Cetuximab Improves Overall Survival In Advanced Colorectal Cancer
- Wednesday, April 18, 2007, 14:07
- Cancer, GastroIntestinal
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Cetuximab (Erbitux), a monoclonal antibody which targets the epidermal growth factor receptor (EGFR), significantly improved overall survival in patients with advanced colorectal cancer, according to results from a major study reported at the 2007 Annual Meeting of the American Association for Cancer Research (14-18 April, 2007; Los Angeles, USA).
The CO.17 trial included 572 patients with advanced colorectal cancer whose disease was no longer responding to any chemotherapy licensed at the time, including irinotecan, oxaliplatin and fluoropyrimidines. All patients had tumours with EGFR detectable by immunohistochemistry. They were randomised to cetuximab (400mg/m2 loading dose followed by a weekly infusion of 250mg/m2) plus best supportive care or to best supportive care alone. Patients’ tumours were assessed every eight weeks by computed tomography (CT) scan until their cancers began to progress.
Results showed a statistically significant 23% improvement in overall survival (the primary outcome of the trial). The median survival was 6.1 months in the cetuximab group compared to 4.6 months with best supportive care alone (hazard ratio 0.77; 95% confidence interval , 0.64 to 0.92; p=0.0046). There was also as a 32% reduction in the risk of disease progression (HR 0.68; 95% CI, 0.57 to 0.80; p<0.0001).
Reporting the findings, Derek Jonker, assistant professor at the University of Ottawa, Canada, and co-chair of the study, said: “Cetuximab significantly improved survival in these patients when all other therapies had failed. The results showed a clear separation of survival curves. This is the first time a single agent biologically targeted therapy has demonstrated a survival advantage in patients with colorectal cancer, and it is also the first time an EGFR-targeting drug has achieved this outcome.
“Earlier studies demonstrated cetuximab could shrink colon tumours, both alone and when combined with chemotherapy. While some patients receiving cetuximab in the CO.17 study had significant tumor shrinkage, many more had the cancer growth arrested, delaying progress of the disease and resulting in patients living longer.”
Cetuximab binds to the EGFR receptor, which is overexpressed in a large proportion of colorectal cancers. This prevents the activation of enzymatic pathways that lead to cancer cell growth and proliferation. In addition, cetuximab promotes antibody dependent cell cytotoxicity, enlisting the body’s immune system by triggering natural killer cells to attack cancer cells.
Dr Jonker concluded: “These promising results will lead to further National Cancer Institute of Canada trials in which cetuximab will be combined with other therapeutics to treat metastatic colorectal cancer.”
The CO.17 trial was run by the National Institute of Canada Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group, with patients being recruited from centres in Canada, Australia, New Zealand and Singapore. It was supported by Bristol-Myers Squibb Company and ImClone Systems Incorporated, the three companies that market cetuximab in different countries.
Second study shows combination of cetuximab plus irinotecan improves progression free survival compared to irinotecan alone as second-line treatment for metastatic colorectal cancer
A second phase III trial reported at the meeting, the Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) study, showed that a combination of cetuximab and irinotecan significantly improved progression free survival compared to irinotecan alone when used as second-line treatment.
The study randomised 1,298 patients with EGFR-expressing metastatic colorectal cancer who had failed oxaliplatin and a fluoropyrimidine to combination treatment with cetuximab (400mg/m2 followed by 250mg/m2 weekly) plus irinotecan (350mg/m2 every 3 weeks) or irinotecan alone.
Median progression free survival was significantly longer in patients treated with a combination of cetuximab plus irinotecan (3.98 months) compared to irinotecan alone (2.56 months; p<0.0001). The tumour response rate in the combination group was also significantly higher (16.36% vs 4.15%; p<0.0001). Disease control was achieved in 61.4% of patients given combination treatment, compared to 45.8% of those given irinotecan alone (p<0.0001).
Alberto Sobrero, head of medical oncology at the San Martino Hospital, Genoa, Italy, and lead investigator of the study, said: “Patients who received both cetuximab and irinotecan experienced longer periods of time spent, on average, without further progression of the disease. From a patient perspective, any improvement in progression-free survival, as well as tumor shrinkage, is worthwhile.”
Despite the positive findings, there was no difference in overall survival between the two groups (median overall survival 10.71 months with combination treatment vs 9.99 months with irinotecan alone; p=0.712). Professor Sobrero suggested that this was probably because nearly half (47%) of the patients who were initially treated with irinotecan alone were given cetuximab when their cancers progressed. This meant that many patients in both groups actually received the same treatment.
Patients who received combination therapy showed increased rates of adverse events, including fatigue, diarrhoea and an acne-like rash previously associated with cetuximab. Correlating severity of rash with overall survival showed a close association, increasing from a median of 5.8 months in patients with no rash to 11.7 months in those with grade 1/2 rash to 15.6 months in those with grade 3/4 rash.
Professor Sobrero concluded: “These data confirm that, despite a moderate increase in side effects, cetuximab is a key therapeutic agent in the optimal treatment of advanced colorectal cancer.”
Richard Goldberg, professor of oncology at the University of North Carolina, USA, and the discussant in the late-breaking trials plenary session, said: “The data from these two studies show that cetuximab has activity both as third- and second-line treatment, with an without irinotecan, in metastatic colorectal cancer. But we really need a biomarker to tell us which patients are likely to benefit from EGFR targeted drugs.” He argued that progression free survival should replace overall survival for regulatory authorities when considering trials where crossover is a possibility, such as in the EPIC study.
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