Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

Timothy S Maughan, Richard A Adams, Christopher G Smith, Angela M Meade, Matthew T Seymour, Richard H Wilson, Shelley Idziaszczyk, Rebecca Harris, David Fisher, Sarah L Kenny, Edward Kay, Jenna K Mitchell, Ayman Madi, Bharat Jasani, Michelle D James, John Bridgewater, M John Kennedy, Bart Claes, Diether Lambrechts, Richard Kaplan, Jeremy P Cheadle, MRC COIN Trial Investigators, T S Maughan, M T Seymour, R H Wilson, R A Adams, H Wasan, A Madi, J Cassidy, M J Kennedy, E Hodgkinson, P Rogers, M Pope, A M Meade, R Kaplan, D Fisher, S L Kenny, J K Mitchell, L Nichols, L Harper, B Sydes, E Kay, L Thompson, L Clement, C Courtney, G Griffiths, C Murphy, M Parmar, C G Smith, R Harris, S Idziaszczyk, B Claes, D Lambrechts, J P Cheadle, B Jasani, S Storkel, R Adams, M James, J Northover, J Brown, M Aapro, R Stout, C Parker, M Mason, R Rudd, P W M Johnson, J Whelan, C Lowdell, R H Phillips, R Ahmad, P Riddle, A Creak, J Cassidy, A McDonald, A Waterston, N Mohammed, J White, H Yosef, A Hennessy, E M Bessell, V Potter, M Seymour, A Anthoney, A Melcher, R Cooper, D Sebag-Montefiore, P Ross, M Leslie, N Maisey, A Gaya, G Mikhaeel, J Summers, M Hill, R James, T S Maugham, A Brewster, T Crosby, S Mukherjee, N Iqbal, J Wadsley, D Furniss, S Pledge, J Hornbuckle, S Clenton, R Glynne-Jones, M Harrison, S Mawdsley, N Anyamene, R Hughes, D Propper, C Cottrill, D Smith, S Myint, N Ali, M Iqbal, P Clark, B Haylock, T Iveson, A Bateman, C Baughan, S Falk, K Hopkins, J Bridgewater, S Karp, C Topham, G Middleton, S Essapen, S Cummins, B Sizer, S Gollins, A Maraveyas, S Tahir, J Bridgewater, C Blesing, H Wasan, M Tighe, S Falk, R Ellis, J Dent, J K Joffe, S Shepherd, K Benstead, D Farrugia, P Mack, A Hamid, M Butt, R Roy, T Hickish, H Yosef, D Tsang, P Leonard, J Prejbisz, J Ledermann, J Bridgewater, T Hickish, R Osborne, A O'Callaghan, S R Muthuramalingam, F Adab, N J Wadd, J Van der Voet, D Wilson, J Wagstaff, C Askill, I Pedley, A Azzabi, E Marshall, R James, F Daniel, R Osborne, T J Iveson, D Jodrell, C McLean, S Clive, L Dawson, H A Philips, S Falk, R James, P Chakraborti, R Kulkarni, L M Samuel, G MacDonald, C Bradley, C Twelves, S Giridharan, F Adab, S Myint, S Gollins, N Stuart, C Bale, J Valle, M Saunders, G Wilson, A Weaver, A Jones, K McAdam, C Jephcott, S Cleator, A Webb, J Glaholm, R Hughes, P M Mulholland, N Steven, A Mayer, T Meyer, N Lo, G Cogill, L Toy, M Wilkins, C Wilson, C Palmer, I Geh, R Thomas, J Nicoll, P Chakraborti, A Azzabi, R Wilson, M Eatock, A Hartley, J Gildersleve, A Freebairn, G P Deutsch, A Webb, M Wilkins, F McKinna, D Cunningham, I Chau, S Susnerwala, M Wise, A Birtle, A Hamid, F J Lofts, J Kennedy, D Whillis, S Susnerwala, L T Tan, C Palmer, N Maisey, M Keane, C Macmillan, K Patel, D Farrugia, G Bertelli, V Vigneswaran, D Smith, R McDermott, S O'Reilly, V Hall, C Hamilton, A Dhadda, C Baughan, H Ford, M Moody, M Tomlinson, L Grogan, O Breathnach, R Soomal, J McCaffrey, C Rees, P J Atherton, S Beesley, W Dobrowsky, G Leonard, R Gupta, J Stewart, D Cunningham, Timothy S Maughan, Richard A Adams, Christopher G Smith, Angela M Meade, Matthew T Seymour, Richard H Wilson, Shelley Idziaszczyk, Rebecca Harris, David Fisher, Sarah L Kenny, Edward Kay, Jenna K Mitchell, Ayman Madi, Bharat Jasani, Michelle D James, John Bridgewater, M John Kennedy, Bart Claes, Diether Lambrechts, Richard Kaplan, Jeremy P Cheadle, MRC COIN Trial Investigators, T S Maughan, M T Seymour, R H Wilson, R A Adams, H Wasan, A Madi, J Cassidy, M J Kennedy, E Hodgkinson, P Rogers, M Pope, A M Meade, R Kaplan, D Fisher, S L Kenny, J K Mitchell, L Nichols, L Harper, B Sydes, E Kay, L Thompson, L Clement, C Courtney, G Griffiths, C Murphy, M Parmar, C G Smith, R Harris, S Idziaszczyk, B Claes, D Lambrechts, J P Cheadle, B Jasani, S Storkel, R Adams, M James, J Northover, J Brown, M Aapro, R Stout, C Parker, M Mason, R Rudd, P W M Johnson, J Whelan, C Lowdell, R H Phillips, R Ahmad, P Riddle, A Creak, J Cassidy, A McDonald, A Waterston, N Mohammed, J White, H Yosef, A Hennessy, E M Bessell, V Potter, M Seymour, A Anthoney, A Melcher, R Cooper, D Sebag-Montefiore, P Ross, M Leslie, N Maisey, A Gaya, G Mikhaeel, J Summers, M Hill, R James, T S Maugham, A Brewster, T Crosby, S Mukherjee, N Iqbal, J Wadsley, D Furniss, S Pledge, J Hornbuckle, S Clenton, R Glynne-Jones, M Harrison, S Mawdsley, N Anyamene, R Hughes, D Propper, C Cottrill, D Smith, S Myint, N Ali, M Iqbal, P Clark, B Haylock, T Iveson, A Bateman, C Baughan, S Falk, K Hopkins, J Bridgewater, S Karp, C Topham, G Middleton, S Essapen, S Cummins, B Sizer, S Gollins, A Maraveyas, S Tahir, J Bridgewater, C Blesing, H Wasan, M Tighe, S Falk, R Ellis, J Dent, J K Joffe, S Shepherd, K Benstead, D Farrugia, P Mack, A Hamid, M Butt, R Roy, T Hickish, H Yosef, D Tsang, P Leonard, J Prejbisz, J Ledermann, J Bridgewater, T Hickish, R Osborne, A O'Callaghan, S R Muthuramalingam, F Adab, N J Wadd, J Van der Voet, D Wilson, J Wagstaff, C Askill, I Pedley, A Azzabi, E Marshall, R James, F Daniel, R Osborne, T J Iveson, D Jodrell, C McLean, S Clive, L Dawson, H A Philips, S Falk, R James, P Chakraborti, R Kulkarni, L M Samuel, G MacDonald, C Bradley, C Twelves, S Giridharan, F Adab, S Myint, S Gollins, N Stuart, C Bale, J Valle, M Saunders, G Wilson, A Weaver, A Jones, K McAdam, C Jephcott, S Cleator, A Webb, J Glaholm, R Hughes, P M Mulholland, N Steven, A Mayer, T Meyer, N Lo, G Cogill, L Toy, M Wilkins, C Wilson, C Palmer, I Geh, R Thomas, J Nicoll, P Chakraborti, A Azzabi, R Wilson, M Eatock, A Hartley, J Gildersleve, A Freebairn, G P Deutsch, A Webb, M Wilkins, F McKinna, D Cunningham, I Chau, S Susnerwala, M Wise, A Birtle, A Hamid, F J Lofts, J Kennedy, D Whillis, S Susnerwala, L T Tan, C Palmer, N Maisey, M Keane, C Macmillan, K Patel, D Farrugia, G Bertelli, V Vigneswaran, D Smith, R McDermott, S O'Reilly, V Hall, C Hamilton, A Dhadda, C Baughan, H Ford, M Moody, M Tomlinson, L Grogan, O Breathnach, R Soomal, J McCaffrey, C Rees, P J Atherton, S Beesley, W Dobrowsky, G Leonard, R Gupta, J Stewart, D Cunningham

Abstract

Background: In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment of advanced colorectal cancer with the aim of assessing effect on overall survival.

Methods: In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448.

Findings: 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months [IQR 10·3-29·2] in the control group vs 17·0 months [9·4-30·1] in the cetuximab group; HR 1·04, 95% CI 0·87-1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months [IQR 5·0-12·5] in the control group vs 8·6 months [5·1-13·8] in the cetuximab group; HR 0·96, 0·82-1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5-27·4); KRAS mutant, 14·4 months (8·5-24·0); all wild-type, 20·1 months (11·5-31·7).

Interpretation: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended.

Funding: Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Trial profile EGFR=epidermal growth factor receptor.
Figure 2
Figure 2
Kaplan-Meier overall survival curves for patients with (A) KRAS wild-type, (B) KRAS mutant, (C) BRAF mutant and KRAS wild-type, and (D) KRAS, NRAS, and BRAF all wild-type tumours HR=hazard ratio.
Figure 3
Figure 3
Tumour mutational status as a prognostic factor for overall survival HR=hazard ratio.
Figure 4
Figure 4
Exploratory predictive factor analyses HR=hazard ratio.

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