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Breast Cancer Bevacizumab in Metastatic... Continued from cover thousands of women with metastatic breast cancer. It is currently the bestselling anticancer drug in history, even with its high price tag—the annual sales have exceeded $6 billion, with $1 billion per year used in breast cancer.1 The main sources of controversy leading to the US Food and Drug Administration’s (FDA) reversal of its approval for this indication, as outlined in the timeline (Table 1), surround several very important as yet unanswered questions that may determine the fate of many investigational agents in the future. The most important and most contested question concerns what is an appropriate, clinically significant end point in clinical trials of new agents to decide their FDA approval: progression-free survival (PFS) or overall survival (OS). Furthermore, when considering the adverse event profile in relation to any apparent benefit, what is an acceptable risk-to-benefit ratio? Adding to the controversy is the valid arguments on both sides of the
Initial Study Achieves Accelerated Approval The historical timeline of bevacizumab for metastatic breast cancer starts in 2005 when the Eastern Cooperative Oncology Group (ECOG, or E) 2100 study was presented amid much excitement at a large international meeting2 and was subsequently published in the New England Journal of Medicine in 2007.3 The E2100 study was a multicenter, randomized, clinical trial of bevacizumab as initial therapy in metastatic breast cancer. This open-label trial enrolled 722 patients with treatmentnaïve metastatic breast cancer to either weekly paclitaxel 90 mg/m2, or to weekMaggie Charpentier, PharmD, BCPS Joanna Schwartz, PharmD, BCOP ly paclitaxel plus bevacizumab 10 mg/kg issues, with breast cancer experts, organi- representing cancer and statistics ex - every 2 weeks until progression. The primary end point was PFS; seczations, and even members within organ- perts, industry, and the public that is izations such the FDA and its Oncologic charged by the FDA to evaluate study ondary end points included objective Drugs Advisory Committee (ODAC) data and to make recommendations to response rate, toxic effects, OS, and appear to be split on these issues. ODAC the FDA about the approval of new quality of life. Patients with HER2-positive breast cancer were eligible, prois a committee that consists of members cancer medications. vided they had received trastuzumab. Ultimately, few patients with HER2Table 1 Timeline of Bevacizumab for Metastatic Breast Cancer positive disease were enrolled. Patients Date Action who received previous taxane therapy as adjuvant or neoadjuvant therapy December 2005 The randomized, phase 3 E2100 trial presented at a national meeting, showing a were required to have received their 5.5-month increase in median PFS with the addition of bevacizumab to paclitaxel for last dose at least 12 months before metastatic breast cancer.a (Results published in the New England Journal of Medicine in enrollment. 2007.b) Results demonstrated a significant improvement in median PFS with the December 2007 ODAC recommends against approval of bevacizumab for metastatic breast cancer to addition of bevacizumab (11.8 months FDA, citing the lack of OS benefit in the E2100 study. vs 5.9 months; hazard ratio [HR], 0.60; February 2008 FDA grants conditional accelerated approval for bevacizumab with paclitaxel as P <.001). Median OS, however, was first-line therapy for metastatic breast cancer contingent upon confirmatory trials to similar between groups (25.2 months further define benefits. in the paclitaxel-alone group vs 26.7 c,d months in the combined therapy July 2010 ODAC meets to review the 2 confirmatory trials, and recommends to FDA to group; HR, 0.88; P = .16). On subremove the breast cancer indication from the label, citing an unfavorable risk-togroup analysis, no subgroup was idenbenefit profile. tified as most likely to benefit from the September 2010 FDA announces it will delay its decision regarding converting the accelerated combination therapy. approval to a full approval or removing the breast cancer indication. Grade 3 and 4 toxicities were more frequent in the combination group than December 2010 FDA proposes removing the metastatic breast cancer indication from in the paclitaxel-alone group, including bevacizumab label. neuropathy, infection, and fatigue; January 2011 The manufacturer (Genentech) files an appeal with FDA and requests an hypertension, cerebrovascular ischemia, administrative hearing that is open to the public. and headaches were all more frequent in June 28, 2011 FDA and ODAC conduct 2-day public hearing involving data presentations from the combination arm. Treatment-related deaths were similar in both groups. the manufacturer and testimonials from patients and physicians, accompanied by Table 2 summarizes trial-related serious expansive media coverage and patient advocacy group demonstrations. adverse events. June 30, 2011 ODAC votes unanimously against allowing the breast cancer indication to remain The debate began in December 2007 on the label; however, the FDA allows public comments to be submitted until when ODAC recommended, in a split July 28, 2011. decision, against approval of bevacizuAugust 5, 2011 The manufacturer files an appeal of decision in its posthearing summary, with mab. The FDA, in a move rare in its history, overrode its own committee in proposed labeling changes. granting conditional accelerated apSeptember 2011 A final decision is awaited from FDA Commissioner. proval on the basis of the pivotal E2100 a 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: study in 2008. This suggested that the 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. FDA accepted the end point of imb 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. c provement in PFS, even with a lack of 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. OS benefit, as observed in the E2100 d 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 study, for approval of an oncology agent, epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260. although most ODAC members apFDA indicates US Food and Drug Administration; ODAC, Oncologic Drugs Advisory Committee; OS, overall survival; PFS, progression-free survival. peared to disagree with this decision.
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OctOber 2011 I VOL 4, NO 7
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