What is Cetuximab and Its Side Effects
Cetuximab (Erbitux) is a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR), used primarily in treating metastatic colorectal cancer and head and neck squamous cell carcinoma, with the most common side effects being skin rash (occurring in ~90% of patients), infusion reactions including anaphylaxis (3%), diarrhea, headache, infection, and venous thromboembolic events. 1, 2, 1
Mechanism of Action
Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of EGFR, blocking the binding of epidermal growth factor and other ligands. 1 This competitive inhibition prevents EGFR phosphorylation and activation of downstream signaling pathways, resulting in:
- Inhibition of cell growth and proliferation 1
- Induction of apoptosis (programmed cell death) 1
- Decreased production of matrix metalloproteinases and vascular endothelial growth factor 1
- Antibody-dependent cellular cytotoxicity (ADCC) against tumor cells 1
The drug has an approximate molecular weight of 152 kDa and is produced in mammalian cell culture. 1
Clinical Indications
Colorectal Cancer
Cetuximab is approved for EGFR-expressing metastatic colorectal cancer in combination with irinotecan for patients refractory to irinotecan-based chemotherapy, or as monotherapy in patients intolerant to irinotecan. 1, 2
- Critical limitation: Only effective in RAS wild-type tumors (KRAS and NRAS wild-type) 2
- Patients with KRAS or NRAS mutations should NOT receive cetuximab as they have virtually no chance of benefit 2
- Response rates range from 10-20% in appropriate patient populations 2
Head and Neck Cancer
The NCCN recommends cetuximab in combination with platinum-based chemotherapy plus 5-FU for first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma. 3
Major Side Effects and Toxicities
Dermatologic Toxicity (Most Common)
Skin reactions occur in approximately 90% of patients treated with cetuximab, with grade 3-4 reactions in 10-18% of cases. 2, 3
- Presents as acneiform (pustular or maculopapular follicular) eruption 4
- Paradoxically, the presence and severity of rash correlates with improved response and survival 2
- Rash development within the first 3 weeks predicts better outcomes 3
- Requires proactive management with topical/oral antibiotics, topical steroids, or immunomodulatory agents 4
Infusion Reactions
Severe infusion reactions, including anaphylaxis, occur in 3% of patients receiving cetuximab. 2
- Requires careful monitoring during administration 1
- Patients experiencing severe reactions to cetuximab may tolerate panitumumab (alternative anti-EGFR antibody) 2
Other Common Adverse Events (≥25% incidence)
According to FDA labeling, the following occur frequently: 1
- Headache
- Diarrhea
- Infection
- Pruritus and nail changes
Serious Adverse Events
Cetuximab carries risk for venous thromboembolic events and other serious complications. 2
- Hypomagnesemia requiring regular monitoring and IV magnesium replacement 3
- Fatigue, nausea, abdominal pain (especially when combined with other agents) 1
Critical Clinical Pitfalls
Combination Therapy Contraindication
The concurrent use of cetuximab with bevacizumab (anti-VEGF agent) is strongly contraindicated based on PACCE and CAIRO2 trial results showing significantly shorter progression-free survival and higher toxicity. 2
Tumor Sidedness in Colorectal Cancer
Cetuximab provides little to no benefit in patients with right-sided primary colorectal tumors (cecum to hepatic flexure), even with RAS wild-type status. 2
- Left-sided tumors (splenic flexure to rectum): Overall survival 39.3 months with cetuximab vs 32.6 months with bevacizumab 2
- Right-sided tumors: Overall survival 13.6 months with cetuximab vs 29.2 months with bevacizumab 2
- For right-sided RAS wild-type tumors, bevacizumab is preferred over cetuximab 2
EGFR Testing Not Predictive
EGFR expression testing by immunohistochemistry does NOT predict response to cetuximab and should not be used to select or exclude patients. 2, 3
- RAS mutation status (KRAS/NRAS) is the critical biomarker, not EGFR expression level 2
Dosing
The standard regimen consists of: 3
- Initial loading dose: 400 mg/m² IV over 120 minutes
- Maintenance dose: 250 mg/m² IV over 60 minutes weekly
- Alternative: 500 mg/m² every 2 weeks (similar pharmacokinetics) 3