Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study
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帕妥珠单抗、曲妥珠单抗和多西他赛治疗her2阳性转移性乳腺癌（CLEOPATRA）：一项双盲、随机、安慰剂对照的3期研究的研究结束结果
DOI：
10.1016/s1470-2045(19)30863-0
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发表时间：
2020-04-01
期刊：
影响因子：
51.1
通讯作者：
Cortes, Javier
中科院分区：
文献类型：
--
作者：
Swain, Sandra M.;Miles, David;Cortes, Javier
CLEOPATRA是一项3期研究，比较了帕妥珠单抗、曲妥珠单抗和多西紫杉醇与安慰剂、曲妥珠单抗和多西紫杉醇在her2阳性转移性乳腺癌患者中的疗效和安全性。在初步分析和随后的报告中，与安慰剂组相比，帕妥珠单抗组的无进展生存期和总生存期显著改善。在这里，我们报告了《埃及艳后》的研究结束分析。这是一项双盲、随机、安慰剂对照的3期试验，在25个国家的204个中心进行。符合条件的患者年龄≥18岁，her2阳性，转移性乳腺癌，既往未因转移性疾病接受化疗或生物治疗，东部肿瘤合作组表现状态为0或1。所有研究药物均静脉给予，每3周一次。患者被分配接受840毫克负荷剂量的帕妥珠单抗或安慰剂，之后420毫克；加上曲妥珠单抗8 mg/kg的负荷剂量，此后为6 mg/kg；多西他赛剂量为75 mg/m(2)，如果耐受则增加到100 mg/m(2)。给予帕妥珠单抗或安慰剂和曲妥珠单抗直至疾病进展；多西他赛给予6个周期，或更长时间由研究者决定。随机化（1:1）通过使用交互式语音应答系统进行，并根据地理区域（亚洲、欧洲、北美或南美）和既往治疗（既往辅助或新辅助化疗vs无）进行分层。主要终点是独立审查机构评估的无进展生存期，这在之前已经报道过。由于在预先指定的研究结束分析之前也进行了验证性总体生存分析，因此本文提出的分析是描述性的。总体生存分析基于意向治疗人群，并在安慰剂组中分析交叉患者；分析没有对交叉到帕妥珠单抗组进行调整，可能是保守的。安全性分析基于所接受的治疗；交叉患者被计算在安慰剂组，直到第一次帕妥珠单抗剂量的前一天。该试验已在ClinicalTrials.gov注册，注册号NCT00567190。在2008年2月12日至2010年7月7日期间，1196名患者接受了资格评估，其中808名患者入组并随机分配。402例患者被分配接受多西他赛+曲妥珠单抗+帕妥珠单抗，406例患者被分配接受多西他赛+曲妥珠单抗+安慰剂。该分析的临床截止日期为2018年11月23日。从2012年7月到临床截止时间，有50名患者从安慰剂组转到帕妥珠单抗组。帕妥珠单抗组中位随访时间为99.9个月（IQR为92.9-106.4），安慰剂组中位随访时间为98.7个月（90.9-105.7）。pertuzuinab组的中位总生存期为57.1个月（95% CI 50-72），安慰剂组为40.8个月（36-48）（风险比0-69,95% CI 0.58-0.82）；帕妥珠单抗组的8年标志性总生存率为37% (95% CI 31-42)，安慰剂组为23%（19-28）。最常见的3-4级不良事件是中性粒细胞减少（帕妥珠单抗组408例患者中有200例[49%1]，安慰剂组396例患者中有183例[146%1]）。帕妥珠单抗组408例患者中有5例（1%）和安慰剂组396例患者中有6例（2%）发生治疗相关死亡。自之前的分析以来，出现了一例新的严重不良事件，提示充血性心力衰竭（帕妥珠单抗组）和一例新的症状性左心室收缩功能障碍（交叉后）。我们的分析表明，与安慰剂、曲妥珠单抗和多西紫杉醇相比，先前观察到的帕妥珠单抗、曲妥珠单抗和多西紫杉醇总生存率的改善在中位随访超过8年后保持不变。帕妥珠单抗、曲妥珠单抗和多西他赛的长期安全性和心脏安全性在总体安全人群和交叉患者中保持不变。her2靶向治疗改变了her2阳性转移性乳腺癌的自然史，帕妥珠单抗和曲妥珠单抗的双重阻断，多西他赛，显示出8年的里程碑式总生存率为37%。爱思唯尔版权所有版权所有。
Background CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA.Methods This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m(2), escalating to 100 mg/m(2) if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randoinisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facilityassessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov , number NCT00567190.Findings Between Feb 12,2008, and July 7,2010,1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23,2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99.9 months in the pertuzumab group (IQR 92.9-106.4) and 98.7 months (90.9-105.7) in the placebo group. Median overall survival was 57.1 months (95% CI 50-72) in the pertuzuinab group and 40.8 months (36-48) in the placebo group (hazard ratio 0-69,95% CI 0.58-0.82); 8-year landmark overall survival rates were 37% (95% CI 31-42) in the pertuzumab group and 23% (19-28) in the placebo group. The most common grade 3-4 adverse event was neutropenia (200 [49%1 of 408 patients in the pertuzumab group, 183 146%1 of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis.Interpretation Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzuinab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%. Copyright (C) 2020 Elsevier Ltd. All rights reserved.