Warnings and Precautions

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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.1

Infusion-related reactions (IRRs)1

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IRRs occurred in 66% of patients treated with RYBREVANT®1

  • The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT® due to IRR1

Of the patients who experienced an IRR, 65% of those IRRs occurred during Week 1, Day 1 and rarely during subsequent infusions. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion.1

IRRs by Infusion
irrs

Monitoring and management1

  • Prior to initial infusion (Week 1, Days 1 and 2), administer antihistamines, antipyretics, and glucocorticoids to reduce the risk of IRRs
  • 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
  • Administer RYBREVANT® via a peripheral line on Week 1 and Week 2 given the high incidence of IRRs during initial treatment
  • 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
Grade 1-3 IRRs1
  • Interrupt RYBREVANT® infusion if IRR is suspected and monitor patient until reaction symptoms resolve
  • For Grade 3, administer supportive care medications
  • Resume the infusion at 50% of the infusion rate at which the reaction occurred
  • If there are no additional symptoms after 30 minutes, the infusion rate may be escalated
  • Include corticosteroid with premedications for subsequent dose
Recurrent Grade 3 or Grade 4 IRRs1 Permanently discontinue RYBREVANT®1

Interstitial lung disease (ILD)/pneumonitis1

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ILD/pneumonitis

ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT®.

  • Grade 3 ILD/pneumonitis occurred in 0.7% of patients
  • ILD/pneumonitis led to discontinuation of RYBREVANT® in 1% of patients

Monitoring and management1

  • Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever)
  • Immediately withhold RYBREVANT® in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed

Inform patients of the risks of ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms.1

Dermatologic adverse reactions1

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RYBREVANT® can cause rash (including dermatitis acneiform), pruritus and dry skin.

Rash

  • 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
  • Rash occurred in 74% of patients treated with RYBREVANT®
  • Grade 3 rash occurred in 3.3% of patients
  • Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT®

Monitoring and management1

  • 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

Instruct patients to limit sun exposure during and for 2 months after treatment. Patients should wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.1

Ocular toxicity1

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ocular toxicity

RYBREVANT® can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis.

Keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT®.

All events were Grade 1-2.

Monitoring and management1

  • Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce, or permanently discontinue RYBREVANT® based on severity

Embryo-fetal toxicity1

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embryo-fetal toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT® can cause fetal harm when administered to a pregnant woman.

Monitoring and management1

  • Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT®
  • Advise pregnant women 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®

Lactation

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 following the final dose of RYBREVANT®.

Safety of RYBREVANT® in patients with EGFR exon 20 insertion mutations (n=129)

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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.1

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.1

Dose interruptions of RYBREVANT® due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRRs) 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.1

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.1

The most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

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 CHRYSALIS1

Adverse Reactions
RYBREVANT® (n=129) All
Grades (%)
Grades
3 or 4 (%)
Skin and subcutaneous tissue disorders
Rasha 84 3.9
Pruritus 18 0
Dry skin 14 0
General disorders and administration site conditions
Infusion related reaction 64 3.1
Fatigueb 33 2.3
Edemac 27 0.8
Pyrexia 13 0
Infections and infestations
Paronychia 50 3.1
Pneumoniad 10 0.8
Musculoskeletal and connective tissue disorders
Musculoskeletal paine 47 0
Respiratory, thoracic and mediastinal disorders
Dyspneaf 37 2.3
Coughg 25 0
Gastrointestinal disorders
Nausea 36 0
Stomatitish 26 0.8
Constipation 23 0
Vomiting 22 0
Diarrhea 16 3.1
Abdominal Paini 11 0.8
Vascular disorders
Hemorrhagei 19 0
Metabolism and nutrition disorders
Decreased appetite 15 0
Nervous system disorders
Peripheral neuropathyk 13 0
Dizziness 12 0.8
Headachel 10 0.8

aRash: 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

bFatigue: asthenia, fatigue

cEdema: eyelid edema, face edema, generalized edema, lip edema, edema, edema peripheral, periorbital edema, peripheral swelling

dPneumonia: atypical pneumonia, lower respiratory tract infection, pneumonia, pneumonia aspiration, and pulmonary sepsis

eMusculoskeletal 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

fDyspnea: dyspnea, dyspnea exertional

gCough: cough, productive cough, upper airway cough syndrome

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

iAbdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and epigastric discomfort

jHemorrhage: epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, mucosal hemorrhage

kPeripheral neuropathy: hypoesthesia, neuralgia, paresthesia, peripheral sensory neuropathy

lHeadache: headache, migraine

11% of patients discontinued treatment due to adverse reactions1

  • 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
  • Dose reductions of RYBREVANT® due to an adverse reaction occurred in 15% of patients

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

Laboratory Abnormality
RYBREVANT®a (n=129) All
Grades (%)
Grades
3 or 4 (%)
Chemistry
Decreased albumin 79 8
Increased glucose 56 4
Increased alkaline phosphatase 53 4.8
Increased creatinine 46 0
Increased alanine aminotransferase 38 1.6
Decreased phosphate 33 8
Increased aspartate aminotransferase 33 0
Decreased magnesium 27 0
Increased gamma-glutamyl transferase 27 4
Decreased sodium 27 4
Decreased potassium 26 6
Hematology
Decreased lymphocytes 36 8

aThe 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.

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

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Reference

1. RYBREVANT® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.