title: A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated.
  
  
  METHODS
  Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  Patients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups.
  
  
  CONCLUSIONS
  The efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.
authors.affiliation: Poole Hospital and Bournemouth University, Longfleet Road, Poole, Dorset BH15 2JB, UK. Electronic address: tamas.hickish@rbch.nhs.uk.
authors.forename: Tamas
authors.initials: T
authors.lastname: Hickish
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Cassidy
authors.affiliation: Experimental Cancer Centre, Barts Cancer Institute, Queen Mary, University of London, St Bartholomew's Hospital, London EC1M 6BQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.affiliation: Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.affiliation: Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Horfield Road, Bristol BS2 8ED, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Falk
authors.affiliation: Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Box 193, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Hugo
authors.initials: H
authors.lastname: Ford
authors.affiliation: Department of Medical Oncology, Southampton University Hospitals NHS Foundation Trust, Mailpoint 307, Tremona Road, Southampton SO16 0YD, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Iveson
authors.affiliation: Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Braun
authors.affiliation: Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Potter
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Macpherson
authors.affiliation: Biometrics and Data Management, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell, Berkshire RG12 8YS, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Finnigan
authors.affiliation: Clinical Research Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell, Berkshire RG12 8YS, UK.
authors.forename: Chooi
authors.initials: C
authors.lastname: Lee
authors.affiliation: Clinical Research Department, Boehringer Ingelheim Ltd, Ellesfield Avenue, Bracknell, Berkshire RG12 8YS, UK.
authors.forename: Hilary
authors.initials: H
authors.lastname: Jones
authors.affiliation: Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harrison
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000284:Administration, Oral; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002430:Cecal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000077716:Afatinib; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: Afatinib; Cetuximab; Colorectal cancer; KRAS mutations