FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer

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


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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cetuximab
  • Codon
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Exons
  • Fluorouracil / administration & dosage
  • Genes, ras*
  • Humans
  • Leucovorin / administration & dosage
  • Mutation*
  • Organoplatinum Compounds / administration & dosage


  • Antibodies, Monoclonal, Humanized
  • Codon
  • Organoplatinum Compounds
  • Cetuximab
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol