Recurrent Glioblastoma: Avastin Efficacy Data

Recurrent glioblastoma (GBM)
Avastin is indicated for the treatment of recurrent glioblastoma in adults.

For adult glioblastoma patients with progressive disease following prior therapy

The EORTC 26101 study was a randomized, multicenter, open-label Phase III trial comparing the efficacy of Avastin plus lomustine vs lomustine alone.

The Phase III EORTC 26101 study: Efficacy data overview

Endpoint   Avastin + chemotherapy Chemotherapy alone HR (95% CI) P value
  Number of patients 283 149    
Primary OS (median) There was no difference in median OS between study arms 0.91 0.4578
Secondary PFS (median) 4.2 months 1.5 months 0.52 (0.41–0.64)  

No difference in OS (HR=0.91, P=0.4578) was observed between arms; therefore, all secondary outcome measures are descriptive only

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

Avastin plus chemotherapy prolonged PFS compared to chemotherapy alone in patients with previously treated GBM[1]

  • 2.7-month increase in median PFS: 4.2 months with Avastin plus lomustine vs 1.5 months with lomustine alone

Corticosteroid use

  • Among the 50% of patients receiving corticosteroids at the time of randomization, a higher percentage of patients in the Avastin with lomustine arm discontinued corticosteroids (23% vs 12%)

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

The EORTC 26101 study: Study design [1,25]

  • Patients were randomized to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n=283) plus lomustine (90 mg/m2 [maximum dose 160 mg] every 6 weeks) or lomustine (n=149) until disease progression or unacceptable toxicity

Patient eligibility criteria[25]

Inclusion criteria Exclusion criteria
  • Patients 18 years of age or older
  • Previously treated (RT concurrent/adjuvant chemotherapy, at least 3 months off the concomitant part of the chemoradiotherapy), histologically confirmed glioblastoma

 

 

 

 

  • Current or recent (within 4 weeks before randomization) treatment with another investigational agent
  • Prior treatment with bevacizumab or other VEGF inhibitors or VEGF-receptor signaling inhibitors
  • Major non–tumor-related surgery within 4 weeks prior to randomization or anticipation of the need for major surgery during the course of treatment
  • ATE or VTE ≤6 months prior to randomization
  • History of stroke or TIAs within 6 months prior to randomization
  • History of pulmonary hemorrhage/hemoptysis grade ≥2 according to the NCI-CTCAE version 4.0 criteria within 1 month prior to randomization

EORTC=European Organisation for Research and Treatment of Cancer; HR=hazard ratio; CI=confidence interval; OS=overall survival; PFS=progression-free survival; IV=intravenous; RT=radiation therapy; VEGF=vascular endothelial growth factor; ATE=arterial thromboembolism; VTE=venous thromboembolism; TIA=transient ischemic attack; NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

The BRAIN study (AVF3708g): Efficacy data overview

Single-agent Avastin demonstrated an objective response for a clinically meaningful duration[1,26]

Endpoint   Single-agent Avastin 95% CI
  Number of patients 85  
Primary Objective response rate* 25.9% 17.0–36.1
Secondary Median duration of response* 4.2 months 3.0–5.7

*Objective response rate and median duration of response were measured by a blinded independent review facility.

The BRAIN study: Study design and patient population

  • The BRAIN study was an open-label, multicenter, randomized, noncomparative Phase II study involving 167 patients with recurrent glioblastoma (rGBM) previously treated with temozolomide (TMZ) and RT. Patients were randomized to receive either Avastin alone (n=85) or Avastin plus irinotecan (n=82) for up to 104 weeks[1,3,26]
    • Inclusion criteria: Prior RT (completed ≥8 weeks prior) and previous treatment with TMZ; ≥4 weeks postsurgery; Karnofsky performance status (KPS) ≥70 was required
    • Exclusion criterion: Active brain hemorrhage
    • Patient characteristics in the single-agent Avastin arm (n=85): median age, 54 years; 32% female; 81% in first relapse; KPS ≥90 in 45% of patients, and between 70 and 80 in 55% of patients

Response assessment was based on World Health Organization (WHO) radiographic criteria and stable or decreasing steroid use in the BRAIN study[1,3]

Criteria for objective response
WHO criteria: ≥50% reduction in enhancing tumor based on MRI assessment
+
Stable or reduced steroid use
+
Confirmed on 2 consecutive assessments ≥4 weeks apart

MRI=magnetic resonance imaging.
and qualitative assessment of non-enhancing tumor.[3,26]

  • Radiologic assessment was based on MRI (using T1 and T2/fluid-attenuated inversion recovery [FLAIR] sequences); MRI does not necessarily distinguish between tumor, edema, and radiation necrosis[1,26]
  • Clinical assessments and MRI, using T1 and T2/FLAIR sequences, were independent review facility (IRF)–assessed by 2 different radiologists and an oncologist[1,3]

In the BRAIN study, stable or decreasing steroid use was required for an objective response[1,3]

Single-agent Avastin outcomes were confirmed in a supportive study conducted by the National Cancer Institute[1,3]

Endpoint   Single-agent Avastin 95% CI
  Number of patients 56  
Primary Objective response rate 19.6% 10.9–31.3
Secondary Median duration of response 3.9 months 2.4–17.4

Confirmed by an IRF.[1,3]