CHICAGO (EGMN) – For the first time, a single agent has significantly extended overall survival in a phase III trial in heavily pretreated metastatic breast cancer.
Women given eribulin mesylate had a median overall survival of 13.12 months versus 10.65 months for those treated at the discretion of their physician with monotherapy or best supportive care only (hazard ratio 0.81, P =.041).
Allowing physicians in the control arm to select the best treatment for their patients represents a real-life situation and reinforces the applicability of the results, explained Dr. Christopher Twelves, a professor at the University of Leeds (England), who presented the findings at the annual meeting of the American Society of Clinical Oncology.
Invited discussant Dr. Harold Burstein of the Dana-Farber Cancer Institute in Boston agreed and said that “the options given by treating physicians reflected the real-world choices we see.”
None of the 247 patients in the control arm received best supportive care or biological therapies only, with 96% receiving chemotherapy. Vinorelbine was the most frequent choice, followed by gemcitabine, capecitabine, taxanes, and anthracyclines.
While there is still a long way to go toward the goal of making breast cancer a chronic disease, Dr. Burstein called the survival advantage associated with eribulin a “very notable result” and said it “makes this drug a most welcome addition to our armamentarium that we use to treat advanced breast cancer.”
Eribulin, also known as E7389, is a synthetic analog of halichondrin B, a natural sea sponge product, and inhibits microtubule dynamics.
Eribulin is not yet available in the United States, Europe, and Japan, but the U.S. Food and Drug Administration granted the agent priority review status May 28 and the agency is expected to make a decision by September.
Dr. Burstein observed that despite a variety of single agents and accepted standard regimens, there is little consensus on how best to use these drugs in metastatic breast cancer. The U.S-based National Comprehensive Cancer Network guidelines suggest consideration of up to three lines of therapy and no further cytotoxic therapy and a transition to palliative care in the absence of a robust response.
“There are remarkable few data on fourth-line treatment outcomes, yet fewer on fifth-line treatment outcomes and essentially no meaningful data for patients who receive six or more lines of therapy,” he said.
Women in the Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE) had received as many as seven prior chemotherapy regimens (median of four) that had to have included an anthracycline and a taxane. Two-thirds had received prior capecitabine, two-thirds were estrogen receptor positive and one-half had at least two sites of metastatic disease. Their median age was 55 years.
Eribulin 1.4 mg/m2 was administered as a short 2- to 5-minute infusion on days 1 and 8 every 21 days.
The secondary outcome of progression-free survival reached statistical significance by investigator review at a median of 3.6 months for eribulin and 2.2 months for control (HR 0.76, P = .002), but not by independent review (median 3.7 vs. 2.2 months; HR 0.87, P = .14).
Dr. Twelves said many women were censored in the independent review because they had disease that wasn’t radiologically assessed and thus the power was insufficient to detect a difference in the outcome.
Dr. Burstein said other explanations for the modest improvement in progression-free survival are that the RECIST criteria for time to progression may not be relevant in heavily pretreated breast cancer and that there may have been some investigator bias in selecting a therapy for randomization after having already contemplated end-of-life care for their patients.
The overall response rate was at 12.2% for eribulin and 4.7% for physician’s choice.
Eribulin’s safety profile was consistent with phase II trial data, showing an increase in grade 3 or 4 neutropenia (21% grade 3/24% grade 4), febrile neutropenia (3%/1%), fatigue (8%/0.6%) and neuropathy (7.8%/0.4%). Dr. Burstein described this as comparable to other treatment options and acceptable for women with metastatic breast cancer.
Outstanding questions include the impact of hormone receptor status on outcomes, the effect of eribulin on symptom control and quality of life, and whether a survival difference would be seen if patients in the physician’s choice arm, who were rechallenged with the same chemotherapy regimen, were omitted from the analysis. Dr. Burstein said more studies are also warranted to understand how best to incorporate eribulin into standard treatment algorithms.
Dr. Twelves has served as a consultant or advisor to and provided expert testimony for Eisai, which is developing eribulin. Dr. Burstein disclosed no financial conflicts of interest.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
芝加哥(EGMN)——一项针对高强度预处理的转移性乳腺癌患者的III期临床试验首次发现一种可以显著延长患者总生存期的单药。
在这项研究中，接受甲磺酸艾日布林治疗的妇女中位总生存时间为13.12个月，而那些由医师决定仅接受单药治疗或者最佳支持治疗的妇女中位总生存时间为10.65个月。
利兹大学(英国)的Christopher Twelves博士在美国临床肿瘤学会年会上报道了他们的研究结果，并解释说，允许医生为其病人选择最佳的治疗代表了一种真实的临床情况，并增强了研究结果的适用性。
波士顿Dana-Farber癌症研究所的特邀评论员Harold Burstein博士同意并表示“研究中医师所给予的治疗选择方案与我们在临床实践中的实际方案相符合。”
对照组中的247名病人中，约有96%的患者接受了化疗，没有患者仅接受最佳支持治疗或生物治疗。化疗中长春瑞滨是应用最多的药物，其次是吉西他滨、卡培他滨、紫杉醇和蒽环类药物。
Burstein博士说，尽管距离将乳腺癌变成一种慢性疾病的目标还很遥远，艾日布林为患者带来的生存效益堪称是一项“显著的结果，”并且他称，这“使得该药成为我们晚期乳腺癌治疗方案中最受欢迎的附加用药。”
艾日布林，也就是E7389，是一种合成的大田软海绵素(halichondrin B)类似物，也是天然海绵中提取的产品，可以抑制细胞微管的运动。
迄今为止，艾日布林尚未在美国、欧洲和日本得到批准应用，但是美国食品药品管理局于5月28日通过了该药物的优先审查，该药有望在今年9月份得到该机构的意见。
Burstein博士观察道，尽管有一些单药已经加入标准化疗方案中，但在晚期乳腺癌治疗中如何以最佳方式应用这些药物还没有达成共识。美国国家癌症综合网的指南建议考虑最多用于三线治疗方案且不进行细胞毒性治疗，并且在没有明显治疗反应的患者中转而进行姑息性治疗。
他还说：“很少有关于四线治疗结果的显著性数据，然而对五线治疗结果的数据则更少，实际上在接受六线或以上治疗的患者也缺少有意义的数据。”
参与“医师选择与E7389的卫材转移性乳腺癌研究”(EMBRACE)的女性患者，之前接受了最多达7种(中位数为4种)包括蒽环类和紫杉醇在内的化疗方案的治疗。2/3的患者接受过卡培他滨治疗，2/3的患者雌激素受体阳性，一半患者具有至少两个部位的远处转移。患者的中位年龄是55岁。
艾日布林给药剂量为1.4 mg/m2，每21天为一个周期，第1、8天给药，并在2~5min内输注完毕。
根据研究者分析结果，次要结局指标即无进展生存期达到统计学意义：艾日布林的中位时间为3.6个月，而对照组为2.2个月(HR 0.76，P = 0.002)，但是根据独立审查结果，则没有统计学意义(中位时间 3.7 对2.2个月；HR 0.87，P = 0.14)。
Twelves博士表示，因为其病变没有经放射学评估，故许多女性患者的数据在独立审查时被删除，进而导致检验效能不足以检出两组在结局指标方面的差异。
Burstein博士对于无进展生存期轻微改善的其他解释是，至进展时间的RECIST标准可能不适用于高强度预处理的乳腺癌，研究人员在已考虑为其患者提供生命末期照护后随机选择治疗方案时可能存在一定偏倚。
艾日布林治疗组总有效率为12.2%，而医师选择组为4.7%。
艾日布林的安全性与II期临床试验中的数据一致，结果显示以下不良事件的发生率增加：3或4级中性粒细胞减少(21% 3级/24% 4级)、发热性中性粒细胞减少(3%/1%)、乏力(8%/0.6%)及神经病变(7.8%/0.4%)。Burstein博士解释说，这与晚期乳腺癌的其他治疗方案相当，对转移性乳腺癌女性患者而言，是可以接受的。
尚待未决的问题包括激素受体状态对治疗结果的影响、艾日布林对症状控制和生活质量的影响以及患者在医师选择组中遇到同样的化疗方案时被从数据中删除因而无法参加数据分析是否会对生存分析造成影响。Burstein说，欲了解将艾日布林纳入标准治疗方案的最佳方式，还需要更多的研究来证实。
Twelves博士是卫材公司的顾问，为研发艾日布林的试验提供了专家证据。Burstein博士声明没有相关的经济利益冲突。
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