埃及艳后：晚期乳腺癌双靶化疗大结局
人类表皮生长因子受体HER2及其蛋白质编码基因ERBB2的发现，是乳腺癌研究最重要的进展之一。20年前，曲妥珠单抗的问世引发了一场革命，随后其他有效的抗HER2靶向药物不断涌现。2008年，以埃及艳后克利奥帕特拉命名的CLEOPATRA研究，开始对帕妥珠单抗＋曲妥珠单抗双重抗HER2靶向治疗＋多西他赛化疗一线治疗HER2阳性晚期乳腺癌患者的有效性和安全性进行比较，无疑又推动该领域向前迈出重要一步。自从2011年《新英格兰医学杂志》首次公布CLEOPATRA研究初步结果以来，帕妥珠单抗与安慰剂相比，患者的无进展生存和总生存显著改善，帕妥珠单抗联合方案已经成为HER2阳性晚期乳腺癌患者新的一线治疗标准方法。
2020年3月12日，英国《柳叶刀》肿瘤学分册在线发表美国乔治城大学医学中心、隆巴迪综合癌症中心、医学之星医疗集团、基因泰克、英国弗农山癌症中心、韩国蔚山大学首尔峨山医院、成均馆大学三星首尔医院、首尔国立大学医院、俄罗斯彼得罗夫肿瘤研究所、西班牙马德里大学国庆日医院、马德里肿瘤研究所、巴塞罗那肿瘤研究所、德国癌症研究中心、海德堡大学医院国家肿瘤疾病中心、澳大利亚墨尔本大学彼得·麦卡伦癌症中心、瑞士罗氏的CLEOPATRA研究8年随访最终结果报告。
CLEOPATRA (A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer): A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (NCT00567190)
该国际多中心双盲随机安慰剂对照三期临床研究于2008年2月12日～2010年7月7日从全球25个国家或地区204个研究中心入组年龄≥18岁HER2阳性晚期乳腺癌转移后尚未化疗或生物学治疗且美国东部肿瘤协作组体力状态评分为0或1分的808例患者，按1∶1的比例随机分为帕妥珠单抗组402例或安慰剂组406例，每3周1次静脉注射帕妥珠单抗或安慰剂＋曲妥珠单抗＋多西他赛。帕妥珠单抗首次840毫克、随后420毫克，曲妥珠单抗每公斤体重首次8毫克、随后6毫克，用药直至疾病进展。多西他赛每平方米体表面积首次75毫克、如果能够耐受随后100毫克，给予6次或根据研究者判断适当延长。按地理区域（亚洲、欧洲、北美、南美）和既往治疗（既往有无术前新辅助化疗或术后辅助化疗）对随机分组进行分层。主要终点为独立审核机构评定的无进展生存，2011年已发表于《新英格兰医学杂志》。次要终点包括总生存，根据帕妥珠单抗组意向治疗人群和安慰剂组转组患者进行分析，由于未对转至帕妥珠单抗组进行校正，故分析结果可能比较保守。对帕妥珠单抗组408例、安慰剂组396例（计数日期为部分患者转组后、帕妥珠单抗首次给药前一天）实际接受治疗患者进行安全性分析。临床数据分析截至2018年11月23日。2012年7月至临床数据截止，50例患者从安慰剂转至帕妥珠单抗组。
结果，帕妥珠单抗组与安慰剂组相比：
中位随访时间：99.9个月比98.7个月（四分位：92.9～106.4、90.9～105.7）
中位总生存时间：57.1个月比40.8个月（95%置信区间：50～72、36～48）
死亡风险低31%（风险比：0.69，95%置信区间：0.58～0.82）
8年总生存率：37%比23%
3～4级中性粒细胞减少：200例比183例（49%比46%）
治疗相关死亡：5例比6例（1%比2%）
帕妥珠单抗组发生充血性心力衰竭1例、有症状左心室收缩功能障碍1例（由安慰剂组转入）。
因此，该研究最终结果表明，经过长达8年中位随访后，帕妥珠单抗＋曲妥珠单抗＋多西他赛与安慰剂＋曲妥珠单抗＋多西他赛相比，HER2阳性晚期乳腺癌患者总生存仍然保持显著改善。对于全部实际接受治疗患者，包括转组患者，帕妥珠单抗＋曲妥珠单抗＋多西他赛的长期安全性和心脏安全性仍然保持。HER2靶向治疗已经改变HER2阳性晚期乳腺癌自然病史，通过帕妥珠单抗＋曲妥珠单抗双重阻断＋多西他赛，8年总生存率达37%。
对此，意大利热那亚大学、圣马蒂诺综合医院、法国巴黎萨克雷大学、古斯塔夫·鲁西癌症研究中心发表同期评论：HER2阳性晚期乳腺癌是否仍然无法治愈？
相关链接
Lancet Oncol. 2020 Mar 12. [Epub ahead of print]
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.
Sandra M Swain, David Miles, Sung-Bae Kim, Young-Hyuck Im, Seock-Ah Im, Vladimir Semiglazov, Eva Ciruelos, Andreas Schneeweiss, Sherene Loi, Estefanía Monturus, Emma Clark, Adam Knott, Eleonora Restuccia, Mark C Benyunes, Javier Cortéson; CLEOPATRA study group.
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; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; N N Petrov Research Institute of Oncology, St Petersburg, Russia; 12 de Octubre University Hospital, Madrid, Spain; National Center for Tumor Diseases, University Hospital, German Cancer Research Center, Heidelberg, Germany; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; F Hoffmann-La Roche, Basel, Switzerland; Roche Products, Welwyn Garden City, UK; Genentech, South San Francisco, CA, USA; IOB Institute of Oncology, Quirónsalud Group, Madrid and Barcelona, Spain; Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
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. 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.
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 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.
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 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%.
FUNDING: F Hoffmann-La Roche and Genentech.
DOI: 10.1016/S1470-2045(19)30863-0
Lancet Oncol. 2020 Mar 12. [Epub ahead of print]
Is HER2-positive metastatic breast cancer still an incurable disease?
Matteo Lambertini, Ines Vaz-Luis.
IRCCS Ospedale Policlinico San Martino, Genova, Italy; University of Genova, Genova, Italy; Institut Gustave Roussy, Université Paris-Saclay, INSERM, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France
The discovery of the HER2 oncogene was one of the most important advances in breast cancer research. 20 years ago, the advent of trastuzumab started a revolution that has continued with the introduction of additional effective targeted agents. Dual anti-HER2 targeting with trastuzumab plus pertuzumab in addition to docetaxel is an unquestionable step forward in the field. Since the publication of the first results of the CLEOPATRA trial in 2012, the pertuzumab-based regimen has become the new standard first-line treatment for patients with HER2-positive metastatic breast cancer.
DOI: 10.1016/S1470-2045(20)30058-9