General Information

Avastin (bevacizumab) is a humanized antibody to vascular endothelial growth factor (VEGF).

Avastin is specifically indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is supplied as a solution for intravenous administration. The recommended initial dose of the drug for renal cell carcinoma is 10 mg/kg every 2 weeks in combination with interferon alfa.

Clinical Results

FDA Approval
The FDA approval of Avastin for renal cell carcinoma was based on a multicenter, randomized, double-blind, international study comparing Avastin plus interferon alfa 2a (IFN- a2a) versus placebo plus IFN-a2a. The trial enrolled 649 patients who had undergone a nephrectomy were randomized (1:1) to receive either Avastin (10 mg/kg IV infusion every 2 weeks; n = 327) or placebo (IV every 2 weeks; n = 322) in combination with IFN-a2a (9 MIU subcutaneously three times weekly, for a maximum of 52 weeks). The subjects were treated until disease progression or unacceptable toxicity. The main outcome measure of the study was investigator-assessed progression free survival (PFS). Secondary outcome measures were overall response rate (ORR) and overall survival (OS). PFS was statistically significantly prolonged among patients receiving Avastin plus IFN-a2a compared to those receiving IFN-a2a alone; median PFS was 10.2 months vs. 5.4 months (p-value<0.0001). Among the 595 subjects with measureable disease, ORR was also significantly higher (30% vs. 12% (p < 0.0001). There was no improvement in OS based on the final analysis conducted after 444 deaths, with a median OS of 23 months in the Avastin plus IFN-a2a arm and 21 months in the IFN-a2a plus placebo arm.

Side Effects

Adverse events associated with the use of Avastin may include, but are not limited to, the following:

epistaxis

headache

hypertension

rhinitis

proteinuria

taste alteration

dry skin

rectal hemorrhage

lacrimation disorder

back pain

exfoliative dermatitis

The Avastin drug label comes with the following Black Box Warning: Gastrointestinal Perforations: The incidence of gastrointestinal perforation, some fatal, in patients receiving Avastin ranges from 0.3% to 3%. Discontinue Avastin in patients who develop gastrointestinal perforations. Surgery and Wound Healing Complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in patients receiving Avastin. Discontinue Avastin in patients who develop wound healing complications that require medical intervention. Withhold Avastin 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. Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with a recent history of hemoptysis. Discontinue in patients who develop Grade 3-4 hemorrhage.

Mechanism of Action

Avastin (bevacizumab) is a humanized antibody to vascular endothelial growth factor (VEGF). It binds VEGF and prevents the interaction of VEGF to 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.

Literature References

Bukowski RM Targeted Therapies: Bevacizumab and interferon-alpha in metastatic renal-cell carcinoma. Nature Reviews. Clinical Oncology 2009 May;6(5):253-4

Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology 2008 Nov 20;26(33):5422-8

Melichar B, Koralewski P, Ravaud A, Pluzanska A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Delva R, Sevin E, Négrier S, McKendrick J, Santoro A, Pisa P, Escudier B First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology 2008 Aug;19(8):1470-6

Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N; AVOREN Trial investigators Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007 Dec 22;370(9605):2103-11