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

Abstract

3506 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 tumors 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 cutoff 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 tumors. New RAS mutations were detected in 63/430 (15%) pts. In those with RAS wt tumors, a significant benefit across all endpoints was associated with the addition of cetuximab to FOLFIRI (Table). In pts with new RAS tumor mutations, no clear difference in efficacy outcomes between treatment groups was seen. In pts with any tumor RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFIRI was apparent. Conclusions: In the first-line treatment of mCRC, pts with RAS wt tumors derived a marked benefit from the addition of cetuximab to FOLFIRI; pts with RAS tumor mutations did not benefit. This finding may allow the further tailoring of cetuximab therapy to maximize pt benefit. Clinical trial information: NCT00154102. Parameter RAS wt* (all loci) New RAS mt* RAS mt† (any locus) FOLFIRI + cet N=178 FOLFIRI N=189 FOLFIRI + cet N=32 FOLFIRI N=31 FOLFIRI + cet N=246 FOLFIRI N=214 Response rate, % 66.3 38.6 34.4 35.5 31.7 36.0 Odds ratio 3.11 1.02 0.85 95% CI 2.03–4.78 0.33–3.15 0.58–1.25 P value‡ <0.0001 0.97 0.40 Median progression-free survival, months 11.4 8.4 7.2 6.9 7.4 7.5 HR 0.56 0.81 1.10 95% CI 0.41–0.76 0.39–1.67 0.85–1.42 P value§ 0.0002 0.56 0.47 Median overall survival, months 28.4 20.2 18.2 20.7 16.4 17.7 HR 0.69 1.22 1.05 95% CI 0.54–0.88 0.69–2.16 0.86–1.28 P value§ 0.0024 0.50 0.64 Abbreviations: cet, cetuximab; HR, hazard ratio; mt, mutant; *RAS evaluable population, N=430; †Subset of CRYSTAL KRAS evaluable population, N=1063; ‡Cochran-Mantel-Haenszel; §log-rank.