What are the adverse effects of amivantamab (Rybrevant)?

Amivantamab Adverse Effects

Amivantamab causes substantial toxicity with 75% of patients experiencing Grade 3 or higher adverse events when combined with lazertinib, compared to 43% with osimertinib alone, with dermatologic toxicities (particularly paronychia and rash) and venous thromboembolism being the most clinically significant concerns. 1

Overall Toxicity Profile

The FDA-approved label and ASCO guidelines consistently identify a high burden of adverse events across all treatment regimens 2:

• Grade ≥3 adverse events: 75% (amivantamab-lazertinib) vs 43% (osimertinib alone)
• Serious adverse events: 49% (amivantamab-lazertinib) vs 33% (osimertinib alone)
• Treatment discontinuation rate: 10% due to treatment-related adverse events 1

Most Common Adverse Events by Regimen

Amivantamab + Lazertinib (≥20% incidence):

• Rash
• Nail toxicity (paronychia)
• Infusion-related reactions
• Musculoskeletal pain
• Stomatitis
• Edema
• Venous thromboembolism (VTE)
• Paresthesia
• Fatigue
• Diarrhea
• Constipation
• Hemorrhage
• Dry skin
• Decreased appetite
• Pruritus
• Nausea
• Ocular toxicity 2

Amivantamab + Carboplatin/Pemetrexed (≥20% incidence):

• Rash
• Nail toxicity
• Infusion-related reactions
• Fatigue
• Nausea
• Stomatitis
• Constipation
• Edema
• Decreased appetite
• Musculoskeletal pain
• Vomiting 2

Amivantamab Monotherapy (≥20% incidence):

• Rash
• Infusion-related reactions
• Paronychia
• Musculoskeletal pain
• Dyspnea
• Nausea
• Fatigue
• Edema
• Stomatitis
• Cough
• Constipation
• Vomiting 2

Critical Safety Warnings

1. Infusion-Related Reactions (IRRs)

Incidence: 66% in initial approval studies 3

• Predominantly mild-to-moderate severity
• Occur mainly during the first infusion cycle
• Require infusion rate reduction or interruption
• Severe cases may require epinephrine 4

Management algorithm:

• Premedicate before each infusion
• Monitor closely during first cycle
• Interrupt infusion at first sign of reaction
• Reduce infusion rate or permanently discontinue based on severity 2

2. Venous Thromboembolism (VTE)

This is a unique and serious risk, particularly with lazertinib combination 2

Critical management requirement:

• Prophylactic anticoagulation is recommended for the first 4 months of amivantamab-lazertinib treatment 2
• VTE events occurred even in patients receiving anticoagulant prophylaxis 4
• Monitor for signs/symptoms of VTE throughout treatment
• Withhold both drugs based on severity
• Resume at same dose once anticoagulation initiated (at provider discretion)
• Permanently discontinue amivantamab (continue lazertinib) for recurrent VTE despite therapeutic anticoagulation 2

Real-world data reveals concerning cardiovascular signals including venous thrombotic diseases as the most common cardiovascular adverse event, with death accounting for 16.3% of all cardiovascular events and MACE mortality rates up to 60% 5.

3. Dermatologic Toxicities

These are more severe and clinically complex than conventional EGFR inhibitors 6

Specific manifestations:

• Paronychia (highest signal intensity in real-world data) 7
• Dermatitis acneiform 7
• Erosive pustular dermatosis (EPD)-like scalp reactions 6
• Anogenital ulcerations 6
• Folliculitis (more prevalent in males) 7
• Skin toxicity (latest onset, median 139 days) 7

Timing:

• Median time-to-onset: 11 days
• Rash occurs earliest (median <1 day)
• Skin toxicity latest (median 139 days) 7

Management approach:

• Early prophylactic dermatologic regimen significantly reduces severity 8
• Grade-based treatment: antibiotics, topical steroids, dose adjustments 4
• Hospitalization is the most common clinical outcome for cutaneous adverse events 7

4. Interstitial Lung Disease (ILD)/Pneumonitis

Less common but severe when it occurs 4

Management:

• Monitor for new or worsening respiratory symptoms
• Immediately withhold amivantamab if ILD/pneumonitis suspected
• Permanently discontinue if confirmed
• Treat with glucocorticoids 2, 4

5. Ocular Toxicity

• Promptly refer patients with worsening eye symptoms to ophthalmologist
• Withhold, reduce dose, or permanently discontinue based on severity 2

Laboratory Abnormalities

Grade 3-4 Laboratory Changes (≥2%):

Amivantamab-Lazertinib:

• Decreased albumin
• Decreased sodium
• Increased ALT
• Decreased potassium
• Decreased hemoglobin
• Increased AST
• Increased GGT
• Increased magnesium 2

Amivantamab-Carboplatin/Pemetrexed:

• Decreased neutrophils
• Decreased leukocytes
• Decreased platelets
• Decreased hemoglobin
• Decreased potassium
• Decreased sodium
• Increased ALT
• Increased GGT
• Decreased albumin 2

Novel Safety Signals from Real-World Data

A comprehensive FAERS database analysis identified 88 safety signals, most of which were novel 9:

Compared to mobocertinib, amivantamab causes significantly more:

• Injury, poisoning, and procedural complications (ROR = 15.54)
• Blood and lymphatic system disorders (ROR = 9.57)
• Immune system disorders (ROR = 6.41)
• Respiratory, thoracic, and mediastinal disorders (ROR = 1.92)
• Infections and infestations (ROR = 1.39) 9

Specific high-risk events:

• Thrombosis events
• Bone marrow suppression
• Skin and soft tissue infections
• Deterioration of respiratory symptoms
• Noninfectious pneumonitis 9

Cardiovascular Adverse Events

Real-world data reveals concerning cardiovascular signals not prominent in initial trials 5:

Positive signals in 4 categories:

1. Venous thrombotic diseases (most common)
2. Abnormal blood pressure
3. Arrhythmia
4. Pericardial effusion

Timing:

• Median time-to-onset: 33 days
• 100% cumulative incidence within 90 days for cardiac failure
• 75% within 90 days for stroke
• 63.16% for arrhythmia
• 44.18% for venous thrombotic diseases 5

Critical Clinical Pitfalls

1. Underestimating dermatologic toxicity severity: These are NOT typical EGFR inhibitor rashes—they are more severe, complex, and require aggressive early intervention 6, 8

2. Inadequate VTE prophylaxis: Prophylactic anticoagulation for the first 4 months is recommended, not optional, when using amivantamab-lazertinib 2

3. Delayed dermatologic intervention: Early prophylactic dermatologic regimens significantly reduce severity—waiting for symptoms to develop leads to worse outcomes 8

4. Missing early cardiovascular signals: Intensified monitoring is crucial in the first 90 days when most cardiovascular events occur 5

5. Inadequate infusion monitoring: The 66% incidence of IRRs requires vigilant first-cycle monitoring and appropriate premedication 3

Embryo-Fetal Toxicity

Amivantamab can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose 2.