Lancet Oncol：帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案可作为HER2阳性的转移性乳腺癌患者的标准治疗方案

CLEOPATRA研究是一个3期临床研究，其主要目的在于比较在HER2阳性的转移性乳腺癌患者中，采用帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案和安慰剂、曲妥珠单抗和多烯紫杉醇方案在治疗的有效性和安全性方面所存在的差异。该研究的主要分析结果显示与安慰剂对照组相比，帕妥珠单抗组的受试者的中位无进展生存期更长。对总体生存期所进行的期中分析显示虽然与安慰剂对照组相比，帕妥珠单抗组的受试者的总体生存期有延长的趋势，但是两组间的差异并不具有显著统计学意义。在本文中，来自于美国Medstar华盛顿医学中心的Sandra M Swain等报道了在经过了额外的随访年限之后，与总体生存期相关的研究结果。他们的研究结果发表在Lancet Oncol 4月的在线期刊上。

CLEOPATRA研究是双盲随机对照研究，该研究在25个国家的204个研究分中心内进行。研究所纳入的受试者为HER2阳性的转移性乳腺癌患者，并且她们既往没有接受过针对转移性病变的化疗或生物治疗。研究者将符合上述标准的受试者按照1:1的比例随机分为两组，一组接受帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案（402名受试者），另一组接受安慰剂、曲妥珠单抗和多烯紫杉醇方案（406名受试者）。同时，研究者根据受试者所处的地理区域的不同和既往所接受的治疗的状态不同而对其进行分层。研究的主要终点是无进展生存期（独立评估），该结果已在既往的论著中发表，针对主要终点事件研究者并没有进行额外的随访。该研究的次要终点包括总体生存期、由研究者所评估的无进展生存期、对治疗的客观反应率和治疗方案的安全性评价。两组受试者的中位随访时间都为30月。研究者采用意向治疗分析法对有效性终点进行评价，才用按治疗方案分析对安全性相关结果进行评价。本研究在ClinicalTrials.gov注册，注册号为NCT00567190。

在接受意向治疗分析的受试者人群中，截止至2012年5月14日共有267名患者发生死亡，其中安慰剂对照组的406名受试者中有154人（38%）死亡，而在帕妥珠单抗组的402名受试者中有113人（28%）死亡。安慰剂对照组受试者的中位生存期为37.6月（95%可信区间为34.3至不可估计），在帕妥珠单抗组中研究者还未观察到受试者的中位生存期（95%可信区间43.4至不可估计），HR为0.66，两组差异具有显著统计学意义。由研究者所评估的中位无进展生存期在安慰剂对照组为12.4月（95%可信区间为10.4-13.5），而在帕妥珠单抗组为18.7月（95%可信区间为16.6-21.6）。在接受安慰剂、曲妥珠单抗和多烯紫杉醇方案治疗的396名受试者中，有115人（29%）发生了严重副反应事件，而在接受帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案治疗的408名受试者中，有148人（36%）发生了严重副反应事件。研究者所观察到的不良反应事件包括发热性中性粒细胞减少、中性粒细胞减少、腹泻、肺炎和蜂窝织炎。总体来看，不良反应事件所发生的频率、严重性和特异性与既往主要分析所报道的结果相似。

来自本研究的分析显示在HER2阳性的转移性乳腺癌患者中，应用帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案能显著改善这类患者的总体生存期。鉴于与安慰剂对照方案相比，上述方案兼具有效和安全的特点，因而帕妥珠单抗、曲妥珠单抗和多烯紫杉醇方案可作为HER2阳性的转移性乳腺癌患者的标准治疗方案。
与乳腺癌相关的拓展阅读：

• JCO：紫杉醇/吉西他滨维持化疗可改善转移性乳腺癌患者生存
• Medpage：他莫西芬或可预防乳腺癌
• AACR2013：他汀类药物可显著降低乳腺癌死亡率
• Ann Surg：肥胖乳腺癌患者术前抗生素预防可降低手术部位感染发生率
• Radiother Oncol：放疗在乳腺癌和前列腺癌患者中的使用有上升趋势
• Lancet：持续三苯氧胺治疗10年能降低雌激素受体阳性的乳腺癌患者的复发率和死亡率
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Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study
Background
CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up.
Methods
The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190.
Findings
In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3—NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4—NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52—0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4—13·5) in the placebo group and 18·7 months (16·6—21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58—0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.
Interpretation
Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.