Monoclonal Antibodies: Cetuximab (Anti-EGFR) and Bevacizumab (Anti-VEGF)

Mechanism

Pharmacological Class and Group

Monoclonal antibodies directed against epidermal growth factor receptor type I (EGFR / ErbB1: Cetuximab) and against soluble vascular endothelial growth factor A (VEGF-A: Bevacizumab).

Mechanism of Action

• Cetuximab: It binds competitively and specifically to the extracellular domain of the EGFR receptor, blocking the binding of the endogenous ligand (EGF or TGF-α) and preventing autophosphorylation and activation of the tyrosine kinase cascade. This stops proliferation mediated by the intracellular RAS-RAF-MAPK axis. *Genetic conditioning:* Blockade is useless in tumors that inherit active mutations in the KRAS or NRAS genes, which constitutively activate the downstream mitogenic pathway independently of the EGFR signal.
• Bevacizumab: It selectively binds to the circulating soluble ligand VEGF-A, physically preventing its coupling with the VEGFR-1 and VEGFR-2 receptors expressed on the surface of the endothelial cells of tumor blood vessels. This overrides angiogenesis signaling, blocking the sprouting of new endothelial capillaries that nourish the tumor stroma.

Mechanism of Antiangiogenic Action of Bevacizumab

The tumor secretes VEGF-A to stimulate endothelial recruitment and increase the permeability of surrounding vessels to facilitate their growth and invasion:

Bevacizumab + Free VEGF-A Complex Inactive VEGFR-2 Receptor Neovessel Regression

By joining bevacizumab, regression of the vascular bed of existing tumor neogenesis is induced, intratumoral tissue perfusion pressure is normalized, facilitating the arrival of concomitant chemotherapy, and progressive metastatic growth is inhibited.

Pharmacokinetics

High Resolution Pharmacokinetics

• Distribution and Metabolism: Distribution limited to the vascular space with low peripheral volume. They do not undergo microsomal or phase II hepatic metabolism. They are cleared by lysosome-mediated proteolytic phagocytosis.
• Half-life (t_1/2): The elimination half-life is long, approximately 3 to 7 days for cetuximab, and 18 to 21 days for bevacizumab.

Indicators and dose

Clinical Indications and Frequent Regimens

• Cetuximab: Metastatic colorectal cancer with KRAS/NRAS wild-type genotype, combined with FOLFIRI or FOLFOX; locally advanced or metastatic squamous cell carcinoma of the head and neck.
• Bevacizumab: Metastatic colorectal cancer (combined with FOLFOX or FOLFIRI), advanced non-squamous non-small cell lung cancer, advanced epithelial ovarian cancer, metastatic renal cell carcinoma.

Dosage and Clinical Adjustment

• Cetuximab IV: Loading dose of 400 mg/m² as a 120-minute infusion; followed by weekly maintenance doses of 250 mg/m² IV as a 60-minute infusion.
• Bevacizumab IV: 5 - 10 mg/kg IV every 14 days or 15 mg/kg every 21 days combined with chemotherapy.
• Clinical Adjustments: In case of grade 3 skin rash due to cetuximab, temporarily suspend; readjust by reducing the dose by 20% if it reappears. For bevacizumab, if 24-hour urine proteinuria exceeds 2 g, temporarily discontinue; definitively suspend in the event of any event of intestinal perforation, internal fistula or acute arterial thrombosis.

Security

Absolute and Relative Contraindications

Contraindications of Bevacizumab

• Tumor territory with imminent risk of digestive perforation or unhealed surgical wounds (hold of 28 days before/after surgery).
• History of massive hemoptysis or active bleeding diathesis.
• Uncontrolled arterial hypertension.
• Recent active arterial thromboembolism.

Contraindications of Cetuximab

• Confirmed presence of mutation in critical KRAS or NRAS codons (due to absolute futility of treatment and unacceptable cost).
• Base interstitial lung dysfunction.

Adverse Effects (ADR) and Specific Toxicity

• Cetuximab: Acneiform eruption (papulopustular rash) in 80% of treated patients. It affects the face, neck, and upper chest, secondary to the physiological role of EGFR in the pilosebaceous follicle. It is a marker of antitumor response. It also presents with profound hypomagnesemia (due to inhibition of active magnesium reabsorption in the renal convoluted tubule through the TRPM6 transporter).
• Bevacizumab: Systemic arterial hypertension (due to decreased synthesis of endothelial nitric oxide), asymptomatic glomerular proteinuria, severe delay in healing, gastrointestinal fistulas or perforation, minor bleeding (epistaxis) and arterial thrombotic events.