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Breast Cancer have several options for treatment of refractory disease that cannot be standardized in trials, as well as the crossover or access to the study agent after trial completion. Another valid argument is that sponsors should still be encouraged to design studies to address this very important end point. Despite these concerns, the recent FDA approvals of other agents for metastatic breast cancer, such as eribulin, were approved on the basis of statistically significant increases in OS.9 Unlike metastatic breast cancer, PFS recently has been validated statistically as a surrogate end point for OS in metastatic colorectal cancer.10 In addition, not all regimens recommended in NCCN guidelines for every cancer site and stage, or treatment line, are FDAapproved regimens. Unfortunately, there are not strong data to support the connection between quality-of-life data and extension of PFS in breast cancer, although this should be a research focus of the near future. Certainly the patient’s perspective about the understandable desire to access alternative treatment options should be considered strongly; and it was considered by the FDA and ODAC officials, during the 2-day public hearing in June 2011. This hearing not only included the manufacturer’s as well as patient perspectives, but also provided for physician testimonials along with much media interest.

The ODAC opinion regarding the lack of OS benefit and the questionable PFS benefit in light of the risk of serious adverse effects remained unchanged as the FDA members voted unanimously against allowing the breast cancer indication to remain on the label. Again, the manufacturer soon appealed, this time proposing labeling changes to enable a continuation of the conditional accelerated approval until a confirmatory trial of paclitaxel plus bevacizumab—the apparent preferred combination—powered to

Even the definitions of serious adverse events and “unmet medical need” are now a source of debate. assess OS can be completed.11 The proposal includes revising the labeling to restrict treatment to women with an “unmet medical need, that have fewer treatment options,” which is detailed in their proposal as women with triple receptor (estrogen/progesterone receptor [ER/PR] and HER2 receptor)-negative breast cancer, or ER-positive women with aggressive (rapidly progressing) disease with symptomatic visceral metastases. They also propose to restrict bevacizumab use to be with paclitaxel only, with updated trial data about differing

efficacy with other chemotherapy partners, and to commence a Risk Evaluation and Mitigation Strategy that would require distribution of a medication guide to every physician and patient containing detailed safety information, including serious adverse events. An Unknown Future The final chapter of this controversy is not written yet, as the FDA Commissioner has not made a final decision on the process of withdrawal of the breast cancer indication, and the date of this decision remains unknown. Even the definitions of serious adverse events and “unmet medical need” are now a source of debate—the manufacturer argues that the risks appear manageable, whereas others report that bleeding and thrombotic events carry significant risks. Experts continue to argue that there are other treatment options for metastatic breast cancer; therefore, bevacizumab is not fulfilling an unmet need. The highrisk subpopulations as defined previously have not been identified statistically to have greater responses to bevacizumab in the clinical trials. Certainly, there is an argument made by patients who have had a good response to this treatment and want to continue to have access to as many options as possible for the treatment of a serious, incurable disease. The impact of this decision also remains unknown and leaves many questions unanswered.

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OctOber 2011 I VOL 4, NO 7

• What is the gold standard study end point required by the FDA: PFS or OS? • Should PFS be considered a clinically meaningful end point and, if so, what is an appropriate risk-tobenefit ratio? • How will the decision impact insurance coverage for women already on bevacizumab for metastatic breast cancer and, until this is known, should any new patients be started on this regimen? • Will this decision impact accrual to clinical trials in breast cancer using bevacizumab? Clearly studies need to continue to clarify whether PFS may be a surrogate for OS in metastatic breast cancer, and whether an increased PFS confers any benefit on quality of life. Ultimately, the goal would be to identify women through genetic or other markers who will most benefit from treatment. Until then, questions remain regarding the use of bevacizumab, including is this the end of the line for this agent in breast cancer? ● References 1. Goren M. Roche may keep some Avastin sales if US breast cancer label lost. Wall Street Journal. June 27, 2011. Accessed September 8, 2011. 2. Miller KD, Wang M, Gralow A, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, TX. 3. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676. 4. US Food and Drug Administration. FDA: Pfizer voluntarily withdraws cancer treatment Mylotarg from U.S. market. June 21, 2010. room/PressAnnouncements/ucm216448.htm. Accessed September 1, 2011. 5. Miles DW, Chan A, Dirix LY, 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;28:3239-3247. 6. Robert NJ, Diéras V, Glaspy J, 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;29:1252-1260. 7. Horning SJ, Labson MS, Schmidt PW. Submission of Genentech, Inc. in response to the Food and Drug Administration’s Notice of Opportunity for a hearing and proposal to withdraw approval of AVASTIN® (bevacizumab) in combination with weekly paclitaxel for the first-line treatment of patients with metastatic breast cancer. Docket No. FDA-2010-N-0621. January 16, 2011. documents/NOOH-Prim-Sub-Doc_FINAL_ 16JAN2011.pdf. Accessed September 10, 2011. 8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2011. pdf. Accessed September 5, 2011. 9. US Food and Drug Administration. Eribulin mesylate. November 23, 2010. Offices/CDER/ucm234527.htm. Accessed September 23, 2011. 10. Grothey A, Hedrick EE, Mass RD, et al. Responseindependent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol. 2008;26:183-189. 11. Horning SJ, Labson MS, Schmidt PW. Post-hearing submission of Genentech, Inc. in support of maintaining the accelerated approval of AVASTIN® (bevacizumab) in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. Docket No. FDA-2010-N-0621. August 4, 2011. load. Accessed August 30, 2011.

Profile for The Oncology Pharmacist

October 2011 Vol4 No7  

The Oncology Pharmacist® features articles written by and for oncology pharmacists and specifically addresses the issues pharmacists and the...

October 2011 Vol4 No7  

The Oncology Pharmacist® features articles written by and for oncology pharmacists and specifically addresses the issues pharmacists and the...