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Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-refractory Metastatic Colorectal Cancer

Background: One of the many established treatments for metastatic colorectal cancer includes the drug irinotecan. Many cases of this type of cancer are refractory to treatment with this drug, which leaves few options for the refractory cancer patient.

Objective: The purpose of this study was to compare the efficacy of cetuximab in monotherapy with that of cetuximab combined with irinotecan in irinotecan-refractory metastatic colorectal cancer.

Methods: This study was an open-labeled, randomized trial with parallel treatment groups. Patients were enrolled from 56 centers in 11 European countries, with a final participant number of 329 at the beginning of the trial. Patients were considered eligible if they met certain inclusion criteria: age > 18 years, stage IV colorectal cancer, Karnofsky score > 60, hemoglobin > 9 g/dL; neutrophils > 1,500/mm3, platelets > 100,000/mm3; and stable renal and hepatic function. Patients also had received one of several pre-study irinotecan regimens for at least six weeks, with documented progression of disease during the regimen, or within three months thereafter. At least one unidimensionally measurable lesion was required, as was immunohistochemical evidence of EGFR expression. Exclusion criteria were anyone who did not meet the inclusion criteria. Patients were randomly assigned to either the cetuximab/irinotecan combination group or the cetuximab alone group in a 2:1 ratio. Randomization was stratified by Karnofsky status, treatment center, and prior use of oxaliplatin. 218 patients were randomized to the cetuximab/irinotecan combination group, and 111 patients to the cetuximab monotherapy group. An independent review committee, blinded to the treatment assignment, assessed disease progression during the pre-study irinotecan regimen, and monitored response and time to disease progression during the study. This study had a power of 80% with a significance level of 0.05 with the two-sided Fisher’s exact test. Intent-to-treat analysis was used. Irinotecan could be added to therapy for patients in the monotherapy group who experienced disease progression.

Results: The primary end-point in this study was the rate of confirmed radiologic tumor response, while secondary end-points included the time to progression; duration of response; overall survival time; and the incidence of adverse effects. The overall response rate in the intention-to-treat population was 22.9% (CI=95%,; 17.5-29.1%) in the combination therapy group, and 10.8% (CI=95%; 5.7-18.1%) in the monotherapy group (p=0.007). Disease control was achieved in 55.5% of patients in the combination group, and 32.4% in the monotherapy group (p<0.001). For patients who had received oxaliplatin previously, the response rate was 22.2% in the combination group, and 8.5% in the monotherapy group (p=0.01). Response rates were higher in patients with skin reactions due to cetuximab therapy than in those without skin reactions, with 25.8% vs. 6.3% in the combination group, and 13.0% vs. 0% in the monotherapy group (p=0.005). The hazard ratio for disease progression in the combination group was 0.54 (CI=95%; 0.42-0.71), (p<0.001). Patients remaining free of symptoms at 3 and 6 months were 54% (CI=95%; 47-61%) and 30% (CI=95%; 23-37%) respectively for the combination group, and 28% (CI=95%; 19-37%) and 8% (CI=95%; 1-14%) respectively for the monotherapy group. Hazard ratio for death with combination therapy as compared with monotherapy was 0.91 (CI=95%; 0.68-1.21), (p=0.48). Survival rates at 6 and 12 months were 66% (CI=95%; 60-72%) and 29% (CI=95%; 22-37%) respectively for the combination therapy, and 58% (CI=95%; 49-67%) and 32% (CI=95%; 23-41%) respectively in the monotherapy group. Adverse events included 4 anaphylactic reactions, as well as an acne-like rash, diarrhea, neutropenia, anemia, thrombocytopenia, asthenia, nausea & vomiting, abdominal pain, stomatitis, dyspnea, and fever. The authors concluded that cetuximab alone, or in combination with irinotecan had clinical activity in irinotecan-refractory colorectal cancer. This confirmed the results of earlier Phase II studies.

Strengths: Appropriate statistical analyses were used to evaluate the study results. An independent blinded review committee, assessed disease progression during the pre-study irinotecan regimen, and monitored response and time to progression during the study. Randomization of the patients was conducted by an independent randomization service. Inclusion/exclusion criteria seemed appropriate.

Weaknesses: One major weakness of this study was the fact that it was an open-labeled trial, which has the potential for bias. The study was funded and statistically analyzed by Merck, manufacturer of cetuximab, and many of the investigators had ties to Merck, which may also introduce bias. Representatives from Merck also helped design the trial and collect the data. Type II error could have been introduced in some of the sub-analyses performed with lower numbers of patients. Because the study was multicenter in several countries, different regimens of irinotecan were used, which could have affected the results seen in the study. The results were not stratified according to the different doses of irinotecan used.

Conclusion: The results of this study show the combination of irinotecan and cetuximab had a significantly higher response rate, and a significantly longer time to progression than monotherapy with cetuximab. This suggests that the cetuximab/irinotecan combination should be the preferred treatment for patients with irinotecan-refractory colorectal cancer. Adverse effects were no more severe than those expected when using irinotecan as a second-line therapy. It should be noted that EGFR expression is not a predictor of responsiveness in all types of cancer, so further study is needed to find out if patients without EGFR expression would benefit from cetuximab. For the meantime, however, cetuximab, either alone or in combination with irinotecan, appears to be a source of hope for patients with irinotecan-refractory colorectal cancer.

Cunningham D, Humblet Y, Siena S, Khayat D, et al, Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:4; July 22, 2004; pp 337-345.

Joseph H. Grimes, PharmD. Candidate