Brand Name: Avastin^®

Generic Name: bevacizumab

Manufacturer: Genentech, Inc.¹

Drug Class: anti-angiogenesis agent^1,2

Uses:

Labeled: metastatic colon/rectal cancer (in combination with IV 5-fluorouracil-based chemotherapy regimens)^1,2,3,4

Unlabeled: breast cancer^5,6,  malignant mesothelioma⁵, prostate cancer⁵, renal cancer^3,7, non-small-cell lung cancer⁸

Mechanism of Action: bevacizumab binds and subsequently inhibits vascular endothelial growth factor (VEGF). VEGF promotes the formation of blood vessels.  Therefore, inhibition of VEGF decreases microvascular proliferation and the subsequent growth of metastatic cancers.^1,3,4,5

Pharmacokinetics:

Efficacy:

(1) Citation: Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42.

Study Design: randomized, double-blind, active-controlled trial

Description: Eight hundred thirteen patients were randomized to one of three groups.  Group 1 received irinotecan 1.25 mg/m², 5-fluorouracil (5-FU) 500 mg/m², leucovorin 20 mg/m², and placebo weekly for 4 weeks every 6 weeks.  The same regimen with bevacizumab 5 mg/kg instead of placebo every 2 weeks was given to the second group, and the third group received 5-FU, leucovorin, and bevacizumab at the same dosages every 2 weeks.  The portion of the study involving this third group was discontinued as previously decided when the safety of bevacizumab with this regimen was established.  The primary outcome measure was overall survival.  Progression-free survival, response rate, duration of response, and safety were followed as secondary endpoints.

Results: Overall survival (measured in months), was significantly longer in the bevacizumab group (median duration of 20.3 months vs. 15.6 months; p<0.001).  The median durations of progression-free survival, response rates, and median duration of response were all significantly different between the two groups (10.6 months vs. 6.2 months, p<0.001; 44.8% vs. 34.8%, p=0.004; 10.4 months vs. 7.1 months, p=0.001; respectively).  Grade 3 hypertension was reported more frequently in the bevacizumab group, but these instances were handled without difficulty.   

Limitations: This study only establishes the efficacy of one treatment regimen, and it does not evaluate the benefits of bevacizumab alone.

Conclusion: When used with 5-FU, irinotecan, and leucovorin, bevacizumab has shown definite efficacy in improving overall survival for patients with metastatic colorectal cancer as well as significantly increasing duration of progression-free survival, response rate, and duration of response.    

(2) Citation:  Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G.  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 Jan 1;21(1):60-5.

Study Design: randomized, double blind, active-controlled trial

Description: One hundred four patients were randomized to one of three groups.  The first group received 5-FU 500 mg/m² and leucovorin 500 mg/m² weekly for 6 weeks every 8 weeks.  The other two groups were given the same regimen every 2 weeks with either bevacizumab 5 mg/kg or bevacizumab 10 mg/kg.  Progression-free survival and objective response rate were the study’s primary endpoint measures.

Results: No significant differences in primary outcomes were noted between the bevacizumab 10 mg group and the group not receiving bevacizumab.  The patients getting bevacizumab 5 mg/kg experienced a significantly higher response rate and median time to progression in months than the control group (40% vs. 17%; p=0.029 and 9.0 vs. 5.2; p=0.005, respectively).  Overall response rate and overall survival were not significantly different between the pooled bevacizumab groups and the control group.

Limitations: Significant differences existed between the treatment groups in terms of baseline serum albumin, gender, and ECOG performance status.

Conclusion: Corrections for the differences in the groups’ characteristics seemed to strengthen the treatment effect of bevacizumab.  Bevacizumab, at the lower dose, appears to positively affect survival, time to progression, and response rate.

(3) Citation: Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003 Jul 31;349(5):427-34.⁷

Study Design: randomized, double-blind, placebo-controlled trial

Description: One hundred sixteen patients were randomized to receive 3 mg/kg or bevacizumab, 10 mg/kg bevacizumab, or placebo every two weeks.  Response rate and time to disease progression were the study’s primary outcomes.  Crossover of patients from the placebo group to the treatment group was permitted.

Results: Patients in the 10 mg/kg treatment group experienced significantly longer median time to progression in months than the placebo group (4.8 vs. 2.5;p<0.001).  No significant overall survival benefit was seen with any of the treatment groups.

Limitations: The relatively small increase in time to progression, though significant, and the absence of an overall survival benefit may be a result of the option to crossover, the relatively strict definition of progression, and the criteria for removal of a patient from the trial.

Conclusion:  Bevacizumab significantly increases the time to progression of disease in patients with metastatic renal cancer.

Adverse Effects: Safety data for bevacizumab was obtained during trials only when bevacizumab was used in combinations with other chemotherapy.  The incidence of adverse effects with bevacizumab alone has not been determined.  Adverse effects occurring in >10% of patients during clinical trials include hypertension, hypotension, thromboembolism, pain, headache, dizziness, alopecia, dry skin, exfoliative dermatitis, skin discoloration, weight loss, hypokalemia, abdominal pain, diarrhea, vomiting, anorexia, constipation, stomatitis, dyspepsia, flatulence, taste disorder, leukopenia, epistaxis, gastrointestinal hemorrhage, neutropenia, weakness, myalgia, proteinuria, upper respiratory tract infection, and dyspnea.  Adverse effects experienced by 1%-10% of patients include moderate to severe deep vein thrombosis, severe intra-arterial thrombosis, confusion, syncope, abnormal gait, skin ulcer, nail disorders, dry mouth, colitis, thrombocytopenia, bilirubinemia, urinary frequency/urgency, and voice alteration.

Drug Interactions: Bevacizumab has not been included in any formal studies assessing drug interactions.  In one study, concentrations of the active metabolite of irinotecan were 33% higher in patients receiving irinotecan, 5-FU, leucovorin, and bevacizumab than similar concentrations in patients who were administered this regimen without bevacizumab.^1,3,4

Dosing/Administration: It is recommended that patients receive 5 mg/kg as an IV infusion every 14 days until disease progression occurs.  No studies have been conducted to evaluate the need for dosage adjustment in pediatric or geriatric populations or in patients with renal or hepatic dysfunction.^1,3,4,5

Conclusion: In combination with 5-FU, irinotecan, and leucovorin, bevacizumab appears to offer a significant survival benefit for patients with metastatic colorectal cancer.

Recommended References:

(1)   Prescribing information accessed online at http://www.avastin.com/avastin/prescribingPIPro.m

(2)   www.avastin.com

(3)   Clinical Pharmacology online

(4)   ePocrates RxPro Version 6.51; last updated July 20, 2004

(5)   Lexi-Comp; Lexi Drugs (Essential); last updated June, 2004

(6)   Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24.

(7)   Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003 Jul 31;349(5):427-34.

(8)   Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004 Jun 1;22(11):2184-91.