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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

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posted on 2017-01-18, 15:55 authored by P. G. Corrie, A. Marshall, J. A. Dunn, M. R. Middleton, P. D. Nathan, M. Gore, N. Davidson, Steve Nicholson, C. G. Kelly, M. Marples, S. J. Danson, E. Marshall, S. J. Houston, R. E. Board, A. M. Waterston, J. P. Nobes, M. Harries, S. Kumar, G Young, P. Lorigan
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. Findings 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. Interpretation Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Funding

We thank all the patients who participated in the AVAST-M trial; all investigators and their research teams; colleagues working in regional cancer networks responsible for referring patients; and the AVAST-M trial coordination team and the National Cancer Research Institute melanoma clinical studies group for their adoption of the trial and support. National Institutes for Health Research funding to the National Clinical Research Network, Biomedical Research Centres and Experimental Cancer Medicine Centres contributed to the undertaking of this trial in various sites. This work was funded by a grant from Cancer Research UK (reference: C7535/A6408 and C2195/A8466). Bevacizumab was provided free of charge by F Hoffman La Roche, Basel, Switzerland. Open Access funded by Cancer Research UK

History

Citation

The Lancet Oncology, 2014; 15: 620–30

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

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  • VoR (Version of Record)

Published in

The Lancet Oncology

Publisher

Elsevier: Lancet

issn

1470-2045

eissn

1474-5488

Available date

2017-01-18

Publisher version

http://www.sciencedirect.com/science/article/pii/S147020451470110X

Language

en

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