Bevacizumab

Compound Name:BevacizumabMolecular Target:VEGF (Vascular Endothelial Growth Factor)Molecular Structure:humanized monoclonal antibodyLicensed Indication:metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-small cell lung cancerManufacturer and/or Distributor:GenentechInitial FDA Approval2004SummaryBevacizumab (Avastin®) is a human monoclonal antibody that binds to and inhibits the function of vascular endothelial growth factor (VEGF-A, all isoforms). This results in the regression of existing microvessels, and the inhibition of neovascularization. Blocking VEGF-A also decreases tumor vascular permeability, which increases the access of chemotherapy to neoplastic tissue.

 Bevacizumab was originally approved as first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Other approved indications are: metastatic renal cell carcinoma in combination with interferon alpha; unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel; glioblastoma as a single agent for adult patients with progressive disease following prior therapy; recurrent/persistent or metastatic cervical cancer in combination with chemotherapy; and metastatic colorectal cancer, in combination with chemotherapy, for second line treatment of patients who have failed first-line Avastin treatment. Avastin was previously approved for treatment of metastatic breast cancer, but the FDA ruled in 2011 that the indication for breast cancer should have its approval withdrawn, as the data were not sufficiently convincing of clinical efficacy. In 2014 the FDA approved bevacizumab solution for iv infusion in combination with paclitaxel and either cisplatin or topotecan for the treatment of persistent, recurrent, or metastatic cervical cancer. The most serious adverse events (black box warnings) associated with bevacizumab across all clinical trials were GI perforation, wound healing complications, and hemorrhage. Other major concerns are: arterial thromboembolus, hypertension, reversible posterior leukoencephalopathy syndrome, nephrotic syndrome, non-gastrointestinal fistula formation, and severe infusion reaction. A retrospective analysis across clinical trials where 5805 patients had received Avastin showed higher rates of elevated serum creatinine levels. Creatinine levels did not return to baseline in approximately one-third of patients who received Avastin.References

Package insert: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125085s225lbl.pdf

1. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3; 350(23):2335-2342.
 http://www.ncbi.nlm.nih.gov/pubmed/15175435



2. Montero AJ, Vogel C. Fighting fire with fire: rekindling the bevacizumab debate. N Engl J Med 2012 Jan 26; 366 (4): 374-5. http://www.ncbi.nlm.nih.gov/pubmed/22276827



3. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004 May;3 (5):391-400. 
http://www.ncbi.nlm.nih.gov/pubmed/15136787



4. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008 Apr 20;26 (12):2013-2019. 
http://www.ncbi.nlm.nih.gov/pubmed/18421054



5. Miles DW, Chan A, Dirix LY, Cortes J, Pivot X, Tomczak P, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-3247.
 http://www.ncbi.nlm.nih.gov/pubmed/20498403



6. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007 Dec 22; 370(9605): 2103-2111. http://www.ncbi.nlm.nih.gov/pubmed/18156031



7. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-2550.
 http://www.ncbi.nlm.nih.gov/pubmed/17167137



8. Zighelboim I, Wright JD, Gao F, Case AS, Massad LS, et al. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013 Jul;130 (1): 64-8. http://www.ncbi.nlm.nih.gov/pubmed/23591400

9. Yonezawa H, Hirano H, Uchida H, Habu M, Hanaya R et al. Efficacy of bevacizumab therapy for unresectable malignant glioma: A retrospective analysis. Mol Clin Oncol. 2017 Jan;6(1):105-110. https://www.ncbi.nlm.nih.gov/pubmed/28123740

10. Aalders KC, Tryfonidis K, Senkus E, Cardoso F. Anti-angiogenic treatment in breast cancer: Facts, successes, failures and future perspectives. Cancer Treat Rev. 2017 Jan 3;53:98-110. https://www.ncbi.nlm.nih.gov/pubmed/28088074

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