Treatment outcome according to tumour RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab.

Adapted from Abstract 3506, which was submitted to ASCO Congress 2014

Treatment outcome according to tumour RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab.

Fortunato Ciardiello, Heinz-Josef Lenz, Claus-Henning Kohne, Volker Heinemann, Sabine Tejpar, Ivan Melezinek, Frank Beier, Christopher Stroh, Eric Van Cutsem; Medical Oncology, Second University of Naples, Naples, Italy; Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Onkologie Klinikum Oldenburg, Oldenburg, Germany; Department of Medical Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany; University Hospitals Leuven, Leuven, Belgium; Merck KGaA, Darmstadt, Germany

Background: The addition of cetuximab to FOLFIRI significantly improved progression-free survival, overall survival and response in the first-line treatment of patients (pts) with KRAS codon 12/13 (hereinafter exon 2) wild-type (wt) mCRC. Pts with KRAS exon 2 tumor mutations showed no
cetuximab treatment benefit.

Methods: Available KRAS exon 2 wt tumours from CRYSTAL study pts 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 (5% sensitivity cut-off selected for analysis). Outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS).

Results: Mutation status was evaluable in 430/666 (65%) pts with KRAS exon 2 wt tumours. New RAS mutations were detected in 63/430 (15%) pts. In those with RAS wt tumours, a significant benefit across all endpoints was associated with the addition of cetuximab to FOLFIRI (Table). In pts with new RAS tumour mutations, no clear difference in efficacy outcomes between treatment groups was seen. In pts with any tumour RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFIRI was apparent.


*RAS evaluable population, N=430; †Subset of CRYSTAL KRAS evaluable population, N=1063; ‡Cochran-Mantel-Haenszel; §log-rank. cet, cetuximab; HR, hazard ratio.

Conclusions: In the first-line treatment of mCRC, pts with RAS wt tumours derived a marked benefit from the addition of cetuximab to FOLFIRI; pts with RAS tumour mutations did not benefit. This finding may allow the further tailoring of cetuximab therapy to maximize pt benefit.