Adding Cetuximab to First-Line FOLFIRI Does Not Benefit Metastatic Colorectal Cancer Patients With RAS Mutations


Key Points

  • The addition of cetuximab to FOLFIRI was associated with significant improvements in overall survival and progression-free survival among patients with wild-type RAS at all loci.
  • No benefit of adding cetuximab was observed among patients with any RAS mutation.

The phase III CRYSTAL trial showed that the addition of cetuximab (Erbitux) to first-line FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved overall survival, progression-free survival, and objective response rates in patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer. In a post hoc analysis in the CRYSTAL population reported in the Journal of Clinical Oncology, Van Cutsem et al found that cetuximab was not of benefit among patients in the trial with RAS mutations at exon 2 or other loci.

Study Details

In CRYSTAL, patients with EGFR-expressing metastatic colorectal cancer were randomly assigned to receive 14-day cycles of FOLFIRI plus weekly cetuximab or FOLFIRI alone as first-line treatment. In the current study, DNA samples from CRYSTAL patients with KRAS exon 2 wild-type tumors were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology; no tissue microdissection was performed.

In total, RAS mutation status was assessable in 430 of the 666 patients (65%) with KRAS exon 2 wild-type tumors, including 210 in the cetuximab-FOLFIRI group and 220 in the FOLFIRI group. Other RAS mutations, using a 5% mutant/wild-type cutoff, were found in 63 of the 430 patients (15%), including 32 patients in the cetuximab-FOLFIRI group and 31 in the FOLFIRI group.

Outcomes According to RAS Status

Among all 430 RAS-assessable patients with wild-type KRAS exon 2 tumors, median overall survival was 26.1 months with cetuximab-FOLFIRI vs 20.2 months with FOLFIRI (hazard ratio [HR] = 0.75, P = .008), median progression-free survival was 11.3 vs 7.7 months (HR = 0.58, P < .001), and objective response rate was 61% vs 38% (P < .001).

Among the 367 patients with wild-type RAS at all loci, overall survival was 28.4 months with cetuximab-FOLFIRI vs 20.2 months with FOLFIRI (hazard ratio [HR] = 0.69, P = .0024), progression-free survival was 11.4 vs 8.4 months (HR = 0.56, P < .001), and objective response rate was 66% vs 39% (P < .001).

Among the 63 patients with RAS mutations, overall survival was 18.2 months with cetuximab-FOLFIRI vs 20.7 months with FOLFIRI (HR = 1.22, P = .50), progression-free survival was 7.2 vs 6.9 months (HR = 0.81, P = .56), and objective response rate was 34% vs 35% (P = .97).

Finally, in a population of 460 patients with any RAS mutation consisting of the 63 patients with RAS mutations and 397 previously identified with KRAS exon 2 mutation in the CRYSTAL population, overall survival was 16.4 months with cetuximab-FOLFIRI vs 17.7 months with FOLFIRI (HR = 1.05, P = .64), progression-free survival was 7.4 vs 7.5 months (HR = 1.10, P = .47), and objective response rate was 32% vs 36% (P = .40).  

The investigators concluded: “In the first-line treatment of [metastatic colorectal cancer], patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not…. [O]ur study supports the use of FOLFIRI plus cetuximab in patients with RAS wild-type tumors and, on the basis of a lack of observed benefit, suggests the exclusion of patients with other RAS mutations. Reserving such first-line treatment for a RAS wild-type population allows the definition of a subgroup more likely to benefit from the addition of cetuximab to FOLFIRI. Molecular testing of tumors for all activating mutations in KRAS and NRAS before considering anti-EGFR therapy is therefore essential in selecting the most effective treatment for patients with [metastatic colorectal cancer].”

Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg/Leuven, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by Merck KGaA. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.