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Clinical Trial
. 2015 Jul;51(10):1243-52.
doi: 10.1016/j.ejca.2015.04.007. Epub 2015 Apr 30.

FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer

C Bokemeyer  1 , C-H Köhne  2 , F Ciardiello  3 , H-J Lenz  4 , V Heinemann  5 , U Klinkhardt  6 , F Beier  7 , K Duecker  8 , J H van Krieken  9 , S Tejpar  10
Affiliations
Clinical Trial

FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer

C Bokemeyer et al. Eur J Cancer. 2015 Jul.

Abstract

Background: The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.

Patients and methods: Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).

Results: Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.

Conclusion: Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.

Keywords: Cetuximab; FOLFOX4; KRAS; NRAS; OPUS; RAS.

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Conflict of interest statement

Conflict of interest statement

CB has a consultancy/advisory relationship with, and has received honoraria from, Merck Serono; C-HK has received honoraria and research funding from Merck KGaA; FC has a consultancy/advisory relationship with, and has received honoraria and research funding from, Merck Serono; H-JL has a consultancy/advisory relationship with, and has received honoraria, research funding and travel/accommodation expenses from, Merck Serono; VH has a consultancy/advisory relationship with, has participated in satellite symposia for, has provided expert testimony for, and has receiving honoraria, research funding and travel/accommodation expenses from, Merck KGaA; FB and KD are compensated employees of Merck KGaA; UK was a compensated employee of Merck KGaA up until submission of the manuscript; JHvK has a consultancy/advisory relationship with, and has received honoraria, research funding and travel/accommodation expenses from, Merck Serono; ST has a consultancy/advisory role with, and has received honoraria, lecture fees and research funding from, Merck Serono.

Figures

Fig. 1.
Fig. 1.
Odds ratios for objective response (A) and hazard ratios for disease progression or death from any cause (B) and death (C) according to tumour KRAS exon 2 and RAS mutation status. HR, hazard ratio.
Fig. 2.
Fig. 2.
Progression-free survival for patients with RAS wild-type (A) and any RAS mutant (B) tumours. CT, chemotherapy; HR, hazard ratio.
Fig. 3.
Fig. 3.
Overall survival for patients with RAS wild-type (A) and any RAS mutant (B) tumours. CT, chemotherapy; HR, hazard ratio; NR, not reached.
See this image and copyright information in PMC

References

    1. Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 2009;27:663–71. - PubMed
    1. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011;22:1535–46. - PubMed
    1. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–705. - PubMed
    1. Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011;39:D945–50. - PMC - PubMed
    1. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol 2014. - PubMed

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