Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial
Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial
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DOI：
10.1016/s1470-2045(17)30313-3
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发表时间：
2017-06-01
期刊：
影响因子：
51.1
通讯作者：
Wildiers, Hans
中科院分区：
文献类型：
--
作者：
Krop, Ian E.;Kim, Sung-Bae;Wildiers, Hans
背景：在随机、平行分配、开放标签的3期TH3RESA研究中，在HER2阳性的晚期乳腺癌患者中，使用曲妥珠单抗的无进展生存期明显长于医生选择的治疗方案。我们报告了TH3RESA试验的最终总体生存分析的结果。方法符合TH3RESA试验条件的患者是中心确诊的HER2阳性晚期乳腺癌的男性和女性(年龄=18岁)，以前接受曲妥珠单抗和拉帕替尼(高级设置)和紫杉烷(任何设置)治疗，并在晚期设置中接受两个或更多HER2指导方案的进展。患者必须有东部合作肿瘤组的表现状态为0-2，左心室射血分数至少50%，以及足够的器官功能。患者由交互式语音和网络响应系统随机分配(2：1)，每组6人，接受曲妥珠单抗EMTANSINE(每21天静脉注射3.6毫克/公斤)或根据当地医生的选择进行治疗。随机化按世界地区、以前治疗晚期乳腺癌的方案数量和是否存在内脏疾病进行分层。2012年9月12日，对研究方案进行了修改，允许疾病进展的患者从医生选择的治疗方案交叉到曲妥珠单抗恩坦辛。TH3RESA的共同终点是研究者评估的意向治疗人群中的无进展存活率和总体存活率。我们报告了预先计划的第二次总体生存中期分析的结果，该分析计划在492例预期死亡中约67%(n=330)发生的情况下进行。这项研究在ClinicalTrials.gov注册，编号NCT01419197。研究结果在2011年9月14日至2012年11月19日期间，来自22个国家的146个中心的602名患者被随机分配到曲妥珠单抗治疗组(n=404)或医生选择的治疗组(n=198)。截至数据截止日期(2015年2月13日)，在医生选择的198名患者中，有93名(47%)改用曲妥珠单抗。与医生选择的治疗相比，曲妥珠单抗治疗的总生存期显著延长(中位数22.7月[95%可信区间19.4~27.5]比15.8个月[13.5~18.7]；风险比0.68[95%可信区间0.54~0.85]；p=0.0007)。由于跨越了总体生存的停止边界，该总体生存分析作为总体生存的最终和验证性分析，研究根据方案终止。曲妥珠单抗治疗组403例患者发生3级以上不良事件161例(40%)，医生选择治疗组184例患者发生严重不良事件87例(47%)。在最常见的3级或更严重的不良事件中(影响两组患者的2%)，在医生选择的治疗比曲妥珠单抗治疗更频繁的两组中，发生率相差3%或更多的是腹泻(曲妥珠单抗恩丹新组403名患者中有3名[1%]，医生选择组的184名患者中有8名[4%])，中性粒细胞减少症(10名[3%]对29名[16%])，以及发热性中性粒细胞减少症(1名
Background In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial.Methods Eligible patients for the TH3RESA trial were men and women (aged >= 18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2: 1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3.6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov, number NCT01419197.Findings Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22.7 months [95% CI 19.4-27.5] vs 15.8 months [13.5-18.7]; hazard ratio 0.68 [95% CI 0.54-0.85]; p=0.0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting >= 2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three [1%] of 403 patients in the trastuzumab emtansine group vs eight [4%] of 184 patients in the treatment of physician's choice group), neutropenia (ten [3%] vs 29 [16%]), and febrile neutropenia (one [