Georgetown University Medical Center, Washington DC, USA; Lombardi Comprehensive Cancer Center, Washington, DC, USA; MedStar Health, Washington, DC, USA.
Mount Vernon Cancer Centre, Northwood, UK.
Lancet Oncol. 2020 Apr;21(4):519-530. doi: 10.1016/S1470-2045(19)30863-0. Epub 2020 Mar 12.
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.
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, escalating to 100 mg/m if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators' discretion. Randomisation (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 facility-assessed 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.
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 pertuzumab 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%] of 408 patients in the pertuzumab group, 183 [46%] 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.
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 pertuzumab, 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%.
F Hoffmann-La Roche and Genentech.
CLEOPATRA 是一项 3 期研究，比较了在曲妥珠单抗和多西他赛基础上加用或不加用帕妥珠单抗治疗人表皮生长因子受体 2（HER2）阳性转移性乳腺癌患者的疗效和安全性。在主要分析和后续报告中，与安慰剂、曲妥珠单抗和多西他赛组相比，帕妥珠单抗组的无进展生存期和总生存期显著改善。在此，我们报告 CLEOPATRA 的最终研究分析结果。
这是一项在 25 个国家的 204 个中心进行的双盲、随机、安慰剂对照的 3 期试验。入组患者年龄 18 岁及以上，患有 HER2 阳性转移性乳腺癌，先前未接受过转移性疾病的化疗或生物治疗，东部肿瘤协作组体力状态为 0 或 1。所有研究药物均静脉输注，每 3 周一次。患者被随机分配接受帕妥珠单抗或安慰剂，初始剂量为 840mg，随后为 420mg；加用曲妥珠单抗，初始剂量为 8mg/kg，随后为 6mg/kg；多西他赛 75mg/m2，可耐受时增至 100mg/m2。帕妥珠单抗或安慰剂和曲妥珠单抗一直用到疾病进展；多西他赛最多用 6 个周期，或根据研究者的判断延长用药。随机分组（1:1）采用交互式语音应答系统进行，按地理区域（亚洲、欧洲、北美或南美）和既往治疗（既往辅助或新辅助化疗与无化疗）分层。主要终点是独立评审机构评估的无进展生存期，此前已报告过该结果。由于确认性总生存期分析也在本预定最终研究分析之前进行，因此这里的分析是描述性的。总生存期分析基于意向治疗人群，交叉患者在安慰剂组中进行分析；分析未针对交叉至帕妥珠单抗组进行调整，结果可能较为保守。安全性分析基于接受的治疗；交叉患者在首次帕妥珠单抗剂量前一天计入安慰剂组。本试验在 ClinicalTrials.gov 注册，编号为 NCT00567190。
2008 年 2 月 12 日至 2010 年 7 月 7 日期间，对 1196 例患者进行了入组评估，其中 808 例符合入组条件并被随机分配。402 例患者被分配接受多西他赛加曲妥珠单抗加帕妥珠单抗治疗，406 例患者被分配接受多西他赛加曲妥珠单抗加安慰剂治疗。本分析的临床截止日期为 2018 年 11 月 23 日。从 2012 年 7 月到临床截止日期，有 50 例患者从安慰剂组交叉至帕妥珠单抗组。帕妥珠单抗组的中位随访时间为 99.9 个月（IQR 92.9-106.4），安慰剂组为 98.7 个月（90.9-105.7）。帕妥珠单抗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）；8 年总生存期的发生率分别为 37%（95%CI 31-42）和 23%（19-28）。最常见的 3-4 级不良事件为中性粒细胞减少症（帕妥珠单抗组 408 例患者中有 200 例[49%]，安慰剂组 396 例患者中有 183 例[46%]）。帕妥珠单抗组 5 例（1%）和安慰剂组 6 例（2%）患者发生与治疗相关的死亡。自上次分析以来，帕妥珠单抗组发生 1 例新的疑似充血性心力衰竭的严重不良事件（1%），以及 1 例新的有症状的左心室收缩功能障碍（交叉后）。
我们的分析表明，与安慰剂、曲妥珠单抗和多西他赛相比，帕妥珠单抗、曲妥珠单抗和多西他赛治疗组的总生存期改善在中位随访超过 8 年后仍得以维持。在总安全性人群和交叉患者中，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特征得以维持。曲妥珠单抗靶向治疗改变了 HER2 阳性转移性乳腺癌的自然病程，帕妥珠单抗联合曲妥珠单抗加多西他赛的 8 年总生存期的发生率为 37%。
罗氏（F Hoffmann-La Roche）和基因泰克（Genentech）。
