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
Open accessAbstract
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.
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In the COIN study, adding cetuximab to chemotherapy had no positive or detrimental effect in RAS-wild and RAS-mutated patients.
“In the COIN study, the effectiveness of cetuximab added to chemotherapy was evaluated, and in contrast to expectations, no positive or detrimental effect of the addition of anti-EGFR was observed in RAS-wild and RAS-mutated patients [13].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [13]
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Cites
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., et al. (2000) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/92.3.205 · Cited by 15,660 · see citing works
Self-citationLynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer
Van Cutsem, E., Köhne, C.-H., Hitre, E., Zaluski, J., Chang Chien, C.-R., Makhson, A., D'Haens, G., Pintér, T., Lim, R., Bodoky, G., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805019 · Cited by 3,877 · see citing works
<i>K-ras</i> Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O'Callaghan, C. J., Tu, D., Tebbutt, N. C., Simes, R. J., Chalchal, H., Shapiro, J. D., Robitaille, S., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804385 · Cited by 3,622 · see citing works
Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.7116 · Cited by 3,207 · see citing works
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., Kalogeras, K. T., Kotoula, V., Papamichael, D., Laurent-Puig, P., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70130-3 · Cited by 2,144 · see citing works
Self-citationDouillard, J., Siena, S., Cassidy, J., Tabernero, J. M., Burkes, R. L., Barugel, M. E., Humblet, Y., Bodoky, G., Cunningham, D., Jassem, J., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.4860 · Cited by 1,802 · see citing works
Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer
Tol, J., Koopman, M., Cats, A., Rodenburg, C. J., Creemers, G. J., Schrama, J. G., Erdkamp, F., Vos, A. H., van Groeningen, C. J., Sinnige, H. A. M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808268 · Cited by 1,330 · see citing works
Khambata-Ford, S., Garrett, C. R., Meropol, N. J., Basik, M., Harbison, C. T., Wu, S., Wong, T. W., Huang, X., Takimoto, C. H., Godwin, A. K., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.10.5437 · Cited by 1,125 · see citing works
Coleman, M. P., Forman, D., Bryant, H., Butler, J., Rachet, B., Maringe, C., Nur, U., Tracey, E. A., Coory, M. D., Hatcher, J., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(10)62231-3 · Cited by 1,114 · see citing works
Chung, K. Y., Shia, J., Kemeny, N. E., Shah, M., Schwartz, G. K., Tse, A., Hamilton, A., Pan, D., Schrag, D., Schwartz, L., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.08.037 · Cited by 1,081 · see citing works
Peeters, M., Price, T. J., Cervantes, A., Sobrero, A. F., Ducreux, M., Hotko, Y., André, T., Chan, E., Lordick, F., Punt, C. J. A., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.27.6055 · Cited by 1,005 · see citing works
Hecht, J. R., Mitchell, E., Chidiac, T., Scroggin, C., Hagenstad, C., Spigel, D., Marshall, J., Cohn, A., McCollum, D., Stella, P., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.19.8135 · Cited by 850 · see citing works
De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba, S., Arena, S., Frattini, M., Piessevaux, H., et al. (2010) · JAMA · doi:10.1001/jama.2010.1535 · Cited by 748 · see citing works
Köhne, C.-H., Cunningham, D., Costanzo, F. D., Glimelius, B. L. G., Blijham, G. H., Aranda, E., Scheithauer, W., Rougier, P. R., Palmer, M. K., Wils, J. A., et al. (2002) · Annals of Oncology · doi:10.1093/annonc/mdf034 · Cited by 463 · see citing works
Adams, R., Meade, A. M., Seymour, M., Wilson, R. H., Madi, A., Fisher, D. J., Kenny, S., Kay, E., Hodgkinson, E., Pope, M., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70102-4 · Cited by 263 · see citing works
Self-citationBokemeyer, C., Bondarenko, I., Hartmann, J. T., de Braud, F., Volovat, C. D., Nippgen, J., Stroh, C., Celik, I., & Koralewski, P. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.26.15_suppl.4000 · Cited by 240 · see citing works
Borner, M., Koeberle, D., Von Moos, R., Saletti, P., Rauch, D., Hess, V., Trojan, A., Helbling, D., Pestalozzi, B., Caspar, C., et al. (2008) · Annals of Oncology · doi:10.1093/annonc/mdn058 · Cited by 124 · see citing works
Cetuximab for the first-line treatment of metastatic colorectal cancer
Meads, C., Round, J. A., Tubeuf, S., Moore, D., Pennant, M. E., Bayliss, S. E., & McCabe, C. J. (2010) · Health Technology Assessment · doi:10.3310/hta14suppl1/01 · Cited by 80 · see citing works
Tveit, K., Guren, T. K., Glimelius, B. L. G., Pfeiffer, P., Sorbye, H., Pyrhönen, S. O., Kure, E. H., Ikdahl, T., Skovlund, E., & Christoffersen, T. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.4_suppl.365 · Cited by 73 · see citing works
on behalf of the COIN trial TMG and investigators, Adams, R., Meade, A. M., et al. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604877 · Cited by 64 · see citing works
Self-citationEllenberg, S. S. (2008) · Wiley Encyclopedia of Clinical Trials · doi:10.1002/9780471462422.eoct531 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
ESMO consensus guidelines for the management of patients with metastatic colorectal cancer
Van Cutsem, E., Cervantes, A., Adam, R., Sobrero, A., Van Krieken, J. H., Aderka, D., Aranda Aguilar, E., Bardelli, A., Benson, A., Bodoky, G., et al. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw235 · Cited by 3,421 · see citing works
Self-citationComprehensive review of targeted therapy for colorectal cancer
Xie, Y.-H., Chen, Y.-X., & Fang, J.-Y. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0116-z · Cited by 1,687 · see citing works
Venderbosch, S., Nagtegaal, I. D., Maughan, T. S., Smith, C. G., Cheadle, J. P., Fisher, D., Kaplan, R., Quirke, P., Seymour, M. T., Richman, S. D., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-0332 · Cited by 772 · see citing works
Self-citationPrice, T. J., Peeters, M., Kim, T. W., Li, J., Cascinu, S., Ruff, P., Suresh, A. S., Thomas, A., Tjulandin, S., Zhang, K., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70118-4 · Cited by 473 · see citing works
Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.42.2592 · Cited by 353 · see citing works
Mechanisms of resistance to anti-EGFR therapy in colorectal cancer
Zhao, B., Wang, L., Qiu, H., Zhang, M., Sun, L., Peng, P., Yu, Q., & Yuan, X. (2017) · Oncotarget · doi:10.18632/oncotarget.14012 · Cited by 319 · see citing works
Biomarker-guided therapy for colorectal cancer: strength in complexity
Sveen, A., Kopetz, S., & Lothe, R. A. (2020) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0241-1 · Cited by 320 · see citing works
Qin, S., Li, J., Wang, L., Xu, J., Cheng, Y., Bai, Y., Li, W., Xu, N., Lin, L.-Z., Wu, Q., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.78.3183 · Cited by 237 · see citing works
Bridgewater, J. A., Pugh, S. A., Maishman, T., Eminton, Z., Mellor, J., Whitehead, A., Stanton, L., Radford, M., Corkhill, A., Griffiths, G. O., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30798-3 · Cited by 255 · see citing works
Self-citationLi, Q.-H., Wang, Y.-Z., Tu, J., Liu, C.-W., Yuan, Y.-J., Lin, R., He, W.-L., Cai, S.-R., He, Y.-L., & Ye, J.-N. (2020) · Gastroenterology Report · doi:10.1093/gastro/goaa026 · Cited by 119 · see citing works
Recommendations on multiple testing adjustment in multi-arm trials with a shared control group
Howard, D. R., Brown, J. M., Todd, S., & Gregory, W. M. (2018) · Statistical Methods in Medical Research · doi:10.1177/0962280216664759 · Cited by 62 · see citing works
Yu, I. S., & Cheung, W. Y. (2018) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2018/9450754 · Cited by 47 · see citing works
Loree, J. M., Wang, Y., Syed, M. A., Sorokin, A. V., Coker, O., Xiu, J., Weinberg, B. A., Vanderwalde, A. M., Tesfaye, A., Raymond, V. M., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0180 · Cited by 43 · see citing works
Elez, E., Hendlisz, A., Delaunoit, T., Sastre, J., Cervantes, A., Varea, R., Chao, G., Wallin, J., & Tabernero, J. (2016) · British Journal of Cancer · doi:10.1038/bjc.2015.480 · Cited by 33 · see citing works
Atreya, C. E., Yaeger, R., & Chu, E. (2017) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_175679 · Cited by 35 · see citing works
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Maughan, T. S., Adams, R. A., Smith, C. G., Meade, A. M., Seymour, M. T., Wilson, R. H., Idziaszczyk, S., Harris, R., Fisher, D., Kenny, S. L., Kay, E., Mitchell, J. K., Madi, A., Jasani, B., James, M. D., Bridgewater, J., Kennedy, M. J., Claes, B., Lambrechts, D., Kaplan, R., & Cheadle, J. P.
- Affiliations
- Cardiff University (GB)
- MRC Clinical Trials Unit at UCL (GB)
- Queen's University Belfast (GB)
- University College London (GB)
- Cancer Trials Ireland (IE)
- KU Leuven (BE)
- Corresponding author
- Kaplan, Richard
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 377
- Issue
- 9783
- Pages
- 2103-2114
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3159415
- OpenAlex
- W2145070131
- Cited by
- 960
- References
- 24
- Citations by year
- 2026: 4 · 2025: 24 · 2024: 31 · 2023: 40 · 2022: 36 · 2021: 43 · 2020: 58 · 2019: 43 · 2018: 60 · 2017: 70 · 2016: 86 · 2015: 97 · 2014: 126 · 2013: 112 · 2012: 96
- FWCI
- 57.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Sanofi
- Cancer Research Wales
- Merck KGaA
- Cancer Research UK
- University College London
- Cardiff University
- Heart Research Institute
- Vlaamse regering
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- cetuximab, oxaliplatin, fluoropyrimidine, first-line chemotherapy, advanced colorectal cancer, anti-EGFR therapy, overall survival, progression-free survival, capecitabine, leucovorin, KRAS mutation, NRAS, BRAF, EGFR status
- MeSH terms
- Cetuximab, Capecitabine, Oxaliplatin, Aged, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Female, Fluorouracil, Humans, Male, Middle Aged, Mutation, Organoplatinum Compounds, Proto-Oncogene Proteins, Colorectal Neoplasms, Survival Rate, Proto-Oncogene Proteins p21(ras), ras Proteins, Proto-Oncogene Proteins B-raf, Antibodies, Monoclonal, Humanized, ErbB Receptors
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