PDF: AVAglio
(2014)Objective
To determine whether the addition of bevacizumab to standard radiotherapy-temozolomide improves progression-free survival and overall survival in newly diagnosed glioblastoma
Study Summary
• Median OS: 16.8 vs 16.7 months; stratified HR 0.88 (95% CI 0.76-1.02), P=0.10
• 1-year OS: 72.4% vs 66.3% (P=0.049); 2-year OS: 33.9% vs 30.1% (P=0.24)
• Baseline health-related QoL and performance status maintained longer with bevacizumab
• Lower glucocorticoid requirement with bevacizumab
• Higher grade 3+ adverse events with bevacizumab (66.8% vs 51.3%)
• No OS benefit despite significant PFS improvement — pseudoresponse effect
Intervention
Bevacizumab (10 mg/kg IV every 2 weeks) or placebo added to standard RT (60 Gy) + TMZ (75 mg/m2/day), then continued as maintenance with adjuvant TMZ (150-200 mg/m2) for 6 cycles, followed by bevacizumab/placebo monotherapy (15 mg/kg every 3 weeks) until progression
Inclusion Criteria
Age >=18 years; newly diagnosed, histologically confirmed supratentorial glioblastoma; WHO performance status <=2; stable or decreasing glucocorticoids for 5 days before randomization; adequate healing of craniotomy/biopsy site; adequate hematologic, hepatic, and renal function; no recent intracranial hemorrhage on MRI
Study Design
Arms: Array
Patients per Arm: Bevacizumab: 458; Placebo: 463
Outcome
• Co-primary (OS): 16.8 vs 16.7 months; HR 0.88 (0.76-1.02), P=0.10
• 1-year OS: 72.4% vs 66.3% (P=0.049)
• 2-year OS: 33.9% vs 30.1% (P=0.24)
• Grade >=3 AEs: 66.8% vs 51.3%
• QoL and performance status maintained longer with bevacizumab
Bottom Line
Adding bevacizumab to RT/TMZ significantly improved median progression-free survival from 6.2 to 10.6 months (HR 0.64, P<0.001) and maintained baseline quality of life and performance status longer, but did not improve overall survival (16.8 vs 16.7 months, HR 0.88, P=0.10). The PFS benefit was likely influenced by antiangiogenic effects on imaging (pseudoresponse) rather than true antitumor efficacy, and bevacizumab was associated with higher rates of adverse events.
Major Points
- AVAglio (BO21990) was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial conducted at 120 sites in 23 countries, enrolling 921 patients.
- The co-primary endpoints were investigator-assessed PFS and overall survival. The alpha was split asymmetrically: 0.01 for PFS and 0.04 for OS.
- Median PFS was significantly longer with bevacizumab: 10.6 vs 6.2 months (stratified HR 0.64; 95% CI 0.55-0.74; P<0.001). Independent review confirmed: 8.4 vs 4.3 months (HR 0.61; P<0.001).
- Overall survival showed no significant difference: median 16.8 vs 16.7 months (stratified HR 0.88; 95% CI 0.76-1.02; P=0.10).
- Quality of life and functional independence were maintained significantly longer in the bevacizumab group, suggesting clinical benefit despite no OS improvement.
- Glucocorticoid requirements were lower in the bevacizumab group, indicating better control of tumor-associated edema.
- Grade 3 or higher adverse events were more common with bevacizumab (66.8% vs 51.3%), including hypertension, thromboembolic events, and wound healing complications.
- The PFS benefit without OS improvement raised concerns about antiangiogenic pseudoresponse — bevacizumab normalizes the blood-brain barrier, reducing contrast enhancement on MRI without necessarily slowing tumor growth.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, and independent radiologic reviewers)
- Sample Size
- 921
- Follow-up
- Median 20.5 months at primary analysis
- Centers
- 120
- Countries
- 23 countries
Primary Outcome
Definition: PFS (investigator-assessed): 10.6 vs 6.2 months; stratified HR 0.64 (95% CI 0.55-0.74); P<0.001 | OS: 16.8 vs 16.7 months; stratified HR 0.88 (95% CI 0.76-1.02); P=0.10
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.64 (0.55-0.74) | P<0.001 |
Citation
N Engl J Med 2014;370:709-22