Cetuximab

Cetuximab is a chimeric monoclonal IgG1 antibody, made by recombinant DNA technology in a mammalian cell line (Sp2/0), that is directed against the epidermal growth factor receptor (EGFR). EGFR signalling controls cell survival, cell-cycle progression, angiogenesis, cell migration and invasion, and the receptor is often over-expressed in colorectal and head and neck tumours. By occupying the receptor, cetuximab stops its natural growth factors from switching these pathways on.

Mechanism of Action

• Receptor blockade: cetuximab binds EGFR with an affinity about 5- to 10-fold higher than that of the receptor’s natural ligands. It attaches to the ligand-binding domain (domain III), blocks ligand binding and keeps the receptor from adopting its active conformation. It does not bind other receptors of the HER family.
• Down-regulation: binding induces internalisation of the antibody–receptor complex, which can lead to down-regulation of EGFR.
• Immune effect: cetuximab directs cytotoxic immune effector cells towards EGFR-expressing tumour cells (antibody-dependent cell-mediated cytotoxicity, ADCC).
• Tumour effects: in laboratory studies it inhibits the proliferation of EGFR-expressing tumour cells and induces apoptosis, reduces the production of angiogenic factors and blocks endothelial cell migration; in animal models it reduces tumour neo-vascularisation and metastasis. It also enhanced the effect of chemotherapy and radiation in laboratory models.
• Role of RAS: RAS is a central signal transducer downstream of EGFR. Mutations of RAS genes at hot-spots in exons 2, 3 and 4 keep RAS proteins constantly active independently of EGFR signalling, so the pathway stays switched on even when the receptor is blocked. This is why RAS wild-type tumour status is required in colorectal cancer.

Pharmacokinetics

• Dose dependence: after intravenous infusion, cetuximab shows dose-dependent pharmacokinetics at weekly doses from 5 to 500 mg/m² of body surface area.
• Distribution: after an initial dose of 400 mg/m², the mean volume of distribution is about that of the vascular space (2.9 L/m², range 1.5–6.2 L/m²) and the mean peak concentration is 185 ± 55 µg/mL.
• Steady state: with the weekly regimen (400 mg/m² first, then 250 mg/m² weekly), stable levels are reached after three weeks of single-agent treatment (mean peak 155.8 µg/mL and trough 41.3 µg/mL in week 3). With the every-other-week regimen (500 mg/m²), stable levels are reached after five weeks (mean peak 297 µg/mL and trough 31.0 µg/mL in week 5).
• Metabolism: like other antibodies, cetuximab is broken down by protein catabolism (including lysosomal and target-mediated pathways) into small peptides and amino acids.
• Elimination: mean clearance is 0.022 L/h per m² of body surface area, and the elimination half-life is long, 70 to 100 hours.
• Special populations: population analyses found no clinically relevant effect of race, age, sex, or renal or hepatic status. Exposure is higher in women, which was not considered clinically relevant.

Erbitux is authorised in the EU for the following uses.

• RAS wild-type metastatic colorectal cancer: patients with epidermal growth factor receptor (EGFR)-expressing, RAS wild-type metastatic colorectal cancer, in three settings:
  • in combination with irinotecan-based chemotherapy;
  • as first-line treatment in combination with FOLFOX (fluorouracil, folinic acid and oxaliplatin);
  • as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.
• BRAF V600E-mutant metastatic colorectal cancer: adults, in combination with encorafenib and FOLFOX for first-line treatment, and in combination with encorafenib in patients who have received prior systemic therapy.
• Squamous cell cancer of the head and neck: in combination with radiation therapy for locally advanced disease, and in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.

For colorectal cancer the tumour must be shown to be RAS wild-type before cetuximab is started (see Special Instructions). For the BRAF V600E-mutant indication, the mutation status is established with a CE-marked diagnostic test or, if none is available, another validated test.

• Known severe (grade 3 or 4) hypersensitivity reactions to cetuximab.
• Combination with oxaliplatin-containing chemotherapy in patients with mutant RAS metastatic colorectal cancer, or in whom the RAS status is unknown.
• Before combination treatment, the contraindications of the chemotherapy or radiation therapy used with cetuximab must also be considered.

The main side effects are skin reactions, which occur in more than 80% of patients, hypomagnesaemia, which occurs in more than 10%, and infusion-related reactions, which are mild to moderate in more than 10% of patients and severe in more than 1%.

Very common (≥1/10): hypomagnesaemia; skin reactions (mainly an acne-like rash and, less often, itching, dry skin, scaling, excess hair growth or nail disorders such as paronychia); mild or moderate infusion-related reactions; mucositis, in some cases severe and sometimes causing nosebleeds; raised liver enzymes (AST, ALT, alkaline phosphatase).

Common (≥1/100 to <1/10): severe infusion-related reactions, in some cases fatal; fatigue; dehydration, especially after diarrhoea or mucositis; hypocalcaemia; anorexia, which may lead to weight loss; headache; conjunctivitis; diarrhoea; nausea; vomiting.

Uncommon (≥1/1,000 to <1/100): blepharitis; keratitis; deep vein thrombosis; pulmonary embolism; interstitial lung disease, which can be fatal.

Very rare (<1/10,000): Stevens-Johnson syndrome and toxic epidermal necrolysis.

Not known: aseptic meningitis; superinfection of skin lesions.

About 15% of the skin reactions are severe, including isolated cases of skin necrosis. Most appear in the first three weeks of treatment and usually resolve without sequelae after treatment is stopped, if the recommended dose adjustments are followed. Skin lesions caused by cetuximab can become infected (for example with Staphylococcus aureus), leading to complications such as cellulitis, erysipelas, staphylococcal scalded skin syndrome, necrotising fasciitis or sepsis, which can be fatal.

When cetuximab is combined with other treatment, the reactions of the partner treatment add to these. With platinum-based chemotherapy, severe leukopenia or neutropenia and the infections that follow (febrile neutropenia, pneumonia, sepsis) are more frequent; with fluoropyrimidines, cardiac ischaemia (including myocardial infarction and congestive heart failure) and hand-foot syndrome are more frequent; with capecitabine and oxaliplatin, severe diarrhoea may be more frequent. With radiation therapy to the head and neck, the usual radiation reactions (mucositis, radiation dermatitis, difficulty swallowing, leukopenia, mainly lymphopenia) occur, and in a controlled trial of 424 patients acute radiation dermatitis and mucositis and late radiation-related events were slightly more frequent than with radiation alone.

In the encorafenib combinations for BRAF V600E-mutant colorectal cancer, the most common reactions (more than 25%) were as follows. With encorafenib (216 patients): fatigue, nausea, diarrhoea, acne-like dermatitis, abdominal pain, joint and musculoskeletal pain, decreased appetite, rash and vomiting. With encorafenib and FOLFOX (259 patients): peripheral neuropathy, neutropenia, nausea, fatigue, anaemia, diarrhoea, vomiting, decreased appetite, rash, thrombocytopenia, abdominal pain, haemorrhage, joint and musculoskeletal pain, fever, constipation, mucosal inflammation and infection. All study drugs were stopped because of an adverse reaction in 1.9% and 3.5% of patients respectively.

Only one formal interaction study has been carried out, with irinotecan; the other interactions below come from experience with combination treatment.

• Platinum-based chemotherapy: severe leukopenia or neutropenia may be more frequent, with more infectious complications (febrile neutropenia, pneumonia, sepsis) than with platinum chemotherapy alone.
• Fluoropyrimidines (for example fluorouracil and capecitabine): cardiac ischaemia, including myocardial infarction and congestive heart failure, and hand-foot syndrome (palmar-plantar erythrodysaesthesia) were more frequent than with fluoropyrimidines alone.
• Capecitabine with oxaliplatin (XELOX): severe diarrhoea may be more frequent.
• Oxaliplatin in RAS-mutant or RAS-unknown tumours: the combination is contraindicated (see Contraindications).
• Irinotecan: a formal study found no change in the pharmacokinetics of cetuximab after a single dose of irinotecan (350 mg/m²), and none in the pharmacokinetics of irinotecan when cetuximab was given.
• Sequence of administration: chemotherapy is given no earlier than 1 hour after the end of the cetuximab infusion, and encorafenib is taken before the cetuximab infusion starts.
• No other formal interaction studies have been performed in humans.

Erbitux must be given under the supervision of a physician experienced in the use of anti-cancer medicines. Patients are monitored closely during the infusion and for at least 1 hour afterwards, and resuscitation equipment must be available. At least 1 hour before the first infusion, patients receive premedication with an antihistamine and a corticosteroid; this is recommended before all later infusions. The solution is given intravenously with an infusion pump, gravity drip or syringe pump, and the dose is based on body surface area.

Recommended Dose

• RAS wild-type metastatic colorectal cancer (with chemotherapy or as a single agent): either weekly, 400 mg/m² for the first dose and 250 mg/m² for each later weekly dose; or every other week, 500 mg/m² each time. Evidence of wild-type RAS (KRAS and NRAS) status is required before treatment starts, determined by an experienced laboratory with validated methods that detect mutations in exons 2, 3 and 4.
• BRAF V600E-mutant metastatic colorectal cancer: with encorafenib in patients who received prior systemic therapy, weekly, 400 mg/m² for the very first dose and 250 mg/m² weekly afterwards; with encorafenib and FOLFOX, every other week, 500 mg/m² each time. Evidence of BRAF V600E mutation status is required before treatment. The doses and dose modifications of encorafenib and of the chemotherapy follow their own product information.
• Colorectal cancer, duration: treatment is recommended to continue until the underlying disease progresses.
• Locally advanced head and neck cancer, with radiation therapy: cetuximab is started one week before radiation therapy and continued until the end of the radiation period. It is given weekly, 400 mg/m² for the first dose and 250 mg/m² for each later weekly dose.
• Recurrent and/or metastatic head and neck cancer, with platinum-based chemotherapy: cetuximab is given with the chemotherapy and then continued alone as maintenance therapy until disease progression, either weekly (400 mg/m² first, then 250 mg/m² weekly) or every other week (500 mg/m² each time).

Infusion Rate and Timing

• The first dose is given slowly to reduce the risk of infusion-related reactions; the recommended infusion period is 120 minutes. Later infusions must not run faster than 10 mg/min.
• If the first infusion is well tolerated, the recommended infusion period is 60 minutes for the weekly 250 mg/m² dose and 120 minutes for the every-other-week 500 mg/m² dose.
• Chemotherapy is not given earlier than 1 hour after the end of the cetuximab infusion. Encorafenib is taken before the cetuximab infusion starts.
• After a mild or moderate infusion-related reaction, the infusion rate may be reduced and kept lower for all later infusions.

Dose Adjustments for Skin Reactions

• A severe skin reaction (grade 3 or higher) or one the patient cannot tolerate means cetuximab must be interrupted; treatment may be resumed only once the reaction has improved to grade 2.
• After a first severe reaction, treatment may resume at the same dose level.
• After a second severe reaction, treatment resumes with a 20% dose reduction (200 mg/m² in the weekly regimen, 400 mg/m² in the every-other-week regimen).
• After a third severe reaction, treatment resumes with a 40% dose reduction (150 mg/m² weekly, 300 mg/m² every other week).
• A fourth severe reaction, or a reaction that does not improve to grade 2 during the interruption, requires permanent discontinuation.

Special Populations

• Elderly: no dose adjustment is required; experience is limited in patients aged 75 years and over.
• Renal impairment: patients with mild (creatinine clearance 60 to below 90 mL/min) and moderate (30 to below 60 mL/min) impairment have been studied; cetuximab has not been evaluated in severe renal impairment (15 to below 30 mL/min) or end-stage renal disease.
• Hepatic impairment: mild impairment has been studied; the effect of moderate or severe impairment has not been assessed.
• Haematological disorders: cetuximab has not been studied in patients with pre-existing haematological disorders.
• Children and adolescents: there is no relevant use of cetuximab in the paediatric population for the authorised indications.

RAS Wild-Type Status Is Required in Colorectal Cancer

Cetuximab must not be used to treat colorectal cancer when the tumour has a RAS mutation or when the RAS status is unknown. Evidence of wild-type RAS (both KRAS and NRAS, exons 2, 3 and 4) must be available before treatment starts, and the test must be done by an experienced laboratory with validated methods. Clinical studies show a negative balance of benefit and risk in tumours with RAS mutations: adding cetuximab to FOLFOX4 had negative effects on progression-free and overall survival. The combination of cetuximab with oxaliplatin-containing chemotherapy is contraindicated in patients with mutant or unknown RAS status. For the BRAF V600E-mutant indication, evidence of the BRAF V600E mutation is also required before treatment.

Infusion-Related and Anaphylactic Reactions

• Severe infusion-related reactions, including anaphylactic reactions, may occur commonly and have been fatal in some cases. They can start during the first infusion, up to several hours afterwards, or with later infusions, and can occur despite premedication. Symptoms may include bronchospasm, urticaria, a rise or fall in blood pressure, loss of consciousness or shock; angina, myocardial infarction or cardiac arrest have been seen in rare cases. A cytokine release syndrome typically appears within an hour of the infusion and is usually most severe with the first infusion.
• Patients should be warned that symptoms can start late and told to contact their doctor if they notice any sign of a reaction.
• A severe reaction requires immediate and permanent discontinuation of cetuximab and may need emergency treatment.
• The risk of anaphylaxis is much higher in patients with a history of allergy to red meat or tick bites, or with positive tests for IgE antibodies against cetuximab (α-1-3-galactose). In them, cetuximab is given only after a careful benefit–risk assessment that considers alternative treatments, under close supervision by well-trained staff with resuscitation equipment ready.
• The first dose is given slowly, with vital signs monitored closely for at least 2 hours. If a reaction occurs within the first 15 minutes of the first infusion, the infusion is stopped and a careful benefit–risk assessment is made, including whether the patient may have pre-existing IgE antibodies, before another infusion is given.
• For a reaction later in an infusion or at a later infusion: grade 1, continue the slow infusion under close supervision; grade 2, continue slowly and treat the symptoms immediately; grade 3 or 4, stop the infusion immediately, treat the symptoms vigorously and do not use cetuximab again.
• Mild or moderate reactions (fever, chills, dizziness, dyspnoea) are very common, mainly with the first infusion. Close monitoring is needed, especially at the first dose and in patients with reduced performance status or existing heart or lung disease.

Skin Reactions

Skin reactions are very common and may become severe, especially in combination with chemotherapy. The risk of secondary infection, mainly bacterial, is increased, and cases of staphylococcal scalded skin syndrome, necrotising fasciitis and sepsis, some of them fatal, have been reported. According to clinical practice guidelines, preventive oral tetracycline antibiotics (6 to 8 weeks) and 1% hydrocortisone cream with a moisturiser should be considered; medium- to high-potency topical corticosteroids or oral tetracyclines have been used to treat the reactions. Interruption and dose reduction for severe reactions are described under Administration and Dosage.

Electrolyte Disturbances

Serum magnesium falls progressively in many patients and can lead to severe hypomagnesaemia, which is reversible after cetuximab is stopped. Hypokalaemia may follow diarrhoea, and hypocalcaemia may occur; severe hypocalcaemia may be more frequent in combination with platinum-based chemotherapy. Serum electrolytes are measured before and periodically during treatment, and replaced as appropriate.

Interstitial Lung Disease

Interstitial lung disease, including fatal cases, has been reported, mostly in patients from Japan; concomitant chemotherapy known to cause it, and existing lung disease, were frequent in the fatal cases. Patients with such risk factors are monitored closely. New dyspnoea, cough, fever or suggestive findings on imaging call for prompt investigation, and cetuximab must be stopped if interstitial lung disease is diagnosed.

Neutropenia and Infections

With platinum-based chemotherapy the risk of severe neutropenia is higher, which can lead to febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended, particularly in patients with skin lesions, mucositis or diarrhoea, which can make infection easier.

Cardiovascular Disorders

An increased frequency of severe, sometimes fatal, cardiovascular events and treatment-emergent deaths has been seen in cetuximab studies, including studies in squamous cell carcinoma of the head and neck and in colorectal carcinoma; in some studies it was linked to age of 65 years or older or to performance status. Before prescribing, the cardiovascular and performance status of the patient and any cardiotoxic co-medication, such as fluoropyrimidines, are taken into account.

Eye Disorders

Patients with signs of keratitis (acute or worsening eye inflammation, lacrimation, sensitivity to light, blurred vision, eye pain or a red eye) should be referred promptly to an ophthalmologist. If ulcerative keratitis is confirmed, cetuximab is interrupted or stopped; if keratitis is diagnosed, the benefits and risks of continuing are weighed carefully. Caution is needed in patients with a history of keratitis, ulcerative keratitis or severe dry eye, and contact lens use is a risk factor.

Laboratory Limits and Other Patient Groups

Cetuximab has not been studied in patients with haemoglobin below 9 g/dL, a leukocyte count below 3,000/mm³, an absolute neutrophil count below 1,500/mm³ or a platelet count below 100,000/mm³. Experience with cetuximab and radiation therapy in colorectal cancer is limited. In children and adolescents under 18 years, efficacy has not been established; no new safety signals were found in a phase I study.

Traceability

As a biological medicine, cetuximab is recorded by name and batch number for each patient treated.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: EGFR is involved in foetal development. Limited animal observations suggest that cetuximab crosses the placenta, as other IgG1 antibodies do. Animal studies showed no teratogenicity but, depending on the dose, more abortions. Data from pregnant women are insufficient, so cetuximab is given during pregnancy, or to a woman not using adequate contraception, only if the potential benefit to the mother justifies the potential risk to the foetus.
• Breastfeeding: women should not breastfeed during treatment and for 2 months after the last dose, because it is not known whether cetuximab passes into breast milk.
• Fertility: there are no human data, and effects on male and female fertility have not been evaluated in formal animal studies.

Effect on Driving

No studies on the ability to drive and use machines have been done. Patients with treatment-related symptoms that affect concentration and reaction should not drive or use machines until the symptoms go away.

Store Erbitux in a refrigerator at 2–8 °C. As a refrigerated biological medicine it is kept in the cold chain (2–8 °C) during transport and storage until use. Erbitux contains no antimicrobial preservative, so once opened it is used immediately; if it is not, in-use storage times and conditions are the responsibility of the user and would normally be no longer than 24 hours at 2–8 °C, unless opening took place under controlled and validated aseptic conditions. Chemical and physical in-use stability has been shown for 48 hours at 25 °C when the solution is prepared as described in SmPC section 6.6.

The solution is supplied in vials of 20 mL or 100 mL (type I glass with a halobutyl rubber stopper), one vial per pack; not all vial sizes may be marketed.

4 years when stored in a refrigerator at 2–8 °C. For the in-use period after opening, see Storage Conditions.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment is started and supervised by a physician experienced in anti-cancer therapy. For colorectal cancer, RAS wild-type status (or the BRAF V600E mutation for the encorafenib combinations) is established before treatment. Erbitux is infused under medical supervision with resuscitation equipment available, so it is supplied to the hospital or clinic that administers it, in the cold chain at 2–8 °C.