Genentech's Avastin

Caryn Domenici, RPh, and Alka Patel, RPh, PharmD
Published Online: Tuesday, May 1, 2007

In February 2004, the FDA approved Avastin (bevacizumab) in combination with intravenous (IV) 5-fluorouracil-based chemotherapy for first-line treatment of metastatic colorectal cancer (MCRC). It was also approved for second-line treatment of MCRC; additionally, in October 2006, it was approved as first-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous, non-small-cell lung cancer (NSCLC), the most common type of lung cancer, in combination with carboplatin and paclitaxel.1

Pharmacology

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that inhibits the activity of human vascular endothelial growth factor (VEGF).2 As VEGF binds to its receptors, it leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Bevacizumab prevents the binding of VEGF to its receptors and is shown to cause the reduction of microvascular growth and inhibition of metastatic disease progression in athymic mice with colon cancer.2

Clinical Trials

Two studies were conducted to evaluate the efficacy and safety of first-line treatment with Avastin for patients with MCRC. The first study was a randomized, double-blind, active-controlled clinical trial, where patients were randomized to bolus-IFL (irinotecan 125 mg/m2, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV given once a week for 4 weeks every 6 weeks) plus placebo (Arm 1); bolus-IFL plus Avastin 5 mg/kg every 2 weeks (Arm 2); or 5-fluorouracil/leucovorin (5-FU/LV) plus Avastin 5 mg/kg every 2 weeks (Arm 3).3 Among the 813 patients randomized, the overall response rate of Arms 1 and 2 was 35% and 45%, respectively (P <.01 by x2 test), with a median duration of response of 7.1 months for Arm 1 and 10.4 months for Arm 2. Of the 110 patients enrolled in Arm 3, the median duration of response was 8.5 months with a 39% overall response rate.2,3

The second study evaluated Avastin in a randomized, active-controlled trial in combination with 5-FU/LV as first-line treatment for MCRC. Patients were randomized to receive either 5-FU/LV (5-fluorouracil 500 mg/m2; leucovorin 500 mg/m2 weekly for 6 weeks every 8 weeks); 5-FU/LV plus Avastin 5 mg/kg every 2 weeks; or 5-FU/LV plus Avastin 10 mg/kg every 2 weeks. The overall response rate was 17% for the 5-FU/LV group; 40% for the 5-FU/LV plus Avastin 5 mg/kg group; and 24% for the 5-FU/LV plus Avastin 10 mg/kg.4

Avastin also was studied for safety and efficacy as a first-line treatment for patients with advanced metastatic or recurrent NSCLC. This was done through a single, large, randomized, active-controlled, open-label, multicenter study (n = 878). Of the 878 participants, 444 were treated with paclitaxel 200 mg/m2 IV over 3 hours with carboplatin, both by IV, over 15 to 30 minutes on day 1 of a 21- day cycle for up to 6 cycles until disease progression or unacceptable adverse events. The other 434 individuals were treated with a paclitaxel regimen plus Avastin 15 mg/kg on day 1 of a 21-day cycle for up to 6 cycles. Then, Avastin was given 15 mg/kg every 3 weeks until disease progression or unacceptable adverse events. The overall response rate for the paclitaxel plus Avastin group was 29%, compared with 12.9% with the group taking paclitaxel alone.5

Safety

The use of Avastin can cause the development of gastrointestinal (GI) perforation, and in some cases may result in death. The incidence of developing GI perforation for patients receiving Avastin for MCRC is 2.4% and 0.9% for patients being treated for NSCLC. The usual presentation of GI perforation was abdominal pain associated with symptoms such as constipation and vomiting. Avastin should be permanently discontinued in patients with GI perforations.1,2

Avastin can cause the development of wound dehiscence and in some instances results in fatality. Patients with wound dehiscence who require medical intervention should discontinue Avastin therapy permanently. Avastin therapy should not be initiated for at least 28 days following major surgery.2 NSCLC patients treated with Avastin can develop fatal pulmonary hemorrhage. Patients with recent episodes of hemoptysis should not receive Avastin. No studies have been documented to examine the pharmacokinetics of Avastin in patients with renal impairment or hepatic dysfunction.

Ms. Domenici and Dr. Patel are both pharmacists at Brigham and Women's Hospital, Boston, Mass.

References

1. Genentech Product Info. Genentech Web site. Available at: www.gene.com. Accessed March 30, 2007.

2. Avastin [package insert]. South San Francisco, Calif: Genentech Inc; 2006.

3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. NEJM. 2004;350:2335-2342.

4. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60-65.

5. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel plus carboplatin with or without bevacizumab (NSC#704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial - E4599. Proc Am Soc Clin Oncol. 2005;23:2s.




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