Cetuximab – Uses, Dosage, Side Effects, Interaction

Cetuximab is an endothelial growth factor receptor binding fragment used to treat colorectal cancer as well as squamous cell carcinoma of the head and neck. Cetuximab is a recombinant chimeric human/mouse IgG1 monoclonal antibody that competitively binds to the epidermal growth factor receptor (EGFR) and competitively inhibits the binding of the epidermal growth factor (EGF).[rx] EGFR is a member of the ErbB family of receptor tyrosine kinases found in both normal and tumor cells; it is responsible for regulating epithelial tissue development and homeostasis.[rx] EGFR has been implicated in various types of cancer, as it is often overexpressed in malignant cells [rx] and EGFR overexpression has been linked to more advanced disease and poor prognosis.[rx] EGFR is often mutated in certain types of cancer and serves as a driver of tumorigenesis.[rx] In vitro, cetuximab was shown to mediate anti-tumor effects in numerous cancer cell lines and human tumor xenografts.[rx]

Approved by the FDA in February 2004 under the brand name ERBITUX, cetuximab is used for the treatment of head and neck cancer and metastatic, KRAS wild-type colorectal cancer, and metastatic colorectal cancer with a BRAF V600E mutation.[trx,rx] It has also been investigated in advanced colorectal cancer, EGFR-expressing non-small cell lung cancer (NSCLC), and unresectable squamous cell skin cancer.[rx] Cetuximab is administered via intravenous infusion and is used as monotherapy or in combination with other chemotherapies, including platinum agents, radiation therapy, leucovorin, fluorouracil, and irinotecan.[rx]

Cetuximab belongs to the class of medications called antineoplastics. Specifically, it is part of the group of medications known as monoclonal antibodies. It works by attaching to cancer cells, resulting in a decrease in tumour growth and increase in tumour cell death.

Mechanism of action

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a type I receptor tyrosine kinase expressed on both normal and malignant cells. It has been investigated as a therapeutic target for anticancer treatment, as it is often upregulated in cancer types, including head and neck, colon, and rectal cancers.[rx] When activated by its ligand, EGFR undergoes a conformational change and dimerization to form homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization of EGFR activates the intracellular tyrosine kinase region of EGFR and promotes autophosphorylation, initiating a series of downstream signaling cascades, including cell differentiation, proliferation, migration, angiogenesis, and apoptosis. This EGFR signaling pathway is often dysregulated in cancer cells, leading to aberrant cell growth and enhanced cell survival.[rx]

Cetuximab is a monoclonal antibody that binds specifically to the EGFR on both normal and tumor cells to competitively inhibit the binding of epidermal growth factor (EGF) and other ligands that are produced by normal and tumor tissue epithelial cells.[rx] Upon binding to domain III of EGFR – which is the binding site for its growth factor ligands – cetuximab prevents the receptor from adopting an extended conformation and thereby inhibits EGFR activation, as well as phosphorylation and activation of receptor-associated kinases (MAPK, PI3K/Akt, Jak/Stat).[rx,rx] Inhibition of the EGFR signaling pathway ultimately leads to inhibition of cell cycle progression, cell survival pathways, and tumor cell motility and invasion.[rx] Cetuximab also induces cell apoptosis and decreases matrix metalloproteinase and vascular endothelial growth factor (VEGF) production.[rx,rx] In vitro, cetuximab was shown to inhibit tumor angiogenesis.[rx] Binding of cetuximab to EGFR also results in the internalization of the antibody-receptor complex, leading to an overall downregulation of EGFR expression.[rx]

K-ras is a small G-protein downstream of EGFR that plays an important role in promoting the EGFR signaling cascade: in some malignant cells, K-ras can acquire activating mutations in exon 2 [rx] and thus be continuously active regardless of EGFR regulation.[rx] Since mutant Ras proteins can isolate the pathway from the effect of EGFR, K-Ras mutations can render EGFR inhibitors like cetuximab ineffective in exerting anti-tumor effects.[rx,rx] Cetuximab is thus only limited in its use for K-Ras wild-type, EGFR-expressing cancers.[rx]

Indications

  • Cetuximab is indicated for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy. It is indicated for treating a recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil. It is indicated for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy.[rx]
  • Cetuximab is also indicated for K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test in combination with FOLFIRI, a chemotherapy combination that includes leucovorin, fluorouracil, and irinotecan; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.[rx]
  • Additionally, cetuximab is also indicated for metastatic colorectal cancer that is BRAF V600E mutation-positive (as determined by an FDA-approved test) in combination with encorafenib but only after prior therapy.[rx]
  • Cetuximab is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown.[rx]
  • Locally Advanced Squamous Cell Carcinomas of the Head and Neck (SCCHN)
  • Metastatic Colorectal Cancer (CRC)
  • Metastatic Squamous Cell Carcinoma of the Head and Neck (HNSCC)
  • Regionally Advanced Squamous Cell Carcinoma of the Head and Neck
  • Recurrent Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Contraindication

  • low amount of magnesium in the blood
  • low amount of calcium in the blood
  • low amount of potassium in the blood
  • coronary artery disease
  • chronic heart failure
  • a type of inflammation of the lung called interstitial pneumonitis
  • a condition where there is a formation of fibrous tissue in the lung called pulmonary fibrosis
  • a bacterial skin infection
  • a skin rash resembling acne
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 2 mg/mL

Colorectal Cancer

As a Single-Agent or in Combination with Irinotecan or FOLFIRI (irinotecan, fluorouracil, leucovorin)

  • Administer weekly or biweekly as below; complete cetuximab administration 1 hour prior to irinotecan or FOLFIRI; continue treatment until disease progression or unacceptable toxicity
  • WEEKLY: Initial Dose: 400 mg/m2 IV over 120 minutes; Maintenance Dose: 250 mg/m2 IV over 60 minutes once a week
  • BIWEEKLY: 500 mg/m2 IV over 120 minutes every 2 weeks

In Combination with Encorafenib:

  • Initial Dose: 400 mg/m2 IV over 120 minutes
  • Maintenance Dose: 250 mg/m2 IV over 60 minutes once a week until disease progression or unacceptable toxicity
  • Patient selection for treatment requires testing for the presence of K-Ras or BRAF V600E mutations; information on FDA-approved tests is available at: https://www.fda.gov/CompanionDiagnostics
  • This drug is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown
  • Premedicate with an H1 antagonist IV 30 to 60 minutes prior to the first dose or subsequent doses as deemed necessary.
  • Dose modifications may be necessary for adverse reactions (See Dosage Adjustment Section)

Colorectal Cancer:
For the treatment of K-Ras wild-type, epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by an FDA-approved test:

  • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for first-line treatment
  • In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy
  • As a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan.
  • For the treatment of mCRC in combination with sorafenib for patients with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy

Head and Neck Cancer

  • In Combination with Radiation Therapy: Complete IV administration 1 hour prior to radiation therapy
  • Initial dose: 400 mg/m2 IV over 120 minutes administered 1 week prior to initiating a course of radiation therapy
  • Maintenance dose: 250 mg/m2 IV over 60 minutes once a week for the duration of radiation therapy (6 to 7 weeks)

As a Single-Agent or In Combination with Platinum-Based Therapy and Fluorouracil:

  • Administer weekly or biweekly as below; complete cetuximab administration 1 hour prior to platinum-based therapy with fluorouracil; continue treatment until disease progression or unacceptable toxicity
  • WEEKLY: Initial dose: 400 mg/m2 IV over 120 minutes; Maintenance dose: 250 mg/m2 IV over 60 minutes once a week
  • BIWEEKLY: 500 mg/m2 IV over 120 minutes every 2 weeks
  • Premedicate with an H1 antagonist IV 30 to 60 minutes prior to the first dose or subsequent doses as deemed necessary.
  • Dose modifications may be necessary for adverse reactions (See Dosage Adjustment Section).

Squamous Cell Carcinoma of the Head and Neck (SCCHN):

  • In combination with radiation therapy for the initial treatment of locally or regionally advanced SCCHN
  • In combination with platinum-based therapy with fluorouracil for the first-line treatment of patients with a recurrent locoregional disease or metastatic SCCHN
  • As a single agent for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed

Dose Adjustments

Dose Modifications for Adverse Reactions
INFUSION REACTIONS:

  • Grade 1 or 2: Reduce infusion rate by 50%.
  • Grade 3 or 4: Immediately and permanently discontinue therapy.

DERMATOLOGIC TOXICITIES AND INFECTIOUS SEQUELAE (e.g., acneiform rash, mucocutaneous disease):

  • First occurrence Grade 3 or 4: Delay infusion 1 to 2 weeks; if improvement, continue at 250 mg/m2; if no improvement, discontinue therapy.
  • Second occurrence Grade 3 or 4: Delay infusion 1 to 2 weeks; if improvement, continue at 200 mg/m2; if no improvement, discontinue therapy.
  • Third occurrence Grade 3 or 4: Delay infusion 1 to 2 weeks; if improvement, continue at 150 mg/m2; if no improvement, discontinue therapy.
  • Fourth occurrence Grade 3 or 4: Discontinue therapy.

PULMONARY TOXICITY:

  • Acute onset or worsening pulmonary symptoms: Delay infusion for 1 to 2 weeks; if improvement, continue at the dose that was being administered at the time of occurrence; if no improvement in 2 weeks or interstitial lung disease (ILD) is confirmed, discontinue therapy.
  • For the dosage or recommended dose modifications of concomitantly used chemotherapeutic agents, refer to the product information for these products.
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US BOXED WARNINGS: INFUSION REACTIONS and CARDIOPULMONARY ARREST

  • Infusion Reactions: This drug can cause serious and fatal infusion reactions. Immediately interrupt and permanently discontinue therapy for serious infusion reactions.
  • Cardiopulmonary Arrest: Cardiopulmonary arrest or sudden death has occurred in patients with squamous cell carcinoma of the head and neck receiving this drug with radiation therapy or with platinum-based therapy and fluorouracil. Monitor serum electrolytes including serum magnesium, potassium, and calcium, during and after administration.

Administration advice:

  • Administer via infusion pump or syringe pump at an infusion rate not to exceed 10 mg/min; do not administer as an IV push or bolus
  • Complete cetuximab administration 1 hour prior to platinum-based therapy with fluorouracil, irinotecan or FOLFIRI
  • Administer through a low protein binding 0.22-microliter in-line filter
  • Administered under the supervision of specialists with experience in prescribing antineoplastic agents, and in a setting where resuscitation equipment is available; see Dosage Adjustments for dose modifications based on infusion reactions
  • Premedicate with a histamine-1 receptor antagonist IV 30 to 60 minutes prior to infusion
  • A one-hour observation period is recommended following the infusion; longer observation periods may be required in patients who experience reactions.

Preparation techniques:

  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration; the solution should be clear and colorless and may contain a small amount of easily visible, white, amorphous, cetuximab particulates; do not use if the solution is discolored, cloudy, or contains foreign particulate matter (an increase in the particulate formation may occur at temperatures at or below 0C (32F)
  • Do not shake or dilute

Side Effects

The Most Common

  • acne-like rash
  • dry or cracking skin
  • itching
  • swelling, pain, or changes in the fingernails or toenails
  • red, watery, or itchy eye(s)
  • red or swollen eyelid(s)
  • pain or burning sensation in eye(s)
  • sensitivity of eyes to light
  • hair loss
  • increased hair growth on head, face, eyelashes, or chest
  • chapped lips
  • headache
  • tiredness
  • weakness
  • confusion
  • numbness, tingling, pain, or burning in arms or legs
  • dry mouth
  • sores on lips, mouth, or throat
  • sore throat
  • nausea
  • vomiting
  • change in the ability to taste food
  • loss of appetite
  • weight loss
  • constipation
  • diarrhea
  • heartburn
  • joint pain
  • bone pain

Further severe infusion reactions include but are not limited to: fevers, chills, rigors, urticaria, itchiness, rash, hypotension, nausea, vomiting, headache, shortness of breath, wheezing, angioedema, dizziness, anaphylaxis, and cardiac arrest. Other common side effects include photosensitivity, hypomagnesemia due to magnesium wasting, and less commonly pulmonary and cardiac toxicity

More Common

  • pain, redness, or swelling at the place the medication was injected
  • loss of vision
  • blistering, peeling or shedding skin
  • red, swollen, or infected skin
  • new or worsening cough, shortness of breath, or chest pain
  • eye pain or redness, puffy eyelids, drainage or crusting in your eyes, vision problems, or increased sensitivity to light;
  • a new or worsening cough, chest pain, or shortness of breath;
  • an acne-like skin rash or any severe skin rash;
  • redness or crusting around your hair follicles;
  • redness, warmth, or puffiness under your skin;
  • slow heartbeats, weak pulse, fainting, slow breathing (breathing may stop);
  • blisters or ulcers in your mouth, red or swollen gums, trouble swallowing;
  • low white blood cell counts–fever, mouth sores, skin sores, sore throat, cough, trouble breathing; or
  • signs of an electrolyte imbalance–increased thirst or urination, constipation, muscle pain or weakness, leg cramps, numbness or tingling, feeling jittery, irregular heartbeats, fluttering in your chest, or a choking feeling.
  • changes in your fingernails or toenails;
  • dry, cracked, or swollen skin;
  • headache;
  • diarrhea; or
  • infection.
  • itching or rash;

Rare

  • lower back or side pain
  • nausea
  • painful or difficult urination
  • pale skin
  • rapid weight gain
  • runny nose
  • severe dry skin
  • skin rash
  • tender, swollen glands in the neck
  • tightness in the chest
  • signs of anemia (low red blood cells; e.g., dizziness,  pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of dehydration (e.g., decreased urine, dry skin, dry and sticky mouth, sleepiness, dizziness, headache, thirst, confusion)
  • signs of electrolyte imbalance (e.g., muscle pain or cramps, weakness, irregular heartbeat, lack of coordination, thirst, confusion)
  • signs of fluid build-up around the lungs (e.g., chest pain, cough, hiccups, rapid breathing)
  • signs of heart problems (e.g., fast, irregular heartbeat or pulse, chest pain, difficulty breathing)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of kidney problems (e.g., increased urination at night, decreased urine production, blood in the urine)
  • symptoms of a urinary tract infection (e.g. pain when urinating, urinating more often than usual, low back or flank pain)
  • vision problems (e.g., redness, blurred vision, eye pain, severe dry eye)
  • infusion-related reactions (e.g., fever, chills, rigors, difficulty breathing, itching, severe dizziness)
  • signs of heart attack (e.g., sudden chest pain or pain radiating to back, down arm, jaw; sensation of tightness or pressure of the chest; nausea; vomiting; sweating; anxiety)signs of meningitis not caused by infection (e.g., headache [severe], throbbing, or with stiff neck or back)
  • signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
  • signs of a severe skin reaction (e.g., blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort)

Drug Interaction

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Pregnancy and Lactation

FDA Pregnancy Category C

Pregnancy

It is not known if cetuximab causes harm to the developing baby if it is used by the mother during pregnancy. This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately. A reliable form of birth control should be used by both males and females during and for 6 months after the last dose of cetuximab.

Breast-feeding

It is not known if cetuximab passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Breastfeeding should be stopped while you are being treated with cetuximab and should not be restarted until at least 60 days after the last dose of medication.

How should this medicine be used?

Cetuximab comes as a solution (liquid) to be infused (injected slowly) into a vein. Cetuximab is given by a doctor or nurse in a medical office or infusion center. The first time you receive cetuximab, it will be infused over a period of 2 hours, then the following doses will be infused over 1 hour. Cetuximab is usually given every 1 to 2 weeks for as long as your doctor recommends that you receive treatment.

Your doctor may need to slow down your infusion, reduce your dosage, delay or stop your treatment, or treat you with other medications if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with cetuximab.

What special precautions should I follow?

Before receiving treatment with cetuximab,

  • tell your doctor and pharmacist if you are allergic to cetuximab, any other medications, red meat, or galactose, or to any of the ingredients in cetuximab. Ask your pharmacist for a list of the ingredients. Also, tell your doctor and pharmacist if you have had or have had tick bites.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have or have ever had heart disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You will have to take a pregnancy test before starting treatment. You should not become pregnant during your treatment with cetuximab and for at least 2 months after your final dose. Talk to your doctor about birth control methods that you can use during your treatment. If you become pregnant while you are receiving cetuximab, call your doctor.
  • tell your doctor if you are breastfeeding. Your doctor may tell you not to breastfeed during your treatment and for 2 months after your final dose.
  • you should know that this medication may decrease fertility in women. Talk to your doctor about the risks of receiving cetuximab.
  • plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, a hat, sunglasses, and sunscreen during your treatment with cetuximab and for 2 months after your treatment.

References