In the German phase II FIRE-4.5 trial reported in the Journal of Clinical Oncology, Stintzing et al found that the addition of cetuximab vs bevacizumab to FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) did not improve objective response rate in the first-line treatment of patients with BRAF V600E–mutant metastatic colorectal cancer.
Study Details
In the open-label multicenter trial, 107 patients (full-analysis set) were randomly assigned 2:1 between November 2016 and December 2020 to receive FOLFOXIRI every 14 days plus cetuximab starting at 400 mg/m2 and then at 250 mg/m2 once weekly (n = 72) or bevacizumab at 5 mg/kg every 14 days (n = 35). Treatment was given for a maximum of 12 cycles. The primary endpoint was objective response rate evaluated in the per-protocol population, consisting of 59 patients in the cetuximab group and 30 patients in the bevacizumab group.
Key Findings
Among patients in the per-protocol population, objective responses were observed in 20 (67%) of 30 patients in the bevacizumab group vs 30 (51%) of 59 patients in the cetuximab group (odds ratio = 1.93, 80% confidence interval [CI] = 1.06–3.52, P = .92). Complete response was observed in two patients (7%) vs three patients (5%). An additional 23% vs 32% of patients had stable disease.
In the full-analysis set, median progression-free survival was 6.7 months (95% CI = 5.7–8.0 months) in the cetuximab group vs 10.7 months (95% CI = 7.4–17.1 months) in the bevacizumab group (hazard ratio [HR] = 1.89, P = .006). Median overall survival was 12.9 months (95% CI = 10.4–17.6 months) in the cetuximab group vs 17.1 months (95% CI = 13.0–34.5 months) in the bevacizumab group (HR = 1.4, P = .20).
In the full-analysis set, grade 3 or 4 adverse events were observed in 87% of patients in the cetuximab group vs 97% of those in the bevacizumab group; most commonly neutropenia (21% vs 26%) and diarrhea (18% vs 20%) in both groups. Grade 3 or 4 skin disorders occurred in 18% vs 0% of patients. Thromboembolic events occurred in 8% of patients in each group.
The investigators concluded, “To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAF V600E–mutant metastatic colorectal cancer. FOLFOXIRI plus cetuximab does not induce a higher objective response rate when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAF V600E–mutant metastatic colorectal cancer. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAF V600E–mutant metastatic colorectal cancer.”
Volker Heinemann, MD, of the Department of Oncology, LMU University Hospital, Munich, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The trial was funded by Merck KGaA. For full disclosures of the study authors, visit ascopubs.org.
