• 22
    May
  • Pharmaceutical-Approval Update: Oncology

OncologyCetuximab (Erbitux™) for IV Use Only

Manufacturer: Imclone Systems, Inc./Bristol-Myers Squibb

Drug Class: Recombinant, human/mouse chimeric monoclonal antibody

Description: Cetuximab binds specifically to the extracellular domain of human epidermal growth factor receptor (EGFR). Produced in mammalian (murine myeloma) cell culture, cetuximab is composed of the fragment variable (Fv) regions of a murine anti-EGFR antibody with human immunoglobulin G1 (IgG1) heavy and kappa light-chain constant regions. Cetuximab binds to EGFR (HER1, c-ERB-1) on both normal and tumor cells and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands (i.e., transforming growth factor-a). The binding of cetuximab to EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibited cell growth, induced apoptosis, and decreased production of matrix metalloproteinase and vascular EGF.

EGFR, a transmembrane glycoprotein, is a member of a subfamily of type-1 receptor tyrosine kinases, including EGFR (HER1), HER2, HER3, and HER4. It is constitutively expressed in many normal epithelial tissues, such as the skin and hair follicles. Overexpression of EGFR is also detected in many human cancers, including those of the colon and rectum. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that overexpress EGFR. The addition of cetuximab to irinotecan (Camptosar®, Tirgan), another chemotherapeutic agent for colorectal cancer, or to irinotecan plus 5-fluorouracil (5-FU) in animal studies increased antitumor activity compared with chemotherapy alone. Indication: In combination with irinotecan, cetuximab is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma that is refractory to irinotecan-based chemotherapy. As a single agent, it is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are intolerant of irinotecan chemotherapy. There has been no clinical evidence linking improvement in disease-related symptoms or increased survival with cetuximab. Pharmacology: The efficacy and safety of cetuximab alone or in combination with irinotecan were studied in a randomized, controlled trial with 329 patients and in combination with irinotecan in 138 patients. All of the patients received both drugs. Cetuximab was further evaluated as a single agent in a third clinical trial involving 57 patients. Safety data from an additional 111 patients who received only cetuximab were also evaluated. All of the trials included patients with EGFR-expressing metastatic colorectal cancer whose disease had progressed after irinotecan therapy.
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For patients with tumors expressing EGFR and who no longer responded to treatment with irinotecan alone or combined with other chemotherapy drugs, the ce-tuximab/irinotecan combination shrank tumors in 22.9% of patients and delayed tumor growth by approximately 4.1 months. For patients who received cetuximab alone, the tumor response rate was 10.8% and tumor growth was delayed by 1.5 months.

Black-Box Warning

Infusion Reactions. Severe infusion reactions occurred in approximately 3% of patients, with rare fatal outcomes (fewer than 1 per 1,000 patients); approximately 90% of these reactions were associated with the first cetuximab infusion. These severe reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, or hoarseness), urticaria, and hypotension). If a severe reaction occurs, the infusion must be interrupted immediately and discontinued permanently.

Warnings

Pulmonary Toxicity. Interstitial lung disease was reported in three of 663 (fewer than 0.5%) patients with advanced colorectal cancer who were receiving cetuximab. Interstitial pneumonitis with noncardiogenic pulmonary edema resulting in death was reported in one case. Two patients had pre-existing fibrotic lung disease and experienced an acute exacerbation of their disease while they were receiving cetuximab/irinotecan. In the clinical investigational program, an additional case of interstitial pneumonitis was reported in a patient with head and neck cancer who received cetuximab and cisplatin (Platinol®, Bristol-Myers Squibb). In all reported cases, symptoms began to appear between the fourth and 11th doses of treatment.

In the event of acute onset or worsening pulmonary symptoms, cetuximab should be discontinued. If interstitial lung disease is confirmed, cetuximab should be discontinued and appropriate treatment should be instituted.
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Dermatological Toxicity. In cynomologus monkeys, cetuximab affected the skin when administered at 0.4 to 4 times the weekly exposure; reactions included inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passages, esophagus, and tongue were similarly affected, and degenerative changes occurred in the renal tubular epithelium. Beginning at about 13 weeks of treatment, 50% of the animals receiving the highest dose died of sepsis.

In clinical studies, dermatological toxicities included acneiform rash, skin drying and fissuring, and inflammatory and infectious sequelae (blepharitis, cheilitis, cellulitis, and cysts). In patients with advanced colorectal cancer, acneiform rash was reported in 88% of all treated patients and was severe (grade 3 or 4) in 12% of these patients.

Staphylococcus aureus-based sepsis and abscesses occurred following the development of severe dermatological toxicities. Patients with rashes should be monitored for the development of inflammation or infection, and these symptoms should be treated promptly.

Precautions: Patients must undergo testing for the presence of EGFR expression. The Food and Drug Administration (FDA) has approved a test kit (Dako Cytomation California, Inc.) for analyzing a colon tissue sample. The kit enables the physician to detect a protein (HER1) in the body that stimulates cancerous tissue cell growth. The presence of this protein indicates that a patient is eligible for colon cancer treatment with cetuximab.
Drug Interactions: There is no pharmacokinetic interaction between cetuximab in combination with irinotecan. Immunogenicity: Potential immunogenic responses to cetuximab must be evaluated in each patient because of the proteinaceous nature of the biological agent. Conclusion: Cetuximab is the first monoclonal antibody approved for patients with advanced colorectal cancer that has spread to other parts of the body. It is indicated as an IV combination treatment with irinotecan or alone if patients do not tolerate irinotecan. It was approved under the FDA’s accelerated program to treat cancer and other serious or life-threatening diseases based on early evidence of a product’s effectiveness. Although cetuximab did not extend patients’ lives, it did shrink tumors in some patients and delay tumor growth, especially when used as a combination treatment.

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