title: Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study.
abstract: BACKGROUND
  Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis.
  
  
  METHODS
  We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306.
  
  
  RESULTS
  1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors.
  
  
  CONCLUSIONS
  Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.
authors.affiliation: Cambridge Cancer Trials Centre, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK. Electronic address: pippa.corrie@addenbrookes.nhs.uk.
authors.forename: Pippa G
authors.initials: PG
authors.lastname: Corrie
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Dunn
authors.affiliation: Oxford National Institute for Health Research Biomedical Research Centre, Oxford, UK.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Nathan
authors.affiliation: Royal Marsden Hospital NHS Trust, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.affiliation: Oncology Research, Broomfield Hospital, Chelmsford, UK.
authors.forename: Neville
authors.initials: N
authors.lastname: Davidson
authors.affiliation: Oncology Department, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Nicholson
authors.affiliation: Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle upon Tyne, UK.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Kelly
authors.affiliation: Cancer Research, St James's University Hospital, Leeds, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Marples
authors.affiliation: Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Danson
authors.affiliation: Cancer and Palliative Care, St Helen's Hospital, St Helens, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Marshall
authors.affiliation: Oncology Department, Royal Surrey County Hospital, Surrey, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Houston
authors.affiliation: Oncology Department, Royal Preston Hospital, Preston, UK.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Board
authors.affiliation: Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Ashita M
authors.initials: AM
authors.lastname: Waterston
authors.affiliation: Clinical Oncology, Norfolk and Norwich University Hospital, Norwich, UK.
authors.forename: Jenny P
authors.initials: JP
authors.lastname: Nobes
authors.affiliation: Guy's and St Thomas' Hospital, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harries
authors.affiliation: Velindre Cancer Centre, Cardiff, UK.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Cambridge Cancer Trials Centre/Cambridge Clinical Trials Unit-Cancer Theme, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Young
authors.affiliation: Deptartment of Medical Oncology, Christie Hospital, Manchester, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000517:prevention & control*; D016016:Proportional Hazards Models; D012307:Risk Factors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab