The addition of cetuximab to FOLFOX4 significantly improves progression-free survival and overall response rate (ORR) when used as first-line therapy in patients with mCRC with KRAS exon 2 wild-type (WT), whereas patients with KRAS exon 2 mutation (mut) show no benefit from the addition of cetuximab. A retrospective analysis of the OPUS study in 118 patients with mCRC KRAS exon 2-WT tumors sought to correlate clinical outcomes according to RAS mutation status by evaluating 26 other mutations in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3, and 4) (Bokemeyer C, et al. ASCO 2014. Abstract 3505). New RAS mutations were detected in 31 of the 118 patients evaluated (26%). In patients with RAS-WT tumors, clinical responses were significantly improved by the addition of cetuximab to FOLFOX4 (ORR to FOLFOX + cetuximab 58% compared with 29% to FOLFOX4 alone; P = .008). In patients with any tumor RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFOX4 was observed; in some cases, addition of cetuximab showed a nonstatistically significant trend for a worse outcome (ORR in RAS-mut patients to FOLFOX4 + cetuximab 37% and to FOLFOX4 alone 51%; P = .087). No statistically significant differences in median overall survival were observed in patients with KRAS-WT or RAS-mut tumors when cetuximab was added to FOLFOX4. Nevertheless, it is advisable to restrict cetuximab administration to patients with mCRC where it will have the greatest benefit—those whose tumors are WT at all RAS loci. This suggests that extensive RAS mutation testing should be conducted on any patient with mCRC in whom FOLFOX4 + cetuximab is being considered as first-line therapy, the cost of which must be added to the value proposition for this agent.
