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U.S. Department of Health and Human Services

Drugs

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Bevacizumab

On January 23, 2013, the U. S. Food and Drug Administration approved bevacizumab (Avastin, Genentech U.S., Inc.) for use in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab-containing regimen.  Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to human vascular endothelial growth factor (VEGF), preventing the interaction of VEGF to its receptors on the surface of endothelial cells.   

 
This approval is based on the results of a randomized, open-label, multinational trial enrolling patients with mCRC that progressed during or within 3 months of discontinuation of bevacizumab-based combination chemotherapy with fluoropyrimidine-oxaliplatin or fluoropyrimidine-irinotecan in the first line.
 
The clinical trial accrued 820 patients who were randomly allocated (1:1) to receive “cross-over” chemotherapy alone (N=411) or “cross-over” chemotherapy in combination with bevacizumab (N=409). Patients received either irinotecan-based therapy or oxaliplatin-based chemotherapy depending on prior treatment (i.e., irinotecan-based regimen for patients who received prior treatment with oxaliplatin and oxaliplatin-based therapy for patients who received prior treatment with irinotecan).   The treatment cycles on both arms were repeated every 2 or 3 weeks, depending on the chemotherapy regimen used, and bevacizumab was administered at a dose of 5 mg/kg by intravenous infusion every two weeks or 7.5 mg/kg by intravenous infusion every three weeks.  Bevacizumab was continued until disease progression or unacceptable toxicity.  
 
The primary efficacy endpoint was overall survival (OS). Treatment assignment was stratified by first-line treatment (irinotecan-based vs. oxaliplatin-based), first-line progression-free survival (PFS) (more than 9 months vs. 9 months or less), time from last bevacizumab dose (more than 42 days vs. 42 days or less), and ECOG performance status (0-1 vs. 2).
 
The median age of the study population was 63 years, 64% were men, and 96% had an ECOG performance status of 0 or 1.  A statistically significant OS  improvement was observed in patients receiving cross-over chemotherapy plus bevacizumab compared to those receiving cross-over chemotherapy alone [HR 0.81 (95% CI: 0.69, 0.94), p=0.0062, unstratified log-rank test]. Median OS was 11.2 and 9.8 months for patients on the cross-over chemotherapy plus bevacizumab and cross-over chemotherapy arms, respectively. PFS was also significantly improved in patients receiving crossover chemotherapy plus bevacizumab compared to those receiving chemotherapy alone [HR 0.68 (95% CI: 0.59, 0.78), p<0.0001].  The median PFS times were 5.7 and 4.0 months, respectively.   
 
No new safety signals were observed in this trial. The safety data was consistent with the known safety profile established in previously approved indications.
 
The recommended dose and schedule in patients receiving bevacizumab in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line bevacizumab containing regimen is 5 mg/kg administered every 2 weeks or 7.5 mg/kg administered every 3 weeks as a 60-minute IV infusion.  
 
Full prescribing information is available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125085s263lbl.pdf
 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).