Effect of KRAS and NRAS mutational status on first-line treatment with FOLFIRI plus cetuximab in patients with metastatic colorectal cancer (mCRC): New results from the CRYSTAL trial.

Abstract

LBA443 Background: The phase III CRYSTAL study showed patients with unresectable KRAS exon 2, codon 12 and 13, wild-type (wt) mCRC (n = 666) to benefit from the addition of cetuximab to FOLFIRI first-line. Progression-free survival (PFS), overall survival (OS) times and response rate (RR) were significantly better in patients who received FOLFIRI plus cetuximab, compared with FOLFIRI alone. Recent retrospective analyses of studies involving EGFR-targeted monoclonal antibody therapy have suggested that patients with KRAS and NRAS mutations in other codons were unlikely to benefit from the addition of an EGFR-targeted agent. Thus, the impact of these additional KRAS and NRAS mutations on the efficacy and safety of FOLFIRI plus cetuximab treatment is under investigation in patients from the CRYSTAL study. Methods: KRAS (eight mutations on exons 3 [codons 59 and 61] and 4 [codons 117 and 146]) and NRAS (18 mutations on exons 2 [codons 12 and 13], 3 [codons 59 and 61] and 4 [codons 117 and 146]) mutation detection is ongoing using BEAMing (Beads, Emulsions, Amplification, and Magnetics) with a mutation detection cut-off of 0.1%. Tumor genomic DNA samples from 541 randomized patients with KRAS exon 2 wt disease (81% of KRAS wt patient population) and tumor material available are currently being screened. Treatment arms will be compared using two-sided log-rank tests for PFS and OS, and the Cochran–Mantel–Haenszel (CMH) test for response. Results: RAS mutation status is currently available from 192 patients (28.8% ascertainment) with further RAS assessment ongoing. Currently 63.5% of the samples are RAS wt and 36.5% are new RAS mutations. Conclusions: Updated information on the full RAS mutation dataset of up to 400 samples combined with the clinical data will be presented and implications for patient care discussed.