Phase II Data on Cetuximab (Erbitux™)

Abstract & Commentary

Synopsis: In a phase II trial of cetuximab (Erbitux™) given once weekly to patients with advanced colorectal cancer who had failed prior irinotecan treatment, a modest response rate was observed and the toxicity profile was shown to be manageable.

Source: Saltz LB, et al. J Clin Oncol. 2004;22: 1201-1208.

In 2003, colorectal cancer was the fourth most common type of cancer in the United States, and the second leading cause of cancer death.1 The current treatment for metastatic disease consists of the use of chemotherapy with the antineoplastic agents fluorouracil (FU), irinotecan and oxaliplatin. However, once a patient’s cancer becomes unresponsive to these agents, there are no effective treatment options. As a result, metastatic colorectal cancer is ultimately fatal and new therapies for this disease are needed. The epidermal growth factor receptor (EGFr) is a transmembrane glycoprotein that is expressed by many tumor types, including colorectal cancer, and is therefore a potential target for anticancer treatment. Upon ligand binding, the intracellular tyrosine kinase is activated, triggering many signaling reactions that control cell growth and survival. Cetuximab is an antibody directed against the ligand-binding domain of the EGFr. Previous studies have demonstrated the ability of this agent block the activation of the EGFr tyrosine kinase by EGF or TGF-a, thereby inhibiting cellular proliferation. Additionally, it has been shown that cetuximab has significantly better activity when administered in conjunction with inactive or minimally active doses of cytotoxic chemotherapy. Saltz and colleagues from the Memorial Sloan-Kettering Cancer Center conducted a Phase II multi site clinical trial with 57 eligible patients. All patients had chemotherapy-refractory colorectal cancer and tumors that expressed EGFr. Additionally, eligible patients had to have previously been treated with and failed irinotecan therapy. All patients were administered cetuximab weekly (400 mg/m2 the first week, 250 mg/m2 each additional week) by intravenous infusion for a median of 6.4 weeks (range, 1-67 weeks) and were subsequently analyzed for antitumor activity and drug toxicity.

Five (9%; 95% confidence interval [CI], 3-19%) of the 57 treated patients obtained a partial response and 21 additional patients had either a minor response (tumor reduction between 25% and 49%) or stable disease (either growth or shrinkage of less than 25%). There was no apparent correlation between response and the observed degree of EGFr expression. The most common adverse events were acne-like skin reactions seen in 86% of patients. Of these, 18% (n = 10) were grade 3 but there were no grade 4 reactions observed. There appeared to be a correlation between the presence and severity of the rash and survival. Patients with skin rash of any grade had a superior survival to patients with no skin rash. Other adverse events included asthenia, fatigue, malaise or lethargy (56% with any grade; 18% with grade 3). The median survival from the time of initiation of cetuximab was 6.4 months.

Comment by William B. Ershler, MD

The data presented in this report have supported the advancement of cetuximab to practicing oncologists. The response rates were modest by all accounts, yet, all the patients treated had advanced disease without available alternative agents with any likelihood of success. It has not been common practice to obtain an analysis of EGFr on colon cancer clinical specimens and it was of interest to note that there was a poor correlation of clinical response to the degree of EGFr expression in this series. Perhaps equivalent response rates will be observed in individuals who do not test positively at all, or other immunohistochemical or molecular techniques will become available that will more precisely predict clinical response.

Where cetuximab will be most effectively used in the treatment of colorectal cancer needs to be clarified. Currently, larger trials incorporating it with chemotherapy as first-line treatment for both the adjuvant setting and for metastatic disease are either underway or in the planning stages. Until such data is available, practicing oncologists may elect to use this new agent in the setting for which it has been FDA approved (ie, for those patients who have progressed on irinotecan therapy). For such patients, with, or without demonstrated EGFr, it would seem that single agent cetuximab offers a better chance for response than any other available agent.


1. Murray JA, et al. CA Cancer J Clin. 2003;53:5-36.

William B. Ershler, MD,INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.