title: 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.
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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Merck KGaA.
authors.affiliation: Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany. Electronic address: volker.heinemann@med.uni-muenchen.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Gesundheitszentrum St Marien, Amberg, Germany.
authors.forename: Ludwig Fischer
authors.initials: LF
authors.lastname: von Weikersthal
authors.affiliation: Oncological Practice, Ravensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Decker
authors.affiliation: Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kiani
authors.affiliation: Oncological Practice, Landshut, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Vehling-Kaiser
authors.affiliation: Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt/Main, Germany.
authors.forename: Salah-Eddin
authors.initials: SE
authors.lastname: Al-Batran
authors.affiliation: Department of Medicine II, Städtisches Klinikum Neuss, Neuss, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Heintges
authors.affiliation: Oncological Practice, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Lerchenmüller
authors.affiliation: Haematology and Oncology, Städtisches Klinikum Magdeburg, Magdeburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahl
authors.affiliation: Oncological Practice, Bad Soden, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Seipelt
authors.affiliation: Department of Medicine I, Klinikum Weiden, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kullmann
authors.affiliation: Oncological Practice, Kronach, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Stauch
authors.affiliation: Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Scheithauer
authors.affiliation: Department of Surgery, Klinikum Chemnitz gGmbH, Chirurgische Onkologie, Chemnitz, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hielscher
authors.affiliation: Department of Medicine, Klinikum Stuttgart Krankenhaus Bad Cannstatt, Stuttgart, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Scholz
authors.affiliation: Oncological Practice, Ansbach, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Medicine I, Westpfalz-Klinikum GmbH, Kaiserslautern, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Link
authors.affiliation: Department of Oncology, Haematology and Palliative Care, Klinikum Leverkusen gGmbH, Leverkusen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Niederle
authors.affiliation: Medical Clinic V (Haematology and Oncology), Klinikum Darmstadt, Darmstadt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rost
authors.affiliation: Klinikum Fulda, Tumorklinik, Fulda, Germany.
authors.forename: Heinz-Gert
authors.initials: HG
authors.lastname: Höffkes
authors.affiliation: Medical Department 1, Johannes-Gutenberg Universität Mainz, Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Reinhard U
authors.initials: RU
authors.lastname: Lindig
authors.affiliation: Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.
authors.forename: Dominik P
authors.initials: DP
authors.lastname: Modest
authors.affiliation: Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany; Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rossius
authors.affiliation: Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Institute of Pathology, University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.affiliation: Department of Medical Oncology & Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stintzing
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001317:Austria; D000068258:Bevacizumab; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D005858:Germany; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D018579:Patient Selection; D011379:Prognosis; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin