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Lancet Oncol. 2014 Sep;15(10):1065-75. doi: 10.1016/S1470-2045(14)70330-4. Epub 2014 Jul 31.

FOLFIRI 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.

Author information

1
Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany. Electronic address: volker.heinemann@med.uni-muenchen.de.
2
Gesundheitszentrum St Marien, Amberg, Germany.
3
Oncological Practice, Ravensburg, Germany.
4
Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany.
5
Oncological Practice, Landshut, Germany.
6
Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main, Germany.
7
Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany.
8
Oncological Practice, Münster, Germany.
9
Haematology and Oncology, Städtisches Klinikum Magdeburg, Magdeburg, Germany.
10
Oncological Practice, Bad Soden, Germany.
11
Department of Medicine I, Klinikum Weiden, Germany.
12
Oncological Practice, Kronach, Germany.
13
Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
14
Department of Surgery, Klinikum Chemnitz gGmbH, Chirurgische Onkologie, Chemnitz, Germany.
15
Department of Medicine, Klinikum Stuttgart Krankenhaus Bad Cannstatt, Stuttgart, Germany.
16
Oncological Practice, Ansbach, Germany.
17
Department of Medicine I, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany.
18
Department of Oncology, Haematology and Palliative Care, Klinikum Leverkusen gGmbH, Leverkusen, Germany.
19
Medical Clinic V (Haematology and Oncology), Klinikum Darmstadt, Darmstadt, Germany.
20
Klinikum Fulda, Tumorklinik, Fulda, Germany.
21
Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz, Germany.
22
Klinik für Innere Medizin II, Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.
23
Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.
24
Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany; Institute of Pathology, University of Munich, Munich, Germany.
25
Institute of Pathology, University of Munich, Munich, Germany.

Abstract

BACKGROUND:

Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer.

METHODS:

In this open-label, randomised, phase 3 trial, we recruited patients aged 18-75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov, number NCT00433927.

FINDINGS:

Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2-67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1-63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85-1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8-10·8) in the cetuximab group and 10·3 months (9·8-11·3) in the bevacizumab group (hazard ratio [HR] 1·06, 95% CI 0·88-1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0-36·6) in the cetuximab group compared with 25·0 months (22·7-27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62-0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 [25%] of 297 patients in the cetuximab group vs 62 [21%] of 295 patients in the bevacizumab group), skin reactions (77 [26%] vs six [2%]), and diarrhoea (34 [11%] vs 40 [14%]).

INTERPRETATION:

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.

FUNDING:

Merck KGaA.

PMID:
25088940
DOI:
10.1016/S1470-2045(14)70330-4
[Indexed for MEDLINE]
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