Genentech's Avastin

In February 2004, the FDA approvedAvastin (bevacizumab) in combinationwith intravenous (IV) 5-fluorouracil-based chemotherapy for first-line treatmentof metastatic colorectal cancer(MCRC). It was also approved for second-linetreatment of MCRC; additionally, inOctober 2006, it was approved as first-linetreatment of unresectable, locallyadvanced, recurrent, or metastatic nonsquamous,non-small-cell lung cancer(NSCLC), the most common type of lungcancer, in combination with carboplatinand paclitaxel.¹

Pharmacology

Bevacizumab is a recombinant humanizedmonoclonal IgG1 antibody thatinhibits the activity of human vascularendothelial growth factor (VEGF).² AsVEGF binds to its receptors, it leads toendothelial cell proliferation and newblood vessel formation in in vitro modelsof angiogenesis. Bevacizumab preventsthe binding of VEGF to its receptors andis shown to cause the reduction ofmicrovascular growth and inhibition ofmetastatic disease progression in athymicmice with colon cancer.²

Clinical Trials

Two studies were conducted to evaluatethe efficacy and safety of first-linetreatment with Avastin for patients withMCRC. The first study was a randomized,double-blind, active-controlled clinicaltrial, where patients were randomized tobolus-IFL (irinotecan 125 mg/m², 5-fluorouracil 500 mg/m² IV, and leucovorin20 mg/m² IV given once a week for 4weeks every 6 weeks) plus placebo (Arm1); bolus-IFL plus Avastin 5 mg/kg every 2weeks (Arm 2); or 5-fluorouracil/leucovorin(5-FU/LV) plus Avastin 5 mg/kgevery 2 weeks (Arm 3).³ Among the 813patients randomized, the overallresponse rate of Arms 1 and 2 was 35%and 45%, respectively (P <.01 by x² test),with a median duration of response of7.1 months for Arm 1 and 10.4 monthsfor Arm 2. Of the 110 patients enrolled inArm 3, the median duration of responsewas 8.5 months with a 39% overallresponse rate.^2,3

The second study evaluated Avastin ina randomized, active-controlled trial incombination with 5-FU/LV as first-linetreatment for MCRC. Patients were randomizedto receive either 5-FU/LV (5-fluorouracil500 mg/m²; leucovorin 500mg/m² weekly for 6 weeks every 8weeks); 5-FU/LV plus Avastin 5 mg/kgevery 2 weeks; or 5-FU/LV plus Avastin10 mg/kg every 2 weeks. The overallresponse rate was 17% for the 5-FU/LVgroup; 40% for the 5-FU/LV plus Avastin 5mg/kg group; and 24% for the 5-FU/LVplus Avastin 10 mg/kg.⁴

Avastin also was studied for safety andefficacy as a first-line treatment forpatients with advanced metastatic orrecurrent NSCLC. This was done througha single, large, randomized, active-controlled,open-label, multicenter study (n =878). Of the 878 participants, 444 weretreated with paclitaxel 200 mg/m² IVover 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 diseaseprogression or unacceptable adverseevents. The other 434 individuals weretreated with a paclitaxel regimen plusAvastin 15 mg/kg on day 1 of a 21-daycycle for up to 6 cycles. Then, Avastinwas given 15 mg/kg every 3 weeks untildisease progression or unacceptableadverse events. The overall responserate for the paclitaxel plus Avastin groupwas 29%, compared with 12.9%with the group taking paclitaxelalone.⁵

Safety

The use of Avastin cancause the development ofgastrointestinal (GI) perforation,and in some cases mayresult in death. The incidence of developingGI perforation for patients receivingAvastin for MCRC is 2.4% and 0.9% forpatients being treated for NSCLC. Theusual presentation of GI perforation wasabdominal pain associated with symptomssuch as constipation and vomiting.Avastin should be permanently discontinuedin patients with GI perforations.^1,2

Avastin can cause the development ofwound dehiscence and in some instancesresults in fatality. Patients withwound dehiscence who require medicalintervention should discontinue Avastintherapy permanently. Avastin therapyshould not be initiated for at least 28days following major surgery.² NSCLCpatients treated with Avastin can developfatal pulmonary hemorrhage. Patientswith recent episodes of hemoptysisshould not receive Avastin. No studieshave been documented to examine thepharmacokinetics of Avastin in patientswith renal impairment or hepatic dysfunction.

Ms. Domenici and Dr. Patel are bothpharmacists at Brigham andWomen'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 trialcomparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LValone 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 paclitaxelplus carboplatin with or without bevacizumab (NSC#704865) in patients withadvanced non-squamous non-small cell lung cancer (NSCLC): an EasternCooperative Oncology Group (ECOG) Trial - E4599. Proc Am Soc Clin Oncol.2005;23:2s.