Epidermal growth factor receptor (EGFR) as a predictive and prognostic marker in patients with advanced colorectal cancer (aCRC): The MRC COIN trial experience.

359 Background: KRAS mutation has been shown to be a more effective (though negative) biomarker for selection of patients for EGFR targeted therapy in aCRC. However, positive EGFR immunohistochemistry (IHC) remains a license requirement and was an inclusion criterion in most trials to date. The MRC COIN trial recruited 2445 pts into 3 arms of oxaliplatin + fluoropyrimidine +/- cetuximab without prior EGFR assessment. This trial provides a unique opportunity to definitively examine the role of EGFR IHC as prognostic and predictive marker and potentially the evidence required to remove this assessment from the license for this drug. METHODS: Formalin-fixed paraffin embedded (FFPE) tissue was stained retrospectively for EGFR using Dako kit in a national reference lab. Results were assessed by 3 reviewers (BJ, SS, RA) using digital imaging software in a blinded fashion, then by BJ/SS providing consensus for discrepancies. EGFR scoring was assessed as a prognostic variable in association with selected patient, tumor and biochemical data. Cut off points examined for +ve vs -ve tumours, in terms of total tumour cells demonstrating membrane staining, were: 0% vs >0%; <10% vs ≥10%; <20% vs ≥20%. RESULTS: EGFR IHC was adequately assessed for 1621 pts (66% of randomised), 22% were negative (0%) and 78% positive (>0%), balanced across arms. EGFR was not prognostic for PFS within KRAS wt pts at the standardized cut off point 0% vs >0% HR=1.11 95% CI 0.91-1.36 p=0.31 but was at <10% vs ≥10% (HR=1.27 95% CI 1.07-1.52 p=0.008) this was robust to other prognostic variables. No effect was seen for overall response or survival. There was no prognostic effect for the KRAS mutant group. In the 1065 assessable pts randomised to +/- cetuximab, no evidence of EGFR IHC as a predictive marker for response or survival outcomes was observed for the addition of cetuximab to chemotherapy (OS HR=1.11 95% CI 0.70-1.75 p=0.66; PFS HR=0.95 95% CI 0.64-1.43 p=0.82). CONCLUSIONS: Extensive assessment of samples from this trial suggest a role for EGFR IHC as a prognostic marker in KRAS wt aCRC but refute the predictive value embedded within the licence for cetuximab used in combination with chemo in first-line therapy. [Table: see text].