## Anti-EGFR Monoclonal Antibodies ### Cetuximab: Mechanism and Clinical Use **Key Point:** Cetuximab is a chimeric mouse-human monoclonal antibody (IgG1) that binds to the extracellular domain of EGFR, preventing ligand binding and receptor dimerization, thereby blocking downstream signaling through the MAPK and PI3K/AKT pathways. ### Clinical Applications in Colorectal Cancer - First-line combination therapy with chemotherapy (5-FU/leucovorin + irinotecan or oxaliplatin) for metastatic CRC - Improves overall survival and progression-free survival in EGFR-expressing tumors - Efficacy is enhanced in KRAS wild-type tumors; KRAS mutations confer resistance - Also approved for squamous cell carcinoma of the head and neck (SCCHN) ### Pharmacokinetics and Adverse Effects - Half-life: 3–7 days; requires weekly or biweekly dosing - Characteristic acneiform rash (grade 1–2 in ~80% of patients) correlates with efficacy - Hypomagnesemia (due to renal wasting) is a unique toxicity requiring monitoring - Infusion reactions in 3–5% of patients, especially with first infusion **High-Yield:** KRAS and NRAS mutation testing is mandatory before cetuximab use in CRC; patients with activating KRAS/NRAS mutations do not benefit and should not receive anti-EGFR therapy. **Mnemonic:** **EGFR-mAbs in CRC** = **C**etuximab, **P**anitumumab (both anti-EGFR); contrast with **B**evacizumab (anti-VEGF) and **T**rastuzumab (anti-HER2). **Clinical Pearl:** Cetuximab is also used in combination with radiation therapy for locally advanced SCCHN, improving locoregional control and overall survival compared to radiation alone. [cite:Harrison 21e Ch 105]
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