Cetuximab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Erbitux: 100 mg/50 mL (50 mL); 200 mg/100 mL (100 mL) [contains galactose-alpha-1,3-galactose]

Pharmacology

Mechanism of Action

Cetuximab is a recombinant human/mouse chimeric monoclonal antibody which binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands. Binding to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production. EGFR signal transduction results in RAS wild-type activation; cells with RAS mutations appear to be unaffected by EGFR inhibition.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: ~2 to 3 L/m²

Half-Life Elimination

~112 hours (range: 63 to 230 hours)

Use: Labeled Indications

Colorectal cancer, metastatic: Treatment of KRAS wild-type (without mutation), epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer as determined by an approved test (in combination with FOLFIRI [irinotecan, fluorouracil, and leucovorin] as first-line treatment, in combination with irinotecan [in patients refractory to irinotecan-based chemotherapy], or as a single agent in patients who have failed irinotecan- and oxaliplatin-based chemotherapy or who are intolerant to irinotecan).

Limitation of use: Cetuximab is not indicated for the treatment of RAS-mutant colorectal cancer or when results of the RAS mutation tests are unknown.

Head and neck cancer, squamous cell: Treatment of squamous cell cancer of the head and neck (as a single agent for recurrent or metastatic disease after platinum-based chemotherapy failure; in combination with radiation therapy as initial treatment of locally or regionally advanced disease; in combination with platinum and fluorouracil-based chemotherapy as first-line treatment of locoregional or metastatic disease).

Use: Off Label

Colorectal cancer, metastatic, refractory (RAS wild-type, BRAF V600E-mutant)b

Data from the multicenter safety lead-in portion of a phase 3 study suggest that cetuximab (in combination with encorafenib and binimetinib) may be efficacious in the treatment of metastatic RAS wild-type colorectal cancer in patients with BRAF V600E-mutant tumors and disease progression following 1 to 2 prior therapies Van Cutsem 2019.

Penile cancer (squamous cell, advanced or metastatic)c

Data from a small single-center retrospective study suggests that cetuximab (either as monotherapy or in combination with other chemotherapy agents) may be beneficial for the treatment of squamous cell carcinoma of the penis in patients who had received at least one prior line of therapy Carthon 2014.

Squamous cell skin cancer, unresectableb

Data from a multicenter phase 2 study evaluating the use of cetuximab in patients with unresectable squamous cell skin cancer supports the use of cetuximab for the treatment of this condition Maubec 2011.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

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

Dosage and Administration

Dosing: Adult

Note: Premedicate with an H₁ antagonist (eg, diphenhydramine) IV 30 to 60 minutes prior to the first dose; premedication for subsequent doses may be necessary based on clinical judgment.

Colorectal cancer, metastatic, KRAS wild-type (without mutation): IV:

Initial loading dose: 400 mg/m² infused over 120 minutes

Maintenance dose: 250 mg/m² infused over 60 minutes weekly until disease progression or unacceptable toxicity

Note: If given in combination with irinotecan or FOLFIRI (irinotecan, fluorouracil, and leucovorin), complete cetuximab infusion 1 hour prior to irinotecan or FOLFIRI.

Off-label combination: IV: Initial loading dose: 400 mg/m², followed by maintenance dose: 250 mg/m² once weekly (in combination with fluorouracil, leucovorin, and oxaliplatin [FOLFOX4 or mFOLFOX6]) (Bokemeyer 2011; Venook 2017)

Colorectal cancer, advanced, biweekly administration (off-label dosing): IV: 500 mg/m² every 2 weeks (initial dose infused over 120 minutes, subsequent doses infused over 60 minutes) in combination with irinotecan (Pfeiffer 2008)

Colorectal cancer, metastatic, refractory (RAS wild-type, BRAF V600E-mutant) (off-label use): IV: Initial loading dose: 400 mg/m², followed by maintenance dose: 250 mg/m² weekly (in combination with encorafenib and binimetinib); continue until disease progression or unacceptable toxicity occurs (Van Cutsem 2019).

Head and neck cancer (squamous cell): IV:

Initial loading dose: 400 mg/m² infused over 120 minutes

Maintenance dose: 250 mg/m² infused over 60 minutes weekly

Note: If given in combination with radiation therapy, administer loading dose 1 week prior to initiation of radiation course; weekly maintenance dose should be completed 1 hour prior to radiation for the duration of radiation therapy (6 to 7 weeks). If given in combination with chemotherapy, administer loading dose on the day of initiation of platinum and fluorouracil-based chemotherapy, cetuximab infusion should be completed 1 hour prior to initiation of chemotherapy; weekly maintenance dose should be completed 1 hour prior to chemotherapy; continue until disease progression or unacceptable toxicity occurs. Monotherapy weekly doses should be continued until disease progression or unacceptable toxicity occurs.

Penile cancer, squamous cell, advanced or metastatic (off-label use; based on limited data): IV: Initial loading dose: 400 mg/m², followed by maintenance dose: 250 mg/m² once weekly (as monotherapy or in combination with other chemotherapy agents) (Carthon 2014).

Squamous cell skin cancer, unresectable (off-label use): IV: Initial loading dose: 400 mg/m², followed by maintenance dose: 250 mg/m² weekly until disease progression (Maubec 2011)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Dermatologic toxicity and infectious sequelae (eg, acneiform rash, mucocutaneous disease):

First occurrence, grade 3 or 4: Delay cetuximab infusion 1 to 2 weeks.

If improvement, continue at 250 mg/m².

If no improvement, discontinue cetuximab.

Second occurrence, grade 3 or 4: Delay cetuximab infusion 1 to 2 weeks.

If improvement, continue at reduced dose of 200 mg/m².

If no improvement, discontinue cetuximab.

Third occurrence, grade 3 or 4: Delay cetuximab infusion 1 to 2 weeks.

If improvement, continue at reduced dose of 150 mg/m².

If no improvement, discontinue cetuximab.

Fourth occurrence, grade 3 or 4: Discontinue cetuximab.

Infusion reactions, grade 1 or 2: Reduce the cetuximab infusion rate by 50%.

Infusion reactions, grade 3 or 4: Immediately and permanently discontinue cetuximab.

Pulmonary toxicity:

Acute onset or worsening pulmonary symptoms: Delay cetuximab infusion 1 to 2 weeks; if improvement occurs, continue at the dose that was being administered at the time of toxicity occurrence. If no improvement in 2 weeks, discontinue cetuximab.

Interstitial lung disease (confirmed): Permanently discontinue cetuximab.

Reconstitution

Reconstitution is not required. Appropriate dose should be added to empty sterile container (solution may contain a small amount of visible white, amorphous cetuximab particles); do not shake or dilute. Discard unused portion of the vial; discard any remaining solution in infusion container after 8 hours at room temperature or after 12 hours refrigerated.

Administration

IV: Administer via IV infusion; loading dose over 2 hours, weekly maintenance dose over 1 hour. Do not administer as IV push or bolus. Do not shake or dilute. Administer via infusion pump or syringe pump. Following the infusion, an observation period (1 hour) is recommended; longer observation time (following an infusion reaction) may be required. Premedication with an H₁ antagonist prior to the initial dose is recommended. The maximum infusion rate is 10 mg/minute. Administer through a low protein-binding 0.22 micrometer in-line filter.

For biweekly administration (off-label frequency and dose), the initial dose was infused over 120 minutes and subsequent doses infused over 60 minutes (Pfeiffer 2007; Pfeiffer 2008).

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze or shake. Increased particulate formation may occur at temperatures ≤0°C (≤32°F). Preparations in infusion containers are stable for up to 12 hours refrigerated at 2°C to 8°C (36°F to 46°F) and up to 8 hours at room temperature of 20°C to 25°C (68°F to 77°F).

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Cardiovascular: Cardiac disorder (6% to 11%)

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

Dermatologic: Desquamation (95%), acneiform eruption (15% to 88%), 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 (29% to 40%), stomatitis (31% to 32%; grades 3/4: 1% to 3%), anorexia (25% to 30%), dyspepsia (14% to 16%), xerostomia (12%)

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

Hepatic: Increased serum alanine aminotransferase (43%), increased serum aspartate aminotransferase (38%), increased serum alkaline phosphatase (33%)

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

Local: Application site reaction (18%)

Neuromuscular & skeletal: Asthenia (≤73%), ostealgia (15%), arthralgia (14%)

Ophthalmic: Conjunctivitis (10% to 18%)

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

Miscellaneous: Fever (22% to 29%), infusion related reaction (8% to 18%)

1% to 10%:

Cardiovascular: Pulmonary embolism (4%), ischemic heart disease (2%)

Gastrointestinal: Dysgeusia (10%)

Immunologic: Antibody development (<5%)

Infection: Sepsis (1% to 4%)

Renal: Renal failure syndrome (1%: colorectal cancer patients; frequency not defined in other populations)

Frequency not defined:

Dermatologic: Hypertrichosis

Endocrine & metabolic: Electrolyte disorder

<1%, postmarketing, and/or case reports: Abscess, acute myocardial infarction, aseptic meningitis, blepharitis, bullous pemphigoid, cardiac arrhythmia, cellulitis, cheilitis, corneal ulcer, interstitial pulmonary disease, keratitis, skin infection, Stevens-Johnson syndrome, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Cardiopulmonary arrest: [US Boxed Warning]: Cardiopulmonary arrest or sudden death occurred in patients with squamous cell carcinoma of the head and neck receiving cetuximab with radiation therapy or a cetuximab product with platinum-based therapy and fluorouracil. Monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab administration. Use with caution in patients with a history of coronary artery disease, heart failure, and arrhythmias; fatalities have been reported.
• Dermatologic toxicity: Acneiform rash has been commonly reported, including severe cases. Acneiform rash usually developed within the first 2 weeks of therapy; rash generally lasted >28 days after cetuximab discontinuation in most patients. Acneiform rash should be treated with topical and/or oral antibiotics; topical corticosteroids are not recommended. In colorectal cancer, the presence of acneiform rash correlates with treatment response and prolonged survival (Cunningham 2004). Life-threatening and fatal bullous mucocutaneous disease (with blisters, erosions, and skin sloughing) has been observed with cetuximab; etiology is not determined; may be due to epidermal growth factor receptor (EGFR) inhibition or to idiosyncratic immune-related effects (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Other dermatologic toxicities, including dry skin, fissures, hypertrichosis, paronychial inflammation, and skin infections, have been reported; related ocular toxicities (blepharitis, conjunctivitis, keratitis, ulcerative keratitis with decreased visual acuity) may also occur. Monitor closely for dermatologic toxicities and potential infectious sequelae; dermatologic toxicity may require dosage modification (based on the severity). Sunlight may exacerbate skin reactions (limit sun exposure).
• Electrolyte abnormalities: Hypomagnesemia is common (may be severe); accompanying electrolyte abnormalities may also occur. The onset of electrolyte disturbance may occur within days to months after initiation of treatment; monitor magnesium, calcium, and potassium weekly during treatment and for at least 8 weeks after completion. May require electrolyte replacement.
• Infusion reactions: [US Boxed Warning]: Cetuximab may cause serious and fatal infusion reactions. Immediately interrupt and permanently discontinue cetuximab for serious infusion reactions. Reactions have included airway obstruction (bronchospasm, stridor, hoarseness), hypotension, loss of consciousness, shock, MI, and/or cardiac arrest. The risk for anaphylactic reactions may be increased in patients with a history of tick bites, allergies to red meat, or when IgE antibodies against galactose-α-1,3-galactose (alpha-gal) are present. Premedicate with an IV H₁ antagonist 30 to 60 minutes prior to the first dose; premedication for subsequent doses is based on clinical judgment and with consideration of prior reaction to the initial infusion. The use of nebulized albuterol-based premedication to prevent infusion reaction has been reported (Tra 2008). Approximately 90% of reactions occur with the first infusion despite the use of prophylactic antihistamines. Infusion reactions may occur during or several hours after the infusion is complete. Immediate treatment for anaphylactic/anaphylactoid reactions should be available during administration. The manufacturer recommends monitoring patients for at least 1 hour following completion of infusion, or longer (until resolution) if a reaction occurs. Mild to moderate infusion reactions (chills, fever, dyspnea) are managed by slowing the infusion rate (by 50%). Immediately and permanently discontinue for severe (grade 3 or 4) infusion reactions. Severe hypersensitivity reaction has been reported more frequently in patients living in the middle south area of the United States, including North Carolina and Tennessee (Chung 2008; O'Neil 2007).
• Pulmonary toxicity: Interstitial lung disease (ILD) has been reported. Monitor for signs and symptoms of pulmonary toxicity. Interrupt or permanently discontinue treatment for acute onset or worsening of pulmonary symptoms. Permanently discontinue with confirmed interstitial lung disease.

Disease-related concerns:

• Colorectal cancer and RAS mutation status: Cetuximab is only indicated for patients with EGFR-expressing metastatic colorectal cancer without RAS (KRAS or NRAS) mutations. Determine RAS mutation status prior to treatment (with an approved test). Patients with a codon 12 and 13 (exon 2), codon 59 and 61 (exon 3), and codon 117 and 146 (exon 4) RAS mutation are unlikely to benefit from EGFR inhibitor therapy (while experiencing toxicities) and should not receive cetuximab treatment; cetuximab is not effective for colorectal cancer with RAS mutations. Cetuximab is also reported to be ineffective in patients with BRAF V600E mutation (Di Nicolantonio 2008). The American Society of Clinical Oncology (ASCO) provisional clinical opinion update recommends that all patients with metastatic colorectal cancer who are candidates for anti-EGFR therapy should be tested (in a certified lab) for mutations in both KRAS and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146); anti-EGFR monoclonal antibody therapy should only be considered in patients whose tumors lack mutations after extended RAS testing (Allegra 2016).
• EGFR expression testing: In trials for colorectal cancer, evidence of EGFR expression was required, although the response rate did not correlate with either the percentage of cells positive for EGFR or the intensity of expression. EGFR expression has been detected in nearly all patients with head and neck cancer; therefore, laboratory evidence of EGFR expression is not necessary for head and neck cancers.

Concurrent drug therapy issues:

• Combination with cisplatin and radiation therapy: In a study of radiation therapy and cisplatin with or without cetuximab in patients with squamous cell head and neck cancer, an increase in the incidence of adverse reactions (eg, grade 3/4 mucositis, radiation recall, acneiform rash, electrolyte abnormalities, and cardiac events including ischemia) was noted in patients receiving cetuximab, including fatal reactions. There was no improvement in the primary end point of progression-free survival. Cetuximab is not approved in combination with radiation and cisplatin for the treatment of squamous cell head and neck cancers.

Other warnings/precautions:

• Anti-cetuximab antibodies: Anti-cetuximab antibodies were detected in <5% of evaluable patients. Relationship between the appearance of antibodies and the safety or antitumor activity of the molecule is unknown.

Monitoring Parameters

KRAS genotyping of tumor tissue in patients with colorectal cancer. Monitor serum magnesium, calcium, and potassium weekly during treatment and for at least 8 weeks following completion of treatment); monitor closely (during and after treatment) for cetuximab plus radiation therapy. Pregnancy test (prior to treatment initiation in females of reproductive potential). Monitor vital signs during infusion and observe for at least 1 hour postinfusion (monitor beyond 1 hour and until resolution in patients who experience a reaction). Monitor for signs/symptoms of dermatologic toxicities (including for the development of complications) and pulmonary toxicities.

Pregnancy

Pregnancy Considerations

Based on animal data and the mechanism of action, cetuximab may be expected to cause fetal harm if administered during pregnancy.

Verify pregnancy status in females of reproductive potential prior to treatment initiation. The manufacturer recommends that females of reproductive potential use effective contraception during therapy and for 2 months following the last dose of cetuximab.

Patient Education

What is this drug used for?

• It is used to treat cancer of the head and neck.
• It is used to treat colorectal cancer.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Acne
• Nail changes
• Dry skin
• Skin irritation
• Loss of strength and energy
• Constipation
• Nausea
• Vomiting
• Diarrhea
• Mouth irritation
• Mouth sores
• Trouble sleeping
• Weight loss
• Sore throat
• Stuffy nose
• Joint pain
• Hair loss
• Bone pain
• Change in taste
• Lack of appetite

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Infection
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting,
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Confusion
• Mood changes
• Eye irritation
• Chest pain
• Fast heartbeat
• Severe dizziness
• Passing out
• Severe headache
• Vision changes
• Burning or numbness feeling
• Severe skin reaction
• Redness or irritation of palms or soles of feet
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.