No Difference in Response Rate but Overall Survival Benefit With First-Line FOLFIRI/Cetuximab vs FOLFIRI/Bevacizumab in Metastatic Colorectal Cancer


Key Points

  • There was no difference in response rate for FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab.
  • FOLFIRI/cetuximab was associated with longer overall survival.
  • Patient follow-up continues.

In a European phase III FIRE-3 trial reported in The Lancet Oncology, Heinemann et al found no difference in response rate, the primary endpoint, between FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus the anti-EGFR antibody cetuximab (Erbitux) vs FOLFIRI plus the anti-VEGF-A antibody bevacizumab (Avastin) in first-line treatment of patients with metastatic colorectal cancer. The cetuximab-containing regimen was associated with a significant overall survival advantage.

Study Details

In this open-label trial, 592 patients with KRAS exon 2 codon 12/13 wild-type metastatic colorectal cancer aged 18 to 75 years from centers in Germany and Austria were randomly assigned between January 2007 and September 2012 to receive FOLFIRI plus either cetuximab (n = 297) or bevacizumab (n = 295). The primary endpoint was objective response in the intention-to-treat population. The study has completed recruitment, but patient follow-up is ongoing.

Response Rates

Objective response was observed in 62.0% (4% with complete response) of patients in the cetuximab group vs 58.0% (complete response in 1%) of patients in the bevacizumab group (odds ratio = 1.18, P = .18).

Overall Survival Outcome

Median durations of follow-up were 33.0 months in the cetuximab group and 39.0 months in the bevacizumab group. Median progression-free survival was 10.0 vs 10.3 months (hazard ratio [HR] = 1.06, P = .55). Median overall survival was 28.7 vs 25.0 months (HR = 0.77, P =  .017).

Second-line anticancer therapy was received by 78% of surviving patients in the cetuximab group and 76% of surviving patients in the bevacizumab, with a similar proportion in each group receiving an oxaliplatin-based regimen (64% and 63%); 47% of cetuximab patients crossed over to receive a bevacizumab-containing regimen, and 41% of bevacizumab patients crossed over to receive anti-EGFR antibody treatment.

Adverse Events

Toxicities were consistent with the known safety profiles of the two study drugs. The most common grade ≥ 3 adverse events in the cetuximab group were skin reaction (26% vs 2% in the bevacizumab group), hematologic toxicity (25% vs 21%), acneiform exanthema/rash (17% vs 0%), and diarrhea (11% vs 11%), and the most common in the bevacizumab group were hematologic toxicity, diarrhea, hypertonia (7% vs 6% in the cetuximab group), and thrombosis (6% vs 6%).

The investigators concluded, “Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer.”

Volker Heinemann, MD, of University of Munich, is the corresponding author for The Lancet Oncology article. 

The study was funded 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®.