Erbitux Edges Avastin for First-Line Colorectal Cancer Therapy

First-line treatment with cetuximab resulted in improved overall survival.

Adding cetuximab (Erbitux) to the standard first-line FOLFIRI chemotherapy regimen resulted in longer overall survival compared with FOLFIRI plus bevacizumab (Avastin) in patients with metastatic colorectal cancer, according to results of the phase III FIRE-3 trial published this month in the Lancet.

This result was seen in patients with a wild-type exon 2 KRAS gene. The longer overall survival was observed despite there being no significant difference in objective response between the two study groups.

The study analyzed data from 592 patients with KRAS exon 2 wild-type colorectal cancer treated with FOLFORI and either cetuximab (an epidermal growth factor receptor inhibitor) or bevacizumab (an angiogenesis inhibitor). Patients were recruited at 116 Austrian and German cancer centers.

Prior studies have shown a benefit for metastatic colorectal cancer patients when either cetuximab or bevacizumab is combined with a FOLFIRI regimen. This is the first randomized study to compare these two combination approaches.

The study did not meet its primary endpoint of a difference in objective response: 62% of patients (184 of 297) in the cetuximab arm achieved an objective response compared with 58% of patients (171 of 295) in the bevacizumab arm (odds ratio = 1.18, P = .18). Thirteen patients (4%) treated with cetuximab achieved a complete response compared with four patients (1%) treated with bevacizumab.

Median duration of treatment in the cetuximab arm was 4.8 months compared with 5.3 months in the bevacizumab arm. The median duration of follow-up was 33 and 39 months for the cetuximab and bevacizumab arms, respectively.

Median progression-free survival did not differ between the two arms: 10 months compared with 10.3 months in the cetuximab and bevacizumab arms, respectively (hazard ratio = 1.06, P = .55). 

The median overall survival was 28.7 months for patients in the cetuximab arm compared with 25 months in the bevacizumab arm (hazard ratio = 0.77, P = .017).

The most common grade 3 and 4 adverse events in both treatment arms were hematological toxicities-25% vs 21% in the cetuximab and bevacizumab arms, respectively. Other high-grade adverse events included skin reactions (26% vs 2%) and diarrhea (11% vs 14%) in the cetuximab and bevacizumab arms, respectively.

In a subgroup analysis of patients whose tumors had no RAS mutations in any exon, there was an even wider difference between the cetuximab and bevacizumab treatment arms-median overall survival of 33.1 months compared with 25.6 months, respectively (hazard ratio = 0.7, P = .011).

“Our data suggest that FOLFIRI plus cetuximab should be the chosen first-line treatment regimen for patients with RAS wild-type metastatic colorectal cancer,” conclude the authors.

Still, the jury may still be out on whether cetuximab is the superior agent when combined with frontline chemotherapy. In a commentary accompanying the article, Francesco Sclafani, MD, and David Cunningham, MD, of the Royal Marsden NHS Foundation in the United Kingdom, state that “FIRE-3 does not provide sufficient evidence to support the routine use of cetuximab over bevacizumab in patients with all RAS wild-type tumors.”

The commentary authors point to the CALGB/SWOG 80405 study which showed similar results when either antibody was combined with chemotherapy. They also highlight that overall survival was a secondary endpoint in the current trial and that the survival curves of the two study arms diverge rather late, suggesting that treatment post-progression played a role in the survival results.