Amivantamab — Drug Monograph

Amivantamab (Rybrevant) — EGFR Exon 20 & MET Bispecific Overview

Amivantamab (Rybrevant) is a bispecific antibody targeting both the epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor for non-small cell lung cancer (NSCLC). It is the first therapy approved for EGFR exon 20 insertion mutations — a subset historically resistant to conventional EGFR TKIs — and is also active against MET alterations and, with lazertinib, EGFR exon 19 deletions and L858R disease. This monograph covers amivantamab indications, weight-based dosing (<80 kg vs ≥80 kg), the mandatory Week 1 split infusion, premedication to reduce infusion-related reactions (IRRs), and monitoring.

Indications (FDA / NCCN)

• First-line EGFR exon 20 insertion NSCLC with carboplatin + pemetrexed
• EGFR exon 20 insertion NSCLC after progression on platinum chemotherapy (single agent)
• First-line EGFR exon 19 del / L858R NSCLC in combination with lazertinib
• EGFR exon 20 insertions confirmed by an FDA-approved test before starting

Dosing

• Weight-based: <80 kg = 1,050 mg; ≥80 kg = 1,400 mg (monotherapy / + lazertinib)
• Week 1 given as a mandatory SPLIT infusion over Day 1 and Day 2 to reduce IRRs
• Weekly for the first 5 weeks, then every 2 weeks from Week 7 (monotherapy)
• With lazertinib: prophylactic anticoagulation for the first 4 months

Monitoring

• Antihistamine + antipyretic before every infusion; glucocorticoid for Week 1
• Infusion-related reactions (IRRs), especially during the first dose
• Acneiform rash and paronychia — early dermatologic intervention
• Pulmonary symptoms (dyspnea, cough, fever) and visual changes

Brand names: Rybrevant

Drug class: Monoclonal Antibody

Mechanism of Action

Amivantamab is a bispecific antibody that binds to the extracellular domains of both the epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor. By binding both receptors, it blocks ligand binding and disrupts signaling pathways that drive tumor growth. It also facilitates the degradation of these receptors and induces antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis by immune effector cells. This dual targeting is particularly effective in tumors with EGFR exon 20 insertion mutations, which are often resistant to traditional TKIs.

FDA Indications

• In combination with carboplatin and pemetrexed for the first-line 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.
• As a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
• In combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.

Common Side Effects

• Rash
• Infusion-related reactions
• Paronychia
• Stomatitis
• Nausea
• Fatigue
• Edema
• Hypoalbuminemia
• Constipation
• Cough

Clinical Pearl

Amivantamab was the first therapy specifically approved for EGFR exon 20 insertions, a historically difficult-to-treat subset of NSCLC. A major clinical challenge is the high rate of infusion-related reactions (IRRs) with the IV formulation, often occurring in >60% of patients during the first dose; the recent approval of the subcutaneous formulation has drastically improved the patient experience. Be aware of "acneiform rash" and "paronychia" as distinct EGFR-related skin toxicities that…

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