Recurrent Glioblastoma: Avastin Efficacy Data

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% Cl)
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-value of 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 [1,49]

  • 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  [49]

Inclusion 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
Exclusion criteria
  • 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; OS=overall survival; PFS=progression-free survival.

The BRAIN study (AVF3708g): Efficacy data overview

Single-agent Avastin demonstrated an objective response for a clinically meaningful duration [1,9]

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

CI=confidence interval
*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 radiotherapy (RT). Patients were randomized to receive either Avastin alone (n=85) or Avastin plus irinotecan (n=82) for up to 104 weeks [1,3,9]
    • Inclusion criteria: Prior RT (completed ≥8 weeks prior) and previous treatment with TMZ; ≥4 weeks postsurgery; Karnofsky performance status (KPS) ≥70 was required [1,3,9]
    • Exclusion criterion: Active brain hemorrhage [1,3,9]
    • 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 [1,3,9]

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
  • 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[1,9]
  • 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 (NCI) [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

Indications

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

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% across clinical studies
    • Discontinue Avastin in patients with GI perforation
  • Surgery and wound healing complications
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • 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, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events 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) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

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 that breastfeeding is not recommended during treatment with Avastin and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • 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
— Rectal 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 events

  • In rGBM Study EORTC 26101, 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, including Boxed WARNINGS, for additional important safety information.