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Survival in patients with metastatic colorectal cancer has improved steadily during the past decade with the advent of new chemotherapeutic and biologic agents. A 2-year median survival time has been achieved, with second- and even third-line chemotherapy defined as standards of care. Agents that target the epidermal growth factor receptor (EGFR) represent new additions to the chemotherapy armamentarium against colorectal cancer. Monoclonal antibodies that block EGFR are active as single agents and, when combined with irinotecan (Camptosar)-based chemotherapy, also help overcome resistance to irinotecan. Although cetuximab (Erbitux) and panitumumab (Vectabix) are used in patients with refractory colorectal cancer, such EGFR-targeted agents have not been shown to confer a survival benefit in patients with advanced disease.
The Canadian and Australasian Clinical Trials Group now reports the results of a partially industry-supported randomized trial involving 572 patients who had colorectal cancer that was refractory to conventional chemotherapy and whose tumors overexpressed EGFR (demonstrated by immunohistochemistry). Treatment with cetuximab (400 mg/m2 bolus, followed by 250 mg/m2 weekly) was compared with best supportive care. The primary endpoint was 1-year overall survival. Treatment arms were balanced for performance status, age, sex, colon or rectal primary cancer, previous radiotherapy, and extent of previous chemotherapy.
A significant overall survival benefit was observed for treatment with cetuximab compared with supportive care alone (hazard ratio, 0.77; 95% confidence interval, 0.64–0.92; P=0.0005); a significantly higher rate of progression-free survival was noted with cetuximab (HR, 0.68; 95% CI, 0.57–0.80; P<0.001). Median overall survival was 6.1 months in the cetuximab arm and 4.6 months in the supportive-care arm. Eight percent of patients in the cetuximab group achieved partial responses (vs. none in the supportive-care group), and disease was stable in 31.4% of the cetuximab group, compared with 10.9% of the supportive-care group. Quality of life, as measured by a slower decline in physical functioning and higher global health scores, also was significantly better in the cetuximab arm than in the supportive-care arm (P<0.05). Adverse events occurred with similar frequency in the two groups, except for non-neutropenic infections, skin rashes, infusion reactions, and hypomagnesemia, which occurred more commonly in the cetuximab group.
Jonker DJ et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007 Nov 15; 357:2040.
Comment
These researchers are the first to demonstrate a survival benefit for advanced colorectal cancer patients after treatment with EGFR-targeted therapy. Previously reported trials of cetuximab and panitumumab as single agents, as well as cetuximab in combination with irinotecan, have shown benefits in response rates and progression-free survival, but not significant lengthening of overall survival, mainly because earlier trial designs permitted patients to cross over to EGFR-targeted agents when disease progression occurred. The current trial design did not permit crossing over and, therefore, clearly demonstrated a survival benefit for cetuximab over supportive care alone. The results of this trial will promote interest in EGFR-targeted therapy both as a first-line treatment for advanced disease and in adjuvant or curative settings.