Pharmacology Update

Bevacizumab Injection (Avastin)

By William T. Elliott, MD, FACP and James, Chan, PhD, PharmD

The FDA has approved the first antineoplastic that acts by the inhibiting the formation of new blood vessels in tumors. Genentech’s bevacizumab, which is approved for the treatment of metastatic colorectal cancer, is a recombinant monoclonal antibody that binds vascular endothelial cell growth factor (VEGF). VEGF is believed to be one of the more important factors responsible for normal as well as abnormal angiogenesis.1 Bevacizumab is marketed by Genentech as Avastin.

Indications

Bevacizumab is approved for use in combination with intravenous 5-fluorouracil-based chemotherapy as first-line treatment of patients with metastatic carcinoma of the colon or rectum.2

Dosage

The recommended dose is 5 mg/kg once every 14 days until disease progression. The drug is administered as an intravenous infusion over 90 minutes. If the first infusion is well tolerated, the second infusion may be given over 60 minutes. If the 60-minute infusion is well tolerated, then subsequent infusion may be given over 30 minutes. A minimum of 28 days should elapse following major surgery and surgical incisions are completely healed before the initiation of bevacizumab therapy.2

Bevacizumab is available as 100 mg (4 mL) and 400 mg (16 mL) single-use vials.

Potential Advantages

The addition of bevacizumab (5 mg/kg) to a regimen of 5-fluorouracil and leucovorin (5-FU/LV) improved time to disease progression and response rate compared to 5-FU/LV alone.2,3 The median time to progression was 9 months vs 5.2 months (P = .005).2,3 Response rates were 40% vs 17% respectively (P = .029). The addition of bevacizumab to irinotecan/5-FU/LV also showed improvement in time to disease progression (10.6 vs 6.4 months; P < .001) and response rate (45% vs 35%; P < .001).2

Potential Disadvantages

Common serious side effects include GI hemorrhage (19-24%), hypertension (23-34%), epistaxis (32-35%), proteinuria (36%), and thromboembolic events (6-9%).2,3 Less common and serious side effects include gastrointestinal perforation and wound dehiscence.2

Comments

Bevacizumab is the first drug to affect angiogenesis. This is based on an anti-VEGF mechanism. VEGF is a cytokine that binds to receptors on the vascular endothelium and results in endothelial cell migration and proliferation, and protects against endothelial cell apoptosis.4 The approval for the treatment of colorectal cancer was based on two clinical trials with time to progression and response rate as primary efficacy end points. One involved adding bevacizumab to 5FU/LV (n = 104) and the other to irinotecan (IFL) and 5FU/LV (n = 813). Both studies showed improved response rate and time to progression. The difference in time to progression is about 4 months. Overall survival was longer with bevacizumab, IFL and 5FU/LV compared to IFL and 5FU/LV (20.3 months vs 15.6 months; P < .001). However, overall survival was not significantly different in the bevacizumab 5FU/LV study. Side effects include thromboembolic events (eg, deep vein thrombosis), hypertension, proteinuria, and epistaxis. Bevacizumab has been reported to prolong the time to progression in patients with metastatic renal-cell cancer.5 The median time to survival was 4.8 months compared to 2.5 months for placebo. Bevacizumab is also being evaluated in other tumors such as non-small cell lung, prostate, and breast cancers. Wholesale cost for one month of therapy ranges from $3300-$4400, depending on the weight of the patient.

Clinical Implications

Colorectal cancer is the third leading cause of cancer death worldwide.6 Treatment for metastatic colorectal cancer has generally involved irinotecan with 5-fluorouracil and leucovorin or oxaliplatin with 5-fluorouracil and leucovorin. Introduction of bevacizumab provides another treatment option. Other novel therapies are on the horizon. Another monoclonal antibody, cetuximab, selective for epidermal growth factor receptor is also being evaluated for colorectal cancer.7

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.

References

1. Ferrara N, et al. Endocr Rev. 1997;18:4-25.

2. Avastin Product Information. Genentech, Inc. February 2004.

3. Kabbinavar F, et al. J Clin Oncol. 2003;21:60-65.

4. Ellis LM. J Clin Oncol. 2003;21(suppl):281-283.

5. Yang JC et al. N Engl J Med. 2003;349:427-34.

6. Gill S, Goldberg R. Drugs. 2004;64(1):27-44.

7. Saltz LB et al. J Clin Oncol. 2004;10:182.