ArticlesFOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial
Introduction
Fluorouracil with folinic acid and irinotecan (FOLFIRI) is a frequently used chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. Results of the phase 3 CRYSTAL trial showed that the addition of the EGFR antibody cetuximab to FOLFIRI in this setting improved clinical outcome in patients whose tumours did not have mutations at KRAS codons 12 and 13.1, 2 Addition of the VEGF-A antibody bevacizumab to a first-line regimen including irinotecan, bolus fluorouracil, and folinic acid was also shown in a phase 3 trial to improve outcome in patients with metastatic colorectal cancer.3 However, a survival benefit associated with the addition of bevacizumab to standard first-line infusional fluorouracil-based regimens has not yet been shown.
The FIRE-3 trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO) was designed to explore whether cetuximab or bevacizumab was a more effective partner for FOLFIRI in the first-line treatment of metastatic colorectal cancer. Patients were initially recruited without regard to KRAS tumour mutation status. However, following reports that cetuximab was not active in patients with tumour KRAS exon 2 mutations (codon 12 or 13),4, 5 enrolment was restricted by protocol amendment to patients without such mutations. Subsequently, an unplanned subgroup analysis was done to compare treatment efficacy in patients with KRAS exon 2 mutations enrolled before the protocol amendment.6
Particular tumour mutations occurring in exons 3 or 4 of KRAS or exons 2–4 of NRAS have recently also been shown to be negative predictors of outcome in patients receiving first-line therapy with the EGFR antibody panitumumab combined with a regimen of folinic acid, fluorouracil, and oxaliplatin (FOLFOX4).7, 8 When patients with such mutations were excluded from the KRAS exon 2 wild-type population, a more pronounced survival benefit associated with the addition of panitumumab to FOLFOX4 was reported than before the exclusion of these patients.7
Our objective in this study was therefore to compare cetuximab or bevacizumab, plus FOLFIRI, in FIRE-3 trial patients without tumour KRAS exon 2 mutations.
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Study design and patients
In this two-group, open-label, multicentre, randomised, phase 3 trial, we recruited patients from hospitals, outpatient clinics, and private practices in Germany and Austria. Eligible patients were those aged 18–75 years with stage IV, histologically confirmed, adenocarcinoma of the colon or rectum, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function (white blood cell count ≥3·0 × 109 cells
Results
Between Jan 23, 2007, and Sept 19, 2012, 752 patients from 116 centres (appendix p 1–2) in Germany (110 centres) and Austria (six centres) were randomly assigned to a treatment group. 592 patients with KRAS exon 2 wild-type tumours who received treatment were subsequently included in the intention-to-treat population; 297 were assigned to FOLFIRI plus cetuximab and 295 to FOLFIRI plus bevacizumab (figure 1). The baseline characteristics of the treatment groups were similar (table 1). With more
Discussion
To our knowledge, this is the first randomised phase 3 trial to compare the efficacy of FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab in the first-line treatment of KRAS exon 2 wild-type metastatic colorectal cancer (panel). In the primary analysis, the difference in the proportion of patients who achieved an objective response between the treatment groups was not statistically significant; both targeted agents seemed to be equally effective in terms of progression-free survival when
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