Erbitux (Cetuximab) - Investigational Biological Cancer Therapy

Developed by the US biopharmaceutical company ImClone Systems, Erbitux is a chimaeric monoclonal antibody (MAb) which is specific for the epidermal growth factor receptor (EGFR). One of several new cancer biotherapies, Erbitux is indicated for the treatment of metastatic colorectal cancer and now locally advanced cancer of the head and neck.

Regulatory approval for the use of Erbitux in metastatic colorectal cancer was obtained in 2004. It is now available in all major markets. In the US it is approved for use in conjunction with irinotecan in irinotecan-refractory metastatic colorectal cancer or as single agent therapy in patients with EGFR-expressing colorectal tumours who are intolerant to irinotecan-based chemotherapy. In Europe it is licensed for use in combination with irinotecan after failure of irinotecan-containing chemotherapy (second-line therapy).

At the end of 2005, regulatory authorities in Switzerland (Swissmedic) granted marketing authorisation for the use of Erbitux in combination with radiotherapy as a treatment for locally advanced squamous cell carcinoma of the head and neck in untreated patients. This marks the first approval for this additional indication. A positive outcome from the EMEA could see Europe-wide use of Erbitux as an adjunctive treatment for head and neck cancer.

Bristol-Myers Squibb has marketing rights to Erbitux in North America, while Merck KGaA has rights to the drug outside the US and Canada as well as joint rights with Bristol-Myers Squibb in Japan.

INHIBITION OF EGFR

Over expression of EGFR is common in many solid tumours, such as colorectal and lung carcinomas as well as cancers of the head and neck. It correlates with increased metastasis, decreased survival and a poor prognosis. EGFR protects malignant tumour cells from the cytotoxic effects of chemotherapy and radiotherapy, making these treatments less effective. Erbitux binds to the extracellular domain of EGFR on the tumour cell, thereby inhibiting receptor-associated tyrosine kinase. This inhibition blocks the intracellular pathways associated with tumour cell proliferation, so preventing tumour growth and dissemination as well as inducing cell death (apoptosis).

By interfering with cell signalling pathways involved in cell proliferation, inhibition of EGFR-associated tyrosine kinase represents a novel approach to the treatment of solid tumours. Erbitux is one of several cancer drugs that target EGFR.

SURVIVAL BENEFIT SEEN IN HEAD AND NECK CANCER

The efficacy and safety of Erbitux has been investigated in clinical trials in patients with advanced cancers of the head and neck, for whom treatment options have been relatively limited and prognosis often poor. Head and neck cancer includes cancers of the tongue, mouth, pharynx and larynx. Although less common than colorectal cancer, they still cause over 10,000 deaths a year in the US and more than three times as many in Europe. Prevalence tends to be highest where rates of smoking and alcohol consumption are high.

Data presented at ASCO 2004 showed that when used in combination with radiotherapy, Erbitux improved survival in patients with locally advanced head and neck cancer. The 424-patient phase III trial showed that median survival was increased to 54 months in the combination treatment arm compared with 28 months for radiation alone (p=0.02). Two-year survival rates were 62% for combination therapy and 55% for radiation alone. Combination therapy also proved significantly more effective in controlling the disease (locoregional control) than radiation alone (p=0.02). These data provided the basis for regulatory approval by Swissmedic.

Oral mucositis is a debilitating side-effect of radiotherapy, which can be exacerbated when radiotherapy is combined with cytotoxic chemotherapy. In the Erbitux head and neck cancer trial, there was no increase in the rate of mucositis between the combination and control treatment arms (55% vs. 52% respectively). Consistent with other clinical trials there was a higher incidence of acne-like skin rash among patients receiving Erbitux. This is a common side effect of EGFR-inhibitors and may be associated with a good response to therapy. The rash generally disappears following cessation of treatment.

These encouraging results, demonstrating for the first time a survival benefit with Erbitux, bode well for expanded use of this new anti-cancer agent which is gaining acceptance as a treatment for metastatic colorectal cancer.

NEW COMMERCIAL MANUFACTURING FACILITY FOR ERBITUX IN THE US

In July 2002, ImClone Systems secured FDA approval for a new commercial manufacturing facility for production of Erbitux. In Europe, Merck KGaA had planned to produce Erbitux and a second investigational anti-EGFR MAb, EM7200, at a new protein drug plant in Jena in the eastern part of Germany. This programme has been put on hold and construction of the new facility will not go ahead. Together with ImClone, Boehringer Ingelheim will undertake production of Erbitux for clinical use.

MARKETING COMMENTARY

Despite its difficult path to market following FDA rejection of the early phase II data in colorectal cancer, Erbitux finally secured approval as a treatment for metastatic colorectal cancer in both the US and Europe in 2004. Approval has now been extended to its use in locally advanced squamous cell carcinoma of the head and neck, albeit only in Switzerland to date. Nonetheless, in this difficult-to-treat cancer, Erbitux offers the prospect of improved disease control and extended survival when combined with radiotherapy.

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