Interim Analysis of Phase III AVAST-M Trial Shows No Overall Survival Benefit of Adjuvant Bevacizumab vs Observation in High-Risk Melanoma
Bevacizumab has exhibited limited activity in advanced melanoma. In an interim analysis of the open-label phase III AVAST-M trial reported in The Lancet Oncology, Corrie et al found that adjuvant bevacizumab (Avastin) in patients with resected melanoma at high risk of recurrence has thus far produced no overall survival benefit but was well tolerated. Five-year overall survival results are awaited.
Study Details
In the trial, 1,343 patients aged ≥ 16 years with stage IIB, IIC, and III cutaneous melanoma at 48 UK centers were randomly assigned between July 2007 and March 2012 to receive adjuvant bevacizumab at 7.5 mg/kg every 3 weeks for 1 year (n = 671) or observation (n = 672). Randomization was stratified by Breslow thickness of the primary tumor, N stage of the primary tumor, tumor ulceration, and sex. The primary endpoint was overall survival on intent-to-treat analysis. The current results are from a preplanned interim analysis.
The bevacizumab and observation groups were generally balanced for sex (56% male in both), age (median, 56 and 55 years), Breslow thickness (< 2 mm in 30% in both, > 2–4 mm in 30% in both, > 4 mm in 33% and 32%), tumor ulceration (39% and 38%), N stage (N0+Nx in 28% and 27%, N1a–N2a in 21% in both), Eastern Cooperative Oncology Group (ECOG) performance status (0 in 90% and 88%, 1 in 10% and 12%), stage (IIB in 15% and 16%, IIC in 13% and 11%, IIIA in 15% and 14%, IIIB in 26% and 38%, IIIC in 21% in both), sentinel lymph node biopsy (32% and 33%), BRAF status established (45% and 51%, wild-type in 58% and 52% of those), and NRAS status established in BRAF wild-type patients (69% and 66%, wild-type in 56% and 55% of those).
No Overall Survival Difference
Median follow-up was 25 months in both the bevacizumab and observation groups. At interim analysis, death had occurred in 21% of bevacizumab patients and 22% of observation patients, with death from melanoma accounting for 96% and 95% of deaths. Median overall survival had not been reached.
There was no significant difference in overall survival on unadjusted analysis (hazard ratio [HR] = 0.97, P = .76) or after adjustment for stratification factors (HR = 1.03, P = .83). Overall survival at 1 year was 95% vs 94%. On multivariate analysis, disease stage, ECOG performance status, and primary melanoma ulceration were independent predictors of overall survival; there was no difference in overall survival between groups after adjustment for these factors (HR = 1.02, P = .89).
Increased Disease-Free Interval
Disease-free interval was significantly longer in the bevacizumab group (events in 39% vs 45%, HR = 0.83, P = .03); at 1 year, 77% vs 70% of patients were disease-free. The difference was significant among patients with BRAF V600 mutation (HR = 0.60, P = .004) but not among those with wild-type BRAF (HR = 0.87, P = .36). There was no significant difference between groups in distant-metastasis–free interval (HR = 0.88, P = .18).
Adverse Events
The median duration of treatment with bevacizumab was 51 weeks, and dose intensity was 86%. Grade 3 or 4 adverse events occurred in 15% of bevacizumab recipients vs 5% of observation patients, with the most common being hypertension (6% vs < 1%); no other grade 3 or 4 adverse events occurred in > 2% of patients in either group. Three serious adverse events in bevacizumab patients were unexpected; one patient had optic neuritis after the first bevacizumab infusion, one had persistent erectile dysfunction, and one, who was later identified as having predisposing cardiovascular risk factors, died of hemopericardium after two infusions.
No significant differences were observed between groups in standardized area under the curve for any of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire scales over 36 months.
The investigators concluded, “Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.”
Pippa G. Corrie, PhD, of Cambridge University Hospitals NHS Foundation Trust, is the corresponding author for The Lancet Oncology article.
The study was funded by Cancer Research UK. For full disclosures of the study authors, visit www.thelancet.com.
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