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

Abstract

SummaryBackgroundIn 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.MethodsIn 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.Findings1630 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).InterpretationThis 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.FundingCancer Research UK, Cancer Research Wales, UK Medical Resear...

Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials

“…Individual patient data were obtained from selected arms of three large randomised trials (FOCUS [ISRCTN 79877428], [13] COIN [ISRCTN 27286448], [14,15] PICCOLO [ISRCTN 93248876] [16,17] to reflect different clinical uses of standard cytotoxic chemotherapy (without targeted therapy) in aCRC (Supplementary Figure 1).…”

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

“…RAS mutations represent the only, molecular, predictive biomarker approved for clinical use, while their prognostic role is still debated. Several randomized studies have shown no significant survival differences between KRAS mutated and KRAS wild-type, CRC patients, independently of anti-EGFR therapy (Price et al, 2011;Hecht et al, 2009;Kastrinakis et al, 1995;Russo et al, 1998;Tol et al, 2010), while others have demonstrated a prognostic role of KRAS in advanced disease (Richman et al, 2009;Maughan et al, 2011;Tejpar et al, 2012). BRAF mutations have been described in about 10% of primary CRC, representing a well-known negative prognostic factor, associated with worse survival outcomes, regardless of any treatment received (Ahn et al, 2014).…”

The prognostic significance of epidermal growth factor receptor expression in patients with anal carcinoma

“…The oral TKIs gefitinib and erlotinib have been applied most and currently, they are use in particular for palliative therapy of non-small cell lung cancer [27]. Monoclonal antibodies against EGFR extracellular receptor domain are another group; among these, cetuximab and panitumumab have been used most, predominantly in the therapy of metastatic colorectal cancer [28][29][30][31][32][33]. With the development of molecular biology revealed that the K-RAS oncogene status, and later the entire RAS complex, was a principal predictive factor for the use of anti-EGFR therapy in metastatic colorectal cancer [29,34].…”