542P - Analysis of progression free survival in the new EPOC study in an all RAS wild-type population

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer Agents
Colon and Rectal Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Biological Therapy
Presenter John Bridgewater
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors J.A. Bridgewater1, S. Pugh2, K. Moutasim3, G.J. Thomas3, R. Thiébaut4, F. Liebaert4, S. Falk5, M. Finch-Jones6, J.W. Valle7, D. O’reilly8, A. Siriwardena9, J. Hornbuckle10, M. Rees11, T. Iveson12, T. Hickish13, M. Bowers14, O.J. Garden15, D. Cunningham16, T.S. Maughan17, J. Primrose3
  • 1Medical Oncology, UCL Cancer Institute, University College London, UK WC1E 6DD - LONDON/GB
  • 2University Surgery, University of Southampton, Southampton/GB
  • 3Cancer Sciences, University of Southampton, Southampton/GB
  • 4Integragen Sa, IntegraGen SA, Evry/FR
  • 5Bristol Haematology And Oncology Centre, Bristol Haematology and Oncology Centre, Bristol/GB
  • 6Department Of Surgery, University Hospitals Bristol NHS Foundation Trust, Bristol/GB
  • 7Medical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 8Department Of Surgery, North Manchester General Hospital, Manchester/GB
  • 9Department Of Surgery, Manchester Royal Infirmary, Manchester/GB
  • 10Department Of Oncology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield/GB
  • 11Department Of Surgery, Basingstoke and North Hampshire Hospital, Basingstoke/GB
  • 12Medical Oncology, Southampton General Hospital, Southampton/GB
  • 13Medical Oncology, Poole Hospital NHS Trust, Poole/GB
  • 14University Of Southampton Clinical Trials Unit, University of Southampton, Southampton/GB
  • 15Department Of Surgery, The University of Edinburgh, Edinburgh/GB
  • 16The Royal Marsden, The Royal Marsden, London/GB
  • 17Gray Institute For Radiation Oncology And Biology, University of Oxford, OX3 7DQ - Oxford/GB



The New EPOC study randomised KRAS exon 2 wild-type (WT) patients with resectable or suboptimally resectable colorectal liver metastases (CRLM) to receive chemotherapy with or without cetuximab before and after liver resection. KRAS status was determined using pyrosequencing in codons 12, 13 and 61. The trial demonstrated a detriment in progression free survival (PFS) from 20·5 to 14·1 months with the addition of cetuximab to chemotherapy (HR 1·48 95%CI 1·04-2·12 p = 0·03). Subsequently, benefit from epidermal growth factor inhibition in advanced disease was shown to be improved by further defining the population as all RAS WT (Douillard NEJM 2013).


Samples of tumour from the primary colorectal and liver resections were obtained. Patients were further analysed using MiSeq for KRAS (codon 12, 13, 61, 117 and 146), BRAF (V600E), NRAS (12, 13, 61, 117 and 146), PIK3CA (547 and 1047) and EGFR S492R. Survival analyses were completed using the Kaplan-Meier method and the log-rank test.


To date 140 samples of primary tumour and 103 samples of CRLM have been analysed. Paired samples of primary tumour and CRLM were analysed for 61 patients. Further mutations were found in samples from 12 patients in the initial “KRAS WT” group, 8 KRAS (4 in codons previously analysed by pyrosequencing) and 4 NRAS. 3 mutations identified in CRLM were not in the matching primary. Analysis of the all RAS WT primary tumour population (chemo alone arm n = 53, chemo plus cetuximab arm n = 72) demonstrated a detriment in median PFS of 20 months to 15 months respectively (HR 1·4 95%CI 0·82-2·4 p = 0·22). 7 tumours were found to be BRAF mutated in all patients sequenced.


In this study the addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients resulted in an inferior PFS. More stringent selection of an all RAS WT cohort did not alter the detriment observed. BRAF mutation is uncommon and likely reflects the selection of a relatively good prognosis cohort. Differences in mutational status between primary and metastasis were infrequent and could reflect either a treatment effect or clonal outgrowth. Initial pyrosequencing failed to detect <1% of mutations subsequently detected and most new mutations were discovered in previously un-interrogated sequences.


J.A. Bridgewater: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board; R. Thiébaut: Employee of IntegraGen SA, Evry, France; F. Liebaert: Employee of IntegraGen SA, Evry, France; S. Falk: reports an Advisory board for Merck pharmaceuticals; J.W. Valle: reports personal fees and non-financial support from Merck J. Hornbuckle: reports non-financial support from Merck UK; T. Iveson: reports personal fees from Advisory Board for Merck Serono; T. Hickish: reports personal fees from Roche, Amgen, Sanofi Aventis, Novartis, Merck Serono advisory boards; D. Cunningham: reports grants from Roche, Amgen, Celgene, Sanofi, Merck Serono, Novartis, Astra Zeneca; T.S. Maughan: reports income from advisory board for Merck;J.N. Primrose: reports personal fees from Merck advisory board, Bayer advisory board, Sanofi-aventis advisory board, and Roche advisory board. All other authors have declared no conflicts of interest.