A Randomized, Double-Blind, Placebo-Controlled, Phase III Study to Assess Efficacy and Safety of Weekly Farletuzumab in Combination With Carboplatin and Taxane in Patients With Ovarian Cancer in First Platinum-Sensitive Relapse

Purpose Farletuzumab is a humanized monoclonal antibody that binds to folate receptor-α, which is highly expressed in ovarian carcinoma and largely absent from normal tissue. Farletuzumab was investigated in a double-blind, randomized phase III study in platinum-sensitive ovarian cancer.

Farletuzumab,是一种拮抗叶酸受体α的人源单克隆抗体，在卵巢癌中高度表达，而在正常组织中基本不表达。在Ⅲ期临床研究中，Farletuzumab用于铂类敏感首次复发的卵巢癌，采取随机、双盲等对照研究方式。

首次复发时间距末次化疗在6-24个月之内，并对铂类和紫杉烷类敏感的卵巢癌患者。所有患者接受卡铂+紫杉烷或多西他赛（6周期化疗，结合随机试验的产品比例为1:1:1，farletuzumab 1.25 mg/kg，farletuzumab 2.5 mg/kg, 和安慰剂），单剂试验产品维持治疗每周，直到疾病进展。主要终点是无进展生存期（PFS）的实体瘤疗效评价标准。额外的分析概述原协议被确定在最终的统计分析计划，包括基线CA-125和Farletuzumab暴露水平的亚组分析。

Patients and Methods Eligible patients had first recurrent ovarian cancer 6-24 months following completion of platinum-taxane chemotherapy. All patients received carboplatin plus paclitaxel or docetaxel (for six cycles combined with randomly assigned test products in a 1:1:1 ratio: farletuzumab 1.25 mg/kg, farletuzumab 2.5 mg/kg, or placebo). The single-agent test product was continued weekly until disease progression. The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors. Additional analyses not outlined in the original protocol were prespecified in the final statistical analysis plan, including a subgroup analysis by baseline CA-125 and farletuzumab exposure levels.

Results A total of 1,100 women were randomly assigned to treatment dose or placebo. PFS from the primary analysis was 9.0, 9.5, and 9.7 months for the placebo, farletuzumab 1.25 mg/kg, and farletuzumab 2.5 mg/kg groups, respectively. Neither farletuzumab group was statistically different from the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.81 to 1.21] and 0.86 [95% CI, 0.70 to 1.06] for farletuzumab 1.25 mg/kg and 2.5 mg/kg group v placebo, respectively). In the prespecified subgroup, baseline CA-125 levels not more than three times the upper limit of normal (ULN) correlated with longer PFS (HR, 0.49; P = .0028) and overall survival (OS) (HR, 0.44; P = .0108) for farletuzumab 2.5 mg/kg versus placebo. Subgroup analysis of farletuzumab exposure above the median, regardless of dose, showed significantly better PFS versus placebo. The most common adverse events were those associated with chemotherapy.

共有1100名妇女被随机分配到治疗剂量或安慰剂：PFS从初步分析为9，9.5，9.7个月，分别对应安慰剂组，Farletuzumab为 1.25 mg/kg组和2.5 mg/kg组；Farletuzumab组与安慰剂组比较，(危险比(HR),0.99(95%可信区间,0.81 - 1.21)，无统计学意义；farletuzumab 1.25毫克/公斤和2.5毫克/公斤对比安慰剂组0.86(95%可信区间,0.70至1.06)，无统计学意义) 。在预先设定的亚组中，基线CA-125水平不超过三倍正常上限（ULN）时较高farletuzumab剂量与安慰剂组比较，无进展生存期（PFS）（HR，0.49；P = 0028）和总生存（OS）（HR，0.44；P =0108）延长。曝光的Farletuzumab中位数以上的亚组分析中，基线CA-125水平不超过三倍正常上限，无论farletuzumab剂量多少，结果比安慰剂组均有更好的PFS。常见的最不良反应是与化疗相关的。

farletuzumab未能达到改善无进展生存期（PFS）的主要终点。 预设亚组分析表明，ca - 125水平不超过三倍ULN患者，较高farletuzumab剂量与安慰剂比较,显示有明显优越的PFS和OS

Conclusion Neither farletuzumab dose met the study’s primary PFS end point. Prespecified subgroup analyses demonstrated that patients with CA-125 levels not more than three times the ULN and patients with higher farletuzumab exposure showed superior PFS and OS compared with placebo.

Farletuzumab,是一种拮抗叶酸受体α的人源单克隆抗体，在卵巢癌中高度表达，而在正常组织中基本不表达。在Ⅲ期临床研究中，Farletuzumab用于铂类敏感首次复发的卵巢癌，采取随机、双盲等对照研究方式。

首次复发时间距末次化疗在6-24个月之内，并对铂类和紫杉烷类敏感的卵巢癌患者。所有患者接受卡铂+紫杉烷或多西他赛（6周期化疗，结合随机试验的产品比例为1:1:1，farletuzumab 1.25 mg/kg，farletuzumab 2.5 mg/kg, 和安慰剂），单剂试验产品维持治疗每周，直到疾病进展。主要终点是无进展生存期（PFS）的实体瘤疗效评价标准。额外的分析概述原协议被确定在最终的统计分析计划，包括基线CA-125和Farletuzumab暴露水平的亚组分析。

共有1100名妇女被随机分配到治疗剂量或安慰剂：PFS从初步分析为9，9.5，9.7个月，分别对应安慰剂组，Farletuzumab为 1.25 mg/kg组和2.5 mg/kg组；Farletuzumab组与安慰剂组比较，(危险比(HR),0.99(95%可信区间,0.81 - 1.21)，无统计学意义；farletuzumab 1.25毫克/公斤和2.5毫克/公斤对比安慰剂组0.86(95%可信区间,0.70至1.06)，无统计学意义) 。在预先设定的亚组中，基线CA-125水平不超过三倍正常上限（ULN）时较高farletuzumab剂量与安慰剂组比较，无进展生存期（PFS）（HR，0.49；P = 0028）和总生存（OS）（HR，0.44；P =0108）延长。曝光的Farletuzumab中位数以上的亚组分析中，基线CA-125水平不超过三倍正常上限，无论farletuzumab剂量多少，结果比安慰剂组均有更好的PFS。常见的最不良反应是与化疗相关的。

farletuzumab未能达到改善无进展生存期（PFS）的主要终点。 预设亚组分析表明，ca - 125水平不超过三倍ULN患者，较高farletuzumab剂量与安慰剂比较,显示有明显优越的PFS和OS

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