O-0020 - Outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer randomized to FOLFIRI with or without cet...

Date 28 June 2014
Event World GI 2014
Session Metastatic colorectal cancer
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Presenter Eric Van Cutsem
Citation Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193
Authors H. Lenz1, C.H. Köhne2, S. Tejpar3, I. Melezinek4, K. Duecker4, H. van Krieken5, F. Ciardiello6
  • 1University of Southern California Norris Comprehensive Cancer Center, Los Angeles/US
  • 2Onkologie Klinikum Oldenburg, Oldenburg/DE
  • 3University Hospital Gasthuisberg, Leuven/BE
  • 4Merck KGaA, Darmstadt/DE
  • 5Radboud University Nijmegen Medical Centre, Nijmegen/NL
  • 6Seconda Universita Degli Studi Di Napoli, Naples/IT



The randomized phase III CRYSTAL study demonstrated that the addition of cetuximab to FOLFIRI significantly improved progression-free survival, overall survival and response in the first-line treatment of patients with KRAS codon 12/13 (hereinafter, exon 2) wild-type metastatic colorectal cancer (mCRC). Patients with KRAS exon 2 tumor mutations showed no cetuximab treatment benefit.


Available KRAS exon 2 wild-type tumors from CRYSTAL study patients were screened for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3 and 4) using BEAMing technology, an approach based on polymerase chain reaction (PCR) amplification of single target DNA molecules on individual magnetic beads within an emulsion. Bead-associated PCR products from tumor DNA samples were subsequently typed for the presence of mutant or wild-type sequences using specific fluorescent probes and flow cytometry. Where mutations were detected, this approach allowed for the determination of the ratio of mutant to wild-type RAS DNA molecules in the original tumor DNA sample. As the predictive value of low prevalence RAS mutations in tumors in which the overwhelming majority of cells were wild-type was not clear, and in line with current clinical practice in relation to KRAS exon 2 screening, a 5% diagnostic cutoff was selected for analysis. Treatment outcome was subsequently assessed according to RAS mutation status (RAS wild-type, new RAS mutant, and RAS mutant [KRAS exon 2 or new RAS]). The effect of selecting different diagnostic cutoffs on the predictive value of mutation status in patients receiving FOLFIRI plus cetuximab was further explored.


Mutation status was evaluable in 430/666 (65%) patients with KRAS exon 2 wild-type tumors. Using a 5% diagnostic cutoff, new RAS mutations were scored in 63/430 (15%) patients. In those with RAS wild-type tumors, a significant benefit across efficacy endpoints was associated with the addition of cetuximab to FOLFIRI (Table). In patients with new RAS tumor mutations, no clear difference in efficacy outcomes between treatment groups was seen. In patients with any tumor RAS mutation (KRAS exon 2 or new RAS), no benefit from the addition of cetuximab to FOLFIRI was apparent. Analysis of treatment outcome in new RAS mutant subgroups defined according to a range of sensitivity cutoffs from 20% down to 0.1% supported the use of 5% as a clinically appropriate threshold for defining a subgroup of patients most likely to benefit from the addition of cetuximab to FOLFIRI.


In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a marked benefit across all efficacy endpoints from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not benefit. This finding may allow the further tailoring of cetuximab therapy to maximize patient benefit.