Bevacizumab plus Chemotherapy after Progression of Metastatic Colorectal Cancer on First-line Therapy Including Bevacizumab 


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

On January 23, 2013, bevacizumab (Avastin) was approved for use in combination with fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy for the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.1,2  Bevacizumab has prior indications in first- and second-line treatment of metastatic colorectal cancer, nonsquamous non–small cell lung cancer, glioblastoma, and metastatic renal cell cancer. It is not indicated for use in adjuvant treatment of colon cancer.

Approval was based on a randomized, open-label, international phase III trial in which patients with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomized to receive second-line therapy with (n = 409) or without (n = 411) bevacizumab at 2.5 mg/kg per week (5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks).2,3 For second-line chemotherapy, patients were switched to irinotecan-based treatment if their first-line regimen was oxaliplatin-based and to oxaliplatin-based chemotherapy if their first-line treatment was irinotecan-based. The primary endpoint was overall survival.

The patient groups were well matched at baseline for sex (65% vs 63% male), age (median of 63 years in both), ECOG performance status (0 in 44% vs 43%), proportion of patients with metastasis to more than one organ (64% vs 61%), and proportion receiving first-line treatment with irinotecan-based (59% vs 58%) or oxaliplatin-based (41% vs 42%) chemotherapy. Patients were also well matched for type of irinotecan- or oxaliplatin-based therapy received in second-line treatment.

Median overall survival was 11.2 months in the bevacizumab group vs 9.8 months in the chemotherapy-alone group, representing a significant 19% reduction in risk of death with bevacizu-
mab treatment (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.69–0.94, = .0062). Median progression-free survival was also significantly prolonged with bevacizumab treatment (5.7 vs 4.1 months, HR = 0.68, P < .0001).

How It Works

Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to human vascular endothelial growth factor (VEGF), preventing the interaction of VEGF with its receptors on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation inmodels of angiogenesis. In xenograft models of colon cancer, bevacizumab reduced microvascular growth and inhibited metastatic disease progression.

How It Is Given

Bevacizumab is given at 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks when used in combination with a fluoropyrimidine/irinotecan- or fluoropyrimidine/oxaliplatin-based chemotherapy regimen in patients who have progressed on a first-line bevacizumab-containing regimen. The first infusion of bevacizumab should be given over 90 minutes; if tolerated, the second infusion should be given over 60 minutes, and all subsequent infusions can be given over 30 minutes if 60-minute infusion is tolerated.

Bevacizumab should not be given until at least 28 days following major surgery and only after full healing of surgical incisions, and should not be given to patients with serious hemorrhage or recent hemoptysis. It should be discontinued for gastrointestinal (GI) perforations, fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage, severe arterial thromboembolic events, hypertensive crisis or hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome, and nephrotic syndrome. Treatment should be suspended at least 4 weeks prior to elective surgery, for severe hypertension not controlled with medical management, for moderate to severe proteinuria pending further evaluation, and for severe infusion reactions.

There are no recommended dose reductions for bevacizumab. Urine protein and blood pressure should be monitored during treatment.

Safety Profile

No new safety signals were observed in the trial supporting the new indication, with safety data being consistent with the known safety profile of bevacizumab established in prior indications.

Grade 3 to 5 adverse events occurred in 64% of the bevacizumab group and 57% of the chemotherapy-alone group, with the most frequent being neutropenia (16% and 13%), diarrhea (10% and 8%), and asthenia (6% and 4%). Grade 3 to 5 adverse events of particular interest that occurred more frequently in the bevacizumab group were bleeding or hemorrhage (2% vs < 1%), GI perforation (2% vs < 1%), and venous thromboembolic events (5% vs 3%).

Of 11 adverse events resulting in death in each group, those considered related to study treatment were upper GI hemorrhage, cerebrovascular accident, sudden death, and neutropenia in one patient each in the bevacizumab group and intestinal perforation, general physical health deterioration, and acute prerenal failure in one patient each in the chemotherapy-alone group. Treatment was discontinued due to adverse events in 16% of the bevacizumab group (including discontinuation of bevacizumab alone in 2%) and in 9% of the chemotherapy-alone group.

Bevacizumab has boxed warnings for GI perforation (occurring in up to 2.4% of patients), surgery and wound healing complications, and hemorrhage (including increased risk of severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding). Bevacizumab also has warnings/precautions for non-GI fistula formation, arterial thromboembolic events, hypertension, reversible posterior leukoencephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure. ■

References

1. U.S. Food and Drug Administration: Bevacizumab. Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm336763.htm. Accessed February 6, 2013.

2. AVASTIN® (bevacizumab) prescribing information, Genentech US, Inc, January 2013. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125085s263lbl.pdf. Accessed February 6, 2013.

3. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomized phase 3 trial. Lancet Oncol 14:29-37, 2013.



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