Cetuximab

Article Author:
Anusha Chidharla
Article Editor:
Anup Kasi
Updated:
10/27/2018 12:31:28 PM
PubMed Link:
Cetuximab

Indications

Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of the following:

FDA-Approved Uses

  1. Colorectal cancer, metastatic, KRAS wild-type (without mutation). Cetuximab improves overall survival and progression-free survival and preserves quality-of-life measures in patients with colorectal cancer in whom other treatments have failed. There is a limitation of use. Patients with a colorectal tumor-bearing mutated K-ras did not benefit from cetuximab, whereas patients with a tumor-bearing wild-type K-ras did benefit from cetuximab. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy.
  2. Head and neck cancer (squamous cell). Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. Cetuximab plus platinum-fluorouracil chemotherapy improved overall survival when given as first-line treatment for patients with recurrent or metastatic squamous-cell carcinoma of the head and neck.

Non-FDA-Approved Uses

  1. Colorectal cancer, advanced, biweekly administration
  2. Non-small cell lung cancer (NSCLC), EGFR-expressing, advanced 
  3. Squamous cell skin cancer, unresectable

Benefits of combined therapy and uses in clinical trials:

EPIC trial: Cetuximab and irinotecan improved progression-free survival and response rate, and result in better quality of life compared to irinotecan alone.

BOND trial: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

CRYSTAL trial: First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, decreased the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors.

The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Mechanism of Action

Cetuximab is a recombinant chimeric human/mouse IgG1 monoclonal antibody which binds to epidermal growth factor receptor (EGFR) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands. EGFR is a member of the ErbB family of receptors. When inactive, EGFR is a monomer, but when bound by epidermal growth factor or transforming growth factor α (TGF-alpha), it forms homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization activates the intracellular tyrosine kinase region of EGFR, resulting in autophosphorylation and initiating a cascade of intracellular events. The EGFR signaling pathway regulates cell differentiation, proliferation, migration, angiogenesis, and apoptosis, all of which become deregulated in cancer cells. Cetuximab binds to EGFR with high specificity and with a higher affinity than either epidermal growth factor or TGF-alpha, thus blocking ligand-induced phosphorylation of EGFR. In addition, cetuximab enhances the effects of irinotecan and radiotherapy in experimental systems. K-ras, a small G-protein downstream of EGFR and an essential component of the EGFR signaling cascade, can acquire activating mutations in exon 2, thus isolating the pathway from the effect of EGFR and rendering EGFR inhibitors ineffective.

Administration

Administer via IV infusion; loading dose over 2 hours, weekly maintenance dose over 1 hour. Do not administer as an IV push or bolus. Do not shake or dilute. Administer via infusion pump or syringe pump. Following the infusion, an observation period of 1 hour is recommended; longer observation time following an infusion reaction may be required. Premedication with an antihistamine alone is acceptable, although the addition of a glucocorticoid (with or without an H2 receptor antagonist) is reasonable for those living in high-incidence areas. Dosing prescribed as initial loading dose 400 mg/m2 infused over 120 minutes and maintenance dose of 250 mg/m2 infused over 60 minutes for both colorectal cancer, metastatic, KRAS wild-type (without mutation) and head and neck cancer (squamous cell).

Adverse Effects

Adverse effects include the following based on body systems:

Central nervous system: Fatigue (91%), malaise (73% or less), pain (59%), peripheral sensory neuropathy (45%; grades 3/4: 1%), headache (19% to 38%), insomnia (27%), confusion (18%), chills (16% or less), rigors (16%or less), anxiety (14%), depression (14%)

Dermatologic: Desquamation (95%), acneiform eruption (15% to 88%; grades 3/4: 1% to 18%), radiodermatitis (86%), xeroderma (14% to 57%), pruritus (14% to 47%), skin rash (28% to 44%), changes in nails (31%), acne vulgaris (14% to 22%), paronychia (20%), palmar-plantar erythrodysesthesia (19%), skin fissure (19%), alopecia (12%)

Endocrine & metabolic: Weight loss (15% to 84%), hypomagnesemia (6% to 55%), dehydration (13% to 25%), hypocalcemia (12%), hypokalemia (12%)

Gastrointestinal: Diarrhea (19% to 72%), nausea (49% to 64%), abdominal pain (59%), constipation (53%), vomiting (40%), stomatitis (31% to 32%), anorexia (25% to 30%), dyspepsia (14% to 16%), xerostomia (12%)

Hematologic and oncologic: Neutropenia (49%; grades 3/4: 31%), leukopenia (grades 3/4: 17%)

Hepatic: Increased serum ALT (43%), increased serum AST (38%), increased serum alkaline phosphatase (33%)

Infection: Infection (13% to 44%), infection without neutropenia (38%)

Local: Application site reaction (18%)

Neuromuscular and skeletal: Weakness (73% or less), ostealgia (15%), arthralgia (14%)

Ophthalmic: Conjunctivitis (10% to 18%)

Respiratory: Dyspnea (49%), cough (30%), pharyngitis (26%)

Miscellaneous: Fever (22% to 29%), infusion related reaction (10% to 18%; grades 3/4: 2% to 5%

Contraindications

United States labeling: There are no contraindications listed.

Canadian labeling: Known severe hypersensitivity to cetuximab or any component of the formulation.

Monitoring

Vital signs during infusion and observe for at least 1-hour post infusion. Patients developing dermatologic toxicities should be monitored for the development of complications. Periodic monitoring of serum magnesium, calcium, and potassium are recommended to continue over an interval consistent with the half-life (8 weeks); monitor closely (during and after treatment) for cetuximab plus radiation therapy. KRAS genotyping of tumor tissue in patients with colorectal cancer.

Toxicity

Cardiopulmonary arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients. Use with caution in patients with a history of coronary artery disease, heart failure, and arrhythmias.

Infusion reactions: Serious infusion reactions occurred with the administration of cetuximab in approximately 3% of patients in clinical trials, with fatal outcomes reported in less than 1 in 1000. Immediately interrupt and permanently discontinue cetuximab infusion for serious infusion reactions. In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose alpha-1,3-galactose. The presence of this oligosaccharide is related to the production of cetuximab in a murine cell line. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%.

Dermatologic toxicity: An acne-like or maculopapular rash, a characteristic side effect of EGFR blockade, is due to the role of EGFR in maintaining the integrity of the skin. Acneiform rash has been reported in 76% to 88% of patients (severe in 1% to 17%), usually developing within the first 2 weeks of therapy; may require dose modification; generally resolved after discontinuation in most patients, although persisted beyond 28 days in some patients. The acneiform rash should be treated with topical and/or oral antibiotics; topical corticosteroids are not recommended.

Interstitial lung disease: use with caution in patients with preexisting lung disease.

Electrolyte abnormality: Hypomagnesemia is common (may be severe). Because EGFR is strongly expressed in the kidney, particularly in the ascending limb of the loop of Henle where 70% of filtered magnesium is reabsorbed, EGFR blockade may interfere with magnesium transport. Because symptoms may be ameliorated rapidly with supplementation, when fatigue or hypocalcemia is encountered during cetuximab therapy, serum magnesium level be measured and replete as necessary. The onset of electrolyte disturbance may occur within days to months after initiation of treatment; monitor magnesium, calcium, and potassium during treatment and for at least 8 weeks after completion.