General Information

Avastin is an anti-VEGF monoclonal antibody for the treatment of solid tumors.

Avastin, used in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum.

The recommended dose of Avastin is 5 mg/kg given once every 14 days as an IV infusion until disease progression is detected.

Clinical Results

FDA approval of Avastin for colorectal cancer was based on two (STUDY 1 / STUDY 2) randomized, controlled trials in combination with intravenous 5-fluorouracil-based chemotherapy.

Study 1 was a double-blind trial enrolling 813 subjects with metastatic carcinoma of the colon or rectum. Subjects were randomized to bolus-IFL (irinotecan 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks) (Arm 2) or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Among the subjects, 57% had an ECOG performance status of 0. The primary endpoint of this trial was overall survival. Results showed that the overall survival in Arms 1 & 2 was 20.3 months with Avastin compared with 15.6 months with placebo. The median progression-free survival was 10.6 months with Avastin compared with 6.4 months with placebo. Data showed that the median overall survival in Arm 3 was 18.3 months, median progression-free survival was 8.8 months, overall response rate was 39%, and median duration of response was 8.5 months.

Study 2 tested Avastin in combination with 5-FU/LV and enrolled as first-line treatment of metastatic colorectal cancer. Subjects were randomized to receive 5-FU/LV (5-fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks) or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) or 5-FU/LV plus Avastin (10 mg/kg every 2 weeks). The primary endpoints of the trial were objective response rate and progression-free survival. Results showed that progression-free survival was significantly better in subjects receiving 5-FU/LV plus Avastin at 5 mg/kg when compared to those not receiving Avastin. However, overall survival and overall response rate were not significantly different. Results for subjects receiving 5-FU/LV plus Avastin at 10 mg/kg were not significantly different than without Avastin.

Side Effects

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

Asthenia

Abdominal Pain

Pain

Deep Vein Thrombosis

Hypertension

Intra-Abdominal Thrombosis

Syncope

Diarrhea

Constipation

Leukopenia

Neutropenia

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

Bevacizumab 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.

In preclinical studies, administration of bevacizumab to xenotransplant models of colon cancer in nude mice caused reduction of microvascular growth and inhibition of metastatic disease progression. In January 2000, preclinical results showed that bevacizumab was more effective at preventing growth of tumor cell lines in animal models when it was combined with sub-threshold doses of cisplatin or trastuzumab.

Literature References

Folprecht G, Kohne CH.The role of new agents in the treatment of colorectal cancer. Oncology. 2004;66(1):1-17

Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593-9

Salgaller ML Technology evaluation: bevacizumab, Genentech/Roche. Curr Opin Mol Ther. 2003 Dec;5(6):657-67.