HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use RYBREVANT™ safely and effectively. See full prescribing information for RYBREVANT.

RYBREVANT (amivantamab-vmjw) injection, for intravenous use Initial U.S. Approval: 2021

-----------------------------INDICATIONS AND USAGE---------------------------

RYBREVANT is a bispecific EGF receptor-directed and MET receptor- directed antibody indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. (1, 2.1)

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. (1)

------------------------DOSAGE AND ADMINISTRATION-----------------------

•    The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. (2.2, 2.5, 2.6)

•    Administer premedications as recommended. (2.3)

•    Administer via a peripheral line on Week 1 and Week 2. (2.6)

•    Administer RYBREVANT weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter. (2.2)

•    Administer diluted RYBREVANT intravenously according to the infusion

rates in Table 5. (2.5, 2.6)

----------------------DOSAGE FORMS AND STRENGTHS---------------------

Injection: 350 mg/7 mL (50 mg/mL) solution in a single-dose vial (3)

-----------------------------CONTRAINDICATIONS---------------------------------

None. (4)

-------------------------WARNINGS AND PRECAUTIONS----------------------

·          Infusion-RelatedReactions(IRR): Interrupt infusion at the first sign of IRRs. Reduce infusion rate or permanently discontinue RYBREVANT based on severity. (2.4, 5.1)

·          InterstitialLungDisease(ILD)/Pneumonitis: Monitor for new or worsening symptoms indicative of ILD. Immediately withhold  RYBREVANT  in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. (2.4, 5.2)

·         Dermatologic Adverse Reactions: May cause rash including acneiform dermatitis and toxic epidermal necrolysis. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity. (2.4, 5.3)

·         Ocular Toxicity: Promptly refer patients with worsening eye symptoms to an  ophthalmologist. Withhold, dose reduce  or permanently discontinue

RYBREVANT based on severity. (5.4)

·          Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. (5.5, 8.1, 8.3)

------------------------------ADVERSE REACTIONS-------------------------------

·       The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. (6.1)

·       The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at

1-800-FDA-1088 or www.fda.gov/medwatch.

-----------------------USE IN SPECIFIC POPULATIONS------------------------

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and

FDA-approved patient labeling.

Revised: 05/2021

FULL PRESCRIBING INFORMATION: CONTENTS*

1      INDICATIONS AND USAGE

2      DOSAGE AND ADMINISTRATION

Dosage Modifications for Adverse Reactions Preparation

Administration

3      DOSAGE FORMS AND STRENGTHS

4      CONTRAINDICATIONS

5      WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

Interstitial Lung Disease/Pneumonitis Dermatologic Adverse Reactions Ocular Toxicity

Embryo-Fetal Toxicity

6      ADVERSE REACTIONS

Clinical Trials Experience Immunogenicity

8     USE IN SPECIFIC POPULATIONS

Lactation

Females and Males of Reproductive Potential Pediatric Use

Geriatric Use

11    DESCRIPTION

12    CLINICAL PHARMACOLOGY

Mechanism of Action Pharmacodynamics Pharmacokinetics

13    NONCLINICAL TOXICOLOGY

    Carcinogenesis, Mutagenesis, Impairment of Fertility

14    CLINICAL STUDIES

16    HOW SUPPLIED/STORAGE AND HANDLING

17    PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

                  Pregnancy                                                                                                                                                                                                      

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1               INDICATIONS AND USAGE

RYBREVANT is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung  cancer  (NSCLC)  with  epidermal  growth  factor  receptor  (EGFR)  exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.1)], whose disease has progressed on or after platinum-based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

     Patient Selection

Select patients for treatment with RYBREVANT based on the presence of EGFR exon 20 insertion mutations[see Clinical Studies (14.1)].Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.

     Recommended Dosage

The recommended doses of RYBREVANT, based on baseline body weight, are provided in Table 1. Administer RYBREVANT weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter until disease progression or unacceptable toxicity. Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.3)]. Administer diluted RYBREVANT intravenously according to the infusion rates in Table 5 [see Dosage and Administration (2.5), (2.6)].

Table 1:         Recommended Dose of RYBREVANT Based on Baseline Body Weight

*        Dose adjustments not required for subsequent body weight changes.

Prior to initial infusion of RYBREVANT (Week 1, Days 1 and 2), administer premedication as described in Table 2 to reduce the risk of infusion-related reactions: [see Warnings and Precautions (5.1)]

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Table 2:         Premedications

*        Required at all doses.

‡       Required at initial dose (Week 1, Days 1 and 2); optional for subsequent doses.

Administer both antihistamine and antipyretic prior to all infusions. Glucocorticoid administration required for Week 1, Days 1 and 2 doses only and as necessary for subsequent infusions.

The recommended RYBREVANT dose reductions for adverse reactions (see Table 4) are listed in Table 3.

Greater than or

1400 mg                    1050 mg                                  700 mg

RYBREVANT

The recommended RYBREVANT dosage modifications for adverse reactions are provided in Table 4.

Table 4:         Recommended RYBREVANT Dosage Modifications for Adverse Reactions

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Table 4:         Recommended RYBREVANT Dosage Modifications for Adverse Reactions

     Preparation

Dilute and prepare RYBREVANT for intravenous infusion before administration.

·                                         Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.

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·                                         Determine the dose required (either 1050 mg or 1400 mg) and number of RYBREVANT vials needed based on patient’s baseline weight [see Dosage and Administration (2.2)]. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.

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

·                                         Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.

·                                         Gently invert the bag to mix the solution. Do not shake.

·                                         Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 59°F to 77°F (15°C to 25°C).

     Administration

Administer the diluted solution [see Dosage and Administration (2.5)]by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer) primed with diluent only. Administration sets must be made of either polyurethane (PU), polybutadiene (PBD) PVC, PP, or PE.

Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 given the high incidence

of infusion-related reactions during initial treatment [see Warnings and Precautions (5.1)].

RYBREVANT may be administered via central line for subsequent weeks. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.

Administer RYBREVANT infusion intravenously according to the infusion rates in Table 5.

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Table 5:         Infusion Rates for RYBREVANT Administration

*    After Week 4, patients are dosed every 2 weeks.

†       Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial.

None.

     Infusion-Related Reactions

RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

Based on the safety population [see Adverse Reactions (6.1)],IRR 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 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% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended[see Dosage and Administration (2.3)]. Administer RYBREVANT via a peripheral line on Week 1 and Week 2[see Dosage and Administration (2.6)].

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Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].

RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population [see Adverse Reactions (6.1)], ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.4)].

RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population [see Adverse Reactions (6.1)], rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)].

Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT. Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT.

Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].

     Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population [see Adverse Reactions (6.1)],keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.4)].

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

The following adverse reactions are discussed elsewhere in the labeling:

·                                         Infusion-Related Reactions[see Warnings and Precautions (5.1)]

·                                         Interstitial Lung Disease/Pneumonitis[see Warnings and Precautions (5.2)]

·                                         Dermatologic Adverse Reactions[see Warnings and Precautions (5.3)]

·                                         Ocular Toxicity[see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT as a single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC who received a dose of 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. Among 302 patients who received RYBREVANT, 36% were exposed for 6 months or longer and 12% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased gamma glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase.

The data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for 6 months or longer and 12% were exposed for greater than one year.

The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight <80 kg.

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Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥ 2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.

Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.

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

The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.

Table 6 summarizes the adverse reactions in CHRYSALIS.

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Table 6:         Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALIS

a        Rash: acne, dermatitis, dermatitis acneiform, eczema, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, perineal rash, rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, skin exfoliation, toxic epidermal necrolysis

b        Fatigue: asthenia, fatigue

c        Edema: eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, peripheral swelling d                Pneumonia: atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, and pulmonary sepsis

e        Musculoskeletal pain: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain

f         Dyspnea: dyspnea, dyspnea exertional

g        Cough: cough, productive cough, upper airway cough syndrome

h        Stomatitis: aphthous ulcer, cheilitis, glossitis, mouth ulceration, mucosal inflammation, pharyngeal inflammation, stomatitis

i         Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort

j         Hemorrhage: epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, mucosal hemorrhage

k        Peripheral neuropathy:  hypoesthesia, neuralgia, paresthesia, peripheral sensory neuropathy

l         Headache: headache, migraine

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Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).

Table 7 summarizes the laboratory abnormalities in CHRYSALIS.

Table 7:                Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT in CHRYSALIS

+          The denominator used to calculate the rate was 126 based on the number of patients with a baseline value and at least one post-treatment value.

     Immunogenicity

As with all therapeutic proteins, there is 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 the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other amivantamab products may be misleading.

In CHRYSALIS, 3 of the 286 (1%) patients who were treated with RYBREVANT and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab-vmjw antibodies (one at 27 days, one at 59 days and one at 168 days after the first dose) with titers of 1:40 or less. There are insufficient data to evaluate the effect of ADA on the pharmacokinetics, safety, or efficacy of RYBREVANT.

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     Pregnancy

Risk Summary

Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal  data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryolethality, malformations, and post-natal death in animals (see Data).Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

No animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.

     Lactation

Risk Summary

There are no data on the presence of amivantamab-vmjw in human milk on milk production, or its effects on the breastfed child. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed infants, advise women not to breast-feed during treatment with RYBREVANT and for 3 months after the final dose.

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RYBREVANT can cause fetal harm when administered to a pregnant woman[see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT.

     Pediatric Use

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

     Geriatric Use

Of the 129 patients treated with RYBREVANT, 41% were 65 years of age or older, and 9% were 75 years of age or older. No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.

Amivantamab-vmjw is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa. RYBREVANT (amivantamab-vmjw) injection for intravenous infusion is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.

Each RYBREVANT vial contains 350 mg (50 mg/mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

   Mechanism of Action

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

In in vitroand in vivostudies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

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The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR exon 20 insertion mutations.

Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1750 mg

(0.25 to 1.25 times the maximum approved recommended dosage). Steady state of amivantamab-vmjw concentrations was achieved by the 9th infusion. The accumulation ratio at steady state was 2.4.

Distribution

The amivantamab-vmjw mean (± SD) volume of distribution is 5.13 (± 1.78) L.

Elimination

The mean (± SD) clearance of amivantamab-vmjw is 360 (± 144) mL/day and the terminal half-life is 11.3 (± 4.53) days.

Specific Populations

No clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range:  32-87 years),  sex,  race,  creatinine  clearance  (CLcr  29  to 276 mL/min), or mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN

< total bilirubin ≤ 1.5 times ULN)]. The pharmacokinetics of amivantamab-vmjw have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or patients with moderate (total bilirubin 1.5 to 3 times ULN) to severe (total bilirubin > 3 times ULN) hepatic impairment.

Body Weight

Increases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30-40% lower in patients who weighed

≥ 80 kg compared to patients with body weight < 80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed  < 80 kg  and  received 1050 mg dose and patients who weighed ≥ 80 kg and received 1400 mg dose.

   Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations, plasma samples from 96% of patients were tested retrospectively using Guardant360® CDx. While 76% of patients had an EGFR exon 20 insertion mutation identified in plasma specimen, 20% did not have an EGFR exon 20 insertion mutation identified in plasma specimen, and 3.7% did not have plasma samples for testing.

Patients received RYBREVANT at 1050 mg (for patient baseline  body  weight  < 80 kg)  or 1400 mg (for patient baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.

The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White,

2.5% were Black; 74% had baseline body weight <80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was 2 (range: 1 to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.

Efficacy results are summarized in Table 8.

Table 8:         Efficacy Results for CHRYSALIS

Based on Kaplan-Meier estimates.

NE=Not Estimable, CI=confidence interval.

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HowSupplied

RYBREVANT™ (amivantamab-vmjw) injection is a sterile, preservative-free, colorless to pale yellow solution for intravenous infusion. Each single-dose vial contains 350 mg/7 mL (50 mg/mL) RYBREVANT. Each vial is individually packed in a single carton. (NDC 57894-501-01).

StorageandHandling

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

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

Infusion-RelatedReactions

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

InterstitialLungDisease/Pneumonitis

Advise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].

DermatologicAdverseReactions

Advise patients of the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure, to use broad spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Warnings and Precautions (5.3)]. Advise patients to apply alcohol free emollient cream to dry skin.

OcularToxicity

Advise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Warnings and Precautions (5.4)].

Paronychia

Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)].

Embryo-FetalToxicity

Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with RYBREVANT and for 3 months after the final dose, and to

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inform  their  healthcare  provider  of  a  known  or  suspected  pregnancy.    [see  Warnings  and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].

Lactation

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

Product of Ireland Manufactured by:

Janssen Biotech, Inc. Horsham, PA 19044

U.S. License Number 1864

© 2021 Janssen Pharmaceutical Companies

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