Recurrent Glioblastoma: Avastin Safety Profile


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]

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

Pooled and single-agent safety from the BRAIN study [1,3,9]

Incidence of Avastin-related adverse events [1,3,9]

Adverse events Pooled (%)
(N=163)
Single-agent Avastin (planned treatment period) (%)
(n=84)
  Grade 1–4 Grade 3–5 Any grade Grade 3–5
Bleeding/hemorrhage 40 2 27 0
Epistaxis 26 0 19 0
Central nervous system (CNS) hemorrhage 5 1 2 0
Hypertension 32 5 30 8
Venous thromboembolic event 8 7 4 4
Arterial thromboembolic event 6 3 5 2
Wound healing complications 6 3 6 2
Proteinuria 4 1 5 0
Gastrointestinal (GI) perforation 2 2 0 0
Reversible posterior leukoencephalopathy syndrome 1 0 0 0
  • The pooled safety data for Avastin-related events combined all adverse events recorded in the BRAIN study, including [1,3]
    • Single-agent Avastin treatment arm
    • Avastin plus irinotecan* treatment arm
  • There were 2 deaths in the study possibly related to Avastin 
    • 1 death due to neutropenic infection in the single-agent Avastin arm
    • 1 death due to retroperitoneal hemorrhage in the Avastin plus irinotecan* arm
  • Postoperative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in 3/84 (4.0%) patients in the single-agent Avastin treatment arm and 1/79 (1.0%) patients in the Avastin plus irinotecan* treatment arm [1]

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

Pooled reports of CNS bleeding from the BRAIN study (N=163) [3]

Grade Number of patients (%)
1 5 (3%)
2 1 (0.6%)
3 1 (0.6%)
4 1 (0.6%)
  • Intracranial hemorrhage occurred in 8 of 163 patients with previously treated GBM; 2 patients had grade 3–4 hemorrhage [1]

Single-agent Avastin safety profile from the BRAIN study [1,9]

Most frequently reported adverse events with Avastin alone [1,9]

  All grades (%) Grade ≥3 (%)
Infection 55 10
Fatigue 45 4
Headache 37 4
Hypertension 30 8
Epistaxis 19 0
Diarrhea 21 1
  • 2 patients (2.4%) experienced grade 1 intracranial hemorrhage in the single-agent Avastin arm [3,9]
  • 4.8% of patients (4/84) discontinued single-agent Avastin due to treatment toxicity [1,9]
  • There was no incidence of any grade of GI perforation in the single-agent Avastin arm. The incidences of GI perforation, some fatal, in Avastin-treated patients ranged from 0.3% to 3.2% across clinical trials for all indications [1,3]

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.