← Back

RTOG 0825

A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma

Share Share Copied! Compare

Year of Publication: 2014

Authors: Mark R. Gilbert, James J. Dignam, Terri S. Armstrong, ..., Minesh P. Mehta

Journal: New England Journal of Medicine

Citation: N Engl J Med 2014;370:699-708

Link: https://doi.org/10.1056/NEJMoa1308573

PDF: https://doi.org/10.1056/NEJMoa1308573

Clinical Question

Does adding bevacizumab to standard radiotherapy-temozolomide improve overall survival or progression-free survival in patients with newly diagnosed glioblastoma?

Bottom Line

Adding bevacizumab to standard RT/TMZ did not improve overall survival (15.7 vs 16.1 months, HR 1.13, P=0.21). Progression-free survival was prolonged (10.7 vs 7.3 months, HR 0.79, P=0.007) but did not meet the prespecified significance threshold (P<0.004). Bevacizumab was associated with worse neurocognitive function and quality of life over time, in contrast to the AVAglio trial findings. No molecular subgroup benefited.

        Major Points
        RTOG 0825 was a US cooperative group randomized, double-blind, placebo-controlled, phase 3 trial enrolling 637 patients with newly diagnosed GBM from April 2009 to May 2011.
The co-primary endpoints were overall survival and progression-free survival, with a threshold of P<0.046 for OS and P<0.004 for PFS to control the type I error rate.
Median overall survival was 15.7 months with bevacizumab and 16.1 months with placebo (HR 1.13; 95% CI 0.93-1.37; P=0.21) — a numerical trend toward harm.
Median PFS was 10.7 vs 7.3 months (HR 0.79; 95% CI 0.66-0.94; P=0.007), but this did not meet the prespecified threshold of P<0.004.
No subset showed improved overall survival with bevacizumab — including analyses by MGMT status, molecular profile (9-gene assay), and RPA class.
A unique feature was the neurocognitive benefits (NCB) substudy: bevacizumab was associated with greater deterioration over time on multiple measures including the MDASI-BT composite symptom score, cognitive functioning (HVLT-R, TMT, COWA), motor dysfunction, and communication deficit.
Quality of life was worse with bevacizumab over time on both MDASI-BT and EORTC QLQ-C30/BN20 instruments — the opposite of AVAglio findings, possibly due to differences in assessment methodology and timing.
The key difference from AVAglio: RTOG 0825 incorporated mandatory MGMT and molecular profiling, started bevacizumab later (week 4 vs week 1), and included an extensive neurocognitive battery revealing harms masked in AVAglio.

      

Design

Study Type: Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial

Randomization: 1

Blinding: Double-blind (patients and investigators); permuted-block design stratified by molecular factors

Enrollment Period: April 2009 - May 2011

Follow-up Duration: Median 20.5 months

Centers: 0

Countries: USA

Sample Size: 637

Analysis: Intention-to-treat; stratified log-rank test; Cox proportional hazards; co-primary endpoints with split alpha (OS P<0.046, PFS P<0.004); 80% power to detect 25% RRR in death and 30% RRR in progression/death

Baseline Characteristics

Characteristic	Control	Active

Arms

Field	Experimental	Control
Intervention	Bevacizumab 10 mg/kg IV Q2W (starting week 4 of RT) + RT (60 Gy) + daily TMZ 75 mg/m2, then bevacizumab 10 mg/kg Q2W + adjuvant TMZ 150-200 mg/m2 (up to 12 cycles) until progression	Placebo Q2W + RT (60 Gy) + daily TMZ, then placebo Q2W + adjuvant TMZ (up to 12 cycles)
Duration

Outcomes

Outcome	Type	HR / OR / RR	P-value
OS: 15.7 vs 16.1 months; HR 1.13 (95% CI 0.93-1.37); P=0.21 \| PFS: 10.7 vs 7.3 months; HR 0.79 (95% CI 0.66-0.94); P=0.007 (did not meet P<0.004 threshold)	Primary	1.13	P=0.21
1-year OS: similar between groups; 2-year OS: similar between groups	Secondary
Neurocognitive function: greater deterioration with bevacizumab (COWA P=0.003, TMT-A P=0.04, HVLT-R P=0.01)	Secondary		P=0.003
QoL worse with bevacizumab: MDASI-BT composite symptom P=0.02, cognitive functioning P=0.01	Secondary		P=0.02
Hypertension grade >=3: 4.2% vs 0.9%; thromboembolic disease: 7.7% vs 4.7%	Secondary
Visceral perforation: 1.2% vs 0.4%; wound dehiscence: 1.5% vs 0.9%	Secondary
Neutropenia grade >=3: 7.3% vs 3.7%; thrombocytopenia grade >=3: 10.2% vs 7.7%	Secondary

Funding

National Cancer Institute (NCI); unrestricted educational grant from Genentech (provided bevacizumab, no role in design or analysis)

Based on: RTOG 0825 (New England Journal of Medicine, 2014)

Authors: Mark R. Gilbert, James J. Dignam, Terri S. Armstrong, ..., Minesh P. Mehta

Citation: N Engl J Med 2014;370:699-708

Content summarized and formatted by NeuroTrials.ai.

RTOG 0825

(2014)

Objective

To determine whether adding bevacizumab to standard radiotherapy-temozolomide improves overall survival and progression-free survival in newly diagnosed glioblastoma

Study Summary

• Median OS: 15.7 months (bevacizumab) vs 16.1 months (placebo); HR 1.13 (95% CI 0.93-1.37), P=0.21
• Median PFS: 10.7 vs 7.3 months; HR 0.79 (95% CI 0.66-0.94), P=0.007 (did not meet prespecified threshold of P<0.004)
• No subset with improved OS from bevacizumab (MGMT status, molecular profile, or RPA class)
• Greater neurocognitive decline and worse symptom burden with bevacizumab over time
• Worse QoL measures in bevacizumab group (MDASI-BT, EORTC QLQ-C30/BN20)
• Increased hypertension (4.2% vs 0.9%), thromboembolic disease (7.7% vs 4.7%), and intestinal perforation (1.2% vs 0.4%)

Intervention

Bevacizumab (10 mg/kg IV every 2 weeks starting week 4 of RT) or placebo added to standard RT (60 Gy) + daily TMZ (75 mg/m2), followed by maintenance TMZ (150-200 mg/m2, up to 12 cycles) + bevacizumab/placebo (10 mg/kg every 2 weeks) until progression

Inclusion Criteria

Age >=18 years; newly diagnosed, centrally confirmed glioblastoma (WHO grade IV); KPS >=70; adequate hematologic, renal, and hepatic function; no active cardiac disease or recent cerebrovascular events; stable or decreasing glucocorticoids; no recent intracranial hemorrhage; tumor tissue block with >=1 cm2 surface area submitted

Study Design

Arms: Array

Patients per Arm: Bevacizumab: 312 analyzed; Placebo: 309 analyzed

Outcome

• Co-primary (OS): 15.7 vs 16.1 months; HR 1.13 (0.93-1.37), P=0.21
• Co-primary (PFS): 10.7 vs 7.3 months; HR 0.79 (0.66-0.94), P=0.007 (did not meet P<0.004 threshold)
• Neurocognitive decline greater with bevacizumab
• QoL worse with bevacizumab over time
• Hypertension: 4.2% vs 0.9%; thromboembolism: 7.7% vs 4.7%
• No subgroup benefited in OS

Bottom Line

Major Points

RTOG 0825 was a US cooperative group randomized, double-blind, placebo-controlled, phase 3 trial enrolling 637 patients with newly diagnosed GBM from April 2009 to May 2011.
The co-primary endpoints were overall survival and progression-free survival, with a threshold of P<0.046 for OS and P<0.004 for PFS to control the type I error rate.
Median overall survival was 15.7 months with bevacizumab and 16.1 months with placebo (HR 1.13; 95% CI 0.93-1.37; P=0.21) — a numerical trend toward harm.
Median PFS was 10.7 vs 7.3 months (HR 0.79; 95% CI 0.66-0.94; P=0.007), but this did not meet the prespecified threshold of P<0.004.
No subset showed improved overall survival with bevacizumab — including analyses by MGMT status, molecular profile (9-gene assay), and RPA class.
A unique feature was the neurocognitive benefits (NCB) substudy: bevacizumab was associated with greater deterioration over time on multiple measures including the MDASI-BT composite symptom score, cognitive functioning (HVLT-R, TMT, COWA), motor dysfunction, and communication deficit.
Quality of life was worse with bevacizumab over time on both MDASI-BT and EORTC QLQ-C30/BN20 instruments — the opposite of AVAglio findings, possibly due to differences in assessment methodology and timing.
The key difference from AVAglio: RTOG 0825 incorporated mandatory MGMT and molecular profiling, started bevacizumab later (week 4 vs week 1), and included an extensive neurocognitive battery revealing harms masked in AVAglio.

Study Design

Study Type: Randomized, double-blind, placebo-controlled, multicenter, phase 3 trial
Randomization: Yes
Blinding: Double-blind (patients and investigators); permuted-block design stratified by molecular factors
Sample Size: 637
Follow-up: Median 20.5 months
Countries: USA

Primary Outcome

Definition: OS: 15.7 vs 16.1 months; HR 1.13 (95% CI 0.93-1.37); P=0.21 | PFS: 10.7 vs 7.3 months; HR 0.79 (95% CI 0.66-0.94); P=0.007 (did not meet P<0.004 threshold)

Control	Intervention	HR/OR	P-value
		1.13 (0.93-1.37)	P=0.21

Citation

N Engl J Med 2014;370:699-708

View Original Publication →

RTOG 0825

A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Funding

Ask about RTOG 0825