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Recurrent Glioblastoma: Avastin Efficacy Data

Recurrent glioblastoma (rGBM)
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

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%) 

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] 

Important Safety Information & Indication

Indication

Recurrent glioblastoma (rGBM)

Avastin is indicated for the treatment of recurrent glioblastoma in adults.

Serious adverse reactions (Warnings and Precautions)

  • Serious and sometimes fatal adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Gastrointestinal (GI) perforation ranged from 0.3% to 3% of patients across clinical studies
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (Grade ≥3, 5%, highest in patients with GBM)
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Hemorrhage (Grade 3–5) ranged from 0.4% to 7% of patients across clinical studies
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (Grade ≥3, 11% seen in GOG-0240)
    • Hypertension (Grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF): Grade ≥3 left ventricular dysfunction (1%)
  • Infusion-related reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.4% of patients
  • Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
  • Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin
  • An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women not to breastfeed during treatment with Avastin and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse reactions

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% were:
    • Epistaxis
    • Headache
    • Hypertension
    • Rhinitis
    • Proteinuria
    • Taste alteration
    • Dry skin
    • Hemorrhage
    • Lacrimation disorder
    • Back pain
    • Exfoliative dermatitis

  • Across all studies, Avastin was discontinued in 8% to 22% of patients because of adverse reactions

Indication-specific adverse reactions

  • In rGBM Study EORTC 26101, the incidence of Grade 3–4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving chemotherapy alone. In this study, 22% of patients discontinued treatment in the Avastin with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information for additional important safety information.

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      Avastin Prescribing Information. Genentech, Inc. 2022.

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