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Bevacizumab in Recurrent Glioblastoma


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On December 5, 2017, bevacizumab (Avastin) was granted regular approval for the treatment of recurrent glioblastoma in adults.1 Bevacizumab was granted accelerated approval in May 2009 for use in treating patients with glioblastoma who had disease progression on prior therapy.

Supporting Efficacy Data

Regular approval was based on the totality of evidence for the benefit of bevacizumab in patients with glioblastoma, including the phase III European Organisation for Research and Treatment of Cancer (EORTC) 26101 trial (ClinicalTrials.gov identifier NCT01290939).1,2 In the trial, adding bevacizumab to lomustine failed to improve overall survival, the primary endpoint, but did improve progression-free survival, a secondary endpoint, compared to lomustine alone. A total of 432 patients with first disease progression following treatment with radiotherapy and temozolomide were randomized 2:1 to receive bevacizumab at 10 mg/kg every 2 weeks with lomustine (Gleostine) at 90 mg/m2 every 6 weeks (n = 283) or lomustine at 110 mg/m2 every 6 weeks (n = 149) until disease progression or unacceptable toxicity.

OF NOTE

Bevacizumab labeling has boxed warnings for gastrointestinal perforation, surgery and wound healing complications, and hemorrhage.

Randomization was stratified by World Health Organization (WHO) performance status, steroid use, largest tumor diameter, and institution. The primary endpoint was overall survival; investigator-assessed progression-free survival was a secondary endpoint.

Patients had a median age of 57 years (25% ≥ 65 years), 61% were male, 66% had a WHO performance status score > 0, and 56% had a largest tumor diameter ≤ 40 mm. Approximately 33% of patients randomized to receive lomustine received bevacizumab following disease progression.

No difference in overall survival was observed between the bevacizumab plus lomustine vs lomustine-alone groups. However, median progression-free survival was improved in the group receiving bevacizumab plus lomustine ( 4.2 vs 1.5 months; HR = 0.52, 95% confidence interval = 0.41–0.64). Among the 50% of patients receiving corticosteroids at randomization, 23% vs 12% discontinued corticosteroid treatment.

How It Works

Bevacizumab binds vascular endothelial growth factor (VEGF), preventing the interaction of VEGF with its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis.

How It Is Used

The recommended dose of bevacizumab in recurrent glioblastoma is 10 mg/kg intravenously every 2 weeks.

Bevacizumab should be withheld at least 28 days prior to elective surgery. In patients undergoing surgery, bevacizumab should not be given until ≥ 28 days following surgery and full healing of the wound.

EXPANDED APPROVAL OF BEVACIZUMAB

  • Bevacizumab (Avastin) was granted regular approval for the treatment of recurrent glioblastoma
    in adults.
  • The recommended dose of bevacizumab in recurrent glioblastoma is 10 mg/ kg intravenously every 2 weeks.

Bevacizumab treatment should be discontinued for the following adverse reactions: gastrointestinal reactions including any-grade gastrointestinal perforation, any-grade tracheoesophageal fistula, grade 4 fistula, and fistula formation involving any internal organ; wound-healing complications requiring medical intervention and necrotizing fasciitis; grade 3 or 4 hemorrhage; severe arterial thromboembolism and grade 4 venous thromboembolism; hypertensive crisis and hypertensive encephalopathy; any posterior reversible encephalopathy syndrome; nephrotic syndrome; severe infusion reaction; and any congestive heart failure.

Treatment should be withheld in patients with a recent history of hemoptysis of at least one-half teaspoon (2.5 mL). In patients with severe hypertension, treatment should be withheld until hypertension is controlled with medical management and can be resumed when control is achieved. In patients with proteinuria ≥ 2 g per 24 hours in the absence of nephrotic syndrome, treatment should be withheld until proteinuria drops below 2 g/24 hours.

In patients with clinically significant infusion reactions, infusion should be interrupted and resumed at a reduced rate once symptoms resolve. In those with mild, clinically insignificant reactions, the infusion rate should be reduced.

Safety Profile

In the EORTC 26101 trial, adverse events led to treatment discontinuation in 22% of the bevacizumab plus lomustine group vs 10% of the lomustine-alone group. Patients in the bevacizumab plus lomustine group had an adverse event profile similar to that observed in other approved indications. Overall, the most common adverse events (incidence > 10%) in patients receiving bevacizumab in clinical trials have been epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Bevacizumab labeling has boxed warnings for gastrointestinal perforation; surgery and wound-healing complications; and hemorrhage, including severe and fatal hemorrhage.

Bevacizumab also carries warnings/precautions for perforation or fistula, arterial thromboembolic events, venous thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, renal injury and proteinuria, infusion reactions, embryofetal toxicity, ovarian failure, and congestive heart failure. ■

REFERENCES

1. Avastin (bevacizumab) injection prescribing information, Genentech, Inc, December 2017. Available at www.gene.com/download/pdf/avastin_prescribing.pdf. Accessed February 21, 2018.

2. Wick W, Gorlia T, Bendszus M, et al: Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377:1954-1963, 2017.

REPORT ADVERSE EVENTS

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


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