Cetuximab

Drug Class:

• Monoclonal antibody — chimeric (mouse/human) IgG1
• Epidermal growth factor receptor (EGFR) inhibitor

Mechanism of Action:

• Binds to extracellular domain of EGFR (HER1) with higher affinity than natural ligands (EGF, TGF-α).
• Blocks ligand-induced receptor phosphorylation → inhibits downstream signaling (RAS/RAF/MEK/ERK & PI3K/AKT pathways).
• Result: inhibition of cell proliferation, angiogenesis, and metastasis; promotes apoptosis.
• Also induces antibody-dependent cellular cytotoxicity (ADCC).

Oncology Indications:

• Metastatic colorectal cancer (mCRC) — KRAS/NRAS wild-type only, in combination with FOLFIRI/FOLFOX or as monotherapy after chemo failure.
• Head and neck squamous cell carcinoma (HNSCC) — in combination with radiation for locally advanced disease, or with platinum/5-FU for recurrent/metastatic disease.

Adult Dosing Examples:

• Loading dose: 400 mg/m² IV over 120 min (max rate 10 mg/min).
• Maintenance: 250 mg/m² IV weekly over 60 min or
  
  500 mg/m² IV every 2 weeks over 120 min (common in combination regimens).

Pharmacokinetics:

• t½ ~112 h; clearance ~0.08 L/h; eliminated via target-mediated disposition and proteolysis.
• No renal/hepatic adjustment required.

Key Toxicities / Warnings:

• Infusion reactions (can be severe, especially in southeastern US due to pre-existing IgE to galactose-α-1,3-galactose from tick bites):
  • Most occur with first infusion → premedicate with H1 antihistamine ± corticosteroid.
• Acneiform rash (EGFR-related) — often correlates with treatment efficacy.
• Hypomagnesemia (and other electrolyte losses — K, Ca) due to renal magnesium wasting; may occur weeks-months after starting.
• Pulmonary toxicity (rare interstitial lung disease).
• Cardiopulmonary arrest (reported in HNSCC patients receiving concomitant radiation).

Monitoring for Pharmacists:

• Electrolytes (Mg, K, Ca) at baseline and periodically during therapy, and for ≥8 weeks after discontinuation.
• Monitor for rash severity, infusion reaction symptoms, pulmonary changes.
• Ensure RAS mutation testing before starting in colorectal cancer — not effective in KRAS/NRAS mutant tumors.

Administration Notes:

• Use 0.22-micron in-line filter during infusion.
• First infusion: 120 min; subsequent: 60 min if tolerated.
• If infusion reaction ≥grade 3 → permanently discontinue.

Drug Interactions:

• No CYP-mediated interactions.
• Avoid live vaccines during therapy.
• Concomitant platinum compounds may enhance electrolyte disturbances.

Clinical Pearls:

• Rash prophylaxis (moisturizers, sunscreen, doxycycline or minocycline) can improve tolerability and adherence.
• Infusion reactions are more common in geographic regions with alpha-gal allergy prevalence — consider regional risk factors.
• Lack of rash may indicate poor response; rash management is key for maintaining therapy.