title: Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial.
abstract: BACKGROUND
  The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC.
  
  
  METHODS
  In this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety.
  
  
  RESULTS
  Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications.
  
  
  CONCLUSIONS
  Regorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain. Electronic address: gargiles@vhebron.net.
authors.forename: Guillem
authors.initials: G
authors.lastname: Argilés
authors.affiliation: The Christie, 550 Wilmslow Road, Manchester M20 4BX, UK. Electronic address: Mark.Saunders@christie.nhs.uk.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Saunders
authors.affiliation: University Hospital 'Marqués de Valdecilla', Avda. De Valdecilla 25, 39008 Santander Cantabria, Spain. Electronic address: oncrhf@humv.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.affiliation: IRCCS San Martino IST Hospital, Largo Rosanna Benzi 10, Genova 16132, Italy. Electronic address: alberto.sobrero@hsanmartino.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Sobrero
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA. Electronic address: ABenson@nmff.org.
authors.forename: Al
authors.initials: A
authors.lastname: Benson
authors.affiliation: University Hospital Ramón y Cajal, Carretera de Colmenar Viejo, km. 9,100, 28034 Madrid, Spain. Electronic address: carmenguillenponce@gmail.com.
authors.forename: Carmen
authors.initials: C
authors.lastname: Guillén Ponce
authors.affiliation: University Hospital Riuniti Umberto I, Via Conca, 60126 Ancona, Italy. Electronic address: cascinu@yahoo.com.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: University Hospitals and KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Eric.VanCutsem@uzleuven.be.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. Electronic address: Iain.Macpherson@glasgow.ac.uk.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Macpherson
authors.affiliation: University Hospitals, Marienhospital Herne, Hölkeskampring 40, 44625 Herne, Germany. Electronic address: dirk.strumberg@marienhospital-herne.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
authors.affiliation: Oldenburg Clinic, Rahel-Straus-Straße 10, 26133 Oldenburg, Germany. Electronic address: koehne.claus-henning@klinikum-oldenburg.de.
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: School of Public Health and Preventive Medicine Faculty of Medicine, Nursing and Health Sciences, Monash University, The Alfred Centre, 99 Commercial Rd, Melbourne 3004, Australia. Electronic address: John.Zalcberg@petermac.org.
authors.forename: John
authors.initials: J
authors.lastname: Zalcberg
authors.affiliation: Bayer Pharma AG, Müllerstraße 178, 13353 Berlin, Germany. Electronic address: andrea.wagner2@bayer.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Bayer S.p.A., Viale Certosa 210, 20156 Milan, Italy. Electronic address: VittorioLuigi.Garosi@bayer.com.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Luigi Garosi
authors.affiliation: Bayer Pharma AG, Aprather Weg 18, 42096 Wuppertal, Germany. Electronic address: julia.grunert@bayer.com.
authors.forename: Julia
authors.initials: J
authors.lastname: Grunert
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Second University Hospital, Via S Pansini 5, 80131 Naples, Italy. Electronic address: fortunato.ciardiello@unina2.it.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D065386:Historically Controlled Study; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D002955:Leucovorin; D005472:Fluorouracil
keywords: Colorectal neoplasms; Fluorouracil; Leucovorin; Oxaliplatin; Regorafenib; Safety; Survival rate; Treatment outcome