Recurrent Glioblastoma: Avastin Efficacy Data


Avastin® (bevacizumab) is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [1]

For adult glioblastoma patients with progressive disease following prior therapy…

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]

Avastin is not approved for use in combination with irinotecan or any other combination regimens. [1]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

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 radiographic response criteria based on MRI assessment
+
Stable or reduced steroid use
+
Confirmed on 2 consecutive assessments ≥4 weeks apart

and qualitative assessment of nonenhancing tumor. [3,9]

  • 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

CI=confidence interval.
Confirmed by an independent review facility (IRF).
[1,3]

The NCI study: Study design and patient population

  • The NCI study was a Phase II, single-arm, single-institution trial involving patients (N=56) with recurrent glioblastoma (rGBM) [1,43]
    • Inclusion criteria: documented disease progression after previous treatment with temozolomide and radiotherapy; Karnofsky performance status (KPS) ≥60 was required [1,43]
    • Patient characteristics: median age, 54 years; 54% male; 98% Caucasian; KPS ≥90 in 68% of patients [1,43]

Indications

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 3.2% 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
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined
    • Discontinue Avastin at least 28 days prior to elective surgery and 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. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 6.9% 
    • Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) 
    • Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), 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
  • Avastin may impair fertility

Most common adverse events

  • Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate 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 8.4% to 21% of patients because of adverse reactions

Indication-specific adverse events

  • In GBM Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection 
  • In GBM patients receiving Avastin alone or Avastin plus irinotecan,a the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and PRES (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

aAvastin is not approved for use in combination with irinotecan or any other combination regimens.

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.