Bevacizumab in the Treatment of Metastatic Breast Cancer: Friend or Foe?
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Metastatic breast cancer (MBC) is a major cause of death among women worldwide. Progress has been made in treating MBC with the advent of anti-estrogen therapies, potent cytotoxic agents, and monoclonal antibodies. Bevacizumab is a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), which was approved in 2008 by the US Food and Drug Administration (FDA), for first-line treatment of HER-2 negative MBC in combination with paclitaxel. The FDA then reversed this decision in December 2010 by recommending removal of the MBC indication from bevacizumab, citing primarily safety concerns, and that these risks did not outweigh the ability of bevacizumab to significantly prolong progression-free survival. This decision was unexpected in the oncology community and remains controversial. This review looks at all available phase 3 data with bevacizumab in the MBC setting to determine whether the data support this decision by the FDA, and discusses the future of bevacizumab in breast cancer.
KeywordsBevacizumab Metastatic breast cancer Randomized control (phase 3) trials Review Chemotherapy Anti-angiogenesis
A. J. Montero: none; M. Escobar: none; G. Lopes: honoraria from Roche and Genentech; S. Glück: honoraria from Genentech; C. Vogel: consultant to Genentech, Amgen, Sandoz, and Merck and educational presentations/speakers’ bureaus for Amgen, GlaxoSmithKline, GTx, Genentech, and Sanofi.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 18.• Martin M, Roche H, Pinter T, Crown J, Kennedy MJ, Provencher L, et al. Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2011;12(4):369–76. This study showed that weekly paclitaxel plus bevacizumab had a median PFS of 11.5 months which was almost identical to that seen in E2100, versus 9.0 for paclitaxel, which was better than what was observed in the control arm in E2100. This study also showed that the oral anti-angiogenic agent motesanib when combined with paclitaxel was no better than placebo. PubMedCrossRefGoogle Scholar
- 19.Ito Y, Aogi K, Masuda N, Ohno S, Oda T, Iwata H, et al. Efficacy of first-line bevacizumab (bev) combined with weekly paclitaxel (wPac) for HER2-negative metastatic breast cancer (MBC): results of a japanese phase II study (n = 120). J Clin Oncol. 2011;29(suppl; abst 1119).Google Scholar
- 20.•• Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias V, Mavroudis D, Mauri D. Bevacizumab in metastatic breast cancer: a meta-analysis of randomized controlled trials. Breast Cancer Res Treat. 2010;122(1):1–7. This meta-analysis shows that the addition of bevacizumab to chemotherapy offers meaningful improvement in PFS and ORR in MBC patients. No significant advantage was observed in OS with the addition of bevacizumab when pooling phase 3 data. PubMedCrossRefGoogle Scholar
- 21.•• Smith IE, Pierga JY, Biganzoli L, Cortes-Funes H, Thomssen C, Pivot X, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: Safety and efficacy in an open-label study in 2,251 patients. Ann Oncol. 2011;22(3):595–602. This study showed in a real world oncology practice setting and in a very large number of women with metastatic breast cancer that combining bevacizumab with different types of chemotherapy was well tolerated and didn’t have greater toxicities than what were reported in the phase 3 trials. PubMedCrossRefGoogle Scholar
- 22.•• Biganzoli L, Di Vincenzo E, Jiang Z, Lichinitser M, Shen Z, Delva R, et al. First-line bevacizumab-containing therapy for breast cancer: results in patients aged > =70 years treated in the ATHENA study. Ann Oncol. 2011 Mar 28. This study is the largest study to date evaluating the side effect profile of bevacizumab plus chemotherapy in older women (70 and older) with MBC. It shows that the combination of weekly paclitaxel and bevacizumab appeared to be particularly active in this patient population, with no additional safety signals. Google Scholar
- 23.FDA begins process to remove breast cancer indication from avastin label [Internet]. U.S. Food and Drug Administration; 2010 [updated 12/16/2010. Available from: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm237172.htm.
- 27.Cortes J, Montero AJ, Gluck S. Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treat Rev. 2011 May 6.Google Scholar
- 30.Cortazar P, Zhang JJ, Sridhara R, Justice RL, Pazdur R. Relationship between OS and PFS in metastatic breast cancer (MBC): review of FDA submission data. J Clin Oncol. 2011;29(suppl; abstr 1035).Google Scholar
- 32.Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26(28):4672–8.PubMedCrossRefGoogle Scholar
- 33.Linderholm BK, Hellborg H, Johansson U, Elmberger G, Skoog L, Lehtio J, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20(10):1639–46.PubMedCrossRefGoogle Scholar
- 34.Dowlati A, Gray R, Sandler AB, Schiller JH, Johnson DH. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non-small cell lung cancer treated with chemotherapy with or without bevacizumab–an eastern cooperative oncology group study. Clin Cancer Res. 2008;14(5):1407–12.PubMedCrossRefGoogle Scholar
- 35.Ronzoni M, Manzoni M, Mariucci S, Loupakis F, Brugnatelli S, Bencardino K, et al. Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol. 2010;21(12):2382–9.PubMedCrossRefGoogle Scholar
- 39.Montero AJ, Gluck S, Lopes Jr GD. The cost-effectiveness of bevacizumab in combination with paclitaxel in first-line treatment of patients with metastatic breast cancer. J Clin Oncol. 2011;29(suppl; abstr 6060).Google Scholar
- 43.Miles DW, Chan A, Romieu G, Dirix LY, Cortes J, Pivot X, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol. 2008;26(43s).Google Scholar
- 44.Robert NJ, Dieras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29(10):1252–60.PubMedCrossRefGoogle Scholar
- 47.Brufsky A, Bondarenko I, Smirnov V, Hurvitz S, Perez E, Ponomarova O, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. Cancer Res. 2009;69(24).Google Scholar