柳叶刀牛年首发乳腺癌研究花落中国
1998年以来，随着曲妥珠单抗的问世，HER2阳性晚期乳腺癌的治疗已经取得了巨大进步。不过，曲妥珠单抗耐药仍然难以避免。2007年，HER1、HER2酪氨酸激酶可逆抑制剂拉帕替尼被批准联合卡培他滨用于HER2阳性晚期乳腺癌，为曲妥珠单抗耐药患者带来了希望。2018年，中国原创HER1、HER2、HER4酪氨酸激酶不可逆抑制剂吡咯替尼被批准联合卡培他滨用于HER2阳性晚期乳腺癌，为曲妥珠单抗耐药患者带来了新希望。
格林威治时间2021年2月11日夜间，英国《柳叶刀》肿瘤学分册在线发表PHOEBE研究报告，对吡咯替尼＋卡培他滨、拉帕替尼＋卡培他滨治疗HER2阳性晚期乳腺癌曲妥珠单抗耐药患者的有效性和安全性进行了头对头比较。
PHOEBE (NCT03080805): A Randomised, Open-label, Parallel Controlled, Multicentre, Phase 3 Clinical Trial of Pyrotinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer
PHOEBE研究报告作者单位
中国医学科学院肿瘤医院、国家癌症中心：徐兵河、马飞
郑州大学附属肿瘤医院、湖南省肿瘤医院：闫敏
复旦大学附属肿瘤医院、上海市肿瘤医院：胡夕春
南京医科大学附属肿瘤医院、江苏省肿瘤医院：冯继峰
中南大学湘雅医学院附属肿瘤医院、湖南省肿瘤医院：欧阳取长
天津医科大学肿瘤医院、天津市肿瘤医院：佟仲生
北京大学肿瘤医院、北京市肿瘤医院：李惠平
哈尔滨医科大学附属肿瘤医院、黑龙江省肿瘤医院：张清媛
中国医科大学附属肿瘤医院、辽宁省肿瘤医院：孙涛
浙江大学医学院附属邵逸夫医院：王娴
南京医科大学第一附属医院、江苏省人民医院：殷咏梅
吉林省肿瘤医院、吉林省第二人民医院：程颖
吉林大学白求恩第一医院：李薇
郑州大学第一附属医院：谷元廷
广州中医药大学第二附属医院、广东省中医院：陈前军
四川省医学科学院四川省人民医院：刘锦平
华中科技大学同济医学院附属协和医院、武汉协和医院：程晶
河北医科大学第四医院、河北省肿瘤医院：耿翠芝
南京大学医学院附属金陵医院、***总医院秦淮医疗区：秦叔逵
中山大学肿瘤防治中心、中山大学附属肿瘤医院：王树森
上海交通大学医学院附属仁济医院：陆劲松
上海交通大学医学院附属瑞金医院：沈坤炜
中山大学孙逸仙纪念医院、中山大学附属第二医院：刘强
中国科学院大学附属肿瘤医院、浙江省肿瘤医院：王晓稼
南昌市第三医院、江西乳腺专科医院：王红
四川大学华西医院：罗婷
西安交通大学附属第一医院：杨谨
南昌大学附属肿瘤医院、江西省肿瘤医院：吴毓东
山东第一医科大学附属肿瘤医院、山东省肿瘤医院：于志勇
江苏恒瑞：朱晓宇、陈春霞、邹建军
该多中心非盲随机对照三期临床研究于2017年7月31日～2018年10月30日从中国29家医院入组年龄18～70岁、经病理证实为HER2阳性晚期乳腺癌、美国东部肿瘤学协作组体力状态评分为0或1、既往曲妥珠单抗和紫杉类治疗失败患者267例，通过集中交互式网络反馈系统按1∶1随机分为两组，每天口服吡咯替尼400毫克或拉帕替尼1250毫克，同时口服卡培他滨。根据激素受体状态和既往晚期乳腺癌化疗方案对分组进行亚组分析。主要研究终点为独立集中复核的无进展生存。对全部用药患者进行有效性和安全性评定。本文为预设中期分析。
结果，其中134例接受吡咯替尼＋卡培他滨、132例接受拉帕替尼＋卡培他滨。2019年3月31日中期分析数据截止时，吡咯替尼＋卡培他滨与拉帕替尼＋卡培他滨相比：
中位无进展生存：12.5个月比6.8个月（95%置信区间：9.7～未达终点、5.4～8.1）
进展或死亡风险：减少61%（风险比：0.39，95%置信区间：0.27～0.56，单侧P<0.0001）
吡咯替尼＋卡培他滨与拉帕替尼＋卡培他滨相比，不良事件发生率：
≥3级腹泻：31%比8%
≥3级手足综合征：16%比15%
严重不良事件：10%比8%
治疗相关死亡：0例比1例（猝死）
因此，该研究结果表明，对于HER2阳性晚期乳腺癌曲妥珠单抗和化疗耐药患者，吡咯替尼＋卡培他滨与拉帕替尼＋卡培他滨相比，无进展生存显著改善、毒性反应可控，为曲妥珠单抗和化疗耐药患者带来了新希望。
相关链接
Lancet Oncol. 2021 Feb 11. Online ahead of print.
Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.
Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Yuanting Gu, Qianjun Chen, Jinping Liu, Jing Cheng, Cuizhi Geng, Shukui Qin, Shusen Wang, Jinsong Lu, Kunwei Shen, Qiang Liu, Xiaojia Wang, Hong Wang, Ting Luo, Jin Yang, Yudong Wu, Zhiyong Yu, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou; PHOEBE Investigators.
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Fudan University Cancer Hospital, Shanghai, China; Jiangsu Cancer Hospital, Nanjing, China; Hunan Cancer Hospital, Changsha, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Beijing Cancer Hospital, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China; Liaoning Cancer Hospital & Institute, Shenyang, China; Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China; The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Jilin Cancer Hospital, Changchun, China; The First Bethune Hospital of Jilin University, Changchun, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China; Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China; Wuhan Union Hospital, Wuhan, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Cancer Centre of Jinling Hospital, Nanjing, China; Sun Yat-Sen University Cancer Center, Guangzhou, China; Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China; Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China; Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Zhejiang Cancer Hospital, Hangzhou, China; The Third Hospital of Nanchang, Nanchang, China; West China Hospital, Sichuan University, Chengdu, China; The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Jiangxi Cancer Hospital, Nanchang, China; Shandong Tumor Hospital, Jinan, China; Jiangsu Hengrui Medicine, Shanghai, China.
BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab.
METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m 2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805.
FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12.5 months [95% CI 9.7-not reached]) than with lapatinib plus capecitabine (6.8 months [5.4-8.1]; hazard ratio 0.39 [95% CI 0.27-0.56]; one-sided p<0.0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related.
INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy.
FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China
DOI: 10.1016/S1470-2045(20)30702-6
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