Background: The use of cetuximab (cetux) with chemotherapy (chemo) in patients with operable liver metastases from colorectal cancer (CRC) conferred a survival disadvantage in New EPOC. Whilst genetic alterations such as emergent sub-clonal mutations in RAS/BRAF,ERBB2 and MET are recognized as mechanisms of resistance to EGFR inhibition (EGFRi), divergent mechanisms such as transcriptomic changes may also be responsible. Of the CRC intrinsic subtypes (CRIS), CRIS-C has elevated EGFR signalling and is thought to have greater sensitivity to EGFRi. Methods: Resected primary tumors (n = 205; pre neoadjuvant treatment) and/or liver metastases (n = 144; post neoadjuvant treatment) from 223 patients, wild type for KRAS (codons 12/13/61) at trial entry, randomized to chemo +/- cetux underwent targeted NGS and/or transcriptome profiling. Primary clinical endpoints were progression free (PFS) and overall survival (OS). Results: Repeat NGS identified additional RAS/BRAF mutations in primary tumors from 49 patients (25 KRAS, 15 NRAS, 9 BRAF V6000E). Of the 148 patients with confirmed RAS/BRAF wild type primary tumors, 46% were classified as CRIS-C with the remainder being CRIS-A (9.5%), CRIS-B (11%), CRIS-D (8.8%) or CRIS-E (8.1%). CRIS-C patients had a similar PFS with ChemoCetux vs Chemo (HR 0.84 95% CI 0.47-1.5 p = 0.55) whereas non-CRIS-C had a shorter PFS (HR 2.12 95%CI 1.24-3.63 p = 0.006; p interaction 0.021). OS results were similar (p interaction 0.067). In liver metastases, genetic changes were comparable (Chemo vs ChemoCetux): KRAS (4.1% v 2.1%), NRAS (4.1% v 0%), BRAF V600E (0% v 0%), ERBB2 gain/amplification (20% v 21%) and MET gain/amplification (25% v 18%). However, gain/amplification of MET resulted in shorter OS with ChemoCetux vs Chemo (HR 5.13 95%CI 1.38-19.15 p = 0.015) whereas those without MET gain/amplification had a similar OS (HR 1.32 95%CI 0.76-2.28 p = 0.32; p interaction 0.029). The same association was found after excluding liver metastases with RAS/BRAF mutations (n = 101, p interaction 0.030). Differential expression/mutation analyses did not identify other stratifiers after false discovery correction. Conclusions: The shorter survival with ChemoCetux was restricted to patients with a non CRIS-C subtype before treatment supporting the use of this transcriptomic classifier to stratify for EGFRi. After neoadjuvant treatment, gain/amplification of MET was associated with a shorter survival with ChemoCetux. By contrast MAPK pathway mutations were largely unchanged supporting earlier findings that alternative resistance mechanisms predominate when EGFRi is combined with chemotherapy. In summary these results highlight the heterogeneity and differential responses to EGFRi that exist within RAS/RAF wild type CRC and provide insights into the substantial survival detriment observed in the New EPOC trial. Clinical trial information: ISRCTN22944367.