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帕妥珠单抗是首个抑制人类表皮生长因子受体HER2与其他HER结合的单克隆抗体。埃及艳后研究已经证实，帕妥珠单抗能够显著改善曲妥珠单抗＋多西他赛一线治疗HER2阳性晚期乳腺癌的无进展生存和总生存结局，故于2012年6月8日获得美国批准。不过，由于埃及艳后研究的中国内陆患者较少，直至2018年12月16日始终未获中国内陆有关部门批准。 前情提要 2020年6月20日，施普林格自然旗下《乳腺癌研究与治疗》在线发表中国医学科学院肿瘤医院徐兵河和李俏、吉林大学第一医院李薇、哈尔滨医科大学附属肿瘤医院暨黑龙江省肿瘤医院张清媛、复旦大学附属肿瘤医院邵志敏、浙江省肿瘤医院暨中国科学院大学附属肿瘤医院王晓稼、北京大学肿瘤医院李惠平、中国医科大学肿瘤医院暨辽宁省肿瘤医院孙涛、江苏省人民医院暨南京医科大学第一附属医院殷咏梅、四川大学华西医院郑鸿、江苏省肿瘤医院暨南京医科大学附属肿瘤医院冯继峰、瑞士罗氏埃利奥诺拉·雷斯托奇亚等学者的海鹦鹉研究报告，调查了帕妥珠单抗＋曲妥珠单抗＋多西他赛一线治疗中国内陆HER2阳性局部复发或晚期乳腺癌患者的有效性和安全性。 PUFFIN: A Phase III, Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Herceptin + Docetaxel Versus Placebo + Herceptin + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer (NCT02896855)
该多中心随机双盲安慰剂对照三期临床衔接研究于2016年9月13日～2017年9月28日从中国内陆15家医院入组HER2阳性局部复发或晚期乳腺癌患者243例，按1∶1的比例随机分为两组，并按内脏或非内脏转移和激素受体状态进行分层，其中122例接受帕妥珠单抗＋曲妥珠单抗＋多西他赛，其余121例接受安慰剂＋曲妥珠单抗＋多西他赛。主要终点为研究者评定的无进展生存。次要终点包括客观缓解率（治疗前病灶可测量患者的完全或部分缓解比例）、总生存和安全性。CLEOPATRA研究808例患者的无进展生存风险比为0.62，故本研究预设至少240例患者的无进展生存风险比临界值为0.81。 结果，帕妥珠单抗组与安慰剂组相比： 中位无进展生存：延长2.1个月（14.5比12.4，95%置信区间：12.5～18.6、10.4～12.7） 进展或死亡风险：减少31%（风险比：0.69，95%置信区间：0.49～0.99） 完全或部分缓解：79.0%比69.1%（83/105、67/97） ≥3级不良事件：70.5%比69.2% 严重不良事件：19.7%比19.2% 心力衰竭或左心室射血分数下降症状：0比0
亚组分层分析表明，无论内脏转移、激素受体、体力状态、早期治疗、治疗间隔、HER2水平如何，无进展生存皆可获益。 
因此，该研究结果表明，帕妥珠单抗能够改善曲妥珠单抗＋多西他赛一线治疗中国内陆HER2阳性晚期乳腺癌的无进展生存结局，总体而言疗效数据与CLEOPATRA研究一致，安全性与帕妥珠单抗已知安全性特征一致，扩充了帕妥珠单抗一线治疗HER2阳性局部复发或晚期乳腺癌的数据总量，证实了帕妥珠单抗对中国内陆患者的疗效与风险特征，并于2018年12月17日获得中国内陆有关部门批准。 Breast Cancer Res Treat. 2020 Jun 20. Online ahead of print.
Pertuzumab, trastuzumab, and docetaxel for Chinese patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer (PUFFIN): a phase III, randomized, double-blind, placebo-controlled study. Binghe Xu, Wei Li, Qingyuan Zhang, Zhimin Shao, Qiao Li, Xiaojia Wang, Huiping Li, Tao Sun, Yongmei Yin, Hong Zheng, Jifeng Feng, Hong Zhang, Guiyuan Lei, Eleonora Restuccia. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China; The Cancer Center, The First Hospital of Jilin University, Jilin, China; Harbin Medical University, Harbin, China; Fudan University Shanghai Cancer Center, Shanghai, China; Zhejiang Cancer Hospital, Hangzhou City, China; Beijing Cancer Hospital, Beijing, China; Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Liaoning, China; Jiangsu Province Hospital, Nanjing, China; West China Hospital, Sichuan University, Chengdu, China; Jiangsu Cancer Hospital, Nanjing, China; Roche (China) Holding Ltd, Shanghai, China; Roche Products Limited, Welwyn Garden City, UK; F. Hoffmann-La Roche Ltd, Basel, Switzerland. PURPOSE: The Chinese bridging study PUFFIN (NCT02896855) aimed to assess consistency of efficacy with CLEOPATRA (NCT00567190), investigating pertuzumab with trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer. METHODS: Patients were randomized 1:1, stratified by visceral/non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (in patients with measurable baseline disease), overall survival, and safety. The consistency threshold for PFS (hazard ratio [HR]<0.81) (maintaining≥50% of the risk reduction determined in CLEOPATRA [HR 0.62]) determined the target sample size (n=240). RESULTS: Two hundred forty-three patients were randomized. Median PFS was 14.5 months in the pertuzumab arm (95% confidence interval [CI] 12.5, 18.6) and 12.4 months in the placebo arm (95% CI 10.4, 12.7) in the intention-to-treat population (HR: 0.69 [95% CI 0.49, 0.99]). Objective responses were recorded in 83/105 (79.0%) and 67/97 (69.1%) patients, respectively. Grade≥3 adverse events (70.5% and 69.2%, respectively) and serious adverse events (19.7% and 19.2%, respectively) were similar across both arms. No heart failure cases or symptomatic left ventricular ejection fraction declines were reported. CONCLUSIONS: PUFFIN met its primary objective. Overall, efficacy data were consistent with CLEOPATRA. Safety was consistent with the known pertuzumab safety profile. PUFFIN adds to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit-risk profile of pertuzumab in Chinese patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02896855 KEYWORDS: Pertuzumab, Metastatic breast cancer, Locally recurrent breast cancer, HER2, Chinese DOI: 10.1007/s10549-020-05728-w 
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