Ning Yang-Min, He Kun, Dagher Ramzi, Sridhara Rajeshwari, Farrell Ann T, Justice Robert, Pazdur Richard
Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration Silver Spring, Maryland 20993-0004, USA.
Oncology (Williston Park). 2007 Nov;21(12):1503-8; discussion 1511, 1513, 1516 passim.
On May 17, 2007, doxorubicin HCl liposome injection (Doxil) in combination with bortezomib (Velcade) received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or refractory multiple myeloma after at least one prior therapy that has not included bortezomib. Liposomal doxorubicin's efficacy and safety were demonstrated in a phase III, randomized, multicenter, international trial comparing the combination of this agent plus bortezomib vs bortezomib alone in multiple myeloma patients who had not previously received bortezomib and had received at least one prior therapy. Here we summarize the FDA review of the data that support this approval.
An interim analysis of time to disease progression (TTP), the primary endpoint, was conducted after 249 TTP events in this study that randomized 324 patients to liposomal doxorubicin plus bortezomib treatment and 322 patients to bortezomib monotherapy. Time to progression was significantly prolonged in the combination arm (median TTP = 9.3 months) compared with bortezomib monotherapy (median TTP = 6.5 months), P < .0001 (log-rank test); hazard ratio = 0.55 (95% confidence interval = 0.43-0.71). The response rates were similar between the two arms and not statistically different; however, among responding patients, the median duration of response was longer with the combination--10.2 months compared to 7.0 months in the monotherapy arm. Adverse reactions occurred more frequently with the combination therapy. As compared to the monotherapy, frequent grade 3/4 adverse reactions with the combination were neutropenia and thrombocytopenia.
Liposomal doxorubicin received FDA approval for use in combination with bortezomib in patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.
2007年5月17日，盐酸多柔比星脂质体注射剂（多美素）联合硼替佐米（万珂）获得美国食品药品监督管理局（FDA）批准，用于治疗在至少接受过一种不包含硼替佐米的前期治疗后复发或难治性多发性骨髓瘤。脂质体多柔比星的疗效和安全性在一项III期、随机、多中心、国际试验中得到证实，该试验比较了该药联合硼替佐米与单独使用硼替佐米在未曾接受过硼替佐米且至少接受过一种前期治疗的多发性骨髓瘤患者中的疗效。在此，我们总结支持该批准的FDA数据审查情况。
在本研究中，将324例患者随机分配至脂质体多柔比星联合硼替佐米治疗组，322例患者至硼替佐米单药治疗组，在发生249例疾病进展时间（TTP）事件后，对主要终点TTP进行了中期分析。与硼替佐米单药治疗组（中位TTP = 6.5个月）相比，联合治疗组的疾病进展时间显著延长（中位TTP = 9.3个月），P <.0001（对数秩检验）；风险比 = 0.55（95%置信区间 = 0.43 - 0.71）。两组的缓解率相似且无统计学差异；然而，在缓解患者中，联合治疗组的中位缓解持续时间更长 - 为10.2个月，而单药治疗组为7.0个月。联合治疗的不良反应发生频率更高。与单药治疗相比，联合治疗常见的3/4级不良反应为中性粒细胞减少和血小板减少。
脂质体多柔比星获得FDA批准，可与硼替佐米联合用于未曾接受过硼替佐米且至少接受过一种前期治疗的多发性骨髓瘤患者。
