High epiregulin (EREG) gene expression plus K-ras wild-type (WT) status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer (ACRC): Results from NCIC CTG CO.17—A phase III trial of cetuximab versus best supportive care (BSC)

Abstract

4016 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p<0.0001) but not for low EREG patients (HR 0.77, p=0.28). The test for interaction showed a non-significantly larger treatment effect in the high EREG group (HR 0.62, p=0.13). High EREG AND K-ras WT status (“Combimarker”) was present in 139 (36%). Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months (HR, 0.31; p<0.0001), and median OS 9.8 vs 5.1 months (HR, 0.43; p<0.001) in the cetuximab vs BSC arms, respectively. In the rest (n=246, 64%) cetuximab was not associated with improved PFS (HR, 0.82; p=0.12) or OS (HR, 0.90; p=0.45). The test for treatment-Combimarker interaction showed a larger cetuximab effect on OS (HR 0.52; p=0.007) and PFS (HR 0.49; p=0.001) in the Combimarker positive group. Conclusions: In the setting of pre-treated ACRC, patients with both high EREG gene expression and K-ras wild- type status may benefit from cetuximab therapy. Determination of EREG gene expression levels should be prospectively evaluated in patient selection for EGFR targeted therapy. [Table: see text]