CO.17 is a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) collaborative group trial of Cetuximab and BSC (best supportive care) versus BSC alone in patients with pre-treated metastatic colorectal carcinoma.  For patients entering the study there was no other standard cancer treatment available and BSC was otherwise the recommended management strategy. 

The trial opened to recruitment in November 2003, and was activated in 28 AGITG sites around Australia, New Zealand and Singapore. The study closed to recruitment in August 2005. 572 patients were randomised worldwide, with 252 of those coming from Australia, New Zealand and Singapore.

Key Results and Publications

Cetuximab prolonged survival compared to best supportive care in the setting of pre-treated metastatic colorectal cancer (NEJM, 2007)

The survival benefit associated with cetuximab was restricted to patients with tumours without Kras mutations (NEJM, 2008).

Quality of life is preserved or improved with cetuximab compared to best supportive care (JCO, 2009).

The incremental cost effectiveness ratio of cetuximab over best supportive care was high and sensitive to drug cost, but reduced when the analysis was restricted to patients with Kras wild type tumours (JNCI, 2009).

In a combined retrospective analysis with datasets from Belgium and Italy, the use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS mutated tumors (JAMA, 2010).

Better performance status was associated with an improved survival, but those with comorbidity also benefited from cetuximab (Annals of Oncology, 2009).

In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor overall survival, even after adjustment for grade of rash (Annals of Oncology, 2013).

Tumour samples from CO.17 were used to analyse and validate a Kras mutation diagnostic test (Therascreen) that is now FDA approved (Archives of Pathology & Laboratory Medicine, 2012).

Patients with high EREG gene expression may benefit more from cetuximab therapy compared to low expression (ASCO poster, 2009).

Change of tumor size 8 weeks after starting cetuximab visualized by waterfall plot analysis was a better predictor of overall survival than standard RECIST categories (ASCO poster, 2011).

The development and severity of rash during cetuximab therapy was associated with improvements in overall and progression-free survival only in those patients whose tumours were KRAS wild type, although only for grade 2 or more severe rash did overall survival exceed that of patients receiving best supportive care only (ASCO poster, 2011).

Neither PIK3CA mutation status nor PTEN expression were predictive of benefit from cetuximab. BRAF mutations are uncommon in this setting (ASCO poster, 2012).

Tumour location within the colon is not prognostic, but is a strong predictor of PFS benefit from cetuximab therapy. Patients with KRAS WT colon cancer were more likely to benefit if the tumour was on the left side (from splenic flexure and more distal) rather than the right (ASCO poster, 2013).

Published manuscripts

Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. New England Journal of Medicine 2007; 357(20): 2040–2048

Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine 2008; 359(17): 1757–1765.

Mittmann N, Au HJ, Tu D, O'Callaghan CJ, Isogai PK, Karapetis CS, Zalcberg JR, Evans WK, Moore MJ, Siddiqui J, Findlay B, Colwell B, Simes J, Gibbs P, Links M, Tebbutt NC, Jonker DJ; Working Group on Economic Analysis of the National Cancer Institute of Canada Clinical Trials Group–Australasian Gastrointestinal Interest Group. Prospective cost-effectiveness analysis of cetuximab in metastatic colorectal cancer: evaluation of National Cancer Institute of Canada Clinical Trials Group CO.17 trial. Journal of the National Cancer Institute 2009: 101(17): 1182–1192. Published online 7 Aug 2009.

Au HJ, Karapetis CS, O’Callaghan CJ, Tu D, Moore MJ, Zalcberg J, Kennecke H, Shapiro JD, Koski S, Pavlakis N, Charpentier D, Wyld D, Jefford M, Knight GJ, Magoski NM, Brundage MD, Jonker DJ. Health-related quality of life in advanced colorectal cancer patients treated with cetuximab: overall and Kras-specific results of the NCIC CTG and AGITG CO.17 trial. Journal of Clinical Oncology 2009; 27(11): 1822–1828. Published online 9 March 2009.

De Roock S, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, Tejpar S. Association of Kras p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 2010; 304(16): 1812–1820.

Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)—results from NCIC CTG CO.17: a phase III trial of cetuximab versus best supportive care. Annals of Oncology 2011; 22(1): 118–126. Published online 5 July 2010.

HarbisonCT, Horak CE, Ledeine JM, Mukhopadhyay P, Malone DP, O'Callaghan C, Jonker DJ, Karapetis CS, Khambata-Ford S, Gustafson N, Trifan OC, Chang SC, Ravetto P, Green GA 4th. Validation of companion diagnostic for detection of mutations in codons 12 and 13 of the KRAS gene in patients with metastatic colorectal cancer: analysis of the NCIC CTG CO.17 trial. Archives of Pathology & Laboratory Medicine. Published online 3 Oct 2012.

Vickers MM, Karapetis CS, Tu D, O'Callaghan CJ, Price TJ, Tebbutt NC, Van Hazel G, Shapiro JD, Pavlakis N, Gibbs P, Blondal J, Lee U, Meharchand JM, Burkes RL, Rubin SH, Simes J, Zalcberg JR, Moore MJ, Zhu L, Jonker DJ. Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17. Annals of Oncology 2013; 24(4): 953–960.