Cetuximab Improves Survival in Patients With Advanced Colorectal Cancer

November 15, 2007 — Cetuximab can improve overall and progression-free survival and preserves quality of life in patients with advanced colorectal cancer whose disease has failed other treatments. According to research reported in the November 15 issue of the New England Journal of Medicine, the addition of cetuximab to supportive care resulted in longer overall survival vs supportive care alone.
"This is the first time a single-agent biologically targeted therapy has been shown to improve survival in patients with advanced colorectal cancer," lead author Derek J. Jonker, MD, an assistant professor of medicine at the University of Ottawa, Ontario, Canada, told Medscape Oncology. "Another biologically targeted therapy, the anti-VEGF [vascular endothelial growth factor] antibody bevacizumab, has improved survival only when combined with chemotherapy, and is relatively ineffective on its own."
The epidermal growth factor receptor (EGFR), which participates in cellular signaling pathways, is often upregulated in colorectal cancer. Cetuximab is a chimeric IgG1 [immunoglobulin G1] monoclonal antibody that binds to the extracellular domain of EGFR, and studies have shown that it has activity in colorectal cancer. It seems to be able to reverse drug resistance in patients with colorectal cancer when it is administered with irinotecan.
"Cetuximab has been studied in combination with other chemotherapy agents and also in smaller studies in combination with the anti-VEGF antibody bevacizumab," said Dr. Jonker. "There is consistent evidence that the combination of cetuximab plus irinotecan results in a better progression-free survival than either drug given on its own."
"The anti-EGFR antibody panitumumab has been shown to improve progression-free survival, but has not demonstrated improved overall survival or quality of life," he added. "Single-agent cetuximab has achieved something important, which is an improvement in overall survival while better preserving quality of life compared to best supportive care alone."
In a collaborative effort by the National Cancer Institute of Canada Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group, Dr. Jonker and colleagues evaluated the effect of cetuximab on survival and quality of life in patients with advanced colorectal cancer. They randomized 572 patients with colorectal cancer expressing immunohistochemically detectable EGFR to either cetuximab with best supportive care (n = 287) or best supportive care alone (n = 285). All patients in the cohort had either been previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin or had contraindications to therapy with these agents.
The median duration of cetuximab treatment was 8.1 weeks, and median follow-up time was 14.6 months. At the time of the analysis, 456 patients had died (222 in the cetuximab group and 234 in the supportive-care group), and all except 6 had died of colorectal cancer.
Cetuximab Improved Survival
The researchers observed that combining cetuximab to supportive care resulted in longer overall survival vs supportive care alone. The median length of survival was 6.1 months for patients who received cetuximab and 4.6 months for those in the supportive-care group. The proportions of patients surviving at 6 and 12 months were 50% and 21%, respectively, in the cetuximab group vs 33% and 16% for the supportive-care group. The difference between the 2 groups remained statistically significant after adjustment for protocol-specified potential prognostic factors.
A planned subgroup analysis showed no significant differences in the relative benefit of cetuximab across subgroups, but an unplanned analysis that excluded all patients who died within 28 days after the beginning of the study period showed a strong correlation in the grade of rash among patients receiving cetuximab and overall survival. In patients who had no rash, the median survival was 2.6 months vs 4.8 months in patients with a grade 1 rash and 8.4 months in patients with a grade 2 rash.
The study authors also noted that among patients receiving cetuximab, 23 (8.0%) experienced a partial response vs none in the supportive-care group. Stable disease was observed in 90 (31.4%) patients who received cetuximab vs 31 (10.9%) in the supportive-care group.
Cetuximab therapy also seemed to improve quality of life. When compared with supportive care alone, cetuximab treatment was associated with a lower rate of deteriorating physical function at 8 weeks by the Wilcoxon test (mean change score, –3.9 vs –8.6) and also at 16 weeks (mean change score, –5.9 vs –12.5). Patients treated with cetuximab also showed less deterioration in global health status at 8 weeks (mean change score, –0.5 vs –7.1) and 16 weeks (mean change score, –3.6 vs –15.2) vs those receiving supportive care alone.
"Cetuximab is now established as an important part of the management of patients with advanced colorectal cancer," Dr. Jonker explained. "In patients for whom chemotherapy is no longer effective, cetuximab can improve survival while better preserving quality of life compared to best supportive care alone."
However, he pointed out that not every patient will benefit from cetuximab therapy, and the next challenge that clinicians face, which is already being addressed, is to find a means of identifying which patients benefit most from cetuximab. "Patients with tumors that express the 'wild-type' or nonmutated KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog] gene appear to be the population who benefit most from anti-EGFR antibodies," he said. "Selecting patients on the basis of the wild-type KRAS is likely to significantly augment the survival benefit seen with cetuximab therapy. These studies are underway."
This study was supported by the National Cancer Institute of Canada, ImClone Systems, and Bristol-Myers Squibb, the maker of cetuximab. Some of the study authors have disclosed various financial relationships with the National Cancer Institute of Canada Clinical Trials Group, Bristol-Myers Squibb, and Amgen Canada. One of the study authors is an employee of Bristol-Myers Squibb. The remaining study authors have disclosed no relevant financial relationships.
N Engl J Med. 2007; 357:2040-2048.