Introduction
Rybrevant (amivantamab-vmjw) is a first-in-class bispecific monoclonal antibody approved by the FDA in May 2021 for the treatment of non-small cell lung cancer (NSCLC) with specific EGFR mutations. It represents a novel therapeutic approach for patients with EGFR exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy.
Mechanism of Action
Amivantamab is a fully human bispecific antibody that targets both epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET). It works through three primary mechanisms: 1. Receptor binding inhibition: Blocks EGFR and MET ligand binding 2. Receptor degradation: Induces receptor internalization and degradation 3. Immune effector function: Engages immune cells through Fc-mediated antibody-dependent cellular cytotoxicity (ADCC)
This multi-targeted approach helps overcome resistance mechanisms that develop with earlier-generation EGFR tyrosine kinase inhibitors.
Indications
Rybrevant is FDA-approved for:
- Adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test
- Patients whose disease has progressed on or after platinum-based chemotherapy
Dosage and Administration
Initial dosing cycle (Cycle 1):- Week 1: 1400 mg (patients <80 kg) or 1750 mg (patients ≥80 kg) IV infusion
- Week 2: 1400 mg (<80 kg) or 1750 mg (≥80 kg) IV infusion
- 1400 mg (<80 kg) or 1750 mg (≥80 kg) every 2 weeks
- Administer as an IV infusion
- Premedicate with antihistamines, acetaminophen, and corticosteroids to reduce infusion-related reactions
- Initial infusion rate: 50 mL/hr for first hour, then may increase if tolerated
- Subsequent infusions may be administered over 2-4 hours if previous infusions were tolerated
- Required for certain adverse reactions including infusion-related reactions, interstitial lung disease, and skin toxicity
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution approximately 5.3 L Metabolism: Expected to be metabolized via proteolytic degradation into small peptides and amino acids Elimination: Half-life approximately 11 days Clearance: Linear pharmacokinetics with clearance of approximately 0.3 L/dayContraindications
No absolute contraindications have been identified. However, use with caution in patients with:
- History of severe hypersensitivity to amivantamab or its components
- Active interstitial lung disease
- Severe hepatic impairment (not studied)
Warnings and Precautions
Infusion-Related Reactions: Occur in up to 66% of patients. Monitor closely during infusion. Have appropriate medical support available. Interstitial Lung Disease (ILD)/Pneumonitis: Can be severe and fatal. Monitor for new or worsening respiratory symptoms. Dermatologic Adverse Reactions: Including rash, dermatitis, and dry skin. May require dose modifications. Ocular Toxicity: Including conjunctivitis, dry eye, and blurred vision. Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential to use effective contraception.Drug Interactions
No formal drug interaction studies have been conducted. However, theoretical interactions include:
- Other EGFR or MET inhibitors: Potential additive toxicity
- Immunosuppressive agents: May interfere with immune-mediated effects
- CYP substrates: Amivantamab may affect enzymes involved in drug metabolism
Adverse Effects
Most common adverse reactions (≥20%):- Rash (86%)
- Infusion-related reactions (66%)
- Paronychia (45%)
- Musculoskeletal pain (32%)
- Dyspnea (25%)
- Nausea (23%)
- Fatigue (22%)
- Edema (22%)
- ILD/pneumonitis (3.3%)
- Rash (0.4%)
- Pulmonary embolism (0.8%)
- Sepsis (0.8%)
Monitoring Parameters
Baseline and ongoing monitoring:- EGFR mutation status confirmation
- Complete blood count with differential
- Comprehensive metabolic panel (including liver and renal function)
- Oxygen saturation and pulmonary function
- Dermatologic examinations
- Ophthalmic examinations if visual symptoms occur
- Signs and symptoms of infusion-related reactions during and after infusion
- Assessment for ILD/pneumonitis (chest imaging if symptoms develop)
Patient Education
Key points to discuss with patients:- Importance of premedication before each infusion
- Recognition of infusion-related reaction symptoms (fever, chills, breathing difficulties)
- Monitoring for skin changes and appropriate skin care
- Reporting any new or worsening respiratory symptoms immediately
- Potential impact on vision and need for ophthalmic evaluation if visual changes occur
- Contraception requirements during treatment and for 3 months after final dose
- Notify all healthcare providers about Rybrevant therapy
- Importance of keeping all scheduled appointments and laboratory tests
References
1. FDA Approval Letter: May 21, 2021 2. Package Insert: Rybrevant (amivantamab-vmjw) [Revised: 2023] 3. Park K, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol. 2021;39(30):3391-3402. 4. Sabari JK, et al. Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer. Expert Rev Anticancer Ther. 2022;22(1):3-14. 5. NCCN Guidelines Version 3.2023: Non-Small Cell Lung Cancer 6. Zhou C, et al. OA04.04 Amivantamab in Patients with NSCLC with EGFR Exon 20 Insertions: First Results from the CHRYSALIS Study. J Thorac Oncol. 2021;16(3):S108-S109.
This information is intended for healthcare professionals and should be verified with current prescribing information and clinical guidelines.