Cetuximab alone or in combination with irinotecan effective against irinotecan-refractory colorectal cancer

Abstract

Results of a multicenter European trial indicate that cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer. The findings appear in The New England Journal of Medicine. Cetuximab is a monoclonal antibody that specifically blocks the epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells and that commonly appears on colorectal-cancer cells. EGFR, a member of the ErbB family of receptors, is relevant in colorectal cancer because expression or up-regulation of the EGFR gene occurs in 60% to 80% of cases. Moreover, studies show that expression of the gene is associated with poor survival. Dr. David Cunningham of Royal Marsden Hospital, London and Surrey, United Kingdom, and colleagues randomly assigned 329 patients whose disease had progressed during or within 3 months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan or cetuximab monotherapy. “Cetuximab (Erbitux, Merck, and Imclone Systems) is a chimeric IgG1 monoclonal antibody that binds to EGFR with high specificity and with a higher affinity than either epidermal growth factor or TGF-α, thus blocking ligand-induced phosphorylation of EGFR,” the report states. “In addition, cetuximab enhances the effects of irinotecan and radiotherapy in experimental systems.” In this trial, the addition of irinotecan to cetuximab monotherapy was permitted in patients whose disease progressed during the investigation. All patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. The authors state that the rate of response in the combination-therapy group was significantly higher than that of the monotherapy group (22.9% [95% confidence interval, 17.5%–29.1%] vs. 10.8% [95% confidence interval, 5.7%–18.1%], P = 0.007). Median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P < 0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P = 0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan. In an accompanying editorial Drs. Charles Erlichman, M.D., and Daniel J. Sargent, Ph.D. of the Mayo Clinic, Rochester, Minnesota, raise a number of issues. They say the trial “implicitly addressed the question of whether adding cetuximab to irinotecan resensitizes tumors that are refractory to irinotecan. In that sense, the findings clearly support the notion that interfering with EGFR signaling can overcome the resistance to irinotecan.” However, they add, “the appropriateness of the authors’ reporting methods warrants discussion. The primary end point of the trial was a tumor response, and the planned sample size was based not on a comparison of groups but on an estimation of the response rate to a specified level of precision. Thus, the trial could be best labeled as a randomized, phase 2 trial.” Based on the response rate, 10.8%, with a median time to progression of 1.5 months, the editorial also questions the magnitude of the benefit of cetuximab alone for patients who may not be able to tolerate the combination. “In essence, the current trial seems to validate the previously reported single-group studies of cetuximab alone and cetuximab plus irinotecan. For these reasons and others that have been well chronicled, the past 3 years have provided no mature data on cetuximab and irinotecan as first-line treatment or in combination with fluorouracil or fluorouracil-and-oxaliplatin regimens. Nonetheless, trials of cetuximab as a component of first-line treatment are ongoing, and the agent is about to be added to an ongoing trial of adjuvant therapy for colon cancer.” More details can be found in N Engl J Med 2004;351:337–345, 391–392.