Safety profile
Warnings and Precautions
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
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
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 |
|
|---|---|
| Recurrent Grade 3 or Grade 4 IRRs1 | Permanently discontinue RYBREVANT®1 |
Interstitial lung disease (ILD)/pneumonitis1
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
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
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
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)
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.