYBREVANT SC has different dosage and administration instructions than intravenous amivantamab. Do not administer intravenously.
• RYBREVANT SC should be administered by a healthcare professional with appropriate medical support to manage administration-related reactions (ARRs) if they occur (see 7 Warnings and Precautions, Immune).
• Administer pre-medications before each dose of RYBREVANT SC as recommended (see 4.2 Recommended Dose and Dosage Adjustment).
• Before initiation of RYBREVANT SC, the presence of an EGFR Exon 19 deletion, Exon 21 L858R substitution, or Exon 20 insertion mutation must be determined using a validated test.
• Adult patients currently receiving intravenous amivantamab may switch to subcutaneous RYBREVANT SC at their next scheduled dose on Week 5 or later (see Table 1, Table 2 and Table 3 and 4.2 Recommended Dose and Dosage Adjustment).
• For patients currently receiving RYBREVANT SC at an every 2-week dosing regimen, an every 4-week dosing regimen may be used as an alternative starting at the next scheduled dose (see Table 1 and 4.2 Recommended Dose and Dosage Adjustment).

4.2. Recommended Dose and Dosage Adjustment

It is recommended that patients are treated with RYBREVANT SC until disease progression or unacceptable toxicity (see 4.4 Administration). Pre-medications should be administered prior to each RYBREVANT SC injection (see Pre-medications and Table 5).

RYBREVANT SC in combination with Lazertinib or monotherapy (Every 4-week or every 2-week dosing)

The recommended dosages of RYBREVANT SC monotherapy or in combination with lazertinib, based on baseline body weight, are provided in Table 1 (every 4-week dosing) and Table 2 (every 2-week dosing).

Table 1: Recommended Dose and Dosing Schedule for RYBREVANT SC in Combination with Lazertinib or Monotherapy (Every 4-week Dosing)

* Dose adjustments not required for subsequent body weight changes

Table 2: Recommended Dose and Dosing Schedule for RYBREVANT SC in Combination with Lazertinib or Monotherapy (Every 2-Week Dosing)

* Dose adjustments not required for subsequent body weight changes

The recommended dosage of lazertinib is 240 mg once daily, taken orally in combination with RYBREVANT SC. When used in combination with lazertinib, RYBREVANT SC should be administered anytime after lazertinib when given on the same day. Refer to the lazertinib product monograph for information on dosing and administration for lazertinib.

RYBREVANT SC in combination with carboplatin and pemetrexed (Every 3-week dosing)

The recommended dosages of RYBREVANT SC, when used in combination with carboplatin and pemetrexed (every 3-week dosing), based on baseline body weight, are provided in Table 3.

Table 3: Recommended Dose and Dosing Schedule for RYBREVANT SC in Combination with Carboplatin and Pemetrexed (Every 3-Week Dosing)

* Dose adjustments not required for subsequent body weight changes

When used in combination with carboplatin and pemetrexed, RYBREVANT SC should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin, and then RYBREVANT SC.

Table 4: Recommended order of administration and regimen for RYBREVANT SC in combination with carboplatin and pemetrexed

RYBREVANT SC in Combination with Carboplatin and Pemetrexed

Administer the regimen in the following order: pemetrexed first, carboplatin second and RYBREVANT SC last.

Drug

Dose

Duration/Timing of Treatment

Pemetrexed

Pemetrexed 500 mg/m² intravenously

Refer to the pemetrexed Product Monograph for complete information.

Every 3 weeks, continue until disease progression or unacceptable toxicity.

Carboplatin

Carboplatin AUC 5 intravenously

Refer to the carboplatin Product Monograph for complete information.

Every 3 weeks for up to 12 weeks.

RYBREVANT SC

RYBREVANT SC, subcutaneously

See Table 3.

Weekly for the first 4 weeks (Week 1 to 4), then every 3 weeks starting at week 7 onwards, continue until disease progression or unacceptable toxicity.

Pre-medications

Prior to initial injection of RYBREVANT SC (Week 1 Day 1), administer pre-medications as described in Table 5 to reduce the risk of ARRs. For subsequent doses, administer antihistamines and antipyretics. Administer glucocorticoids as needed (see Table 5).

Table 5: Pre-Medications

^* Required at all doses

^‡ Required at initial dose (Week 1 Day 1) or at the next subsequent dose in the event of an administration-related reaction.

^§ Optional for subsequent doses

Dose Modifications

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

Table 6: Dose Reductions for Adverse Reactions for RYBREVANT SC

* The dose volume should be 6.6 mL for 1050 mg dose.

^† The dose volume should be 4.4 mL for 700 mg dose.

^‡ The dose volume should be 10 mL for 1600 mg dose.

^§ The dose volume should be 14 mL for 2240 mg dose.

^¶ The dose volume should be 15 mL for 2400 mg dose.

^# The dose volume should be 21 mL for 3360 mg dose.

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

Table 7: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANT SC

Recommended Dose Modifications for Adverse Reactions for RYBREVANT SC in Combination with Carboplatin and Pemetrexed or in Combination with Lazertinib

When administering RYBREVANT SC in combination with carboplatin and pemetrexed, or in combination with lazertinib, follow the recommended dose modifications for adverse reactions for RYBREVANT SC as shown in Table 7. Refer to the Product Monographs for carboplatin, pemetrexed, and lazertinib for their dosage modification recommendations.

Renal impairment

No formal studies of RYBERVANT SC in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min) or moderate (29 ≤ CrCl < 60 mL/min) renal impairment. Data in patients with severe renal impairment are limited. No data are available in patients with end stage renal disease (15 ≤ CrCl < 29 mL/min) (see 10.3 Pharmacokinetics).

Hepatic impairment

No formal studies of RYBREVANT SC in patients with hepatic impairment have been conducted. Based on population PK analyses, no dosage adjustment is necessary for patients with mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)]. Data in patients with moderate hepatic impairment are limited (1.5 x ULN < total bilirubin ≤ 3 x ULN and any AST)). No data are available in patients with severe hepatic impairment (total bilirubin >3 x ULN) (see 10.3 Pharmacokinetics).

Pediatrics (<18 years)

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

Geriatrics (≥65 years)

No dose adjustment of RYBREVANT SC is required in patients aged 65 years or older (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics).

4.4. Administration

• RYBREVANT SC should be administered by a healthcare professional.
• To prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is RYBREVANT SC for subcutaneous injection and not intravenous amivantamab. RYBREVANT SC subcutaneous formulation is not intended for intravenous administration and should be administered via a subcutaneous injection only.
• RYBREVANT SC is for single use only and is supplied ready to use.
• RYBREVANT SC should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if opaque particles, discoloration, or other foreign particles are present.
• Prepare the dosing syringe in aseptic conditions.
• Each injection volume should not exceed 15 mL.

Preparation for administration

Refer to Table 8 for the preparation of RYBREVANT SC.

Table 8: Dosing volumes for RYBREVANT SC

† Divide the dose volume approximately equally into two syringes (each syringe should not exceed 15 mL).

• Remove the appropriate number of RYBREVANT SC vial(s) from refrigerated storage (2°C to 8°C)
• Once removed from refrigerated storage, equilibrate RYBREVANT SC to room temperature (15 °C to 30 °C) for at least 15 minutes. Do not warm RYBREVANT SC in any other way. Do not shake.
• Withdraw the required injection volume of RYBREVANT SC from the vial(s) into an appropriately sized syringe using a transfer needle (see Table 8). Smaller syringes require less force during preparation and administration.
• If preparation does not require the full vial contents, dispose of excess volume in accordance with local requirements.
• Each injection volume should not exceed 15 mL. Divide doses requiring greater than 15 mL into approximately equal volumes in multiple syringes.

• RYBREVANT SC is compatible with stainless steel injection needles, polypropylene and polycarbonate syringes, and polyethylene, polyurethane, and polyvinylchloride subcutaneous

  • infusion sets. A 0.9% sodium chloride solution may also be used to flush an infusion set if needed.
• Replace the transfer needle with appropriate ancillaries for transport or administration. Use of a 21G to 23G needle or infusion set is recommended to ensure ease of administration.

Storage of prepared syringe

The prepared syringes of RYBREVANT SC should be administered immediately. If immediate administration is not possible, store the prepared syringes of RYBREVANT SC refrigerated at 2°C to 8°C for up to 24 hours followed by at room temperature of 15°C to 30°C for up to 24 hours. Discard the prepared syringe if stored for more than 24 hours refrigerated or more than 24 hours of being at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration.

Administration of RYBREVANT SC

• If only one dosing syringe is required, the required volume of RYBREVANT SC should be injected into the subcutaneous tissue of the abdomen over approximately 5 minutes.
• If multiple dosing syringes are required, RYBREVANT SC injections should be consecutively administered in separate quadrants of the abdomen, with each injection taking approximately 5 minutes.
• Rotate injection sites at the next scheduled dose.
• Pause or slow down 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 the full dose is delivered through the infusion set. 0.9% sodium chloride solution may be utilized to flush the remaining drug product through the line.
• 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.
• Any unused product or waste material should be disposed in accordance with local requirements.

4.5. Missed Dose

For a 4-week or 2-week dosing schedule:

• If a dose of RYBREVANT SC is missed between Weeks 1 to 4, administer within 24 hours.
• If a dose of RYBREVANT SC is missed from Week 5 onward, administer within 7 days.

For a 3-week dosing schedule:

• If a dose of RYBREVANT SC is missed between Weeks 1 to 3, administer within 24 hours.
• If a dose of RYBREVANT SC is missed from Week 4 onward, administer within 7 days.

If the missed dose is not administered according to this guidance, do not administer the missed dose. Administer the next dose per the usual dosing schedule.

5. Overdose

There is no information on overdosage with RYBREVANT SC. There is no known specific antidote for

RYBREVANT SC overdose. In the event of an overdose, stop RYBREVANT SC, monitor patient for any signs or symptoms of adverse reactions and undertake general supportive measures until clinical toxicity has diminished or resolved.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products, healthcare professionals should record both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 9: Dosage Forms, Strengths, and Composition

* Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously

Description

RYBREVANT SC is available as a colourless to pale yellow preservative-free solution for subcutaneous administration. Each single-dose vial contains 160 mg / mL of amivantamab.

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

No animal studies have been performed to evaluate the carcinogenic or mutagenic potential of amivantamab (see 16 Non-Clinical Toxicology).

Cardiovascular

Left Ventricular Dysfunction and Cardiomyopathy

In patients treated with RYBREVANT SC in combination with lazertinib, left ventricular ejection fraction (LVEF) reductions (>10 percentage points and a drop below lower limit of normal) and cardiomyopathy events (defined as cardiac failure, chronic cardiac failure, congestive cardiac failure, pulmonary edema, ejection fraction decreased, left ventricular dysfunction) have been reported. Refer to the lazertinib product monograph (see 7 Warnings and Precautions, Monitoring and Laboratory Tests and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

Venous Thromboembolic (VTE) Events

In patients treated with RYBREVANT SC in combination with lazertinib, venous thromboembolic (VTE) events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), including fatal events, have been reported. VTE events occurred predominately in the first four months of therapy (see 8 Adverse Reactions and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

Prophylactic anticoagulants are recommended to be used for the first four months of treatment to prevent VTE. Prophylactic anticoagulation beyond 4 months may be considered based on individual patient risk factors. Use of anticoagulants should align with clinical guidelines; use of Vitamin K antagonists is not recommended.

Monitor for signs and symptoms of VTE events. Treat patients with VTE events with anticoagulants as clinically indicated (see 4.2 Recommended Dose and Dosage Adjustment).

For patients with Grade 4 or recurrent Grade 2 or 3 VTE events despite therapeutic levels of anticoagulation, permanently discontinue RYBREVANT SC and withhold lazertinib. Administer anticoagulation treatment as clinically indicated. Once anticoagulation treatment has been initiated, treatment can continue with lazertinib at the same dose level at the discretion of the healthcare professional (see 4.2 Recommended Dose and Dosage Adjustment).

Driving and Operating Machinery

No studies on the effects on the ability to drive and use machines have been performed. Exercise caution when driving or operating a vehicle or potentially dangerous machinery.

If patients experience treatment-related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

Immune

Administration-related reactions (ARRs) may occur in patients treated with RYBREVANT SC. The most frequent signs and symptoms include chills, dyspnea, flushing, fever and chest discomfort (see 8. Adverse Reactions and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

Prior to initial injection (Week 1, Day 1) of RYBEVANT SC, administer antihistamines, antipyretics and glucocorticoids to reduce the risk of ARRs (Table 5). For subsequent doses, administer antihistamines and antipyretics (see 4.2 Recommended Dose and Dosage Adjustment).

Treat patients with RYBEVANT SC in a setting with appropriate medical support necessary to treat ARRs. Interrupt RYBEVANT SC injection, if ongoing, at the first sign of ARRs and administer supportive care as clinically indicated. Upon resolution of symptoms, resume RYBEVANT SC administration. For Grade 4 or recurrent Grade 3 ARRs, permanently discontinue RYBEVANT SC (see 4.2 Recommended Dose and Dosage Adjustment).

Monitoring and Laboratory Tests

Prior to initiating therapy with RYBREVANT SC in combination with lazertinib, electrolyte levels (calcium, potassium, and magnesium) should be assessed. Refer to the lazertinib product monograph (see 8 Adverse Reactions).

For patients with cardiac risk factors and those with conditions that can affect left ventricular ejection fraction (LVEF), refer to the lazertinib product monograph.

Ophthalmologic

Eye disorders may occur in patients treated with RYBREVANT SC. These include keratitis, dry eye, blurred vision, eye pruritis, visual impairment, lacrimation increased, ocular hyperemia, eyelid ptosis, aberrant eyelash growth, conjunctival hyperemia, blepharitis, and uveitis (see 8. Adverse Reactions and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

Refer patients presenting with worsening eye symptoms promptly to an ophthalmologist and advise discontinuation of contact lenses until symptoms are evaluated. Withhold, dose reduce or permanently discontinue RYBREVANT SC based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

Reproductive Health

Due to the risk that RYBREVANT SC can cause fetal harm when administered to pregnant women, advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT SC (see 7.1.1 Pregnancy). Male patients must use effective contraception (e.g., condom) and not donate or store semen during treatment and for 3 months after the last dose of RYBREVANT SC.

• Fertility

  No data are available to determine potential effects of RYBREVANT SC on fertility in males or females (see 7.1.1 Pregnancy, 16 Non-Clinical Toxicology).

Respiratory

Interstitial lung disease (ILD)/ pneumonitis, including fatal events, may occur in patients treated with RYBREVANT SC (see 8 Adverse Reactions and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the clinical studies.

Monitor patients for symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). If symptoms develop, interrupt treatment with RYBREVANT SC pending investigation of these symptoms. Evaluate suspected ILD and initiate appropriate treatment as necessary. Discontinue RYBREVANT SC in patients with confirmed ILD (see 4.2 Recommended Dose and Dosage Adjustment).

Skin

Skin and nail reactions may occur in patients treated with RYBREVANT SC. This includes severe rash, dermatitis acneiform, palmar-plantar erythrodysesthesia, pruritus, dry skin and paronychia. Toxic epidermal necrolysis (TEN) has occurred with RYBREVANT treatment (8. Adverse Reactions and 8.2 Clinical Trial Adverse Reactions, Select Adverse Reactions).

When initiating treatment with RYBREVANT SC, consider prophylactic therapy to reduce the risk and severity of skin and nail reactions. This includes administration of an oral antibiotic (doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment. After completion of oral antibiotic therapy, application of a topical antibiotic lotion to the scalp (clindamycin 1% once daily), should be used for the next 9 months of RYBREVANT SC treatment. Recommend a non-comedogenic skin moisturizer (ceramide based or other formulations that provide long-lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and 4% chlorhexidine solution to wash hands and feet, while on treatment. Instruct patients to limit sun exposure during and for 2 months after RYBREVANT SC therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable.

If skin or nail reactions develop, administer supportive care, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 or poorly-tolerated Grade 2 events, add systemic antibiotics and oral steroids and consider dermatologic consultation. For Grade 4 skin reactions, permanently discontinue RYBREVANT SC. 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 SC based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

7.1. Special Populations

7.1.1. Pregnancy

There are no human or animal data to assess the risk of RYBREVANT SC in pregnancy. Administration of other EGFR and MET inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, RYBREVANT SC could cause fetal harm when administered to a pregnant woman.

RYBREVANT SC should not be used during pregnancy unless the benefit of treatment to the woman is considered to outweigh potential risks to the fetus. If the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus.

7.1.2. Breastfeeding

No studies have been conducted to determine if RYBREVANT SC is excreted in human or animal milk or affects milk production. RYBREVANT SC is a fully human, Immunoglobulin G1 (IgG1) based bispecific antibody. In general, human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to lower concentrations soon afterwards. Because of the potential for serious adverse reactions from RYBREVANT SC in breastfed infants, advise women not to breastfeed during treatment with RYBREVANT SC and for 3 months following the last dose of RYBREVANT SC.

7.1.3. Pediatrics

The efficacy and safety of RYBREVANT SC in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

No overall differences in effectiveness were observed between patients treated with RYBREVANT SC who were ≥65 years of age and younger patients.

There are limited clinical data on the combination of RYBREVANT SC with lazertinib in patients 75 years or over.

In patients treated with RYBREVANT (intravenous formulation) as monotherapy, in combination with carboplatin and pemetrexed, or in combination with lazertinib, differences in safety were observed in patients who were ≥65 years of age as compared to younger patients, as described below.

In MARIPOSA, older patients (≥65 years of age) treated with RYBREVANT in combination with lazertinib reported more Grade 4 and Grade 5 adverse reactions compared to patients <65 years of age (21% vs.

7%). The incidence of serious adverse reactions was 62% in patients ≥65 years of age and 38% in patients <65 years of age. While the rates of drug interruptions and dose reductions were similar, the rate of adverse reactions leading to any treatment discontinuation was higher in patients ≥ 65 years of age compared to patients < 65 years of age (47% vs. 25%).

Of the 281 patients treated with RYBREVANT in PAPILLON and MARIPOSA-2, 38% were 65 years of age or older, and 9% were 75 years of age or older. No clinically relevant differences in effectiveness were observed based on age. Adverse events that led to discontinuation of any study agent were reported for 13.8% of patients under 65 years old and 33.6% of patients aged 65 years or older.

Of the 302 patients treated with RYBREVANT in CHRYSALIS (EDI1001), 39.4% were 65 years of age or older, and 11.3% were 75 years of age or older. No clinically relevant differences in effectiveness were observed based on age. There was a higher incidence of serious adverse events observed in patients aged 65 years or older (39.5%) as compared to younger patients (25.1%). There was also a higher incidence of adverse events leading to dose interruptions observed in patients aged 65 years or older (44.5%) as compared to younger patients (28.4%).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The following adverse reactions observed with RYBREVANT SC or RYBREVANT when used in combination with lazertinib, or in combination with carboplatin and pemetrexed, or when used alone as a monotherapy are discussed in the Warnings and Precautions section (7. Warnings and Precautions and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions).

• Left Ventricular Dysfunction and Cardiomyopathy and Venous Thromboembolic Events (see 7. Warnings and Precautions, Cardiovascular and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions)
• Administration Related Reactions (see 7. Warnings and Precautions, Immune and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions)
• Eye Disorders (see 7. Warnings and Precautions, Ophthalmologic and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions)
• Interstitial Lung Disease (ILD)/Pneumonitis (see 7. Warnings and Precautions, Respiratory and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions)
• Skin and Nail Reactions (see 7. Warnings and Precautions, Skin and 8.2. Clinical Trial Adverse Reactions, Select Adverse Reactions)

RYBREVANT SC (Subcutaneous Formulation)

RYBREVANT SC in combination with Lazertinib

Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

The safety of RYBREVANT SC in combination with lazertinib described in the Adverse Reactions section reflects the exposure of 206 patients enrolled in the PALOMA-3 study. The most common adverse reactions (≥20%) in patients who received RYBREVANT SC in combination with lazertinib were rash, nail toxicity, fatigue, stomatitis, edema, nausea, decreased appetite, vomiting, diarrhea and constipation. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocyte count, decreased sodium, decreased potassium, decreased albumin, increased alanine aminotransferase, decreased platelet count, increased aspartate aminotransferase, increased gamma glutamyl transferase, and decreased hemoglobin.

RYBREVANT (Intravenous Formulation)

RYBREVANT in Combination with Lazertinib

First-line Treatment of NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutation

The safety of RYBREVANT in combination with lazertinib described in the Adverse Reactions section reflects the exposure of 421 patients enrolled in the MARIPOSA study. The most common adverse reactions (≥20%) of patients who received RYBREVANT in combination with lazertinib were paronychia, infusion related reaction (amivantamab-specific), rash, hypoalbuminemia (amivantamab-specific), alanine aminotransferase increased, edema peripheral, constipation, diarrhea, dermatitis acneiform, stomatitis, aspartate aminotransferase increased, COVID-19, decreased appetite, pruritus, anemia, nausea, and hypocalcemia. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin, increased alanine aminotransferase, decreased sodium, decreased potassium, decreased hemoglobin, increased aspartate aminotransferase, increased magnesium, and increased gamma-glutamyltransferase.

RYBREVANT in Combination with Carboplatin and Pemetrexed

The pooled safety population described in the Adverse Reactions section also reflects exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies:

• MARIPOSA-2 (NSC3002) in 130 patients
• PAPILLON (NSC3001) in 151 patients

Among 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for 6 months or longer and 24% were exposed for greater than one year.

Two hundred and eighty-one patients were exposed to RYBREVANT with carboplatin and pemetrexed in PAPILLON (N=151) and MARIPOSA-2 (N=130) for a median duration of 7.75 months (range 0 to 26.9) months and to carboplatin and pemetrexed (N=398) for a median duration of 4.86 (range 0 to 25.3) months.

The most common adverse reactions (≥20%) were rash, neutropenia, infusion related reactions, paronychia, fatigue, anemia, nausea, thrombocytopenia, stomatitis, constipation, edema, decreased appetite, leukopenia, hypoalbuminemia, alanine aminotransferase increased, aspartate aminotransferase increased, and vomiting.

The most common grade 3 to grade 4 laboratory abnormalities (≥2%) were decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, decreased platelet count, decreased hemoglobin, decreased potassium, decreased sodium, decreased albumin, increased alanine aminotransferase, and increased gamma glutamyl transferase.

RYBREVANT Monotherapy

Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations

The safety of RYBREVANT described in the Adverse Reactions section reflects the exposure of 129 patients enrolled in the CHRYSALIS study. The most common adverse reactions (≥20%) were dermatitis acneiform, rash, infusion related reactions (IRRs), nausea, paronychia, fatigue, hypoalbuminemia, constipation, stomatitis, peripheral edema, and alanine aminotransferase increased. The most common

Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin, decreased phosphates, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyltransferase, decreased sodium, increased alanine aminotransferase, decreases in lymphocytes, neutrophils, hemoglobin, and white blood cells.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

RYBREVANT SC (Subcutaneous Formulation)

RYBREVANT SC in combination with Lazertinib

Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

The safety of RYBREVANT SC in combination with lazertinib in patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 L858R substitution mutation was evaluated in the PALOMA-3 study. Patients received RYBREVANT SC (N=206) or RYBREVANT (intravenous [IV] amivantamab; N=212), both in combination with lazertinib, at the recommended dosages in the PALOMA-3 study (see 14.1 Clinical Trials by Indication) Additionally, 164 patients (80%) receiving RYBREVANT SC and 171 patients (81%) receiving RYBREVANT took prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin within the first four months of study treatment. Among patients receiving RYBREVANT SC, 33% were exposed for ≥ 6 months and 3.4% were exposed for >1 year. For details on the study population, (see 14.1 Clinical Trials by Indication).

Overall, the safety profile of RYBREVANT SC was consistent with the established safety profile of RYBREVANT.

The most common adverse reactions (≥10%) observed in the PALOMA-3 study are reported in Table 10.

Permanent discontinuations of RYBREVANT SC due to an adverse reaction occurred in 7% of patients. Adverse reactions leading to RYBREVANT SC discontinuation in ≥ 1% of patients were ILD (4.9%) and rash (1.5%).

Adverse reactions requiring RYBREVANT SC dose interruption in ≥5% of patients were rash (18%) and nail toxicity (9%). Adverse reactions requiring RYBREVANT SC dose reductions in ≥ 5% of patients were rash (8%) and nail toxicity (6%).

Serious adverse reactions in ≥2% of patients who received RYBREVANT SC in combination with lazertinib included ILD (6%) and fatigue (2.4%). A fatal adverse reaction of ILD occurred in 1 (0.5%) patient who received RYBREVANT SC and 3 (1.4%) patients who received intravenous amivantamab, both in combination with lazertinib.

The overall incidence of VTE was 11%; the incidence of VTE in the RYBREVANT SC + lazertinib arm was 9% and in the intravenous amivantamab + lazertinib arm, was 13%. The rate of anticoagulation use was similar in the two treatment arms (80% for RYBREVANT SC and 81% for intravenous amivantamab). In patients treated with RYBREVANT SC in combination with lazertinib, the incidence of VTE was 16.7% among those who did not receive prophylactic anticoagulants and 6.5% among those who received prophylactic anticoagulants. For details on the study population, see 14. Clinical Trials.

Table 10 summarizes the adverse reactions (≥10%) in PALOMA-3.

Table 10: Adverse Reactions (≥10%) in Patients Who Received RYBREVANT SC or RYBREVANT (IV Amivantamab) in NSC3004 (PALOMA-3)

RYBREVANT (Intravenous Formulation)

RYBREVANT in Combination with Lazertinib

First-line Treatment of NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutation

The safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 L858R substitution mutation in the MARIPOSA study. Patients in MARIPOSA received lazertinib 240 mg orally once daily and RYBREVANT 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. Patients in the osimertinib arm received 80 mg osimertinib once daily.

The median treatment duration was 18.5 months (range 0.2 to 31.4 months) for the RYBREVANT + lazertinib arm and the median treatment duration was 18.0 months (range: 0.2 to 32.7 months) for the osimertinib arm. Among the 421 patients who received RYBREVANT in combination with lazertinib, 72.9% were exposed to RYBREVANT for ≥ 6 months and 59.1% were exposed to RYBREVANT for >1 year. For details on the study population, see 14. Clinical Trials by Indication.

The adverse reactions reported in ≥20% of patients who received RYBREVANT in combination with lazertinib were paronychia, infusion related reaction (amivantamab-specific), rash, hypoalbuminemia (amivantamab-specific), alanine aminotransferase increased, edema peripheral, constipation, diarrhea, dermatitis acneiform, stomatitis, aspartate aminotransferase increased, COVID-19, decreased appetite, pruritus, anemia, nausea, and hypocalcemia.

Dose interruptions of RYBREVANT in combination with lazertinib due to an adverse reaction occurred in 81% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included infusion related reactions, rash, nail toxicity, venous thromboembolism, alanine aminotransferase increased, edema, hypoalbuminemia, fatigue, stomatitis, and aspartate aminotransferase increased.

Dose reductions of RYBREVANT in combination with lazertinib due to an adverse reaction occurred in 42% of patients. Adverse reactions requiring dose reductions in ≥5% of patients included rash and nail toxicity.

Permanent discontinuations of RYBREVANT due to an adverse reaction occurred in 22% of patients. Adverse reactions leading to RYBREVANT discontinuation in ≥1% of patients were rash, nail toxicity, infusion related reactions, ILD, venous thromboembolism, edema, fatigue, and hypoalbuminemia.

Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with lazertinib. Serious adverse reactions in >2% of patients who received RYBREVANT in combination with lazertinib included pulmonary embolism (6.2%), pneumonia (4.0%), deep vein thrombosis (2.9%),

ILD/pneumonitis (2.9%), COVID-19 (2.4%) infusion related reaction (2.1%; amivantamab-specific), rash (2.1%) and pleural effusion (2.1%).

Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib, which included 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).

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

Table 11: Adverse Reactions (≥10%) in First-line Treatment of Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA

RYBREVANT in combination with carboplatin and pemetrexed

Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

The safety of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NSC3002), which included 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 osimertinib. (see 14.1 Clinical Trials by Indication). Patients received RYBREVANT, 1400 mg (for patients <80 kg) or 1750 mg (for patients ≥80 kg) by intravenous infusion once weekly for 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients <80 kg) or 2100 mg (for patients ≥80 kg) starting at Week 7 until disease progression or unacceptable toxicity.

Patients were exposed to RYBREVANT with carboplatin and pemetrexed (N=130) for a median treatment duration of 6.3 months (range: 0 to 14.7) months and to carboplatin and pemetrexed (N=243) for a median treatment duration of 3.7 months (range: 0 to 15.9) months.

The most common TEAE (≥20%) in patients who received RYBREVANT in combination with carboplatin and pemetrexed were infusion related reactions, neutropenia, nausea, rash, thrombocytopenia, anemia, constipation, paronychia, edema peripheral, stomatitis, decreased appetite, leukopenia, fatigue, asthenia, vomiting, hypoalbuminemia, COVID-19, alanine aminotransferase increased, and dermatitis acneiform. The most common TEAE (≥20%) in patients who received carboplatin and pemetrexed were neutropenia, anemia, nausea, thrombocytopenia, constipation, leukopenia, alanine aminotransferase increased, aspartate aminotransferase increased, and decreased appetite.

Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion related reactions (IRRs) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included neutropenia, thrombocytopenia, COVID-19, leukopenia, and rash. Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. The most commonly reported adverse reactions requiring dose reductions in ≥2% of patients included neutropenia and rash.

Fifteen percent of patients permanently discontinued RYBREVANT due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation in ≥1% of patients were infusion related reactions.

The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.

Serious adverse events occurred in 32.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed, and in 20.2% of patients treated with chemotherapy alone. In MARIPOSA-2 ACP arm, Grade ≥3 TEAEs were reported for 79.0% of Asians and in 64.1% of non-Asians. SAEs were reported for 40.3% of Asians and in 23.4% of non-Asians.

Serious adverse events in ≥2% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included thrombocytopenia, dyspnea, sepsis, and pulmonary embolism. Serious adverse events in ≥2% who received chemotherapy alone included neutropenia, thrombocytopenia, febrile neutropenia, and pneumonia. Fatal adverse reactions, irrespective of relatedness to treatment occurred in 3 patients (2.3%) who received RYBREVANT in combination with carboplatin and pemetrexed. Fatal adverse reactions, irrespective of relatedness to treatment occurred in 3 patients (1.2%) who received chemotherapy alone. The fatal adverse events that occurred in patients treated with RYBREVANT in combination with carboplatin and pemetrexed included dyspnea, sepsis, and ventricular fibrillation. The fatal adverse reactions that occurred in patients treated with chemotherapy alone included dyspnea, pneumonia, and respiratory failure.

Table 12 summarizes TEAEs reported in ≥5% of patients in MARIPOSA-2.

Table 12: Treatment-Emergent Adverse Events (≥5%) 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

First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with EGFR Exon 20 Insertion Mutations

The safety of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in the PAPILLON study, a randomized, open-label trial in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations (see 14.1. Clinical Trials by Indication). In the PAPILLON study, 151 patients were treated with RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage and 155 patients were treated with carboplatin and pemetrexed (chemotherapy alone). Among patients who received RYBREVANT in combination with carboplatin and pemetrexed, the median exposure was 9.7 months (range: 0.1 to 26.9 months). The median exposure for patients who received chemotherapy alone was 6.7 months (range: 0.0 to 25.3 months). The median age was 62 years (range: 27 to 92 years); 57.8% were female; 61.4% were Asian, 36.0% were White and 84.4% had baseline body weight <80 kg.

The most common TEAE (≥20%) in patients who received RYBREVANT in combination with carboplatin and pemetrexed were rash, neutropenia, paronychia, anaemia, stomatitis, infusion related reactions, hypoalbuminaemia, edema, constipation, leukopenia, nausea, thrombocytopenia, decreased appetite, fatigue, ALT increased, AST increased, COVID-19, hypokalaemia, vomiting, and diarrhea. The most common TEAE (≥20%) in patients who received chemotherapy alone were anaemia, neutropenia, nausea, fatigue, ALT increased, AST increased, leukopenia, constipation, thrombocytopenia, and decreased appetite.

Serious adverse events occurred in 37.1% of patients who received RYBREVANT in combination with carboplatin and pemetrexed, and in 31.0% of patients treated with chemotherapy alone. Serious adverse events in ≥2% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pneumonia, COVID-19, pulmonary embolism, thrombocytopenia, rash, interstitial lung disease/pneumonitis, vomiting, and hypokalemia. Serious adverse events in ≥2% of patients who received chemotherapy alone included pneumonia, pulmonary embolism, dyspnoea, pleural effusion, thrombocytopenia, and anaemia. Fatal adverse events, irrespective of relatedness to treatment, occurred in 7 patients (4.6%) who received RYBREVANT in combination with carboplatin and pemetrexed and 4 (2.6%) patients who received chemotherapy alone. The fatal adverse events that occurred in patients who received RYBREVANT in combination with carboplatin and pemetrexed included pneumonia, cardiovascular accident, cardio-respiratory arrest, COVID-19, sepsis and death. The fatal adverse events that occurred in patients treated with chemotherapy alone included sepsis, acute myocardial infarction, dyspnoea and death.

Permanent discontinuation of RYBREVANT due to an adverse event occurred in 11.3% of patients. Adverse events resulting in permanent discontinuation of RYBREVANT in ≥1% of patients were rash and ILD/pneumonitis.

Dose interruptions of RYBREVANT due to an adverse event occurred in 64.2% of patients. Infusion related reactions (IRRs) requiring infusion interruptions occurred in 37.7% of patients. Adverse events requiring dose interruption in ≥5% of patients included rash, neutropenia, paronychia, COVID-19, thrombocytopenia, and hypokalemia.

Dose reductions of RYBREVANT due to an adverse event occurred in 35.8% of patients. Adverse events requiring dose reductions in ≥5% of patients included rash and paronychia.

The most common Grade 3 to 4 laboratory abnormalities (≥2%) observed in patients who received RYBREVANT in combination with carboplatin and pemetrexed were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyltransferase, decreased sodium, decreased potassium, decreased magnesium and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes. The most common Grade 3 to 4 laboratory abnormalities (≥2%) observed in patients who received chemotherapy alone were decreased sodium, increased gamma-glutamyltransferase and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.

Table 13 summarizes the TEAEs reported in ≥5% of patients in the PAPILLON study.

Table 13: Treatment-emergent Adverse Events (≥5%) in Patients with NSCLC with Exon 20 Insertion Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON

RYBREVANT monotherapy

Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations

The safety of RYBREVANT monotherapy in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy was evaluated in 129 patients enrolled in CHRYSALIS. Patients received RYBREVANT 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) by intravenous infusion once weekly for 4 weeks, then every 2 weeks starting at Week 5, until disease progression or unacceptable toxicity. The median treatment duration was 5.6 months (range: 0.03 to 23.9 months), with 44.2% of patients for at least 6 months. The median age was 62 years (range: 36 to 84 years) with 41.1% of patients 65 years of age or older, and 8.5% of patients 75 years of age or older; 61.2% were female; 55.0% were Asian, 2.3% were Black, and 34.9% were White. Eighty-two percent of patients (n=106) had baseline body weight <80 kg and 18% (n=23) had baseline body weight ≥80 kg.

The most common adverse reactions ≥20% were dermatitis acneiform, rash, infusion related reactions (IRRs), nausea, paronychia, fatigue, hypoalbuminemia, constipation, stomatitis, and peripheral edema, and alanine aminotransferase increased. Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis, dyspnea, back pain, and muscular weakness. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥1% of patients were pneumonia, IRR, pneumonitis, and pleural effusion.

Dose reductions due to an adverse reaction occurred in 15% of patients who received RYBREVANT. Adverse reactions requiring dose reductions in ≥2% of patients included dermatitis acneiform, and paronychia.

Grade 5 treatment-emergent adverse events, irrespective of relatedness to RYBREVANT, were reported in 7.0% of patients. The most common events were pneumonia and dyspnea.

Table 14 presents adverse reactions reported in ≥5% of patients treated with RYBREVANT in CHRYSALIS. There were no new safety signals observed with longer term follow-up and additional patients, and therefore no meaningful changes occurred in the safety profile of RYBREVANT.

Table 14: Adverse reactions in CHRYSALIS Reported in ≥5% of Patients

Select Adverse Reactions

The safety data presented under Select Adverse Reactions reflects the safety profile of 702 patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations, this includes 421 patients who received RYBREVANT in combination with lazertinib in the MARIPOSA study and 281 who received RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 and PAPILLON studies. The safety data presented under Select Adverse Reactions also reflects the safety profile of 302 patients with locally advanced or metastatic NSCLC who received RYBREVANT as a monotherapy in the CHRYSALIS study. This includes 129 patients with locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

Left Ventricular Dysfunction and Cardiomyopathy

RYBREVANT in combination with lazertinib

Left Ventricular Ejection Fraction (LVEF) reductions of >10 percentage points and a drop to below lower limit of normal occurred in 3.4% of patients treated with RYBREVANT in combination with lazertinib and who had a baseline LVEF assessment. A total of 7.4% of patients treated with RYBREVANT in combination with lazertinib reported cardiomyopathy events (defined as cardiac failure, chronic cardiac failure, congestive cardiac failure, pulmonary edema, ejection fraction decreased, left ventricular dysfunction).

Venous Thromboembolic (VTE) Events

RYBREVANT in combination with lazertinib

Venous thromboembolic events (VTE) occurred in 35.6% of patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 10.7% of patients. VTE events with a fatal outcome was reported in 0.5% of patients. The median time to onset was 83.5 days (range 6 to 777 days). The incidence of RYBREVANT dose reduction and dose interruption due to VTE was 1.0% and 9.0%, respectively and twelve patients (2.9%) permanently discontinued RYBREVANT due to VTE.

Infusion-Related Reactions (IRR)

RYBREVANT in combination with lazertinib

Infusion related reactions (IRRs) occurred in 62.9% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 52.5% experienced an IRR, while the incidence of IRR was 3.2% with the Day 2 infusion, 1.3% with the Week 2 infusion, and cumulatively 1.4% with the Week 3 and Week 4 infusions. The majority of reported IRRs were Grade 1-2 (93.5%). Grade 3 IRRs were reported in 5.5% of patients and Grade 4 IRRs were reported in 1.0% of patients. The median time to onset was 1.0 hours (range 0 to 52.5 hours) after start of infusion. The incidence of RYBREVANT dose reduction due to IRR was 0.7%, and 4.5% of patients permanently discontinued RYBREVANT due to IRR.

RYBREVANT in combination with carboplatin and pemetrexed

IRRs occurred in 49.5% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 45.7% experienced an IRR, while the incidence of IRR was 1.5% with the Day 2 infusion, 2.1% with the Week 2 infusion, and cumulatively 8.2% with subsequent infusions. Of the cases that reported IRRs, 93.5.% were Grade 1-2, 6.5% were Grade 3, and 0% were Grade 4. The median time to onset was 1.0 hours (range 0.0 to 7 hours) after start of infusion. The incidence of dose reduction due to IRR was 0.4%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR.

RYBREVANT as monotherapy

IRRs occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the cases that reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62.3% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Eye Disorders

RYBREVANT in combination with lazertinib

Eye disorders including keratitis (2.6%), occurred in 26.4% of patients treated with RYBREVANT. Reported adverse reactions included dry eye, blurred vision, eye pruritus, visual impairment, ocular hyperemia, aberrant eyelash growth, conjunctival hyperemia, blepharitis, conjunctivitis, episcleritis, visual acuity reduced, non-infective conjunctivitis, and eye disorder. The majority of events were Grade 1-2, with Grade 3-4 occurring in 1.0% of patients.

RYBREVANT in combination with carboplatin and pemetrexed

Eye disorders, including keratitis (0.4%), occurred in 10.7% of patients treated with RYBREVANT. Other reported adverse reactions included dry eye, blurred vision, eye pruritus, visual impairment, ocular hyperemia, aberrant eyelash growth, conjunctival hyperemia, blepharitis, and uveitis. All events were Grade 1-2.

RYBREVANT as monotherapy

Eye disorders, including keratitis (0.7%), occurred in 13.2% patients treated with RYBREVANT. Other reported adverse reactions included dry eye, blurred vision, eye pruritus, lacrimation increased, visual impairment, ocular hyperemia, eyelid ptosis, aberrant eyelash growth, and uveitis. All events were Grade 1-2.

Interstitial lung disease (ILD)/pneumonitis

RYBREVANT in combination with lazertinib

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) occurred in 3.1% of patients treated with RYBREVANT, with 1.2% of patients experiencing Grade 3-4 ILD. Twelve patients (2.9%) discontinued RYBREVANT due to ILD/pneumonitis.

RYBREVANT in combination with carboplatin and pemetrexed

ILD or ILD-like adverse reactions (e.g. pneumonitis) occurred in 2.1% of patients treated with RYBREVANT, with 1.8% of patients experiencing Grade 3 ILD. Six patients (2.1%) discontinued RYBREVANT due to ILD/pneumonitis.

RYBREVANT as monotherapy

ILD or ILD-like adverse reactions (e.g. pneumonitis) occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Skin and Nail Reactions

RYBREVANT in combination with lazertinib

Rash (including dermatitis acneiform) (88.4%), pruritus (23.5%) and dry skin (26.1%) occurred in patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3-4 events occurring in 26.4% of patients. Rash leading to dose reduction occurred in 23.5% of patients, and RYBREVANT discontinuation due to rash occurred in 5.0 % of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Nail toxicity occurred in patients treated with RYBREVANT. Most events were Grade 1 or 2, with Grade 3-4 nail toxicity occurring in 0.5% of patients.

RYBREVANT in combination with carboplatin and pemetrexed

Rash (including dermatitis acneiform) (81.9%), pruritus (10.7%) and dry skin (15.7%) occurred in patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3 events occurring in 15.3% of patients. Rash leading to dose reduction occurred in 13.5% of patients, and RYBREVANT discontinuation due to rash occurred in 2.5% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days (range: 1 to 311 days). Nail toxicity occurred in patients treated with RYBREVANT. All events were Grade 1 or 2, with Grade 3-4 nail toxicity occurring in 0% of patients.

RYBREVANT as monotherapy

Rash (including dermatitis acneiform) (73.5%), pruritis (17.9%) and dry skin (10.9%) occurred in patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3 events occurring in 3.6% of patients. Rash leading to dose reduction occurred in 5% of patients and RYBREVANT discontinuation due to rash occurred in 0.7% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days (range: 1 to 276 days). Paronychia occurred in patients treated with RYBREVANT. Most events were Grade 1 or 2, with Grade 3 paronychia occurring in 1.4% of patients.

Toxic epidermal necrolysis (TEN) occurred in one patient (0.2%) treated with RYBREVANT. Permanently discontinue RYBREVANT if TEN is confirmed.

8.3. Less Common Clinical Trial Adverse Reactions

RYBREVANT SC (Subcutaneous Formulation)

RYBREVANT SC in combination with Lazertinib

Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT SC in combination with lazertinib in PALOMA-3 included:

Eye disorders: visual impairment (2.4%), growth of eyelashes (1.5%), keratitis (0.5%) (see 7. Warnings and Precautions, Ophthalmologic)

Gastrointestinal disorders: abdominal pain (8%), hemorrhoids (6%)

Respiratory, thoracic and mediastinal disorders: ILD (6%) (see 7. Warnings and Precautions, Respiratory)

RYBREVANT (Intravenous Formulation)

RYBREVANT in combination with Lazertinib

First-line Treatment of NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutation

Clinically relevant adverse reactions in <10% of patients who received RYBREVANT in combination with lazertinib include:

Eye disorders: Dry eye (9%), vision blurred (3%), keratitis (3%), trichomegaly (1%), visual acuity reduced (1%), visual impairment (1%), eye disorders (1%), and growth of eyelashes (1%) (see 7. Warnings and Precautions, Ophthalmologic)

Hepatobiliary disorders: hyperbilirubinemia (7%)

Gastrointestinal disorders: gingival bleeding (5%)

Metabolism and nutrition disorders: Hypomagnesemia (5%)

Skin and subcutaneous tissue disorders: nail toxicity (8%, including ingrowing nail, nail disorder, nail infection, nail toxicity, onychoclasis, onycholysis, onychomadesis); palmar-plantar erythrodysesthesia syndrome (6%); skin ulcer (5%); alopecia (4%); and urticaria (1%) (see 7. Warnings and Precautions, Skin)

Renal and urinary disorders: hematuria (5%)

Respiratory, thoracic and mediastinal disorders: epistaxis (8%), interstitial lung disease (ILD) / pneumonitis (3%) (see 7. Warnings and Precautions, Respiratory)

RYBREVANT in combination with carboplatin and pemetrexed

Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

The following are clinically significant TEAEs reported in <5% of RYBREVANT-treated patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations in MARIPOSA-2:

Musculoskeletal and connective tissue disorders: myalgia

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease/Pneumonitis (see 7. Warnings and Precautions, Respiratory)

First-line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations

The following are clinically significant TEAEs reported in <5% of patients receiving RYBREVANT in the PAPILLON Study:

Infections and infestations: Skin infection

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease/Pneumonitis (see 7. Warnings and Precautions, Respiratory); Epistaxis

RYBREVANT monotherapy

Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations

The following are clinically significant adverse reactions reported in <5% of patients receiving RYBREVANT in the CHRYSALIS Study:

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease (ILD) (see 7. Warnings and Precautions, Respiratory).

Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis (TEN) (see 7. Warnings and Precautions, Skin).

Interstitial lung disease or ILD-like adverse reactions have been reported with the use of RYBREVANT as well as with other EGFR inhibitors.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

RYBREVANT SC (Subcutaneous Formulation)

RYBREVANT SC in combination with Lazertinib

Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

Table 15 summarizes the laboratory abnormalities (≥20%) that worsened from baseline in patients with EGFR exon 19 deletions or exon 21 L858R substitution mutation treated with RYBREVANT SC in combination with lazertinib in PALOMA-3.

Table 15: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations in NSC3004 (PALOMA-3) ^†

RYBREVANT (Intravenous Formulation)

RYBREVANT in combination with Lazertinib

First-line Treatment of NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutation

Table 16 summarizes the laboratory abnormalities in MARIPOSA.

Table 16: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in First-line Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA⁺

RYBREVANT in combination with carboplatin and pemetrexed

Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

Table 17 summarizes the laboratory abnormalities in MARIPOSA-2.

Table 17: Laboratory Abnormalities (≥20%) That Worsened from Baseline in 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

First-line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations

Laboratory abnormalities in PAPILLON are summarized in Table 18

Table 18: Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 20 Insertion Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON

RYBREVANT monotherapy

Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations

Laboratory abnormalities in CHRYSALIS are summarized in Table 19.

Table 19: Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Who Received RYBREVANT in CHRYSALIS

8.5. Post Market Adverse Reactions

The following adverse reactions were identified during post marketing experience with amivantamab. 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.

Skin and subcutaneous tissue disorders: Skin ulcer

9. Drug Interactions

No drug interaction studies have been performed.

10. Clinical Pharmacology

10.1. Mechanism of Action

Amivantamab is a bispecific antibody that binds to the extracellular domains of the EGFR and MET receptors, disrupting EGFR and MET signaling functions through blocking ligand binding and enhancing degradation of these receptors. 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.

10.2. Pharmacodynamics

After the first full dose of RYBREVANT SC, mean serum EGFR and MET concentrations decreased substantially and remained suppressed for the duration of treatment for all studied doses.

Albumin

Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks; thereafter, albumin concentration stabilized for the remainder of amivantamab treatment. SC administration is likely to slightly increase the incidence of hypoalbuminemia due to higher amivantamab exposure compared to IV administration

10.3. Pharmacokinetics

The exposure of RYBREVANT SC increases in a dose-proportional fashion across the recommended dosing regimen. 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.

Amivantamab exposure and accumulation following the approved recommended dosages are provided in Table 20.

Table 20: Amivantamab Exposure and Accumulation

^‡C_trough,max = observed maximum trough concentration (Cycle 2, Day 1 predose)

^†C_{trough,steady-state} = observed trough concentration at steady-state (Cycle 4, Day 1 predose)

*AUC_1Week = AUC 1 week after the Cycle 2, Day 1 dose, following the weekly dose regimen, compared with the first dose.

Adult patients with NSCLC were randomized (1:1) to RYBREVANT SC 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 SC as compared to intravenous amivantamab (see 14.1 Clinical Trials by Indication).

The PALOMA-3 study demonstrated noninferior exposures of RYBREVANT SC 1600 mg (2240 mg for body weight ≥80 kg) to RYBREVANT 1050 mg (1400 mg for body weight ≥80 kg) as shown in Table 21.

Table 21: Summary of subcutaneous amivantamab pharmacokinetic parameters in patients with NSLC (PALOMA-3); Geometric mean (%CV) and Geometric mean ratio (90% CI)

Absorption

Following subcutaneous administration, the geometric mean (%CV) of amivantamab bioavailability is 66.6% (14.9%) with a median time to reach maximum concentration of 3 days.

Distribution

The geometric mean (%CV) total volume of distribution for amivantamab administered subcutaneously is 5.69 L (23.8%).

Elimination

Amivantamab is cleared by parallel linear and nonlinear saturable target mediated clearances after subcutaneous administration. The estimated geometric mean (%CV) linear CL and associated terminal half-life is 0.224 L/day (26.0%) and 18.8 days (34.3%), respectively.

Special populations and conditions

• Pediatrics (<18 years): The pharmacokinetics of RYBREVANT SC in pediatric patients have not been investigated.
• Geriatrics (≥65 years): No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (28-85 years).
• Sex: The clearance of amivantamab was 21% higher in males than in females; however, no clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on gender with weight-tiered dosage.

• Pregnancy and breastfeeding:

  No studies have been conducted to determine if RYBREVANT SC is excreted in human or animal milk or affects milk production.

• Hepatic Insufficiency: No clinically meaningful difference in the pharmacokinetics of amivantamab was observed in patients with mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN and any AST)] or moderate hepatic impairment (1.5 x ULN < total bilirubin ≤ 3 x ULN and any AST). Data in patients with moderate hepatic impairment are limited (n=1). The pharmacokinetics of amivantamab have not been studied in patients with severe hepatic impairment (total bilirubin > 3 x ULN and any AST).
• Renal Insufficiency: No clinically meaningful difference in the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min) and moderate (29 ≤ CrCl < 60 mL/min) or severe (15 ≤ CrCl < 29 mL/min) renal impairment. Data in patients with severe renal impairment are limited (n=1). The pharmacokinetics of amivantamab have not been studied in patients with end stage renal disease (CrCl <15 mL/min).
• Body Weight: Increases in body weight increased the volume of distribution and clearance of RYBREVANT SC. With the recommended weight-tiered doses, exposures of RYBREVANT SC were comparable between patients who weighed <80 kg and received 1600 mg (every 2-week dosing)/2400 mg (every 3-week dosing)/3520 mg (every 4-week dosing) and patients who weighed ≥80 kg and received 2240 mg (every 2-week dosing)/3360 mg (every 3-week dosing)/4640 mg (every 4-week dosing).

10.4. Immunogenicity

All therapeutic proteins have the potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.

Among the 729 participants who received RYBREVANT SC monotherapy or as part of combination therapy, 3 participants (0.4%) was positive for treatment-emergent antibodies to amivantamab. Due to the low incidence of immunogenicity to RYBREVANT SC, the effect of immunogenicity remains unknown.

Among the 741 participants who received RYBREVANT SC as monotherapy or as part of combination therapy, 66 participants (9%) were positive for treatment-emergent antibodies to rHuPH20. The immunogenicity to rHuPH20 observed in these participants did not impact the pharmacokinetics of amivantamab.

1. 11. Storage, Stability, and Disposal

Unopened vials:

Store in a refrigerator at 2°C to 8°C. Do not shake or freeze. Store in the original package in order to protect from light.

Shelf life of prepared syringe:

The prepared syringes of RYBREVANT SC should be administered immediately. If immediate administration is not possible, store the prepared syringes of RYBREVANT SC refrigerated at 2°C to 8°C for up to 24 hours followed by at room temperature of 15°C to 30°C for up to 24 hours. Discard the prepared syringe if stored for more than 24 hours refrigerated or more than 24 hours of being at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): amivantamab

Molecular formula and molecular mass: 148 kDa

Structure (for biologics)/Structural formula: Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumors with activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab binds to the extracellular domains of EGFR and MET

Physicochemical properties: RYBREVANT SC (amivantamab injection) is available as a colorless to pale yellow preservative-free solution for subcutaneous administration.

Product Characteristics:

Amivantamab is produced by a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.

Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is produced by mammalian (CHO) cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). It is a glycosylated single-chain protein with an approximate molecular weight of 61 kD.

14. Clinical Trials

14.1. Clinical Trials by Indication

RYBREVANT SC (Subcutaneous Formulation)

Previously treated patients with Locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

NSC3004 (PALOMA-3) Study [Every 2-week dosing]

Table 22: Summary of patient demographics for PALOMA-3 (NSC3004) in previously treated patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations

PALOMA-3 was a Phase 3, open-label, randomized study of RYBREVANT SC in combination with lazertinib compared with RYBREVANT + lazertinib in patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletion or Exon 21 L585R substitution mutations who have progressed on or after treatment with osimertinib (or another 3^rd generation EGFR TKI) and platinum-based chemotherapy. A total of 418 patients were randomized (1:1) to receive RYBREVANT SC by subcutaneous injection in combination with lazertinib (N=206) or intravenous amivantamab (RYBREVANT) in combination with lazertinib (N=212), until documented clinical or radiographic disease progression (see Table 22 for dosing information).

This study was designed to demonstrate pharmacokinetic non-inferiority of treatment with RYBREVANT SC versus intravenous amivantamab based on C_trough of amivantamab at steady-state and AUC_D1-D15 in Cycle 2 (see 10.3 Pharmacokinetics). The efficacy of RYBREVANT SC was assessed as a secondary endpoint.

Of the 418 patients randomized (1:1) to receive RYBEVANT SC in combination with lazertinib or RYBREVANT in combination with lazertinib, the median age was 61 years with 40% of patients ≥ 65 years; 67% were female; and 61% were Asian, 37% were White, 1% were Black. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (29%) or 1 (72%); 68% never smoked; 34% had prior brain metastases; and 82% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status, 65% were exon 19 deletions and 35% were exon 21 L858R substitution mutations.

The results show that the pharmacokinetics of RYBREVANT SC is non-inferior to amivantamab administered intravenously (RYBREVANT) (see 10.3 Pharmacokinetics).

The efficacy results for ORR from PALOMA-3 are provided in Table 23.

Table 23: Summary of Efficacy Results for NSC3004 (PALOMA-3)

RYBREVANT (Intravenous Formulation)

Clinical experience of amivantamab intravenous formulation

The following sections present clinical trial information from a separate Product Monograph for RYBREVANT intravenous formulation studies:

• In combination with lazertinib for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858% substitution mutations
• In combination with carboplatin and pemetrexed for the treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with osimertinib
• In combination with carboplatin and pemetrexed for the first-line treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic NSCLC with EGFR exon 20 insertion mutations
• As monotherapy for the treatment of adult patients with locally advanced (not amenable to curative therapy) or metastatic non-small cell lung cancer (NSCLC) with EGFR Exon 20 insertion mutations whose disease has progressed on or after treatment with osimertinib

First-line Treatment of Adult Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations.

NSC3003 (MARIPOSA) Study

Table 24: Description of the MARIPOSA Study in treatment-naïve patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations treated with intravenous amivantamab in combination with lazertinib

The MARIPOSA study is a randomized, active-controlled, multicenter Phase 3 study assessing the efficacy and safety of RYBREVANT in combination with lazertinib as compared to osimertinib monotherapy as first-line treatment in patients with EGFR-mutated locally advanced or metastatic NSCLC not amenable to curative therapy. Patient samples were required to have one of the two common EGFR mutations (exon 19 deletion or exon 21 L858R substitution mutation), as identified by local testing.

The primary efficacy endpoint for the MARIPOSA study was progression-free survival (PFS), defined as the time from randomization until the date of objective disease progression or death, whichever came first, based on blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints were overall survival (OS), overall response rate (ORR) and duration of response (DOR).

A total of 1074 patients were randomized (2:2:1) to receive open label treatment with RYBREVANT in combination with lazertinib, and double-blinded treatment with osimertinib monotherapy, or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), race (Asian or non-Asian), and history of brain metastasis (yes or no). Evaluation of efficacy relied upon comparison between the RYBREVANT + lazertinib arm and the osimertinib arm.

Baseline demographics and disease characteristics were balanced across the treatment arms. The median age in the RYBREVANT + lazertinib arm was 64 (range: 25–88) years, and 63 (range 28-88) years in the osimertinib arm. In the RYBREVANT + lazertinib arm, 45% of patients were ≥65 years, 64% were female, 58% were Asian, and 38% were White. In the osimertinib arm, 45% of patients were ≥65 years, 59% were female, 59% were Asian and 38% were White. In the RYBREVANT + lazertinib arm, baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (33%) or 1 (67%); 70% never smoked; 41% had prior brain metastases; and 97% had Stage IV cancer at screening. In the osimertinib arm, baseline ECOG performance status was 0 (35%) or 1 (65%); 69% never smoked; 40% had prior brain metastases, and 97% had Stage IV cancer at screening. With regard to EGFR mutation status, 60% were exon 19 deletions and 40% were exon 21 L858R substitution mutations for both treatment arms.

Table 25, Figure 1 and Figure 2 summarize key efficacy results for RYBREVANT in combination with lazertinib.

Table 25: Efficacy Results in the MARIPOSA Study by BICR Assessment

BICR = blinded independent central review; CI = confidence interval; NE = not estimable

^a BICR by RECIST v1.1.

^b Based on the results of the final analysis of OS with a median follow-up of 37.8 months.

^c Confirmed responses in ITT population.

^d In confirmed responders

Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment

Figure 2: Kaplan-Meier curve of OS in previously untreated patients

Results of pre-specified exploratory analyses of central nervous system (CNS) ORR by BICR in the subset of patients with measurable intracranial lesions at baseline for the combination of RYBREVANT and lazertinib demonstrated similar intracranial ORR to the control. Per protocol, all patients in MARIPOSA had serial brain MRIs to assess intracranial response and duration. Results are summarized in Table 26.

Table 26: Intracranial ORR by BICR assessment in subjects with measurable intracranial lesions at baseline

Subgroup Analyses

The outcomes of the subgroup analyses for PFS and OS were generally consistent across the prespecified subgroups; however, differences were seen in subgroups of geriatric patients. No formal statistical testing was planned for subgroup analyses and the clinical interpretation of the subgroup analyses is therefore limited (see Table 27 and Table 28).

Table 27: Progression-Free survival for pre-defined subgroups based on age in MARIPOSA study by BICR assessment

Table 28: Overall Survival for pre-defined subgroups based on age in MARIPOSA study

Based on the results of the final analysis of OS with a median follow-up of 37.8 months

Previously Treated Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

NSC3002 (MARIPOSA-2) Study

Table 29: Summary of patient demographics for MARIPOSA-2 clinical trial (NSC3002) in patients with previously treated NSLC with EGFR Exon 19 deletions or Exon 21 L585R Substitution Mutations

*AUC5 = area under the concentration-time curve 5 mg/mL per minute

The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (characterized by a validated test at or after the time of locally advanced or metastatic disease diagnosis, as identified by local or central testing) who had previously received osimertinib as first or second line therapy in MARIPOSA-2, an open-label, multicenter phase 3 clinical trial. In MARIPOSA-2, patients were randomized (2:2:1) to receive carboplatin and pemetrexed (CP, N=263), RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131) and RYBREVANT in combination with lazertinib, carboplatin, and pemetrexed (N=263) in a separate arm of the study (an unapproved regimen for EGRFm NSCLC).

Patients were stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no).

The primary efficacy endpoint was progression-free survival (PFS) as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy endpoints were overall response rate (ORR) and overall survival (OS). PFS and ORR were evaluated at the first interim analysis. There are two interim, and one final analysis planned for OS.

Of the 394 patients randomized to the RYBREVANT-CP arm or CP arm, the median age was 62 (range: 31–85) years, with 37.8% of the patients ≥ 65 years of age; 60.4% were female; and 48.2% were Asian and 46.4% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (39.6%) or 1 (60.4%); 65.5% never smoked; 45.2% had history of brain metastasis, and 91.6% had Stage IV cancer at initial diagnosis. Osimertinib had been given as first-line systemic therapy for 70.5% of participants and second-line therapy for 29.4% of participants.

Efficacy results are summarized in Table 30 and Figure 3.

Table 30: Efficacy results in MARIPOSA-2

CI = confidence interval

NE = not estimatable

^a Blinded Independent Central Review by RECIST v1.1

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

The median duration of response was 6.90 months (95% CI: 5.52, NE months) for patients who received RYBREVANT plus carboplatin and pemetrexed and 5.5 months (95% CI: 4.17, 9.56 months) for patients treated with carboplatin and pemetrexed alone.

The estimated OS HR at the first interim analysis was 0.77 [95% CI: 0.49, 1.21], however OS remains immature at the time of this analysis.

Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. In an exploratory sub-group analysis, in patients with stable intracranial metastases, the observed median intracranial PFS for RYBREVANT-CP was 12.45 months vs 8.31 months in the CP arm; HR=0.55 (95%CI 0.38, 0.79).

First-Line Treatment of Patients with Locally Advanced or Metastatic NSCLC with activating EGFR Exon 20 insertion mutations.

NSC2001 (PAPILLON) Study

Table 31: Summary of patient demographic for the PAPILLON clinical trial (NSC3001) in patients with previously untreated NSCLC with Exon 20ins mutations.

*AUC5 = area under the concentration-time curve 5 mg/mL per minute

PAPILLON (NSC3001) is a randomized, open-label, multicenter phase 3 study comparing treatment with RYBREVANT in combination with carboplatin and pemetrexed to treatment as compared to chemotherapy alone (carboplatin and pemetrexed) in subjects with treatment-naïve, locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations, as identified prospectively by local testing.

Patients with squamous NSCLC, untreated brain metastases, with a medical history of ILD, or any evidence of clinically active ILD were excluded from the clinical study.

Randomization was stratified by ECOG performance status and prior brain metastases.

The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) using RECIST 1.1. Secondary efficacy outcome measures were overall response rate (ORR) and overall survival (OS). Subjects randomized to the carboplatin and pemetrexed arm who had confirmed disease progression were permitted to cross over to receive RYBREVANT monotherapy.

A total of 308 subjects were randomized (1:1) to RYBREVANT in combination with carboplatin and pemetrexed (N=153) or carboplatin and pemetrexed (N=155). The median age was 62 (range: 27 to 92) years, with 39% of the subjects ≥65 years of age; 58% were female; and 61% were Asian and 36% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (35%) or 1 (65%); 58% never smoked; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis (99% had Stage IV cancer at screening).

The median follow-up time at the time of the PFS analysis was 14.9 (range: 0.3 to 27.0) months.

Efficacy results for PAPILLON are summarized in Table 32 and Figure 4.

Table 32: Efficacy Results in PAPILLON

CI = confidence interval

^a Blinded Independent Central Review by RECIST v1.1

^b p-value is from a log-rank test stratified by ECOG PS (0 or 1) and history of brain metastases (yes or no).

^c Including Unconfirmed Response.

^d p-value is from a logistic regression model stratified by ECOG PS (0 or 1) and history of brain metastases (yes or no).

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

The overall response rate (ORR) for patients who had a confirmed response was 67.1% for patients who received RYBREVANT plus carboplatin and pemetrexed and 36.2% for patients treated with carboplatin and pemetrexed alone. For patients who achieved a confirmed objective response, the median duration of response was 10.1 months (range: 1.4 to 22.3 months) for patients who received RYBREVANT plus carboplatin and pemetrexed and 5.6 months (range: 1.3 to 22.4 months) for patients treated with carboplatin and pemetrexed alone.

At this PFS analysis, 65 (42%) patients who were randomized to the carboplatin and pemetrexed arm had crossed over to receive subsequent RYBREVANT monotherapy. At the prespecified first interim analysis for overall survival (OS), conducted at the time of the primary analysis of PFS, statistical significance had not been reached (HR=0.72 [95% CI: 0.44, 1.17]).

Previously Treated NSCLC with EGFR Exon 20 insertion Mutations

EDI1001 (CHRYSALIS) Study

Table 33: Summary of patient demographics for the CHRYSALIS clinical trial (EDI1001) in patients with previously treated NSCLC with Exon 20ins mutations

CHRYSALIS (EDI1001) was a multicenter, open-label, multi-cohort study conducted to assess the safety and efficacy of RYBREVANT in patients with locally advanced or metastatic NSCLC. Efficacy was evaluated in 81 patients with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertion mutation, with measurable disease, whose disease had progressed on or after platinum-based chemotherapy. For enrollment, EGFR exon 20 insertion mutation status was determined prospectively by local testing using tissue and/or plasma samples. 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. The median follow-up for the efficacy population was 9.7 months.

RYBREVANT was administered intravenously at 1050 mg for patients <80 kg or 1400 mg for patients ≥80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 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). Duration of response (DOR) by BICR was assessed as an additional measure of efficacy.

The median age was 62 (range: 42–84) years, with 9% of the patients ≥75 years of age; 59% were female; and 49% were Asian and 37% were White; 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 therapies). At baseline, 99% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; 53% never smoked; 75% had Stage IV cancer; and 22% had previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (24%), S768 (16%), D770 (11%), and N771 (11%).

Efficacy results are summarized in Table 34.

Table 34: Results from CHRYSALIS: Patients with EGFR Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy

a Blinded Independent Central Review by RECIST v1.1

^b Confirmed response.

^c Based on Kaplan-Meier estimate.

NE=Not Estimable

15. Microbiology

No microbiology information is required for this product.

16. Non-Clinical Toxicology

In repeat-dose toxicity studies in cynomolgus monkeys, amivantamab was well-tolerated at weekly doses up to 120 mg/kg intravenously for 3 months and up to 125 mg/kg subcutaneously for 2 weeks. There were no effects on cardiovascular, respiratory, and nervous system function. Clinical pathology demonstrated non adverse elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and globulins, and non-adverse decreases in albumin when compared to the control group. All these values returned to normal ranges in recovery groups.

Genotoxicity: No animal studies have been performed to evaluate the genotoxic potential of amivantamab. Routine genotoxicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.

Carcinogenicity: No animal studies have been performed to establish the carcinogenic potential of amivantamab. Routine carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.

Reproductive and developmental toxicology: No long-term animal studies have been performed to evaluate whether amivantamab affects fertility in males or females or reproduction.

Based on its mechanism of action, amivantamab could cause fetal harm or developmental abnormalities when administered to a pregnant woman. Evidence from published literature showed that inhibition of EGFR and/or MET signaling pathways during pregnancy can cause impaired embryo-fetal development, embryo lethality and abortions in mice, rats and non-human primates. Therefore, it is reasonable to expect that amivantamab may cause adverse effects on embryo-fetal and postnatal development in humans.

No systemic exposure of hyaluronidase was detected in monkeys given 220,000 U/kg subcutaneously (at least 118 times higher than the human equivalent dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is at least 45 times higher than the human equivalent dose. There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is at least 134 times higher than the human equivalent doses.

17. Supporting Product Monographs

1. 1. RYBREVANT (amivantamab, concentrate for intravenous infusion, 350 mg / 7mL), Product Monograph, Janssen Inc (a Johnson & Johnson Co.)