Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Lancet Oncol. 2017 Jun;18(6):743-754. doi: 10.1016/S1470-2045(17)30313-3. Epub 2017 May 16.
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.
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.
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 [<1%] vs seven [4%]); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 [6%] of 403 patients vs five [3%] of 184 patients) and haemorrhage of any type (17 [4%] of 403 vs one [<1%] of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related).
In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy.
F Hoffman-La Roche/Genentech.
在随机、平行分组、开放性、III 期 TH3RESA 研究中，与医生选择的治疗相比，曲妥珠单抗-美坦新偶联物（trastuzumab emtansine）使先前接受过曲妥珠单抗和拉帕替尼（晚期）以及紫杉烷（任何阶段）治疗的 HER2 阳性晚期乳腺癌患者的无进展生存期显著延长。我们报告了 TH3RESA 试验最终总生存分析的结果。
TH3RESA 试验的合格患者为年龄≥18 岁的男性和女性，经中心确认为 HER2 阳性晚期乳腺癌，先前已接受过曲妥珠单抗和拉帕替尼（晚期）以及紫杉烷（任何阶段）治疗，且在晚期阶段接受了两种或多种 HER2 定向方案治疗后进展。患者的东部合作肿瘤学组表现状态必须为 0-2，左心室射血分数至少为 50%，且器官功能良好。患者通过具有交互语音和网络响应系统的按比例随机化（分为 6 个块的 2:1），以随机分配接受曲妥珠单抗-美坦新偶联物（3.6mg/kg，每 21 天静脉注射一次）或医生选择的治疗方案，根据当地实践进行治疗。随机化按世界区域、晚期乳腺癌的先前治疗方案数量和内脏疾病的存在进行分层。2012 年 9 月 12 日，该研究方案被修订，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-美坦新偶联物。TH3RESA 的主要终点是研究者评估的无进展生存期和意向治疗人群的总生存期。我们报告了针对总生存期的第二次计划中期分析结果，该分析是在预计将发生 492 例预期死亡中的 67%（n=330）时进行的。本研究在 ClinicalTrials.gov 注册，编号为 NCT01419197。
2011 年 9 月 14 日至 2012 年 11 月 19 日，来自 22 个国家的 146 个中心共纳入 602 例患者，并随机分配至曲妥珠单抗-美坦新偶联物组（n=404）或医生选择的治疗组（n=198）。截止 2015 年 2 月 13 日，医生选择组的 198 例患者中有 93 例（47%）交叉到曲妥珠单抗-美坦新偶联物组。与医生选择的治疗相比，曲妥珠单抗-美坦新偶联物使总生存期显著延长（中位数 22.7 个月[95%CI 19.4-27.5] vs 15.8 个月[13.5-18.7]；风险比 0.68[95%CI 0.54-0.85]；p=0.0007）。由于总生存期的停止边界已经越过，该总生存期分析是总生存期的最终和确认性分析，根据方案研究已经终止。曲妥珠单抗-美坦新偶联物组的 403 例患者中发生了 161 例（40%）和医生选择的治疗组的 184 例患者中发生了 87 例（47%）的 3 级或更严重不良事件。最常见的 3 级或更严重不良事件（影响每组≥2%的患者）中，与医生选择的治疗相比，曲妥珠单抗-美坦新偶联物组的发生率差异为 3%或更大的那些事件是腹泻（曲妥珠单抗-美坦新偶联物组的 403 例患者中有 3 例[1%]，医生选择的治疗组的 184 例患者中有 8 例[4%]）、中性粒细胞减少症（曲妥珠单抗-美坦新偶联物组的 403 例患者中有 10 例[3%]，医生选择的治疗组的 184 例患者中有 29 例[16%]）和发热性中性粒细胞减少症（曲妥珠单抗-美坦新偶联物组的 1 例[<1%]，医生选择的治疗组的 7 例[4%]）；而与曲妥珠单抗-美坦新偶联物组相比，更常见的是血小板减少症（曲妥珠单抗-美坦新偶联物组的 403 例患者中有 24 例[6%]，医生选择的治疗组的 184 例患者中有 5 例[3%]）和任何类型的出血（曲妥珠单抗-美坦新偶联物组的 403 例患者中有 17 例[4%]，医生选择的治疗组的 184 例患者中有 1 例[<1%]）。曲妥珠单抗-美坦新偶联物组的 403 例患者中有 102 例（25%）和医生选择的治疗组的 184 例患者中有 41 例（22%）报告了严重不良事件。在医生选择的治疗组中，有 3 例患者（2%）发生了与治疗相关的死亡，在曲妥珠单抗-美坦新偶联物组中，有 9 例患者（2%）发生了与治疗相关的死亡。
在接受了两种或多种 HER2 定向方案治疗后进展的患者中，与医生选择的治疗相比，曲妥珠单抗-美坦新偶联物治疗使总生存期显著改善。这些数据进一步证实了曲妥珠单抗-美坦新偶联物在治疗先前接受过治疗的 HER2 阳性晚期乳腺癌患者中的作用，并验证了 HER2 作为治疗靶点，即使在多次先前治疗后也是如此。
F Hoffman-La Roche/Genentech。
